Cri-du-chat syndrome was first described by Lejeune et al. (1963) as a hereditary congenital syndrome associated with deletion of part of the short arm of chromosome 5. The deletions can vary in size from extremely small and involving only band 5p15.2 to the entire short arm. Although the majority of deletions arise as new mutations, approximately 12% result from unbalanced segregation of translocations or recombination involving a pericentric inversion in one of the parents.

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.

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

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

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.

Borjeson-Forssman-Lehmann syndrome (BFLS) is an uncommon X-linked intellectual developmental disorder that evolves with age. Clinical manifestations in males are quite variable, with the most consistent features being initial hypotonia, mild to moderate impaired intellectual development, large fleshy ears, underdeveloped genitalia, gynecomastia, truncal obesity, tapering fingers, and shortening of the fourth and fifth toes. Heterozygous females may have a milder similar clinical phenotype, which can include hypothyroidism; however, many carrier females appear unaffected (summary by Crawford et al., 2006).

Wiedemann-Rautenstrauch syndrome (WDRTS) is a rare autosomal recessive neonatal progeroid disorder characterized by intrauterine growth retardation, failure to thrive, short stature, a progeroid appearance, hypotonia, and variable mental impairment (summary by Toriello, 1990). Average survival in WDRTS is 7 months, although survival into the third decade of life has been reported (Akawi et al., 2013).

GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) and Bayram et al. (2014) noted that optic atrophy is not a consistent feature of the disorder.

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).

Proud syndrome is an X-linked developmental disorder characterized by agenesis of the corpus callosum, severely impaired intellectual development, seizures, and spasticity. Males are severely affected, whereas females may be unaffected or have a milder phenotype (Proud et al., 1992). Proud syndrome is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome to infantile spasms without brain malformations (DEE1; 308350) to syndromic (309510) and nonsyndromic (300419) mental retardation (Kato et al., 2004; Wallerstein et al., 2008).

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).

Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the PAK3 gene.

Craniolenticulosutural dysplasia is characterized by facial dysmorphism, late-closing fontanels, cataract, and skeletal defects (summary by Boyadjiev et al., 2011).

X-linked intellectual deficit-cerebellar hypoplasia, also known as OPHN1 syndrome, is a rare syndromic form of cerebellar dysgenesis characterized by moderate to severe intellectual deficit and cerebellar abnormalities.

Uruguay faciocardiomusculoskeletal syndrome (FCMSU) is an X-linked disorder in which affected males have a distinctive facial appearance, muscular hypertrophy, and cardiac ventricular hypertrophy leading to premature death. Additional features include large, broad, and deformed hands and feet, congenital hip dislocation, and scoliosis (summary by Xue et al., 2016).

Siderius-type syndromic intellectual developmental disorder (MRXSSD) is an X-linked disorder in which affected males have mildly impaired intellectual development, mild dysmorphic features, and bilateral or unilateral cleft lip/palate (summary by Koivisto et al., 2007).

The Shashi type of X-linked syndromic intellectual developmental disorder (MRXSSH) is characterized by moderately impaired intellectual development and distinctive craniofacial skeletal structure and dysmorphism (Shashi et al., 2015).

Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.

An autosomal recessive condition caused by mutation(s) in the ERCC4 gene, encoding DNA repair endonuclease XPF. it is characterized by characterized by cutaneous photosensitivity and progeroid features in multiple organ systems.

A syndromic X-linked intellectual disability characterized by moderate intellectual disability with variable occurrence of asthenic body habitus, dysmorphic features, autistic features, macrocephaly, seizures, myoclonic jerks, and hyporeflexia that has material basis in mutation in the GRIA3 gene on chromosome Xq25.

Greenberg dysplasia (GRBGD), also known as hydrops-ectopic calcification-moth-eaten (HEM) skeletal dysplasia, is a rare autosomal recessive osteochondrodysplasia characterized by gross fetal hydrops, severe shortening of all long bones with a moth-eaten radiographic appearance, platyspondyly, disorganization of chondroosseous calcification, and ectopic ossification centers. It is lethal in utero. Patient fibroblasts show increased levels of cholesta-8,14-dien-3-beta-ol, suggesting a defect of sterol metabolism (summary by Konstantinidou et al., 2008). Herman (2003) reviewed the cholesterol biosynthetic pathway and 6 disorders involving enzyme defects in postsqualene cholesterol biosynthesis: Smith-Lemli-Opitz syndrome (SLOS; 270400), desmosterolosis (602398), X-linked dominant chondrodysplasia punctata (CDPX2; 302960), CHILD syndrome (308050), lathosterolosis (607330), and HEM skeletal dysplasia.

Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XII is an autosomal recessive form characterized by recurrent fractures, mild bone deformations, generalized osteoporosis, delayed teeth eruption, progressive hearing loss, no dentinogenesis imperfecta, and white sclerae (summary by Lapunzina et al., 2010).

The Nascimento type of X-linked syndromic intellectual developmental disorder (MRXSN) is characterized by dysmorphic features, including large head, synophrys, prominent supraorbital ridges, almond-shaped and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, abnormal hair whorls, micropenis, and onychodystrophy. Female carriers have normal cognition, but may show subtle facial features (summary by Budny et al., 2010).

Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the DOCK8 gene.

Pontocerebellar hypoplasia type 7 (PCH7) is a severe neurologic condition characterized by delayed psychomotor development, hypotonia, breathing abnormalities, and gonadal abnormalities (summary by Anderson et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

CHD8-related neurodevelopmental disorder with overgrowth (CHD8-NDD) is characterized by generalized overgrowth, developmental delay / intellectual disability (DD/ID), autism spectrum disorder (ASD), neuropsychiatric issues, neurologic problems, sleep disturbance, and gastrointestinal issues The most common findings are the development of macrocephaly (most often during infancy) and tall stature (most typically during puberty), which is often accompanied by ASD and/or DD/ID. Most, if not all, affected individuals have some degree of DD, most commonly speech and motor delays. When present, ID is most often in the mild-to-moderate range. Sleep disturbance is characterized by difficulty with both initiation (delayed sleep onset) and maintenance (frequent night awakenings) of sleep. The most common gastrointestinal issue is constipation with or without periods of diarrhea. Less common features are hypotonia (about 30% of affected individuals), seizures (10%-15%), dystonia (rare), and Chiari I malformation (rare).

Axenfeld-Rieger syndrome is an autosomal dominant disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, and results in blindness from glaucoma in approximately 50% of affected individuals (Fitch and Kaback, 1978). Systemic anomalies are associated, including dental hypoplasia, failure of involution of periumbilical skin, and maxillary hypoplasia (Alkemade, 1969). Genetic Heterogeneity of Axenfeld-Rieger Syndrome Linkage studies indicate that a second type of Axenfeld-Rieger syndrome maps to chromosome 13q14 (RIEG2; 601499). A third form of Axenfeld-Rieger syndrome (RIEG3; 602482) is caused by mutation in the FOXC1 gene (601090) on chromosome 6p25. See 109120 for a form of Axenfeld-Rieger syndrome associated with partially absent eye muscles, hydrocephalus, and skeletal abnormalities.

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.

A rare, genetic, neurodevelopmental disorder characterized by global developmental delay, borderline to severe intellectual disability, feeding difficulties, behavioral anomalies, vision anomalies and mild facial dysmorphism. Other associated features may include microcephaly, short stature, urogenital or palatal anomalies (e.g. cleft palate), minor cardiac defects, recurrent infections or hearing loss.

Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the FBXO31 gene.

Kosaki overgrowth syndrome (KOGS) is characterized by a facial gestalt involving prominent forehead, proptosis, downslanting palpebral fissures, broad nasal bridge, thin upper lip, and pointed chin. Affected individuals are tall, with an elongated lower segment, and have large hands and feet. Skin is hyperelastic and fragile. Patients exhibit progressive dilatory and vascular changes in basilar/vertebral and coronary arteries starting in the teenage years (Takenouchi et al., 2015; Takenouchi et al., 2021).

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).

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.

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).

WDR26-related intellectual disability (ID) is characterized by developmental delay / intellectual disability, characteristic facial features, hypotonia, epilepsy, and infant feeding difficulties. To date 15 individuals, ages 24 months to 34 years, have been reported. Developmental delay is present in all individuals and ranges from mild to severe. All individuals have delayed speech. Although some begin to develop speech in the second year, others have remained nonverbal. Seizures, present in all affected individuals reported to date, can be febrile or non-febrile (tonic-clonic, absence, rolandic seizures); most seizures are self limited or respond well to standard treatment. Affected individuals are generally described as happy and socially engaging; several have stereotypies / autistic features (repetitive or rocking behavior, abnormal hand movements or posturing, and at times self-stimulation).

