FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population.

Hallermann-Streiff syndrome is characterized by a typical skull shape (brachycephaly with frontal bossing), hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia, skin atrophy, dental anomalies, and proportionate short stature (Hallermann, 1948; Streiff, 1950; Francois, 1958). Mental retardation is present in a minority of cases (Gorlin et al., 1990).

Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in TRPS1) and TRPS II (caused by contiguous gene deletion of TRPS1, RAD21, and EXT1). Both types of TRPS are characterized by distinctive facial features; ectodermal features (fine, sparse, depigmented, and slow growing hair; dystrophic nails; and small breasts); and skeletal findings (short stature; short feet; brachydactyly with ulnar or radial deviation of the fingers; and early, marked hip dysplasia). TRPS II is characterized by multiple osteochondromas (typically first observed clinically on the scapulae and around the elbows and knees between ages 1 month and 6 years) and an increased risk of mild-to-moderate intellectual disability.

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

The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.

Multiple endocrine neoplasia type 2 (MEN2) includes the following phenotypes: MEN2A, FMTC (familial medullary thyroid carcinoma, which may be a variant of MEN2A), and MEN2B. All three phenotypes involve high risk for development of medullary carcinoma of the thyroid (MTC); MEN2A and MEN2B involve an increased risk for pheochromocytoma; MEN2A involves an increased risk for parathyroid adenoma or hyperplasia. Additional features in MEN2B include mucosal neuromas of the lips and tongue, distinctive facies with enlarged lips, ganglioneuromatosis of the gastrointestinal tract, and a marfanoid habitus. MTC typically occurs in early childhood in MEN2B, early adulthood in MEN2A, and middle age in FMTC.

Orofaciodigital syndrome II (OFD2), also known as Mohr syndrome, is characterized by cleft lip/palate, lobulated tongue with nodules, dental anomalies including tooth agenesis, maxillary hypoplasia, conductive hearing loss, and poly-, syn-, and brachydactyly. Mesomelic shortening of the limbs has also been observed (Mohr, 1941; Gorlin, 1982; Monroe et al., 2016).

Nail-patella syndrome (NPS) (previously referred to as Fong's disease), encompasses the classic clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns. Nail changes are the most constant feature of NPS. Nails may be absent, hypoplastic, or dystrophic; ridged longitudinally or horizontally; pitted; discolored; separated into two halves by a longitudinal cleft or ridge of skin; and thin or (less often) thickened. The patellae may be small, irregularly shaped, or absent. Elbow abnormalities may include limitation of extension, pronation, and supination; cubitus valgus; and antecubital pterygia. Iliac horns are bilateral, conical, bony processes that project posteriorly and laterally from the central part of the iliac bones of the pelvis. Renal involvement, first manifest as proteinuria with or without hematuria, occurs in 30%-50% of affected individuals; end-stage renal disease occurs up to 15% of affected individuals. Primary open-angle glaucoma and ocular hypertension occur at increased frequency and at a younger age than in the general population.

Neurofibromatosis 1 (NF1) is a multisystem disorder characterized by multiple café au lait macules, intertriginous freckling, multiple cutaneous neurofibromas, and learning disability or behavior problems. About half of people with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically. Plexiform neurofibromas can cause pain, neurologic deficits, and abnormalities of involved or adjacent structures. Less common but potentially more serious manifestations include optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, vasculopathy, and gastrointestinal, endocrine, or pulmonary disease.

In its rare complete form, 'prune belly' syndrome (PBS) comprises megacystis (massively enlarged bladder) with disorganized detrusor muscle, cryptorchidism, and thin abdominal musculature with overlying lax skin (summary by Weber et al., 2011).

Mucopolysaccharidosis type VII (MPS7) is an autosomal recessive lysosomal storage disease characterized by the inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al., 1993). MPS VII was the first autosomal mucopolysaccharidosis for which chromosomal assignment was achieved.

Aarskog-Scott syndrome is a genetic disorder that affects the development of many parts of the body, most commonly the head and face, the hands and feet, and the genitals and urinary system (genitourinary tract). This condition mainly affects males, although females may have mild features of the syndrome.\n\nPeople with Aarskog-Scott syndrome often have distinctive facial features, such as widely spaced eyes (hypertelorism), a small nose, a long area between the nose and mouth (philtrum), and a widow's peak hairline. They frequently have mild to moderate short stature during childhood, but their growth usually catches up with that of their peers during puberty. Hand abnormalities are common in this syndrome and include short fingers (brachydactyly), curved pinky fingers (fifth finger clinodactyly), webbing of the skin between some fingers (cutaneous syndactyly), and a single crease across the palm. Affected individuals can also have wide, flat feet with broad, rounded toes. Other abnormalities in people with Aarskog-Scott syndrome include heart defects and a split in the upper lip (cleft lip) with or without an opening in the roof of the mouth (cleft palate).\n\nMost males with Aarskog-Scott syndrome have a shawl scrotum, in which the scrotum surrounds the penis instead of hanging below. Less often, they have undescended testes (cryptorchidism) or a soft out-pouching around the belly-button (umbilical hernia) or in the lower abdomen (inguinal hernia).\n\nThe intellectual development of people with Aarskog-Scott syndrome varies widely. Most individuals with Aarskog-Scott syndrome have normal intelligence; however, some may have mild learning and behavior problems, and in rare cases, severe intellectual disability has been reported.

Williams syndrome (WS) is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Feeding difficulties often lead to poor weight gain in infancy. Hypotonia and hyperextensible joints can result in delayed attainment of motor milestones.

The FLNB disorders include a spectrum of phenotypes ranging from mild to severe. At the mild end are spondylocarpotarsal synostosis (SCT) syndrome and Larsen syndrome; at the severe end are the phenotypic continuum of atelosteogenesis types I (AOI) and III (AOIII) and Piepkorn osteochondrodysplasia (POCD). SCT syndrome is characterized by postnatal disproportionate short stature, scoliosis and lordosis, clubfeet, hearing loss, dental enamel hypoplasia, carpal and tarsal synostosis, and vertebral fusions. Larsen syndrome is characterized by congenital dislocations of the hip, knee, and elbow; clubfeet (equinovarus or equinovalgus foot deformities); scoliosis and cervical kyphosis, which can be associated with a cervical myelopathy; short, broad, spatulate distal phalanges; distinctive craniofacies (prominent forehead, depressed nasal bridge, malar flattening, and widely spaced eyes); vertebral anomalies; and supernumerary carpal and tarsal bone ossification centers. Individuals with SCT syndrome and Larsen syndrome can have midline cleft palate and hearing loss. AOI and AOIII are characterized by severe short-limbed dwarfism; dislocated hips, knees, and elbows; and clubfeet. AOI is lethal in the perinatal period. In individuals with AOIII, survival beyond the neonatal period is possible with intensive and invasive respiratory support. Piepkorn osteochondrodysplasia (POCD) is a perinatal-lethal micromelic dwarfism characterized by flipper-like limbs (polysyndactyly with complete syndactyly of all fingers and toes, hypoplastic or absent first digits, and duplicated intermediate and distal phalanges), macrobrachycephaly, prominant forehead, hypertelorism, and exophthalmos. Occasional features include cleft palate, omphalocele, and cardiac and genitourinary anomalies. The radiographic features at mid-gestation are characteristic.

DA3, or Gordon syndrome, is distinguished from other distal arthrogryposes by short stature and cleft palate (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA3 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 5 (DA5; 108145) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of ocular abnormalities and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition. For a phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1 (108120).

Congenital contractural arachnodactyly (CCA) appears to comprise a broad phenotypic spectrum. Classic CCA is characterized by arachnodactyly; flexion contractures of multiple joints including elbows, knees, hips, ankles, and/or fingers; kyphoscoliosis (usually progressive); a marfanoid habitus (a long and slender build, dolichostenomelia, pectus deformity, muscular hypoplasia, highly arched palate); and abnormal "crumpled" ears. At the mildest end, parents who are diagnosed retrospectively upon evaluation of their more severely affected child may show a lean body build, mild arachnodactyly, mild contractures without impairment, and minor ear abnormalities. At the most severe end is "severe CCA with cardiovascular and/or gastrointestinal anomalies," a rare phenotype in infants with pronounced features of CCA (severe crumpling of the ears, arachnodactyly, contractures, congenital scoliosis, and/or hypotonia) and severe cardiovascular and/or gastrointestinal anomalies. Phenotypic expression can vary within and between families.

Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (Twigg et al., 2004; Wieland et al., 2004).

The Marshall-Smith syndrome (MRSHSS) is a malformation syndrome characterized by accelerated skeletal maturation, relative failure to thrive, respiratory difficulties, mental retardation, and unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia (Adam et al., 2005).

The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.

Coffin-Lowry syndrome (CLS) is usually characterized by severe-to-profound intellectual disability in males; less severely impaired individuals have been reported. Neuropsychiatric concerns can include behavioral problems, loss of strength, progressive spasticity or paraplegia, sleep apnea, or stroke. Stimulus-induced drop attacks (SIDAs) in which unexpected tactile or auditory stimuli or excitement triggers a brief collapse but no loss of consciousness are present in approximately 20% of affected individuals. Typically SIDAs begin between mid-childhood and the teens. Characteristic facial features may be more apparent with age. Upper-extremity differences may be subtle and include short, soft, fleshy hands with tapered fingers as well as fleshy forearms. Progressive kyphoscoliosis is one of the most difficult aspects of long-term care. Affected females tend to have intellectual disability in the mild-to-moderate range and may also have the typical facial, hand, and skeletal findings noted in males.

Miller syndrome, also known as postaxial acrofacial dysostosis (POADS), is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (summary by Ng et al., 2010).

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

Kniest dysplasia is characterized by skeletal and craniofacial anomalies. Skeletal anomalies include disproportionate dwarfism, a short trunk and small pelvis, kyphoscoliosis, short limbs, and prominent joints and premature osteoarthritis that restrict movement. Craniofacial manifestations include midface hypoplasia, cleft palate, early-onset myopia, retinal detachment, and hearing loss. The phenotype is severe in some patients and mild in others. There are distinct radiographic changes including coronal clefts of vertebrae and dumbbell-shaped femora. The chondrooseous morphology is pathognomonic with perilacunar 'foaminess' and sparse, aggregated collagen fibrils resulting in an interterritorial matrix with a 'Swiss-cheese' appearance (summary by Wilkin et al., 1999).

Classic Ehlers-Danlos syndrome (cEDS) is a connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft and doughy to the touch, and hyperextensible, extending easily and snapping back after release (unlike lax, redundant skin, as in cutis laxa). The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching of scars after apparently successful primary wound healing is characteristic. Complications of joint hypermobility, such as dislocations of the shoulder, patella, digits, hip, radius, and clavicle, usually resolve spontaneously or are easily managed by the affected individual. Other features include hypotonia with delayed motor development, fatigue and muscle cramps, and easy bruising. Mitral valve prolapse can occur infrequently, but tends to be of little clinical consequence. Aortic root dilatation has been reported, appears to be more common in young individuals, and rarely progresses.

Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication.

Occipital horn syndrome (OHS) is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by Das et al., 1995).

Multiple synostoses syndrome is characterized by multiple joint fusions, usually commencing in the hands, conductive deafness, and characteristic facial features, including a broad, tubular-shaped nose and a thin upper vermilion. Other features include brachydactyly, hypoplastic or absent middle phalanges, radial head dislocation, and pectus carinatum (summary by Takahashi et al., 2001). Genetic Heterogeneity of Multiple Synostoses Syndrome Other forms of multiple synostoses syndrome include SYNS2 (610017), caused by mutation in the GDF5 gene (601146) on chromosome 20q11; SYNS3 (612961), caused by mutation in the FGF9 gene (600921) on chromosome 13q12; and SYNS4 (617898), caused by mutation in the GDF6 gene (601147) on chromosome 8q22.

D-bifunctional protein deficiency is a disorder of peroxisomal fatty acid beta-oxidation. See also peroxisomal acyl-CoA oxidase deficiency (264470), caused by mutation in the ACOX1 gene (609751) on chromosome 17q25. The clinical manifestations of these 2 deficiencies are similar to those of disorders of peroxisomal assembly, including X-linked adrenoleukodystrophy (ALD; 300100), Zellweger cerebrohepatorenal syndrome (see 214100) and neonatal adrenoleukodystrophy (NALD; see 601539) (Watkins et al., 1995). DBP deficiency has been classified into 3 subtypes depending upon the deficient enzyme activity. Type I is a deficiency of both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase; type II is a deficiency of hydratase activity alone; and type III is a deficiency of dehydrogenase activity alone. Virtually all patients with types I, II, and III have a severe phenotype characterized by infantile-onset of hypotonia, seizures, and abnormal facial features, and most die before age 2 years. McMillan et al. (2012) proposed a type IV deficiency on the basis of less severe features; these patients have a phenotype reminiscent of Perrault syndrome (PRLTS1; 233400). Pierce et al. (2010) noted that Perrault syndrome and DBP deficiency overlap clinically and suggested that DBP deficiency may be underdiagnosed.

