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).

Mucopolysaccharidosis type III (MPS III) is a multisystem lysosomal storage disease characterized by progressive central nervous system degeneration manifest as severe intellectual disability (ID), developmental regression, and other neurologic manifestations including autism spectrum disorder (ASD), behavioral problems, and sleep disturbances. Disease onset is typically before age ten years. Disease course may be rapidly or slowly progressive; some individuals with an extremely attenuated disease course present in mid-to-late adulthood with early-onset dementia with or without a history of ID. Systemic manifestations can include musculoskeletal problems (joint stiffness, contractures, scoliosis, and hip dysplasia), hearing loss, respiratory tract and sinopulmonary infections, and cardiac disease (valvular thickening, defects in the cardiac conduction system). Neurologic decline is seen in all affected individuals; however, clinical severity varies within and among the four MPS III subtypes (defined by the enzyme involved) and even among members of the same family. Death usually occurs in the second or third decade of life secondary to neurologic regression or respiratory tract infections.

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.

The phenotypic spectrum associated with RPS6KA3 pathogenic variants is a continuum. Coffin-Lowry syndrome (CLS) classically manifests in males with developmental delay, intellectual disability, neurologic manifestations (hypotonia, stimulus-induced drop attacks, spastic paraparesis, and seizures), musculoskeletal manifestations (kyphoscoliosis and pectus deformity), and characteristic craniofacial and hand findings. Dental issues, sensorineural hearing loss, and obstructive sleep apnea also occur. The milder end of the continuum in males includes neurodevelopmental disabilities with or without less pronounced multisystem involvement. Heterozygous females often exhibit clinical manifestations that can be consistent with clinically defined CLS but are typically less severe than those seen in affected males. Developmental delay and intellectual disability comprise the core phenotypic findings, and quality of life and prognosis are variably affected by the presence and severity of neurologic and musculoskeletal involvement.

Pallister-Killian syndrome (PKS) is a dysmorphic condition involving most organ systems, but is also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987).

Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive nonlysosomal inborn error of neutral lipid metabolism. Patients present with a nonbullous erythrodermic form of ichthyosis (NCIE; see 242300) with variable involvement of other organs, such as liver, central nervous system, eyes, and ears. Intracellular triacylglycerol droplets are present in most tissues, and diagnosis can be confirmed by a simple blood smear, in which the characteristic lipid droplets are observed in the cytoplasm of granulocytes (summary by Lefevre et al., 2001). Another form of neutral lipid storage disease without ichthyosis but with myopathy (NLSDM; 610717) is caused by mutation in the PNPLA2 gene (609059).

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.

Harlequin ichthyosis is a rare severe form of congenital ichthyosis, which may be fatal. The neonate is encased in an 'armor' of thick scale plates separated by deep fissures. There is bilateral ectropion and eclabium, and the nose and ears are flattened and appear rudimentary. Constricting bands around the extremities can restrict movement and cause digital necrosis. As the skin barrier is severely compromised, neonates are more prone to sepsis, dehydration, and impaired thermoregulation. Treatment with oral retinoids encourages shedding of the grossly thickened skin. Babies who survive into infancy and beyond develop skin changes resembling severe nonbullous congenital ichthyosiform erythroderma (see 242300) (summary by Rajpopat et al., 2011). Tonofibrils are fibrillar structural proteins in keratinocytes which, although already present in dividing basal cells, are formed in increasing amounts by the differentiating cells. They are the morphologic equivalent of the biochemically well-characterized prekeratin and precursors of the alpha-keratin of horn cells. Four genetic disorders of keratinization are known to have a structural defect of tonofibrils (Anton-Lamprecht, 1978): (1) In the harlequin fetus, an abnormal x-ray diffraction pattern of the horn material points to a cross-beta-protein structure instead of the normal alpha-protein structure of keratin. (2) Bullous ichthyosiform erythroderma (113800) is characterized by an early formation of clumps and perinuclear shells due to an abnormal arrangement of tonofibrils. (3) In the Curth-Macklin form of ichthyosis hystrix (146590), concentric unbroken shells of abnormal tonofilaments form around the nucleus. (4) In ichthyosis hystrix gravior (146600) only rudimentary tonofilaments are found with compensatory production of mucous granules. At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass lamellar ichthyosis (LI), nonbullous congenital ichthyosis erythroderma (NCIE), and harlequin ichthyosis (Oji et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

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.

TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures), with profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures; familial infantile myoclonic epilepsy (FIME), with early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability; progressive myoclonus epilepsy (PME), with action myoclonus, tonic-clonic seizures, ataxia, and progressive neurologic decline; rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC); developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS); autosomal recessive nonsyndromic hearing loss (DFNB); and autosomal dominant nonsyndromic hearing loss (DFNA).

A syndrome of mental retardation, short stature, delayed puberty, polydactyly, synmetracarpalia, ocular torticollis, orofacial dysmorphism, and multiple cardiac malformations.

The phenotypic spectrum associated with RPS6KA3 pathogenic variants is a continuum. Coffin-Lowry syndrome (CLS) classically manifests in males with developmental delay, intellectual disability, neurologic manifestations (hypotonia, stimulus-induced drop attacks, spastic paraparesis, and seizures), musculoskeletal manifestations (kyphoscoliosis and pectus deformity), and characteristic craniofacial and hand findings. Dental issues, sensorineural hearing loss, and obstructive sleep apnea also occur. The milder end of the continuum in males includes neurodevelopmental disabilities with or without less pronounced multisystem involvement. Heterozygous females often exhibit clinical manifestations that can be consistent with clinically defined CLS but are typically less severe than those seen in affected males. Developmental delay and intellectual disability comprise the core phenotypic findings, and quality of life and prognosis are variably affected by the presence and severity of neurologic and musculoskeletal involvement.

SMARCA2-related Nicolaides-Baraitser syndrome (SMARCA2-NCBRS) is characterized by commonly shared dysmorphic features including sparse scalp hair, prominence of the interphalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly (typically acquired), seizures, and developmental delay / intellectual disability. Developmental delay / intellectual disability is severe in nearly half of affected individuals, moderate in one third, and mild in the remainder. Nearly one third never develop speech or language skills. Seizures are of various types and can be difficult to manage, requiring multiple anti-seizure medications to achieve reasonable control. Regression or lack of developmental progress has been noted with the onset of seizures in some affected individuals. Behavioral issues can include autistic-like features (perseveration, hyperacusis), with a minority of affected individuals being diagnosed clinically with an autism spectrum disorder. Cryptorchidism is common in males. About half of affected individuals have growth deficiency and short stature. Delayed tooth eruption with hypo- or oligodontia has also been reported. Radiographic findings may include cone-shaped epiphyses, metaphyseal flaring of the phalanges, and shortening of the phalanges, metacarpals, and/or metatarsals (especially of the 4th and 5th rays) of the hands; platyspondyly; flat intervertebral disc space; and pelvic/femoral anomalies. Rare findings include conductive hearing loss, refractive error / astigmatism, and congenital heart defects.

Axenfeld-Rieger syndrome is a disorder of morphogenesis that results in abnormal development of the anterior segment of the eye, which results in blindness from glaucoma in approximately 50% of affected individuals. Systemic abnormalities, including cardiac and dental anomalies, are associated. For a general phenotypic description and a discussion of genetic heterogeneity and nomenclature of Axenfeld-Rieger syndrome, see RIEG1 (180500).

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).

Goldberg-Shprintzen syndrome (GOSHS) is an autosomal recessive multiple congenital anomaly syndrome characterized by impaired intellectual development, microcephaly, and dysmorphic facial features. Most patients also have Hirschsprung disease and/or gyral abnormalities of the brain, consistent with defects in migration of neural crest cells and neurons. Other features, such as megalocornea or urogenital anomalies, may also be present. Goldberg-Shprintzen syndrome has some resemblance to Mowat-Wilson syndrome (MOWS; 235730) but is genetically distinct (summary by Drevillon et al., 2013).