SOST-related sclerosing bone dysplasias include sclerosteosis and van Buchem disease, both disorders of progressive bone overgrowth due to increased bone formation. The major clinical features of sclerosteosis are progressive skeletal overgrowth, most pronounced in the skull and mandible, and variable syndactyly, usually of the second (index) and third (middle) fingers. Affected individuals appear normal at birth except for syndactyly. Facial distortion due to bossing of the forehead and mandibular overgrowth is seen in nearly all individuals and becomes apparent in early childhood with progression into adulthood. Hyperostosis of the skull results in narrowing of the foramina, causing entrapment of the seventh cranial nerve (leading to facial palsy) with other, less common nerve entrapment syndromes including visual loss (2nd cranial nerve), neuralgia or anosmia (5th cranial nerve), and sensory hearing loss (8th cranial nerve). In sclerosteosis, hyperostosis of the calvarium reduces intracranial volume, increasing the risk for potentially lethal elevation of intracranial pressure. Survival of individuals with sclerosteosis into old age is unusual, but not unprecedented. The manifestations of van Buchem disease are generally milder than sclerosteosis and syndactyly is absent; life span appears to be normal.

Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (NEDMAGA) is characterized by infantile-onset global developmental delay with severe to profound intellectual disability, mildly delayed walking with broad-based and unsteady gait, and absence of meaningful language. Patients have features of autism, with repetitive behaviors and poor communication, but usually are socially reactive and have a happy demeanor. More variable neurologic features include mild seizures, spasticity, and peripheral neuropathy (summary by Palmer et al., 2017).

Imagawa-Matsumoto syndrome (IMMAS) is characterized by variable pre- and postnatal overgrowth; dysmorphic features including postnatal macrocephaly, prominent forehead, round face, hypertelorism, downslanting palpebral fissures, and low and broad nasal bridge; and variable musculoskeletal abnormalities. Developmental delay and impaired intellectual development are common, whereas abnormalities of cerebral imaging are uncommon but may be significant. Some patients exhibit genitourinary abnormalities, and respiratory issues have been reported (Cyrus et al., 2019).

Deafness, cataract, impaired intellectual development, and polyneuropathy (DCIDP) is characterized by early-onset of deafness, cataract, severe developmental delay, and severely impaired intellectual development. Patients later develop polyneuropathy of the lower extremities, associated with depigmentation of the hair in that area (Kroll-Hermi et al., 2020).

Otospondylomegaepiphyseal dysplasia (OSMED) is characterized by sensorineural hearing loss, enlarged epiphyses, disproportionate shortness of the limbs, abnormalities in vertebral bodies, and typical facial features (summary by Harel et al., 2005).

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).

Intellectual disability and myopathy syndrome (IDMYS) is an autosomal recessive developmental disorder characterized by global developmental delay with mildly impaired intellectual development, hypotonia, muscle weakness and fatigue, and white matter abnormalities on brain imaging. Variable additional features may include sensorineural hearing loss, dysmorphic facies, and progressive heart disease (summary by Smeland et al., 2019).

Developmental delay with variable intellectual disability and dysmorphic facies (DIDDF) is a clinically heterogeneous disorder characterized by neurologic deficits and characteristic dysmorphic facial features apparent from infancy or early childhood. Affected individuals usually show impaired intellectual development, speech delay, learning difficulties, and/or behavioral problems. Additional features may include hypotonia, hand or foot deformities, and palatal defects (Verberne et al., 2021; Verberne et al., 2022).

Jeffries-Lakhani neurodevelopmental syndrome (JELANS) is an autosomal recessive disorder characterized by hypotonia, early-onset seizures, and global developmental delay apparent from infancy. Affected individuals have motor delay, speech delay, and impaired intellectual development, and about half of patients are nonambulatory and/or nonverbal. Some patients have cardiac arrhythmia, but congenital cardiac septal defects are only rarely observed. Additional features may include feeding difficulties, recurrent infections, ocular defects, and nonspecific dysmorphic features. Premature death due to cardiac arrhythmia or epilepsy may occur (Jeffries et al., 2024).

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.