ATP6V0A2-related cutis laxa is characterized by generalized cutis laxa, findings associated with generalized connective tissue disorder, developmental delays, and a variety of neurologic findings including abnormality on brain MRI. At birth, hypotonia, overfolded skin, and distinctive facial features are present and enlarged fontanelles are often observed. During childhood, the characteristic facial features and thick or coarse hair may become quite pronounced. The skin findings decrease with age, although easy bruising and Ehlers-Danlos-like scars have been described in some. In most (not all) affected individuals, cortical and cerebellar malformations are observed on brain MRI. Nearly all affected individuals have developmental delays, seizures, and neurologic regression.

Abnormalities of the digits can affect both the fingers and the toes in people with oral-facial-digital syndrome. These abnormalities include fusion of certain fingers or toes (syndactyly), digits that are shorter than usual (brachydactyly), or digits that are unusually curved (clinodactyly). The presence of extra digits (polydactyly) is also seen in most forms of oral-facial-digital syndrome.\n\nDistinctive facial features often associated with oral-facial-digital syndrome include a split in the lip (a cleft lip); a wide nose with a broad, flat nasal bridge; and widely spaced eyes (hypertelorism).\n\nOther features occur in only one or a few types of oral-facial digital syndrome. These features help distinguish the different forms of the disorder. For example, the most common form of oral-facial-digital syndrome, type I, is associated with polycystic kidney disease. This kidney disease is characterized by the growth of fluid-filled sacs (cysts) that interfere with the kidneys' ability to filter waste products from the blood. Other forms of oral-facial-digital syndrome are characterized by neurological problems, particular changes in the structure of the brain, bone abnormalities, vision loss, and heart defects.\n\nAbnormalities of the oral cavity that occur in many types of oral-facial-digital syndrome include a split (cleft) in the tongue, a tongue with an unusual lobed shape, and the growth of noncancerous tumors or nodules on the tongue. Affected individuals may also have extra, missing, or defective teeth. Another common feature is an opening in the roof of the mouth (a cleft palate). Some people with oral-facial-digital syndrome have bands of extra tissue (called hyperplastic frenula) that abnormally attach the lip to the gums.\n\nThe signs and symptoms of oral-facial-digital syndrome vary widely. However, most forms of this disorder involve problems with development of the oral cavity, facial features, and digits. Most forms are also associated with brain abnormalities and some degree of intellectual disability.\n\nResearchers have identified at least 13 potential forms of oral-facial-digital syndrome. The different types are classified by their patterns of signs and symptoms. However, the features of the various types overlap significantly, and some types are not well defined. The classification system for oral-facial-digital syndrome continues to evolve as researchers find more affected individuals and learn more about this disorder.\n\nOral-facial-digital syndrome is actually a group of related conditions that affect the development of the oral cavity (the mouth and teeth), facial features, and digits (fingers and toes).

Oral-facial-digital syndrome is actually a group of related conditions that affect the development of the oral cavity (the mouth and teeth), facial features, and digits (fingers and toes).\n\nResearchers have identified at least 13 potential forms of oral-facial-digital syndrome. The different types are classified by their patterns of signs and symptoms. However, the features of the various types overlap significantly, and some types are not well defined. The classification system for oral-facial-digital syndrome continues to evolve as researchers find more affected individuals and learn more about this disorder.\n\nThe signs and symptoms of oral-facial-digital syndrome vary widely. However, most forms of this disorder involve problems with development of the oral cavity, facial features, and digits. Most forms are also associated with brain abnormalities and some degree of intellectual disability.\n\nAbnormalities of the oral cavity that occur in many types of oral-facial-digital syndrome include a split (cleft) in the tongue, a tongue with an unusual lobed shape, and the growth of noncancerous tumors or nodules on the tongue. Affected individuals may also have extra, missing, or defective teeth. Another common feature is an opening in the roof of the mouth (a cleft palate). Some people with oral-facial-digital syndrome have bands of extra tissue (called hyperplastic frenula) that abnormally attach the lip to the gums.\n\nOther features occur in only one or a few types of oral-facial digital syndrome. These features help distinguish the different forms of the disorder. For example, the most common form of oral-facial-digital syndrome, type I, is associated with polycystic kidney disease. This kidney disease is characterized by the growth of fluid-filled sacs (cysts) that interfere with the kidneys' ability to filter waste products from the blood. Other forms of oral-facial-digital syndrome are characterized by neurological problems, particular changes in the structure of the brain, bone abnormalities, vision loss, and heart defects.\n\nDistinctive facial features often associated with oral-facial-digital syndrome include a split in the lip (a cleft lip); a wide nose with a broad, flat nasal bridge; and widely spaced eyes (hypertelorism).\n\nAbnormalities of the digits can affect both the fingers and the toes in people with oral-facial-digital syndrome. These abnormalities include fusion of certain fingers or toes (syndactyly), digits that are shorter than usual (brachydactyly), or digits that are unusually curved (clinodactyly). The presence of extra digits (polydactyly) is also seen in most forms of oral-facial-digital syndrome.

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.

Most females with osteopathia striata with cranial sclerosis (OS-CS) present with macrocephaly and characteristic facial features (frontal bossing, hypertelorism, epicanthal folds, depressed nasal bridge, and prominent jaw). Approximately half have associated features including orofacial clefting and hearing loss, and a minority have some degree of developmental delay (usually mild). Radiographic findings of cranial sclerosis, sclerosis of long bones, and metaphyseal striations (in combination with macrocephaly) can be considered pathognomonic. Males can present with a mild or severe phenotype. Mildly affected males have clinical features similar to affected females, including macrocephaly, characteristic facial features, orofacial clefting, hearing loss, and mild-to-moderate learning delays. Mildly affected males are more likely than females to have congenital or musculoskeletal anomalies. Radiographic findings include cranial sclerosis and sclerosis of the long bones; Metaphyseal striations are more common in males who are mosaic for an AMER1 pathogenic variant. The severe phenotype manifests in males as a multiple-malformation syndrome, lethal in mid-to-late gestation, or in the neonatal period. Congenital malformations include skeletal defects (e.g., polysyndactyly, absent or hypoplastic fibulae), congenital heart disease, and brain, genitourinary, and gastrointestinal anomalies. Macrocephaly is not always present and longitudinal metaphyseal striations have not been observed in severely affected males, except for those who are mosaic for the AMER1 pathogenic variant.

Osteoglophonic dysplasia (OGD) is characterized by rhizomelic dwarfism, nonossifying bone lesions, craniosynostosis, prominent supraorbital ridge, and depressed nasal bridge (summary by White et al., 2005).

Homocystinuria caused by cystathionine ß-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ? or only one ? of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.

Recombinant chromosome 8 syndrome (Rec8 syndrome) is a chromosomal disorder found among individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have impaired intellectual development, congenital heart defects, seizures, a characteristic facial appearance with hypertelorism, thin upper lip, anteverted nares, wide face, and abnormal hair whorl, and other manifestations (Sujansky et al., 1993, summary by Graw et al., 2000).

Kleefstra syndrome is characterized by intellectual disability, autistic-like features, childhood hypotonia, and distinctive facial features. The majority of individuals function in the moderate-to-severe spectrum of intellectual disability although a few individuals have mild delay and total IQ within low-normal range. While most have severe expressive speech delay with little speech development, general language development is usually at a higher level, making nonverbal communication possible. A complex pattern of other findings can also be observed; these include heart defects, renal/urologic defects, genital defects in males, severe respiratory infections, epilepsy / febrile seizures, psychiatric disorders, and extreme apathy or catatonic-like features after puberty.

Jacobsen syndrome (JBS) is a contiguous gene deletion syndrome with major clinical features of growth retardation, psychomotor retardation, trigonocephaly, divergent intermittent strabismus, epicanthus, telecanthus, broad nasal bridge, short nose with anteverted nostrils, carp-shaped upper lip, retrognathia, low-set dysmorphic ears, bilateral camptodactyly, hammertoes, and isoimmune thrombocytopenia (Fryns et al., 1986, Epstein, 1986).

Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.

Peters plus syndrome is characterized by anterior chamber eye anomalies, short limbs with broad distal extremities, characteristic facial features, cleft lip/palate, and variable developmental delay / intellectual disability. The most common anterior chamber defect is Peters' anomaly, consisting of central corneal clouding, thinning of the posterior cornea, and iridocorneal adhesions. Cataracts and glaucoma are common. Developmental delay is observed in about 80% of children; intellectual disability can range from mild to severe.

Microphthalmia-ankyloblepharon-intellectual disability syndrome is characterized by microphthalmia, ankyloblepharon and intellectual deficit. It has been described in seven male patients from two generations of a Northern Ireland family. The causative gene is localized to the Xq27-q28 region. The syndrome is transmitted as an X-linked recessive trait.

MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders.

Primrose syndrome is characterized by macrocephaly, hypotonia, developmental delay, intellectual disability with expressive speech delay, behavioral issues, a recognizable facial phenotype, radiographic features, and altered glucose metabolism. Additional features seen in adults: sparse body hair, distal muscle wasting, and contractures. Characteristic craniofacial features include brachycephaly, high anterior hairline, deeply set eyes, ptosis, downslanted palpebral fissures, high palate with torus palatinus, broad jaw, and large ears with small or absent lobes. Radiographic features include calcification of the external ear cartilage, multiple Wormian bones, platybasia, bathrocephaly, slender bones with exaggerated metaphyseal flaring, mild epiphyseal dysplasia, and spondylar dysplasia. Additional features include hearing impairment, ocular anomalies, cryptorchidism, and nonspecific findings on brain MRI.

Renpenning syndrome is an X-linked syndromic intellectual developmental disorder with clinically recognizable features. Affected individuals have microcephaly, short stature, small testes, and dysmorphic facies, including tall narrow face, upslanting palpebral fissures, abnormal nasal configuration, cupped ears, and short philtrum. The nose may appear long or bulbous, with overhanging columella. Less consistent manifestations include ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. Stevenson et al. (2005) proposed that the various X-linked mental retardation syndromes due to PQBP1 mutations be combined under the name of Renpenning syndrome.

The Richieri-Costa/Guion-Almeida syndrome is characterized by mild mental retardation, short stature, microbrachycephaly, ptosis, esotropia, cleft lip/palate (Richieri-Costa and Guion-Almeida, 1992).

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palatal abnormalities); and commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal anomalies. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.

Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, speech abnormalities, and seizures. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.

The core phenotype of Elsahy-Waters syndrome consists of brachycephaly, facial asymmetry, marked hypertelorism, proptosis, blepharochalasis, midface hypoplasia, broad nose with concave nasal ridge, and prognathism; radicular dentin dysplasia with consequent obliterated pulp chambers, apical translucent cysts, recurrent infections, and early loss of teeth; vertebral fusions, particularly at C2-C3; and moderate mental retardation. Skin wrinkling over the glabellar region seems common, and in males, hypospadias has always been present. Inter- and intrafamilial variability has been reported regarding the presence of vertebral fusions, hearing loss, and dentigerous cysts. Midface hypoplasia, facial asymmetry, progressive dental anomalies, and impaired cognitive development become more evident in adulthood (summary by Castori et al., 2010).

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.

Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech and motor) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy. To date, 16 affected individuals have been reported.

Shprintzen-Goldberg syndrome (SGS) is characterized by: delayed motor and cognitive milestones and mild-to-moderate intellectual disability; craniosynostosis of the coronal, sagittal, or lambdoid sutures; distinctive craniofacial features; and musculoskeletal findings including olichostenomelia, arachnodactyly, camptodactyly, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, and C1-C2 spine malformation. Cardiovascular anomalies may include mitral valve prolapse, secundum atrial septal defect, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, and myopia are also characteristic findings.

Traboulsi syndrome is characterized by dislocated crystalline lenses and anterior segment abnormalities in association with a distinctive facies involving flat cheeks and a beaked nose. Some affected individuals develop highly unusual nontraumatic conjunctival cysts (filtering blebs), presumably caused by abnormal thinning of the sclera (Patel et al., 2014).