Intellectual disability-brachydactyly-Pierre Robin syndrome is a rare developmental defect during embryogenesis syndrome characterized by mild to moderate intellectual disability and phsychomotor delay, Robin sequence (incl. severe micrognathia and soft palate cleft) and distinct dysmorphic facial features (e.g. synophris, short palpebral fissures, hypertelorism, small, low-set, and posteriorly angulated ears, bulbous nose, long/flat philtrum, and bow-shaped upper lip). Skeletal anomalies, such as brachydactyly, clinodactyly, small hands and feet, and oral manifestations (e.g. bifid, short tongue, oligodontia) are also associated. Additional features reported include microcephaly, capillary hemangiomas on face and scalp, ventricular septal defect, corneal clouding, nystagmus and profound sensorineural deafness.

Congenital melanocytic nevus syndrome is characterized by pigmentary skin defects apparent at birth. Most individuals have 1 or more large or giant lesions greater than 20 cm and up to over 60 cm in diameter, which may cover up to 80% of total body area. These lesions may or may not be hairy. Smaller 'satellite' pigmented lesions numbering in the hundreds may also be present all over the body. Congenital melanocytic nevi (CMN) can be associated with malignant melanoma (see CMM1, 155600), but the risk appears to be low, ranging from 1 to 2% for all individuals, but rising to 10 to 15% in those with very large nevi (greater than 40 cm). A small subset of patients with CMNS have abnormalities of the central nervous system, known as 'neurocutaneous melanosis' or 'neuromelanosis' (249400), which may be symptomatic. Patients with CMNS also tend to have a characteristic facial appearance, including wide or prominent forehead, periorbital fullness, small short nose with narrow nasal bridge, round face, full cheeks, prominent premaxilla, and everted lower lip (summary by Kinsler et al., 2008; Kinsler et al., 2012). Spitz nevi are benign melanocytic melanomas composed of epithelioid or spindle cell melanocytes. They usually present as solitary skin tumors but can occur in multiple patterns, having agminated, dermatomal, and disseminated forms (summary by Sarin et al., 2013). Nevus spilus, also known as speckled lentiginous nevus, is a congenital hyperpigmented patch that progressively evolves, with affected individuals developing dark macules and papules during childhood and adolescence. Over time, nevus spilus may give rise to common lentigines, melanocytic nevi, Spitz nevi, and melanomas (summary by Sarin et al., 2014).

Nablus mask-like facial syndrome (NMLFS) is a rare entity defined by distinctive facial features, including blepharophimosis, tight-appearing glistening facial skin, an abnormal hair pattern with an upswept frontal hairline, sparse arched eyebrows, flat and broad nose, long philtrum, distinctive ears, and a happy demeanor (summary by Jain et al., 2010).

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal-lethal disorder to an asymptomatic type. The characterization of three major clinical types (1, 2, and 3) and two clinical forms (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. Cardiopulmonary complications have been described with all the clinical phenotypes, although varying in frequency and severity. Type 1 GD is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia, thrombocytopenia, lung disease, and the absence of primary central nervous system disease. Type 2 GD is characterized by primary central nervous system disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years. Type 3 GD is characterized by primary central nervous system disease with childhood onset, a more slowly progressive course, and survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia.

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).

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).

An ectodermal dysplasia syndrome characterized by severe generalized lamellar icthyosis at birth with alopecia, eclabium, ectropion and intellectual disability. Although similar to Sjogren-Larsson syndrome, this syndrome lacks the presence of neurologic or macular changes. There have been no further descriptions in the literature since 1987.

Koolen-de Vries syndrome (KdVS) is characterized by congenital malformations, developmental delay / intellectual disability, neonatal/childhood hypotonia, epilepsy, dysmorphisms, 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. Behavior in most is described as friendly, amiable, and cooperative.

Pierpont syndrome (PRPTS) is a multiple congenital anomaly syndrome associated with learning disability. Key features include distinctive facial characteristics, especially when smiling, plantar fat pads, and other limb anomalies (summary by Burkitt Wright et al., 2011).