Aymé-Gripp syndrome is classically defined as the triad of bilateral early cataracts, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities. The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears. Hearing loss is often congenital. Other features may include postnatal short stature, seizure disorder, nonspecific brain abnormalities on head imaging, skeletal abnormalities, and joint limitations. A subset of individuals have been found to have pericarditis or pericardial effusion during the neonatal or infantile period. All affected individuals have had developmental delay, but the degree of cognitive impairment is extremely variable. Other features including gastrointestinal and endocrine abnormalities, ectodermal dysplasia (i.e., nail dystrophy and mammary gland hypoplasia), dental anomalies, and chronic glomerulopathy with proteinuria have been reported in rare affected individuals.

Van den Ende-Gupta syndrome (VDEGS) is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (summary by Patel et al., 2014).

Mitral valve prolapse (MVP) has a prevalence of approximately 2 to 3% in the general population. It is characterized by fibromyxomatous changes in mitral leaflet tissue, with upward displacement of 1 or both leaflets into the left atrium during systole; MVP is diagnosed when the movement of the mitral leaflets exceeds 2 mm. In classic MVP, leaflets are at least 5 mm thick, whereas in nonclassic MVP, they are less than 5 mm thick. Auscultatory findings, when present, consist of a midsystolic click and/or a late systolic murmur. The natural history of MVP varies from benign, with a normal life expectancy, to severe complications associated with the development of significant mitral regurgitation, including congestive heart failure, bacterial endocarditis, atrial fibrillation, thromboembolism, and even sudden death. However, complications are uncommon, affecting less than 3% of individuals with MVP (Freed et al., 1999; Grau et al., 2007; Delling and Vasan, 2014). Grau et al. (2007) provided a detailed review of the genetics of mitral valve prolapse. Delling and Vasan (2014) reviewed the epidemiology and pathophysiology of MVP, with discussion of disease progression, genetics, and molecular basis. Genetic Heterogeneity of Familial Mitral Valve Prolapse The locus for MVP1 has been mapped to chromosome 16p; the locus for MVP2 (607829) has been mapped to chromosome 11p. Mitral valve prolapse-3 (MVP3; 610840) is caused by mutation in the DZIP1 gene (608671) on chromosome 13q32.

The Borochowitz-Cormier-Daire type of spondyloepimetaphyseal dysplasia (SEMDBCD) is a rare type of autosomal recessive short-limb short-trunk dwarfism. Affected individuals have significant short stature with pronounced leg bowing, lumbar lordosis, and a waddling gait (summary by Borochowitz et al., 2004 and Shyamasundar et al., 2020).

The classic features of TARP syndrome are talipes equinovarus, atrial septal defect, Robin sequence (micrognathia, cleft palate, and glossoptosis), and persistent left superior vena cava. Not all patients have all classic features. Some patients have the additional features of central nervous system dysfunction, renal abnormalities, variable cardiac anomalies including hypertrophic obstructive cardiomyopathy, and variable distal limb defects including syndactyly. Most patients die in late prenatal or early postnatal stages (summary by Kaeppler et al., 2018).

Acrocapitofemoral dysplasia (ACFD) is an autosomal recessive skeletal dysplasia characterized by postnatal-onset disproportionate short stature, relatively large head, narrow thorax, lumbar lordosis, short limbs, and brachydactyly with small broad nails (Ozyavuz Cubuk and Duz, 2021).

The X-linked otopalatodigital (X-OPD) spectrum disorders, characterized primarily by skeletal dysplasia, include the following: Otopalatodigital syndrome type 1 (OPD1). Otopalatodigital syndrome type 2 (OPD2). Frontometaphyseal dysplasia type 1 (FMD1). Melnick-Needles syndrome (MNS). Terminal osseous dysplasia with pigmentary skin defects (TODPD). In OPD1, most manifestations are present at birth; females can present with severity similar to affected males, although some have only mild manifestations. In OPD2, females are less severely affected than related affected males. Most males with OPD2 die during the first year of life, usually from thoracic hypoplasia resulting in pulmonary insufficiency. Males who live beyond the first year of life are usually developmentally delayed and require respiratory support and assistance with feeding. In FMD1, females are less severely affected than related affected males. Males do not experience a progressive skeletal dysplasia but may have joint contractures and hand and foot malformations. Progressive scoliosis is observed in both affected males and females. In MNS, wide phenotypic variability is observed; some individuals are diagnosed in adulthood, while others require respiratory support and have reduced longevity. MNS in males results in perinatal lethality in all recorded cases. TODPD, seen only in females, is characterized by a skeletal dysplasia that is most prominent in the digits, pigmentary defects of the skin, and recurrent digital fibromata.

Catel-Manzke syndrome is characterized by the Pierre Robin anomaly, which comprises cleft palate, glossoptosis, and micrognathia, and a unique form of bilateral hyperphalangy in which there is an accessory bone inserted between the second metacarpal and its corresponding proximal phalanx, resulting in radial deviation of the index finger (summary by Manzke et al., 2008).

Claes-Jensen type of X-linked syndromic intellectual developmental disorder (MRXSCJ) is characterized by impaired intellectual development with substantial clinical heterogeneity in affected males. However, males are usually reported to have short stature, microcephaly, hyperreflexia, and aggressive behavior. In rare cases, female carriers exhibit mildly impaired intellectual development or learning difficulties (summary by Guerra et al., 2020).

Corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome is a developmental anomalies syndrome characterized by coloboma of the iris and optic nerve, facial dysmorphism (high forehead, microretrognathia, low-set ears), intellectual deficit, agenesis of the corpus callosum (ACC), sensorineural hearing loss, skeletal anomalies and short stature.

Al-Gazali-Bakalinova syndrome (AGBK) is characterized by multiple epiphyseal dysplasia, macrocephaly, and distinctive facial features including frontal bossing, hypertelorism, flat malar regions, low-set ears, and short neck. Other features include pectus excavatum, spindle-shaped fingers, clinodactyly, prominent joints, and genu valgum (summary by Ali et al., 2012).

CHIME syndrome, also known as Zunich neuroectodermal syndrome, is an extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME). Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties (summary by Ng et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Teebi-Shaltout syndrome is characterized by slow hair growth, scaphocephaly with prominent forehead, bitemporal depression, absence of primary teeth, camptodactyly, and caudal appendage with sacral dimple (summary by Aldemir et al., 2013).

Spondylometaepiphyseal dysplasia, short limb-hand type is an autosomal recessive disorder with clinical and radiologic features of disproportionate short stature, platyspondyly, abnormal epiphyses and metaphyses, shortening of the lower and upper limbs, short and broad fingers, and premature calcifications. The disorder is progressive with respect to the severity of the bowing of the lower limbs and the appearance of calcifications, with some patients being wheelchair-bound from age 11 years (Bargal et al., 2009).

Patients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.

Pulmonary lymphangiectasia is a rare congenital vascular dysplasia characterized by an increased number of dilated pulmonary lymphatics in the subpleural, peribronchial, and interlobular septa. Respiratory distress is usually noted immediately after birth (summary by Stevenson et al., 2006).

Raine syndrome (RNS) is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by Simpson et al., 2009). Some patients survive infancy (Simpson et al., 2009; Fradin et al., 2011).

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized clinically by bone fragility and increased susceptibility to fractures. Osteogenesis imperfecta type IX (OI9) is a severe autosomal recessive form of the disorder (summary by van Dijk et al., 2009).

A rare multiple congenital malformations/dysmorphic syndrome characterized by osteogenesis imperfecta with multiple prenatal bone fractures, joint laxity, severe microcephaly, and bilateral cataracts. Additional reported manifestations include dysmorphic facial features (such as blue sclerae, hypertelorism, and low-set ears), lissencephaly, hydrocephalus, and cardiac and genital anomalies. The syndrome is lethal <i>in utero</i> or shortly after birth. There have been no further descriptions in the literature since 1978.

NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies. Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis. Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus. Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate. Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones. Infants may demonstrate feeding difficulties with poor weight gain.

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Osteogenesis imperfecta is a connective tissue disorder characterized by bone fragility and low bone mass. OI type VII is an autosomal recessive form of severe or lethal OI (summary by Barnes et al., 2006).

Syndrome with characteristics of a combination of distal limb abnormalities (syndactyly of all fingers and toes, preaxial polydactyly in the feet and/or hands) and upper sternum malformations. It has been described in 22 patients from a six-generation Turkish family. It is transmitted as an autosomal dominant trait and the causative gene is located at 7q36.

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

The primary characteristics of the Frank-ter Haar syndrome (FTHS) are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (summary by Maas et al., 2004). Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).

Pyruvate dehydrogenase deficiency is characterized by the buildup of a chemical called lactic acid in the body and a variety of neurological problems. Signs and symptoms of this condition usually first appear shortly after birth, and they can vary widely among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. People with pyruvate dehydrogenase deficiency usually have neurological problems as well. Most have delayed development of mental abilities and motor skills such as sitting and walking. Other neurological problems can include intellectual disability, seizures, weak muscle tone (hypotonia), poor coordination, and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right halves of the brain (corpus callosum), wasting away (atrophy) of the exterior part of the brain known as the cerebral cortex, or patches of damaged tissue (lesions) on some parts of the brain. Because of the severe health effects, many individuals with pyruvate dehydrogenase deficiency do not survive past childhood, although some may live into adolescence or adulthood.

Mowat-Wilson syndrome (MWS) is characterized by distinctive facial features (widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes with a central depression), congenital heart defects with predilection for abnormalities of the pulmonary arteries and/or valves, Hirschsprung disease or chronic constipation, genitourinary anomalies (particularly hypospadias in males), and hypogenesis or agenesis of the corpus callosum. Most affected individuals have moderate-to-severe intellectual disability. Speech is typically limited to a few words or is absent, with relative preservation of receptive language skills. Growth restriction with microcephaly and seizure disorder are also common. Most affected people have a happy demeanor and a wide-based gait that can sometimes be confused with Angelman syndrome.

A very rare syndrome including short stature, facial dysmorphism, hand abnormalities and shawl scrotum. It has been observed in 16 subjects from five distantly related sibships of a large Kuwaiti Bedouin tribe. The affected patients had no intellectual deficit. Transmitted as an autosomal recessive trait.

Becker nevus (BN) is a cutaneous hamartoma affecting approximately 1 in 200 individuals that appears in childhood as a unilateral tan patch, and increases in thickness, pigmentation, and hair growth during adolescence. Histologically, epidermal acanthosis is accompanied by irregularly dispersed ectopic smooth muscle bundles and increased terminal hair follicles (summary by Cai et al., 2017). Becker nevus syndrome (BNS) is a phenotype characterized by the presence of a Becker nevus in association with unilateral hypoplasia of breast or other cutaneous, muscular, or skeletal defects (Happle and Koopman, 1997).

Cenani-Lenz syndactyly syndrome (CLSS) is an autosomal recessive disorder characterized mainly by anomalies of distal limb development, with fusion and disorganization of metacarpal and phalangeal bones, radius and ulnar shortening, radioulnar synostosis, and severe syndactyly of hands and feet. Mild facial dysmorphism is present in most patients. Kidney anomalies, including renal agenesis and hypoplasia, occur in over half of patients (summary by Li et al., 2010).

Arterial tortuosity syndrome (ATS) is characterized by widespread elongation and tortuosity of the aorta and mid-sized arteries as well as focal stenosis of segments of the pulmonary arteries and/or aorta combined with findings of a generalized connective tissue disorder, which may include soft or doughy hyperextensible skin, joint hypermobility, inguinal hernia, and diaphragmatic hernia. Skeletal findings include pectus excavatum or carinatum, arachnodactyly, scoliosis, knee/elbow contractures, and camptodactyly. The cardiovascular system is the major source of morbidity and mortality with increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree, and for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs).

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Distal arthrogryposis type 5 is distinguished from other forms of DA by the presence of ocular abnormalities, typically ptosis, ophthalmoplegia, and/or strabismus, in addition to contractures of the skeletal muscles. Some cases have been reported to have pulmonary hypertension as a result of restrictive lung disease (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA5 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of cleft palate and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders might represent variable expressivity of the same condition. For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120). Genetic Heterogeneity of Distal Arthrogryposis 5 A subtype of DA5 due to mutation in the ECEL1 gene (605896) on chromosome 2q36 has been designated DA5D (615065). See NOMENCLATURE.

This syndrome has characteristics of camptodactyly, tall stature, scoliosis, and hearing loss (CATSHL). It has been described in around 30 individuals from seven generations of the same family. The syndrome is caused by a missense mutation in the FGFR3 gene, leading to a partial loss of function of the encoded protein, which is a negative regulator of bone growth.

Koolen-de Vries syndrome (KdVS) is characterized by developmental delay / intellectual disability, neonatal/childhood hypotonia, dysmorphisms, congenital malformations, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism (71% of males). Behavior in most is described as friendly, amiable, and cooperative.

Bleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.\n\nMany people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.\n\nAn unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.\n\nThe various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.\n\nOther types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.\n\nEhlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.

Pterygia, impaired intellectual development, and distinctive craniofacial features is a chromosomal disorder characterized by these cardinal features. Craniofacial features include trigonocephaly and retrognathia. Intellectual development may be severely impaired (summary by Devriendt et al., 2000).

MDDGC4 is an autosomal recessive muscular dystrophy with onset in infancy or early childhood. Cognition and brain structure are usually normal (Godfrey et al., 2006). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009).

Legius syndrome is characterized by multiple café au lait macules without neurofibromas or other tumor manifestations of neurofibromatosis type 1 (NF1). Additional clinical manifestations reported commonly include intertriginous freckling, lipomas, macrocephaly, and learning disabilities / attention-deficit/hyperactivity disorder (ADHD) / developmental delays. Current knowledge of the natural history of Legius syndrome is based on the clinical manifestations of fewer than 300 individuals with a molecularly confirmed diagnosis; better delineation of the clinical manifestations and natural history of Legius syndrome will likely occur as more affected individuals are identified.

A rare genetic developmental defect during embryogenesis disorder with characteristics of craniofacial dysmorphism (including brachycephaly, prominent forehead, sparse lateral eyebrows, severe hypertelorism, upslanting palpebral fissures, epicanthal folds, protruding ears, broad nasal bridge, pointed nasal tip, flat philtrum, anteverted nostrils, large mouth, thin upper vermilion border, highly arched palate and mild micrognathia) associated with osteopenia leading to repeated long bone fractures, severe myopia, mild to moderate sensorineural or mixed hearing loss, enamel hypoplasia, sloping shoulders and mild intellectual disability. There is evidence the disease can be caused by homozygous mutation in the IRX5 gene on chromosome 16q11.2.

Any X-linked syndromic intellectual disability in which the cause of the disease is a mutation in the UPF3B gene.

Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity.

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

An extremely rare type of spondyloepiphyseal dysplasia described in about 5 patients to date with clinical signs including short stature, peculiar facies with blepharophimosis, upward slanted eyes, abundant eyebrows and eyelashes, coarse voice, and short hands and feet.

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.

10q26 deletion syndrome is a condition that results from the loss (deletion) of a small piece of chromosome 10 in each cell. The deletion occurs on the long (q) arm of the chromosome at a position designated 10q26.\n\nThe signs and symptoms of 10q26 deletion syndrome vary widely, even among affected members of the same family. Among the more common features associated with this chromosomal change are distinctive facial features, mild to moderate intellectual disability, growth problems, and developmental delay. People with 10q26 deletion syndrome often have delayed development of speech and of motor skills such as sitting, crawling, and walking. Some have limited speech throughout life. Affected individuals may experience seizures, attention-deficit/hyperactivity disorder (ADHD), poor impulse control (impulsivity), or exhibit autistic behaviors that affect communication and social interaction.\n\nA range of facial features is seen in people with 10q26 deletion syndrome, but not all affected individuals have these features. Facial features of people with 10q26 deletion syndrome may include a prominent or beaked nose, a broad nasal bridge, a small jaw (micrognathia), malformed ears that are low set, a thin upper lip, and an unusually small head size (microcephaly). Many affected individuals have widely spaced eyes (hypertelorism) that do not look in the same direction (strabismus). Some people with this condition have a short neck with extra folds of skin (webbed neck).\n\nLess common signs and symptoms can occur in 10q26 deletion syndrome. Skeletal problems include a spine that curves to the side (scoliosis), limited movement in the elbows or other joints, or curved fifth fingers and toes (clinodactyly). Slow growth before and after birth can also occur in affected individuals. Males with this condition may have genital abnormalities, such as a small penis (micropenis), undescended testes (cryptorchidism), or the urethra opening on the underside of the penis (hypospadias). Some people with 10q26 deletion syndrome have kidney abnormalities, heart defects, breathing problems, recurrent infections, or hearing or vision problems.

3q29 recurrent deletion is characterized by neurodevelopmental and/or psychiatric manifestations including mild-to-moderate intellectual disability (ID), autism spectrum disorder (ASD), anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), executive function deficits, graphomotor weakness, and psychosis/schizophrenia. Age at onset for psychosis or prodrome can be younger than the typical age at onset in the general population. Neurodevelopmental and psychiatric conditions are responsible for the majority of the disability associated with the 3q29 deletion. Other common findings are failure to thrive and feeding problems in infancy that persist into childhood, gastrointestinal disorders (including constipation and gastroesophageal reflux disease [GERD]), ocular issues, dental anomalies, and congenital heart defects (especially patent ductus arteriosus). Structural anomalies of the posterior fossa may be seen on neuroimaging. To date more than 200 affected individuals have been identified.

Distal monosomy 6p is responsible for a distinct chromosome deletion syndrome with a recognizable clinical picture including intellectual deficit, ocular abnormalities, hearing loss, and facial dysmorphism.

1q41q42 microdeletion syndrome is a chromosomal anomaly characterized by a severe developmental delay and/or intellectual disability, typical facial dysmorphic features, brain anomalies, seizures, cleft palate, clubfeet, nail hypoplasia and congenital heart disease.

Chromosome 2p16.1-p15 deletion syndrome is a neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and variable but distinctive dysmorphic features, including microcephaly, bitemporal narrowing, smooth and long philtrum, hypertelorism, downslanting palpebral fissures, broad nasal root, thin upper lip, and high palate. Many patients have behavioral disorders, including autistic features, as well as structural brain abnormalities, such as pachygyria or hypoplastic corpus callosum. Those with deletions including the BCL11A gene (606557) also have persistence of fetal hemoglobin (HbF), which is asymptomatic and does not affected hematologic parameters or susceptibility to infection (summary by Funnell et al., 2015). Point mutation in the BCL11A gene causes intellectual developmental disorder with persistence of fetal hemoglobin (617101), which shows overlapping features. See also fetal hemoglobin quantitative trait locus-5 (HBFQTL5; 142335).

The 1q21.1 recurrent microdeletion itself does not appear to lead to a clinically recognizable syndrome as some persons with the deletion have no obvious clinical findings and others have variable findings that most commonly include microcephaly (50%), mild intellectual disability (30%), mildly dysmorphic facial features, and eye abnormalities (26%). Other findings can include cardiac defects, genitourinary anomalies, skeletal malformations, and seizures (~15%). Psychiatric and behavioral abnormalities can include autism spectrum disorders, attention deficit hyperactivity disorder, autistic features, and sleep disturbances.

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a neurodevelopmental disorder with a highly variable phenotype. Some affected families show X-linked recessive inheritance, with only males being affected and carrier females having no abnormal findings. In other affected families, males are severely affected, and female mutation carriers show milder cognitive abnormalities or dysmorphic features. In addition, there are female patients with de novo mutations who show the full phenotype, despite skewed X-chromosome inactivation. Affected individuals show global developmental delay from infancy, with variably impaired intellectual development and poor or absent speech, often with delayed walking. Dysmorphic features are common and can include macrocephaly, microcephaly, deep-set eyes, hypotelorism, small palpebral fissures, dysplastic, large, or low-set ears, long face, bitemporal narrowing, high-arched palate, thin upper lip, and scoliosis or mild distal skeletal anomalies, such as brachydactyly or tapered fingers. Males tend to have cryptorchidism. Other features, such as hypotonia, seizures, and delayed bone age, are more variable (summary by Moortgat et al., 2018).

Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with three M syndrome have hypogonadism and occasionally hypospadias.

Waardenburg syndrome type 2 (WS2) is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; and the absence of 'dystopia canthorum,' the lateral displacement of the inner canthus of each eye, which is seen in some other forms of WS (review by Read and Newton, 1997). Individuals with WS type 2E (WS2E) may have neurologic abnormalities, including mental impairment, myelination defects, and ataxia. Waardenburg syndrome type 2 is genetically heterogeneous (see WS2A, 193510). For a description of other clinical variants of Waardenburg syndrome, see WS1 (193500), WS3 (148820), and WS4 (277580).

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

A very rare inherited connective tissue disorder with characteristics of macrocephaly, sparse scalp hair, soft redundant and hyperextensible skin, joint hypermobility, and scoliosis. Patients have progressive facial coarsening with downslanted palpebral fissures, upper eyelid fullness/infraorbital folds, thick/everted vermillion, gingival overgrowth and abnormal position of the teeth. Rare manifestations such as abnormal high-pitched voice, bronchiectasis, hypergonadotropic hypergonadism and brachydactyly have also been reported. Caused by homozygous mutation in the RIN2 gene on chromosome 20p11.

The phenotype of autosomal recessive cutis laxa type II (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (summary by Morava et al., 2009). No specific clinical features distinguish ARCL2A (219200), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (Morava et al., 2009; Guernsey et al., 2009). For a phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).

Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. These glycoconjugates play critical roles in metabolism, cell recognition and adhesion, cell migration, protease resistance, host defense, and antigenicity, among others. CDGs are divided into 2 main groups: type I CDGs (see, e.g., CDG1A, 212065) comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein, whereas type II CDGs refer to defects in the trimming and processing of the protein-bound glycans either late in the endoplasmic reticulum or the Golgi compartments. The biochemical changes of CDGs are most readily observed in serum transferrin (TF; 190000), and the diagnosis is usually made by isoelectric focusing of this glycoprotein (reviews by Marquardt and Denecke, 2003; Grunewald et al., 2002). Genetic Heterogeneity of Congenital Disorder of Glycosylation Type II Multiple forms of CDG type II have been identified; see CDG2B (606056) through CDG2Z (620201), and CDG2AA (620454) to CDG2BB (620546).

A variant of neurofibromatosis type 1 characterized by the combination of features of neurofibromatosis type 1, such as café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, optic nerve glioma and multiple neurofibromas; and Noonan syndrome, with features such as short stature, typical facial features, congenital heart defects and unusual pectus deformity.

Syndromic multisystem autoimmune disease due to Itch deficiency is a rare, genetic, systemic autoimmune disease characterized by failure to thrive, global developmental delay, distinctive craniofacial dysmorphism (relative macrocephaly, dolichocephaly, frontal bossing, orbital proptosis, flattened midface with a prominent occiput, low, posteriorly rotated ears, micrognatia), hepato- and/or splenomegaly, and multisystemic autoimmune disease involving the lungs, liver, gut and/or thyroid gland.

16p13.3 microduplication syndrome is a rare chromosomal anomaly syndrome resulting from a partial duplication of the short arm of chromosome 16 and manifesting with a variable phenotype which is mostly characterized by: mild to moderate intellectual deficit and developmental delay (particularly speech), normal growth, short, proximally implanted thumbs and other hand and feet malformations (such as camptodactyly, syndactyly, club feet), mild arthrogryposis and characteristic facies (upslanting, narrow palpebral fissures, hypertelorism, mid face hypoplasia, bulbous nasal tip and low set ears). Other reported manifestations include cryptorchidism, inguinal hernia and behavioral problems.

Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) is a developmental disorder resembling Noonan syndrome (NS1; 163950) and is characterized by facial dysmorphism, a wide spectrum of cardiac disease, reduced growth, variable cognitive deficits, and ectodermal and musculoskeletal anomalies. There is extensive phenotypic heterogeneity and variable expressivity. Patients with heterozygous germline CBL mutations have an increased risk for certain malignancies, particularly juvenile myelomonocytic leukemia (JMML; 607785), as seen in patients with Noonan syndrome (summary by Martinelli et al., 2010 and Niemeyer et al., 2010).

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.

Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae (M-SDV) in combination with abnormalities of the ribs, is characterized clinically by: a short trunk in proportion to height; short neck; non-progressive mild scoliosis in most affected individuals, and occasionally, more significant scoliosis. Respiratory function in neonates may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development; however, even then life-threatening complications can occur, especially pulmonary hypertension in children with severely restricted lung capacity from birth. Males with SCDO appear to be at increased risk for inguinal hernia.

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Ogden syndrome (OGDNS) is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Many patients also have cardiac malformations or arrhythmias (summary by Popp et al., 2015).

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

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.

Congenital myopathy-10A (CMYO10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (Logan et al., 2011). Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYO10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYO10B) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

EFEMP2-related cutis laxa, or autosomal recessive cutis laxa type 1B (ARCL1B), is characterized by cutis laxa and systemic involvement, most commonly arterial tortuosity, aneurysms, and stenosis; retrognathia; joint laxity; and arachnodactyly. Severity ranges from perinatal lethality as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems.

Syndrome that has characteristics of dysmorphic features and intellectual deficit. It has been described in seven patients within one family. 17q11.2 microduplication encompasses the NF1 region. The underlying mechanism may be non-allelic homologous recombination. The study of pedigree suggests that this microduplication segregates within the family for at least two generations. Two patients displayed a normal clinical presentation, suggesting an autosomal dominant pattern of inheritance with incomplete penetrance.

Ectopia lentis is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene et al., 2010). Citing the revised Ghent criteria for Marfan syndrome, Loeys et al. (2010) proposed the designation 'ectopia lentis syndrome' (ELS) for patients with ectopia lentis and a mutation in the FBN1 gene who lack aortic involvement, to highlight the systemic nature of the condition and to emphasize the need for assessment of features outside the ocular system (see DIAGNOSIS). Genetic Heterogeneity of Isolated Ectopia Lentis An autosomal recessive form of isolated ectopia lentis (ECTOL2; 225100) is caused by mutation in the ADAMTSL4 gene (610113).

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is characterized by inappropriately low serum concentrations of the gonadotropins LH (luteinizing hormone) and FSH (follicle-stimulating hormone) in the presence of low circulating concentrations of sex steroids. IGD is associated with a normal sense of smell (normosmic IGD) in approximately 40% of affected individuals and an impaired sense of smell (Kallmann syndrome) in approximately 60%. IGD can first become apparent in infancy, adolescence, or adulthood. Infant boys with congenital IGD often have micropenis and cryptorchidism. Adolescents and adults with IGD have clinical evidence of hypogonadism and incomplete sexual maturation on physical examination. Adult males with IGD tend to have prepubertal testicular volume (i.e., <4 mL), absence of secondary sexual features (e.g., facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido, erectile dysfunction, and infertility. Adult females have little or no breast development and primary amenorrhea. Although skeletal maturation is delayed, the rate of linear growth is usually normal except for the absence of a distinct pubertal growth spurt.

Malan syndrome (MALNS) is clinically characterized by overgrowth, advanced bone age, macrocephaly, and dysmorphic facial features. Patients develop marfanoid habitus, with long and slender body, very low body mass, long narrow face, and arachnodactyly, with age. Impaired intellectual development and behavior anomalies are present (summary by Martinez et al., 2015).

Carpenter syndrome-2 (CRPT2) is an autosomal recessive multiple congenital malformation disorder characterized by multisuture craniosynostosis and polysyndactyly of the hands and feet, in association with abnormal left-right patterning and other features, most commonly obesity, umbilical hernia, cryptorchidism, and congenital heart disease (summary by Twigg et al., 2012). For a discussion of genetic heterogeneity of Carpenter syndrome, see 201000.

PIK3CA-related overgrowth spectrum (PROS) encompasses a range of clinical findings in which the core features are congenital or early-childhood onset of segmental/focal overgrowth with or without cellular dysplasia. Prior to the identification of PIK3CA as the causative gene, PROS was separated into distinct clinical syndromes based on the tissues and/or organs involved (e.g., MCAP [megalencephaly-capillary malformation] syndrome and CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome). The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest), and face, all usually in an asymmetric distribution. Generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa. Vascular malformations may include capillary, venous, and less frequently, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations. Lymphatic malformations may be in various locations (internal and/or external) and can cause various clinical issues, including swelling, pain, and occasionally localized bleeding secondary to trauma. Lipomatous overgrowth may occur ipsilateral or contralateral to a vascular malformation, if present. The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., polymicrogyria), and hydrocephalus. Many children have feeding difficulties that are often multifactorial in nature. Endocrine issues affect a small number of individuals and most commonly include hypoglycemia (largely hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency.

\n\nThe features of Cowden syndrome overlap with those of another disorder called Bannayan-Riley-Ruvalcaba syndrome. People with Bannayan-Riley-Ruvalcaba syndrome also develop hamartomas and other noncancerous tumors.  Some people with Cowden syndrome have relatives diagnosed with Bannayan-Riley-Ruvalcaba syndrome, and other affected individuals have the characteristic features of both conditions. Based on these similarities, researchers have proposed that Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome represent a spectrum of overlapping features known as PTEN hamartoma tumor syndrome (named for the genetic cause of the conditions) instead of two distinct conditions.\n\nSome people do not meet the strict criteria for a clinical diagnosis of Cowden syndrome, but they have some of the characteristic features of the condition, particularly the cancers. These individuals are often described as having Cowden-like syndrome. Both Cowden syndrome and Cowden-like syndrome are caused by mutations in the same genes.\n\nCowden syndrome is associated with an increased risk of developing several types of cancer, particularly cancers of the breast, a gland in the lower neck called the thyroid, and the lining of the uterus (the endometrium). Other cancers that have been identified in people with Cowden syndrome include kidney cancer, colorectal cancer, and an agressive form of skin cancer called melanoma. Compared with the general population, people with Cowden syndrome develop these cancers at younger ages, often beginning in their thirties or forties. People with Cowden syndrome are also more likely to develop more than one cancer during their lifetimes compared to the general population. Other diseases of the breast, thyroid, and endometrium are also common in Cowden syndrome. Additional signs and symptoms can include an enlarged head (macrocephaly) and a rare, noncancerous brain tumor called Lhermitte-Duclos disease. A small percentage of affected individuals have delayed development, intellectual disability, or autism spectrum disorder, which can affect communication and social interaction.\n\nAlmost everyone with Cowden syndrome develops hamartomas. These growths are most commonly found on the skin and mucous membranes (such as the lining of the mouth and nose), but they can also occur in the intestine and other parts of the body. The growth of hamartomas on the skin and mucous membranes typically becomes apparent by a person's late twenties.\n\nCowden syndrome is a genetic disorder characterized by multiple noncancerous, tumor-like growths called hamartomas and an increased risk of developing certain cancers.

A rare multiple congenital anomalies syndrome with characteristics of distinctive facial appearance (low frontal hairline, bilateral ptosis, prominent eyes, flat midface, broad, ?at nares, Cupid''s bow upper lip vermilion and small, low-set, posteriorly rotated ears), cleft palate, conductive hearing loss, heart defects (atrial or ventricular septal defect) and mild developmental delay/intellectual disability.

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.

The features of Ehlers-Danlos syndrome spondylodysplastic type 2 (EDSSPD2) include an aged appearance, developmental delay, short stature, craniofacial disproportion, generalized osteopenia, defective wound healing, hypermobile joints, hypotonic muscles, and loose but elastic skin (Okajima et al., 1999). For a discussion of genetic heterogeneity of the spondylodysplastic type of Ehlers-Danlos syndrome, see 130070.

Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.

Hennekam lymphangiectasia-lymphedema syndrome (HKLLS1) is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (summary by Alders et al., 2014). Genetic Heterogeneity of Hennekam Lymphangiectasia-Lymphedema Syndrome See also HKLLS2 (616006), caused by mutation in the FAT4 gene (612411) on chromosome 4q28, and HKLLS3 (618154), caused by mutation in the ADAMTS3 gene (605011) on chromosome 4q13.

Desbuquois dysplasia, which belongs to the multiple dislocation group of disorders, is characterized by dislocations of large joints, severe pre- and postnatal growth retardation, joint laxity, and flat face with prominent eyes. Radiologic features include short long bones with an exaggerated trochanter that gives a 'monkey wrench' appearance to the proximal femur, and advanced carpal and tarsal ossification (summary by Bui et al., 2014). For a discussion of genetic heterogeneity of Desbuquois dysplasia, see DBQD1 (251450).

ADNP-related disorder is characterized by hypotonia, severe speech and motor delay, mild-to-severe intellectual disability, and characteristic facial features (prominent forehead, high anterior hairline, wide and depressed nasal bridge, and short nose with full, upturned nasal tip) based on a cohort of 78 individuals. Features of autism spectrum disorder are common (stereotypic behavior, impaired social interaction). Other common findings include additional behavioral problems, sleep disturbance, brain abnormalities, seizures, feeding issues, gastrointestinal problems, visual dysfunction (hypermetropia, strabismus, cortical visual impairment), musculoskeletal anomalies, endocrine issues including short stature and hormonal deficiencies, cardiac and urinary tract anomalies, and hearing loss.

Any familial thoracic aortic aneurysm and aortic dissection in which the cause of the disease is a mutation in the MFAP5 gene.

Ruijs et al. (2003) reported a Moroccan boy with a chromosomal breakage who died of hepatocellular carcinoma at age 17 years. The boy was noted to have growth retardation at age 3 years; at age 7 he was found to have thoracic kyphosis, frontal bossing, and a delayed bone age of approximately 3 years. He underwent surgery for severe bilateral posterior subcapsular cataracts at age 14. Examination at age 15 showed short stature and low weight, with premature graying of scalp hair, small frontotemporal diameter, small deep-set eyes, bulbous nose with high nasal bridge, small upper lip, and micrognathia. In addition, he had thoracic kyphoscoliosis, sloping shoulders, mild pectus excavatum, moderate bilateral contractures of both elbows, bilateral clinodactyly, and pes planus. At age 17, he developed abdominal pain, and ultrasonography revealed a liver mass; biopsy confirmed hepatocellular carcinoma. Because of the advanced stage, no treatment was possible, and he died 2 months later. Although his parents were not known to be consanguineous, they originated from the same small Moroccan village. Lessel et al. (2014) studied 2 brothers from a nonconsanguineous Australian family of European ancestry who exhibited low body weight, micrognathia, triangular face, muscular atrophy, lipodystrophy, bilateral simian creases, delayed bone age, and mild joint restrictions in the fingers and elbows. In addition, both brothers developed early-onset hepatocellular carcinoma, at ages 16 and 14 years, respectively. The older brother died at age 18 from complications of acute fulminant hepatic failure. Analysis of patient tumor biopsies showed strong focal accumulations of cancer biomarkers as well as a high proliferative index compared to healthy liver or to cells from idiopathic hepatocellular carcinoma.

Osteofibrous dysplasia (OSFD) is a tumor-like bone lesion that usually presents as a painless swelling or anterior bowing of the tibia (Park et al., 1993), although pain may occur in up to 25% of cases and presentation may follow pathologic fracture. Most reports of osteofibrous dysplasia describe isolated tibial lesions, although a significant subgroup describe isolated and ipsilateral fibular involvement. Cases with ulnar and radial involvement have been reported (summary by Hunter and Jarvis, 2002). OSFD is characterized by radiolucent lesions located at the periosteal surface of the diaphyseal cortex, almost exclusively of the tibia and fibula. These lesions are congenital and spontaneously resolve during skeletal maturation; the residuum is most commonly mild bowing at the affected site. Prior to their resolution, secondary complications such as nonunion fractures and pseudoarthrosis formation can occur. Histologically, OSFD lesions exhibit 'zonal architecture' characterized by spindle-shaped fibroblast-like cells in the center of the lesions that are progressively replaced with peripherally located, more differentiated cells from the osteoblastic lineage. The cells lying at the center of the lesions stain for markers of undifferentiated mesenchymal cell states, whereas bridging zones of osteoid with surface osteoblasts and embedded osteocytic cells are interspersed between the lesions. In OSFD, the unossified zones eventually mineralize after replacement with normal osteoid and, finally, bone. This histologic progression corresponds with the clinical and radiographic resolution of the lesions (summary by Gray et al., 2015). Hunter and Jarvis (2002) noted that there may be a relationship between osteofibrous dysplasia and adamantinoma of long bones (102660), although the latter condition usually presents at a later age.

Lymphatic malformation-6 is a form of generalized lymphatic dysplasia (GLD), which is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. In LMPHM6, there is a high incidence of nonimmune hydrops fetalis (NIHF) with either death or complete resolution of the neonatal edema, but childhood onset of lymphedema with or without systemic involvement also occurs. Mild facial edema is often present. Patients have normal intelligence and no seizures (summary by Fotiou et al., 2015). For a discussion of genetic heterogeneity of lymphatic malformation, see 153100.

Microcephaly, short stature, and impaired glucose metabolism-2 (MSSGM2) is an autosomal recessive syndrome characterized by microcephaly associated with impaired intellectual development, and short stature. Patients develop diabetes in the second or third decade of life, and hypothyroidism and delayed puberty have also been reported (Abdulkarim et al., 2015; Kernohan et al., 2015). For a discussion of genetic heterogeneity of microcephaly, short stature, and impaired glucose metabolism, see MSSGM1 (616033).

Congenital symmetric circumferential skin creases is characterized by the folding of excess skin, which leads to ringed creases, primarily of the limbs. Affected individuals also exhibit intellectual disability, cleft palate, and dysmorphic features (summary by Isrie et al., 2015). For a discussion of genetic heterogeneity of congenital symmetric circumferential skin creases, see CSCSC1 (156610).

Au-Kline syndrome is characterized by developmental delay and hypotonia with moderate-to-severe intellectual disability, and typical facial features that include long palpebral fissures, ptosis, shallow orbits, large and deeply grooved tongue, broad nose with a wide nasal bridge, and downturned mouth. There is frequently variable autonomic dysfunction (gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, abnormal sweating). Congenital heart disease, hydronephrosis, palate abnormalities, and oligodontia are also reported in the majority of affected individuals. Additional complications can include craniosynostosis, feeding difficulty, vision issues, osteopenia, and other skeletal anomalies.

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

PPP2R1A-related neurodevelopmental disorder (NDD) is characterized by: severe, persistent hypotonia; developmental delay with variable intellectual outcomes, typically in the moderate-to-severe intellectual disability range; seizures (more commonly seen in individuals with microcephaly and/or severe intellectual disability); attention-deficit/hyperactivity disorder and other behavioral problems (anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorder); feeding and swallowing issues; and dysmorphic features of the head and face. A minority of affected individuals have ear anomalies, hearing loss, ptosis, generalized joint hypermobility, and patent ductus arteriosus. Brain MRI findings are nonspecific but typically include complete or partial agenesis of the corpus callosum. Nonprogressive ventriculomegaly may be seen in a subset of affected individuals and is often associated with specific pathogenic variants in PPP2R1A: c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp).

Cole-Carpenter syndrome-2 (CLCRP2) is a skeletal dysplasia associated with low bone mass or an osteogenesis imperfecta-like syndrome. It is characterized by bone fragility with craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features such as marked frontal bossing, midface hypoplasia, and micrognathia (summary by Takeyari et al., 2018).

Arboleda-Tham syndrome (ARTHS) is an autosomal dominant disorder with the core features of impaired intellectual development, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications (summary by Kennedy et al., 2019).

X-linked syndromic intellectual developmental disorder-33 (MRXS33) is an X-linked recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, and characteristic facial features (summary by O'Rawe et al., 2015).

Any familial thoracic aortic aneurysm and aortic dissection in which the cause of the disease is a mutation in the LOX gene.

Ehlers-Danlos syndrome is a group of disorders that affect connective tissues supporting the skin, bones, blood vessels, and many other organs and tissues. Defects in connective tissues cause the signs and symptoms of these conditions, which range from mildly loose joints to life-threatening complications.\n\nOther types of Ehlers-Danlos syndrome have additional signs and symptoms. The cardiac-valvular type causes severe problems with the valves that control the movement of blood through the heart. People with the kyphoscoliotic type experience severe curvature of the spine that worsens over time and can interfere with breathing by restricting lung expansion. A type of Ehlers-Danlos syndrome called brittle cornea syndrome is characterized by thinness of the clear covering of the eye (the cornea) and other eye abnormalities. The spondylodysplastic type features short stature and skeletal abnormalities such as abnormally curved (bowed) limbs. Abnormalities of muscles, including hypotonia and permanently bent joints (contractures), are among the characteristic signs of the musculocontractural and myopathic forms of Ehlers-Danlos syndrome. The periodontal type causes abnormalities of the teeth and gums.\n\nThe various forms of Ehlers-Danlos syndrome have been classified in several different ways. Originally, 11 forms of Ehlers-Danlos syndrome were named using Roman numerals to indicate the types (type I, type II, and so on). In 1997, researchers proposed a simpler classification (the Villefranche nomenclature) that reduced the number of types to six and gave them descriptive names based on their major features. In 2017, the classification was updated to include rare forms of Ehlers-Danlos syndrome that were identified more recently. The 2017 classification describes 13 types of Ehlers-Danlos syndrome.\n\nAn unusually large range of joint movement (hypermobility) occurs in most forms of Ehlers-Danlos syndrome, and it is a hallmark feature of the hypermobile type. Infants and children with hypermobility often have weak muscle tone (hypotonia), which can delay the development of motor skills such as sitting, standing, and walking. The loose joints are unstable and prone to dislocation and chronic pain. In the arthrochalasia type of Ehlers-Danlos syndrome, infants have hypermobility and dislocations of both hips at birth.\n\nMany people with the Ehlers-Danlos syndromes have soft, velvety skin that is highly stretchy (elastic) and fragile. Affected individuals tend to bruise easily, and some types of the condition also cause abnormal scarring. People with the classical form of Ehlers-Danlos syndrome experience wounds that split open with little bleeding and leave scars that widen over time to create characteristic "cigarette paper" scars. The dermatosparaxis type of the disorder is characterized by loose skin that sags and wrinkles, and extra (redundant) folds of skin may be present.\n\nBleeding problems are common in the vascular type of Ehlers-Danlos syndrome and are caused by unpredictable tearing (rupture) of blood vessels and organs. These complications can lead to easy bruising, internal bleeding, a hole in the wall of the intestine (intestinal perforation), or stroke. During pregnancy, women with vascular Ehlers-Danlos syndrome may experience rupture of the uterus. Additional forms of Ehlers-Danlos syndrome that involve rupture of the blood vessels include the kyphoscoliotic, classical, and classical-like types.

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

Myofibrillar myopathy-8 (MFM8) is an autosomal recessive myopathy characterized by slowly progressive proximal muscle weakness and atrophy affecting the upper and lower limbs, resulting in increased falls, gait problems, difficulty running or climbing stairs, and upper limb weakness or scapular winging. Some patients develop distal muscle weakness and atrophy. The phenotype may also be consistent with a clinical diagnosis of limb-girdle muscular dystrophy (LGMD). Age at symptom onset ranges from infancy to adulthood. Ambulation is generally preserved and cardiac involvement is rare, but respiratory compromise with decreased forced vital capacity often occurs. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization; some patients have been reported to have dystrophic changes on muscle biopsy (O'Grady et al., 2016; Daimaguler et al., 2021). There is significant phenotypic variation, even in patients with the same mutation, which must be taken into account when counseling affecting individuals (Woods et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

Chitayat syndrome (CHYTS) is a rare condition characterized by respiratory distress presenting at birth, bilateral accessory phalanx resulting in shortened index fingers with ulnar deviation, hallux valgus, and characteristic facial features including prominent eyes, hypertelorism, depressed nasal bridge, full lips, and upturned nose (summary by Balasubramanian et al., 2017).

Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia characterized by supraorbital hyperostosis, undermodeling of the small bones, and small and large joint contractures, as well as extraskeletal developmental abnormalities, primarily of the cardiorespiratory system and genitourinary tract. Patients with FMD2 appear to have a propensity for keloid formation (summary by Wade et al., 2016). For a discussion of genetic heterogeneity of frontometaphyseal dysplasia, see FMD1 (305620).

A rare congenital muscular dystrophy characterised by neonatal hypotonia, life-threatening respiratory failure and feeding difficulties, furthermore by delayed motor development, severe muscle weakness predominantly affecting axial muscles (leading to poor head control, rigid cervical spine, and severe scoliosis), generalised joint laxity with no or mild contractures, as well as dry skin with follicular hyperkeratosis. Serum creatine kinase is normal or slightly elevated. Muscle biopsy shows fibre size variability, rounded fibres with mild increase of endomysial connective tissue and adipose replacement, abundant minicore lesions, increase of centrally located nuclei, angular fibres and cap lesions.

TRIO-related intellectual disability (ID) is characterized by delay in acquisition of motor and language skills, mild to borderline intellectual disability, and neurobehavioral problems (including autistic traits or autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or aggression). Neonatal or infantile feeding difficulties including poor suck, impaired bottle feeding, and failure to thrive are common and are often the presenting finding. Other findings can include microcephaly, variable hand and dental abnormalities, and suggestive facial features. Only ten of the 20 individuals with a TRIO pathogenic variant reported to date had sufficient information to make preliminary generalizations about clinical manifestations; it is anticipated that the phenotype of this newly described disorder will continue to evolve.

GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.

You-Hoover-Fong syndrome (YHFS) is an autosomal recessive disorder with clinical features of global developmental delay, impaired intellectual development, dysmorphic facial features, microcephaly, abnormal movements, and abnormal auditory and visual function (You et al., 2016).

The marfanoid-progeroid-lipodystrophy syndrome (MFLS) is characterized by congenital lipodystrophy, premature birth with an accelerated linear growth disproportionate to weight gain, and progeroid appearance with distinct facial features, including proptosis, downslanting palpebral fissures, and retrognathia. Other characteristic features include arachnodactyly, digital hyperextensibility, myopia, dural ectasia, and normal psychomotor development (Takenouchi et al., 2013). Takenouchi et al. (2013) noted phenotypic overlap with Marfan syndrome (154700) and Shprintzen-Goldberg craniosynostosis syndrome (182212).

Congenital myopathy-24 (CMYO24) is an autosomal recessive congenital myopathy characterized by onset of slowly progressive muscle weakness in the first decade. Affected individuals present with gait difficulties due to proximal muscle weakness and atrophy mainly affecting the lower limbs and neck. Muscle biopsy shows nemaline bodies. Some patients may have mild cardiac or respiratory involvement, but they do not have respiratory failure (summary by Miyatake et al., 2017). For a discussion of genetic heterogeneity of congenital myopathy, see 117000. For a discussion of genetic heterogeneity of nemaline myopathy, see 256030.

An inherited condition caused by autosomal dominant mutation(s) in the PPP1CB gene, encoding serine/threonine-protein phosphatase PP1-beta catalytic subunit. The condition is characterized by facial features similar to those seen in Noonan syndrome but may also include short stature, cognitive deficits, relative macrocephaly, small posterior fossa resulting in Chiari I malformation, hypernasal voice, cardiac defects, and ectodermal abnormalities, which typically presents as slow-growing, sparse, and/or unruly hair.

Congenital heart defects and skeletal malformations syndrome (CHDSKM) is characterized by atrial and ventricular septal defects, with aortic root dilation in adulthood. Skeletal defects are variable and include pectus excavatum, scoliosis, and finger contractures, and some patients exhibit joint laxity. Failure to thrive is observed during infancy and early childhood (Wang et al., 2017).

Mitochondrial myopathy and ataxia (MMYAT) is an autosomal recessive mtDNA depletion disorder characterized by cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic, and pigmentary retinopathy (summary by Donkervoort et al., 2019).

Galloway-Mowat syndrome is a renal-neurologic disease characterized by early-onset nephrotic syndrome associated with microcephaly, gyral abnormalities of the brain, and delayed psychomotor development. Most patients have dysmorphic facial features, often including hypertelorism, ear abnormalities, and micrognathia. Other features, such as arachnodactyly and visual impairment, are more variable. Most patients die in the first years of life (summary by Braun et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.

Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in DVL1, is characterized by normal stature, persistent macrocephaly, increased bone mineral density with skull osteosclerosis, and hearing loss, in addition to the typical features described above.

Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.

Autosomal recessive primary hypertrophic osteoarthropathy-1 (PHOAR1) is a rare familial disorder characterized by digital clubbing, osteoarthropathy, and acroosteolysis, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease (summary by Uppal et al., 2008; Radhakrishnan et al., 2020). Secondary hypertrophic osteoarthropathy, or pulmonary hypertrophic osteoarthropathy, is a different disorder characterized by digital clubbing secondary to acquired diseases, most commonly intrathoracic neoplasm (Uppal et al., 2008). Touraine et al. (1935) recognized pachydermoperiostosis as a familial disorder with 3 clinical presentations or forms: a complete form characterized by periostosis and pachydermia; an incomplete form with bone changes but without pachydermia; and a 'forme fruste' with pachydermia and minimal skeletal changes. Genetic Heterogeneity Autosomal recessive primary hypertrophic osteoarthropathy-2-enteropathy syndrome (PHOAR2E; 614441) is caused by mutation in the SLCO2A1 gene (601460) on chromosome 3q22. Families with an autosomal dominant form of primary hypertrophic osteoarthropathy, in which patients may also experience gastrointestinal symptoms, have been reported (PHOAD; 167100).

Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. The characteristic craniofacial features are downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with EP300-RSTS have normal intellect. Additional features include ocular abnormalities, hearing loss, respiratory difficulties, congenital heart defects, renal abnormalities, cryptorchidism, feeding problems, recurrent infections, and severe constipation.

Loeys-Dietz syndrome (LDS) is characterized by vascular findings (cerebral, thoracic, and abdominal arterial aneurysms and/or dissections), skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus, cervical spine malformation and/or instability), craniofacial features (widely spaced eyes, strabismus, bifid uvula / cleft palate, and craniosynostosis that can involve any sutures), and cutaneous findings (velvety and translucent skin, easy bruising, and dystrophic scars). Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms and pregnancy-related complications including uterine rupture and death. Individuals with LDS can show a strong predisposition for allergic/inflammatory disease including asthma, eczema, and reactions to food or environmental allergens. There is also an increased incidence of gastrointestinal inflammation including eosinophilic esophagitis and gastritis or inflammatory bowel disease. Wide variation in the distribution and severity of clinical features can be seen in individuals with LDS, even among affected individuals within a family who have the same pathogenic variant.

Osteogenesis imperfecta type XIX (OI19) is characterized by prenatal fractures and generalized osteopenia, with severe short stature in adulthood, as well as variable scoliosis and pectal deformity, and marked anterior angulation of the tibia (Lindert et al., 2016).

SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by Oates et al., 2013). For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).

Coffin-Siris syndrome (CSS) is classically characterized by aplasia or hypoplasia of the distal phalanx or nail of the fifth and additional digits, developmental or cognitive delay of varying degree, distinctive facial features, hypotonia, hirsutism/hypertrichosis, and sparse scalp hair. Congenital anomalies can include malformations of the cardiac, gastrointestinal, genitourinary, and/or central nervous systems. Other findings commonly include feeding difficulties, slow growth, ophthalmologic abnormalities, and hearing impairment.

External ophthalmoplegia with rib and vertebral anomalies (EORVA) is characterized by congenital nonprogressive external ophthalmoplegia and ptosis, with torticollis and scoliosis developing during childhood. In addition, patients exhibit hypoplastic or missing ribs with fusion anomalies (Di Gioia et al., 2018).

Krakow-type spondyloepimetaphyseal dysplasia is characterized by severe skeletal dysplasia, severe immunodeficiency, and developmental delay (Csukasi et al., 2018).

Osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD) is characterized by bilateral symmetric skeletal defects that primarily affect the limbs. Affected individuals have mild short stature due to shortening of the lower leg bones, as well as hand and foot malformations, predominantly brachydactyly and overlapping digits. Other skeletal defects include scoliosis, dislocated patellae and fibulae, and pectus excavatum (Shabbir et al., 2018).

Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).

A rare genetic overgrowth syndrome characterised by global developmental delay, macrosomia with subsequent somatic overgrowth, bilateral cystic lung lesions, congenital nephromegaly and bilateral Wilms tumour. Craniofacial dysmorphism includes macrocephaly, frontal bossing, large anterior fontanelle, mild hypertelorism, ear pit, flat nasal bridge, anteverted nares and mild micrognathia. Additional features may include brain and skeletal anomalies, enlarged protuberant abdomen, fat pads on dorsum of feet and toes, and rugated soles with skin folds, as well as umbilical/inguinal hernia and autistic behaviour.

Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) is characterized by severe progressive cerebropulmonary symptoms, resulting in death in infancy from respiratory failure. Features include malabsorption, progressive growth failure, recurrent infections, chronic hemolytic anemia, and transient liver dysfunction. Neuropathology shows increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and granuloma-like lesions are seen in the lungs, and there is hepatomegaly with steatosis and collagen accumulation (Uusimaa et al., 2018).

IDDCDF is an autosomal recessive syndromic neurodevelopmental disorder characterized by globally impaired development with intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Additional features, such as distal skeletal anomalies, may also be observed (Stephen et al., 2018).

Galloway-Mowat syndrome-7 (GAMOS7) is an autosomal recessive disorder characterized by developmental delay, microcephaly, and early-onset nephrotic syndrome (summary by Rosti et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Turnpenny-Fry syndrome (TPFS) is characterized by developmental delay, impaired intellectual development, impaired growth, and recognizable facial features that include frontal bossing, sparse hair, malar hypoplasia, small palpebral fissures and oral stoma, and dysplastic 'satyr' ears. Other common findings include feeding problems, constipation, and a range of brain, cardiac, vascular, and skeletal malformations (Turnpenny et al., 2018).

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Stolerman neurodevelopmental syndrome (NEDSST) is a highly variable disorder characterized by developmental delay, often with motor and speech delay, mildly impaired intellectual development (in most patients), learning difficulties, and behavioral abnormalities, including autism spectrum disorder. Psychosis is observed in a small percentage of individuals over the age of 12 years. Most individuals have nonspecific and mild dysmorphic facial features without a common gestalt. A subset of patients may have involvement of other organ systems, including gastrointestinal with poor early feeding or gastroesophageal reflux, distal skeletal anomalies, and congenital heart defects. Most mutations occur de novo, but rare autosomal dominant inheritance with incomplete penetrance has been observed (Stolerman et al., 2019; Rots et al., 2023).

Shukla-Vernon syndrome (SHUVER) is an X-linked recessive neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development, and behavioral abnormalities, including autism spectrum disorder and ADHD. Dysmorphic features are common and may include tall forehead, downslanting palpebral fissures, and tapering fingers. Some patients may have seizures and/or cerebellar atrophy on brain imaging. Carrier mothers may have mild manifestations, including learning disabilities (summary by Shukla et al., 2019).

Multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first months of life. Patients have severe global developmental delay, and may have additional variable features, including dysmorphic or coarse facial features, visual defects, and mild skeletal or renal anomalies. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Starr et al., 2019). For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Neurodevelopmental disorder with brain anomalies, seizures, and scoliosis (NEDBSS) is an autosomal recessive disorder characterized by severely impaired psychomotor development, hypotonia, seizures, and structural brain anomalies, including thin corpus callosum and cerebellar atrophy. Other features include scoliosis, dysmorphic facies, and visual impairment. Affected individuals are usually unable to walk or speak and may require tube feeding in severe cases. The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis (summary by Knaus et al., 2019). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Neurodevelopmental disorder with hypotonia and variable intellectual and behavioral abnormalities (NEDHIB) is characterized by early-onset hypotonia, delayed walking, poor speech, and impaired intellectual development. Additional features may include feeding difficulties, dysmorphic features, and visual defects. Brain imaging tends to show delayed myelination, thin corpus callosum, and/or enlarged ventricles. The severity of the disorder is highly variable; initial evidence suggests that the severity may depend on the type of mutation (summary by Haijes et al., 2019).

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Neurodevelopmental disorder with dysmorphic facies and distal skeletal anomalies (NEDDFSA) is a global neurodevelopmental disorder with highly variable features. Patients often show poor feeding, poor overall growth, and hypotonia from early infancy, followed by mildly delayed motor development, poor language acquisition, and behavioral abnormalities. Intellectual development varies from severe with absent speech to mild with the ability to attend special schools. Common features include dysmorphic facial features with notable eye anomalies, joint hypermobility, and mild skeletal anomalies of the hands and feet (summary by Carapito et al., 2019).

De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by Kivuva et al., 2008). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219100. Genetic Heterogeneity of de Barsy Syndrome Also see ARCL3B (614438), caused by mutation in the PYCR1 gene (179035) on chromosome 17q25.

Emery-Dreifuss muscular dystrophy inherited in an X-linked recessive pattern and caused by mutations in the EMD gene, encoding emerin.

Hackmann-Di Donato-type X-linked syndromic intellectual developmental disorder (MRXSHD) is an X-linked recessive phenotype characterized by global developmental delay with hypotonia, delayed speech, and mildly delayed walking associated with somatic marfanoid features, including tall stature, long fingers, and mildly dysmorphic facies. Some patients may have cardiac defects, such as mitral valve regurgitation, as well as other anomalies related to connective tissue defects, such as scoliosis (summary by Fiordaliso et al., 2019).

Anauxetic dysplasia-3 (ANXD3) is characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. Radiographs show short metacarpals, broad middle phalanges, and metaphyseal irregularities. Most patients also exhibit motor and cognitive delays (Narayanan et al., 2019). For a discussion of genetic heterogeneity of anauxetic dysplasia, see ANXD1 (607095).

CSGALNACT1 deficiency is characterized by mild skeletal dysplasia, joint hypermobility, and advanced bone age. Shortness of long bones is evident prenatally, and patients exhibit short stature and relative macrocephaly. Advanced carpotarsal bone age and monkey-wrench appearance of the femur observed in infancy may disappear with age (Mizumoto et al., 2020).

ROR2-related Robinow syndrome is characterized by distinctive craniofacial features, skeletal abnormalities, and other anomalies. Craniofacial features include macrocephaly, broad prominent forehead, low-set ears, ocular hypertelorism, prominent eyes, midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth with exposed incisors and upper gums, gum hypertrophy, misaligned teeth, ankyloglossia, and micrognathia. Skeletal abnormalities include short stature, mesomelic or acromesomelic limb shortening, hemivertebrae with fusion of thoracic vertebrae, and brachydactyly. Other common features include micropenis with or without cryptorchidism in males and reduced clitoral size and hypoplasia of the labia majora in females, renal tract abnormalities, and nail hypoplasia or dystrophy. The disorder is recognizable at birth or in early childhood.

Approximately 5 to 20% of all patients with neurofibromatosis type I (162200) carry a heterozygous deletion of approximately 1.4 Mb involving the NF1 gene and contiguous genes lying in its flanking regions (Riva et al., 2000; Jenne et al., 2001), which is caused by nonallelic homologous recombination of NF1 repeats A and C (Dorschner et al., 2000). The 'NF1 microdeletion syndrome' is often characterized by a more severe phenotype than that observed in the majority of NF1 patients. In particular, patients with NF1 microdeletion often show variable facial dysmorphism, mental retardation, developmental delay, an excessive number of early-onset neurofibromas (Venturin et al., 2004), and an increased risk for malignant peripheral nerve sheath tumors (De Raedt et al., 2003).

Rajab interstitial lung disease with brain calcifications-1 (RILDBC1) is an autosomal recessive multisystem disorder with a highly variable phenotype. Most patients present in infancy or early childhood with poor growth and interstitial lung disease, which may lead to death. Some may also have liver, skeletal, and renal abnormalities, and most have intracranial calcifications on brain imaging. Some may have early impaired motor development, but most have normal cognitive development (summary by Xu et al., 2018). Genetic Heterogeneity of Rajab Interstitial Lung Disease with Brain Calcifications Also see Rajab interstitial disease with brain calcifications-2 (RILDBC2; 619013), caused by mutation in the FARSA gene (602918).

Congenital myopathy-17 (CMYO17) is an autosomal recessive muscle disorder. Affected individuals present at birth with hypotonia and respiratory insufficiency associated with high diaphragmatic dome on imaging. Other features include poor overall growth, pectus excavatum, dysmorphic facies, and renal anomalies in some. The severity of the disorder is highly variable: some patients may have delayed motor development with mildly decreased endurance, whereas others have more severe hypotonia associated with distal arthrogryposis and lung hypoplasia, resulting in early death (summary by Watson et al., 2016 and Lopes et al., 2018). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) is characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, including ataxia and spasticity, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. Dysmorphic facial features may also be observed. Most patients have early-onset seizures; some may develop a demyelinating peripheral neuropathy. The clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).

Vertebral hypersegmentation and orofacial anomalies (VHO) is characterized by supernumerary cervical, thoracic, and/or lumbar vertebrae, in association with supernumerary ribs. Most patients also exhibit orofacial clefting and ear anomalies (Cox et al., 2019).

Mandibuloacral dysplasia progeroid syndrome (MDPS) is an autosomal recessive severe laminopathy-like disorder characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis, and hypertension (Elouej et al., 2020).

Osteogenesis imperfecta type XXI (OI21) is a progressively deforming disorder, characterized by multiple fractures that often occur after minor trauma. Fractures may be present at birth in some affected individuals. Patients exhibit disproportionate short stature and scoliosis, and are often wheelchair-bound by adulthood (van Dijk et al., 2020).

Coffin-Siris syndrome-12 (CSS12) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, speech and language delay, and behavioral abnormalities, such as autism or hyperactivity. Affected individuals may have hypotonia and poor feeding in infancy. There are variable dysmorphic facial features, although most patients do not have the classic hypoplastic fifth digit/nail abnormalities that are often observed in other forms of CSS (Barish et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).

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

Neurofacioskeletal syndrome with or without renal agenesis (NFSRA) is characterized by developmental delay and/or intellectual disability; corpus callosum hypoplasia or agenesis; facial dysmorphism, including upslanting palpebral fissures, broad nasal tip, and wide mouth; and skeletal abnormalities, including short stature, scoliosis, and flexion contractures, with broad fingertips and/or toes. Renal agenesis, unilateral or bilateral, has also been observed in some patients (Schneeberger et al., 2020).

VCTERL syndrome is characterized by anomalies of the vertebrae, heart, trachea, esophagus, kidneys, and limbs. Some patients also exhibit craniofacial abnormalities. Incomplete penetrance and markedly variable disease expression have been observed, including intrafamilial variability (Martin et al., 2020).

Multifocal fibromuscular dysplasia (FMDMF) is characterized histologically by medial fibroplasia and angiographically by multiple arterial stenoses with intervening mural dilations. Arterial tortuosity, macroaneurysms, dissections, and rupture may occur (summary by Richer et al., 2020).

Autosomal recessive spinocerebellar ataxia-31 (SCAR31) is a complex neurodevelopmental disorder characterized by global developmental delay with hypotonia and variably impaired intellectual and language development. Affected individuals have an ataxic gait, tremor, and dysarthria; more severely affected patients also have spasticity with inability to walk. Most have optic atrophy. Brain imaging shows cerebellar hypoplasia, enlarged ventricles, and atrophy of the posterior corpus callosum. Additional features may include retinitis pigmentosa, sensorineural deafness, dysmorphic facial features, and possibly endocrine dysfunction (summary by Collier et al., 2021).

Autosomal recessive cutis laxa type IIE (ARCL2E) is characterized by connective tissue features, including generalized cutis laxa and inguinal hernia, craniofacial dysmorphology, variable mild heart defects, and prominent skeletal features, including craniosynostosis, short stature, brachydactyly, clinodactyly, and syndactyly (Pottie et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).

VISS syndrome is a generalized connective tissue disorder characterized by early-onset thoracic aortic aneurysm and other connective tissue findings, such as aneurysm and tortuosity of other arteries, joint hypermobility, skin laxity, and hernias, as well as craniofacial dysmorphic features, structural cardiac defects, skeletal anomalies, and motor developmental delay (Van Gucht et al., 2021). Immune dysregulation has been observed in some patients (Ziegler et al., 2021).

Congenital disorder of glycosylation type IIw (CDG2W) is an autosomal dominant metabolic disorder characterized by liver dysfunction, coagulation deficiencies, and profound abnormalities in N-glycosylation of serum specific proteins. All reported patients carry the same mutation (602671.0017) (summary by Ng et al., 2021). For an overview of congenital disorders of glycosylation, see CDG1A (212065) and CDG2A (212066).

Boudin-Mortier syndrome (BOMOS) is characterized by tall stature, arachnodactyly, disproportionately elongated great toes, and multiple extra epiphyses. Some patients also show joint hypermobility and dilation of the aortic root (Boudin et al., 2018). Mutation in the NPR2 gene (108961) results in a similar phenotype of increased stature and elongation of the digits, particularly of the great toes, with multiple extra epiphyses (epiphyseal chondrodysplasia, Miura type; 615923).

Autosomal recessive Usmani-Riazzudin syndrome (USRISR) is a neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development and speech delay, hypotonia, spasticity, and behavioral abnormalities, most commonly aggressive behavior. More variable additional features may include seizures, scoliosis, and joint laxity (Usmani et al., 2021).

Developmental delay with variable neurologic and brain abnormalities (DENBA) is characterized most often by motor and speech delay apparent from early childhood. Most patients have delayed walking and variably impaired intellectual development. Additional neurologic features may include seizures, spasticity, and ocular abnormalities. Brain imaging often shows thin corpus callosum and may show white matter atrophy, myelination abnormalities, or enlarged ventricles. The severity of the disorder and clinical manifestations are highly variable (summary by Malhotra et al., 2021).

Ferguson-Bonni neurodevelopmental syndrome (FERBON) is an autosomal recessive disorder characterized by global developmental delay, impaired intellectual development, and hypotonia with early motor delay. Additional features may include dysmorphic facies, mild skeletal abnormalities, and hearing loss (summary by Ferguson et al., 2022).

DYRK1A syndrome is characterized by intellectual disability including impaired speech development, autism spectrum disorder including anxious and/or stereotypic behavior problems, and microcephaly. Affected individuals often have a clinically recognizable phenotype including a typical facial gestalt, feeding problems, seizures, hypertonia, gait disturbances, and foot anomalies. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. Other medical concerns relate to febrile seizures in infancy; the development of epilepsy with seizures of the atonic, absence, and generalized myoclonic types; short stature; and gastrointestinal problems. Ophthalmologic, urogenital, cardiac, and/or dental anomalies have been reported.

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-2 (CFSMR2) is characterized by flat face, low-set ears, and cleft lip and palate, as well as costovertebral anomalies including bifid and fused ribs, vertebral segmentation defects, and scoliosis. Intellectual delay can be severe, with absent speech (Alanay et al., 2014). For a general phenotypic description and discussion of genetic heterogeneity of CFSMR, see CFSMR1 (213980).

Noonan syndrome-14 (NS14) is a recessive developmental disorder within the RASopathy clinical spectrum. Patients exhibit developmental delay, impaired intellectual development, and short stature, as well as distinctive dysmorphic features including bitemporal narrowing, hypertelorism, low-set posteriorly rotated ears, prominent nasal bridge, low posterior hairline with a short webbed neck, and pectus excavatum (Motta et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of Noonan syndrome, see NS1 (163950).

Familial thoracic aortic aneurysm-12 (AAT12) is characterized by dilation of the arterial wall associated with a progressive loss of its ability to withstand the wall tension generated by high intraluminal pressure, which can lead to intramural or complete acute vessel wall rupture. Some patients have dolichostenomelia (summary by Elbitar et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of thoracic aortic aneurysm, see AAT1 (607086).

Autosomal dominant intellectual developmental disorder-66 (MRD66) is characterized by global developmental delay with mildly to moderately impaired intellectual development and mild speech delay. The phenotype and severity are highly variable. Some patients have behavioral problems or autism spectrum disorder, and about 50% have variable types of seizures. Additional features may include nonspecific dysmorphic facial features, tall or short stature, and mild skeletal anomalies (Rahimi et al., 2022).

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1) is characterized by cranial involvement with macrocrania at birth, brachycephaly, anomalies of middle fossa structures including hypoplasia of corpus callosum, enlargement of septum pellucidum, and dilated lateral ventricles, as well as cortical atrophy and hypodensity of the gray matter. Facial dysmorphisms include flat face, hypertelorism, epicanthal folds, synophrys, broad nasal bridge, cleft lip and cleft palate, and low-set posteriorly rotated ears. Patients also exhibit short neck and multiple costal and vertebral anomalies. The face is rather characteristic, and various authors have consistently reported affable/friendly personality, despite intellectual delay (summary by Alanay et al., 2014). Genetic Heterogeneity of Craniofacial Dysmorphism, Skeletal Anomalies, and Impaired Intellectual Development Syndrome CFSMR2 (616994) is caused by mutation in the RAB5IF gene (619960) on chromosome 20q11.

Chilton-Okur-Chung neurodevelopmental syndrome (CHOCNS) is characterized mainly by global developmental delay with variably impaired intellectual development and occasional speech delay. Most patients have behavioral abnormalities, including autism spectrum disorder, ADHD, and aggression. About half of patients have dysmorphic facial features, and about half have nonspecific brain abnormalities, including thin corpus callosum. Rare involvement of other organ systems may be present. At least 1 child with normal development at age 2.5 years has been reported (Chilton et al., 2020).

Congenital myopathy-4B (CMYO4B) is an autosomal recessive disorder of the skeletal muscle characterized by the onset of muscle weakness in infancy or early childhood. The severity and pattern of muscle weakness varies, but most affected individuals show congenital contractures, delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty walking or inability to walk. Affected individuals have respiratory insufficiency due to muscle weakness, which may be life-threatening. Other common features include myopathic facies, chest deformities, distal joint laxity, and scoliosis. Variable histologic findings on skeletal muscle biopsy are observed, including nemaline rods, type 1 fiber predomination, and centralized nuclei (Tan et al., 1999; Lehtokari et al., 2008). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Neurodevelopmental disorder with hypotonia, dysmorphic facies, and skeletal anomalies, with or without seizures (NEDFSS), is characterized by these features and global developmental delay with delayed or absent walking, moderate to severely impaired intellectual development, and poor or absent speech acquisition. Affected individuals may also have behavioral abnormalities. About half of patients develop various types of seizures that are usually well-controlled with medication. Rare patients are noted to have heat intolerance or insensitivity to pain (Lines et al., 2022).

Autosomal recessive intellectual developmental disorder-78 (MRT78) is a neurodevelopmental disorder characterized by impaired intellectual development that is usually mild, but shows variable severity. Affected individuals have microcephaly and mild short stature. Additional features may include ocular abnormalities and mild skeletal defects (Haag et al., 2021).

Multiple types of congenital heart defects-9 (CHTD9) is characterized by common arterial trunk (truncus arteriosus communis) in most patients, associated with other cardiac defects, including tetralogy of Fallot, interrupted aortic arch, right aortic arch, ventricular hypoplasia, and hypoplastic left heart, as well as other vascular and valvular anomalies (Ta-Shma et al., 2013; Guimier et al., 2023). For a general phenotypic description and discussion of genetic heterogeneity of multiple types of congenital heart defects, see CHTD1 (see 306955).

Classic congenital myopathy-22A (CMYO22A) is an autosomal recessive muscle disorder characterized by onset of muscle weakness in utero or soon after birth. Early features may include fetal hypokinesia, breech presentation, and polyhydramnios. Affected individuals are born with severe hypotonia and require respiratory and feeding assistance. Those who survive the neonatal period show a 'classic' phenotype of congenital myopathy with delayed motor development, difficulty walking, proximal muscle weakness of the upper and lower limbs, facial and neck muscle weakness, easy fatigability, and mild limb contractures or foot deformities. Some have persistent respiratory insufficiency; dysmorphic facial features may be present (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Severe fetal congenital myopathy-22B (CMYO22B) is an autosomal recessive muscle disorder characterized by in utero onset of severe muscle weakness manifest as fetal akinesia. The pregnancies are often complicated by polyhydramnios, and affected individuals develop fetal hydrops with pulmonary hypoplasia, severe joint contractures, and generalized muscle hypoplasia. Those who are born have respiratory failure resulting in death. Dysmorphic facial features may be present. The features in these patients overlap with fetal akinesia deformation sequence (FADS; see 208150) and lethal congenital contractures syndrome (LCCS; see 253310) (Zaharieva et al., 2016). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity (NEDIHSS) is an autosomal recessive disorder characterized by prenatal or neonatal onset of intracranial hemorrhage, usually with ventriculomegaly and calcifications, resulting in parenchymal brain damage. Some affected individuals have symptoms incompatible with life and die in utero. Those that survive show profound global developmental delay with almost no motor or cognitive skills, hypotonia, spasticity, and seizures. Other features may include facial dysmorphism, retinal vascular abnormalities, and poor overall growth. The pathogenesis of the disease likely results from dysfunction of vascular endothelial cells in the brain (Lecca et al., 2023).

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

Fliedner-Zweier syndrome (FZS) is a neurodevelopmental disorder characterized by variable manifestations including mild intellectual disability, seizures, behavioral abnormalities, and various skeletal and structural anomalies (Fliedner et al., 2020).

Hoxha-Aliu syndrome (HXAL) is characterized by mildly impaired intellectual development and digital anomalies of the hands and feet (Hoxha and Aliu, 2023; Guo et al., 2023). Biallelic missense mutations in the ERI1 gene have been reported to cause a more severe bone disorder, spondyloepimetaphyseal dysplasia, Guo-Campeau type (SEMDGC; 620663).

The Guo-Campeau type of spondyloepimetaphyseal dysplasia (SEMDGC) is characterized by severe bone dysplasia resulting in significant short stature with variable anomalies of the spine, pelvis, hips, and extremities, including short, rudimentary, or absent digits. Patients also exhibit variable facial dysmorphisms (Guo et al., 2023). Biallelic null mutations in the ERI1 gene have been reported to cause a less severe disorder, Hoxha-Alia syndrome, involving digital anomalies and mild intellectual disability (HXAL; 620662).

Neuroocular syndrome-1 (NOC1) encompasses a broad spectrum of overlapping anomalies, with developmental delay or impaired intellectual development as a consistent finding. Eye abnormalities show marked variability in the type and severity of defects, and include anophthalmia, microphthalmia, and coloboma. Other common systemic features include congenital heart and kidney defects, hypotonia, failure to thrive, and microcephaly (summary by Chowdhury et al., 2021). Genetic Heterogeneity of Neuroocular Syndrome See also NOC2 (168885), caused by mutation in the DAGLA gene (614015) on chromosome 11q12.