This syndrome has characteristics of severe intellectual deficit, patella luxations, acromicria, hypogonadism, facial dysmorphism (including midface hypoplasia and premature frontotemporal balding). It has been described in three unrelated males.

MBD5 haploinsufficiency is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, severe speech impairment, seizures, sleep disturbances, and abnormal behaviors. Most children lack speech entirely or have single words, short phrases, or short sentences. Seizures are present in more than 80% of children; onset is usually around age two years. Sleep disturbances, present in about 90%, can result in excessive daytime drowsiness. Abnormal behaviors can include autistic-like behaviors (80%) and self-injury and aggression (>60%).

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.

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).

SLC25A24 Fontaine progeroid syndrome is a multisystem connective tissue disorder characterized by poor growth, abnormal skeletal features, and distinctive craniofacial features with sagging, thin skin, and decreased subcutaneous fat suggesting an aged appearance that is most pronounced in infancy and improves with time. Characteristic radiographic features include turribrachycephaly with widely open anterior fontanelle, craniosynostosis, and anomalies of the terminal phalanges. Cardiovascular, genitourinary, ocular, and gastrointestinal abnormalities may also occur. To date, 13 individuals with a molecularly confirmed diagnosis of SLC25A24 Fontaine progeroid syndrome have been described.

Dermatosparaxis (meaning 'tearing of skin') is an autosomal recessive disorder of connective tissue resulting from deficiency of procollagen peptidase, an enzyme that aids in the processing of type I procollagen. The disorder and the responsible biochemical defect was first observed in cattle (Lapiere et al., 1971). Lapiere and Nusgens (1993) reviewed the discovery of dermatosparaxis in cattle, the elucidation of the disorder, its occurrence in other animals, and the delayed recognition of the disorder in the human.

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).

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.

The chromosome 13q14 deletion syndrome is characterized by retinoblastoma (180200), variable degrees of mental impairment, and characteristic facial features, including high forehead, prominent philtrum, and anteverted earlobes (summary by Caselli et al., 2007).

An autosomal recessive muscular dystrophy caused by mutations in the POMGNT1 gene. It is associated with characteristic brain and eye malformations, profound mental retardation, and death usually in the first years of life.

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.

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.

NFIX-related Malan syndrome (MALNS) is characterized by prenatal and postnatal overgrowth, macrocephaly, advanced bone age and/or skeletal anomalies (scoliosis, pes planus), slender body habitus, developmental delay / intellectual disability (typically in the moderate-to-severe range), behavioral problems (including a specific anxious profile and attention-deficit/hyperactivity disorder [ADHD]), and ocular findings (most commonly strabismus, refractive errors, and blue sclerae). Affected individuals typically have distinctive facial features, including a long and triangular face, high anterior hair line with prominent forehead, depressed nasal bridge, deep-set eyes, downslanted palpebral fissures, short nose with anteverted nares and upturned tip, long philtrum, small mouth that is often held open, thin vermilion of the upper lip, an everted lower lip, and a prominent chin. Other findings may include autonomic signs (episodic ataxia with dizziness and nausea and/or postural fainting), seizures or EEG abnormalities, hypotonia, dental anomalies, long bone fractures, and (rarely) congenital heart defects. Four individuals with aortic root dilatation have been reported, with one adult individual experiencing progressive aortic dilation and dissection at age 38 years. Additionally, one individual with rib osteosarcoma and another with Wilms tumor have been reported (an overall prevalence of malignancy of about 2%). Therefore, MALNS appears to be in the same low risk group as Sotos syndrome and Weaver syndrome with respect to a low likelihood of developing cancer.

Short ulna-dysmorphism-hypotonia-intellectual disability syndrome is a rare, genetic, multiple congenital anomalies/dysmorphic syndrome characterized by mild to severe global development delay, severe intellectual disability, mild hypotonia, a short ulna, hirsutism of the face and extremities, minimal scoliosis, and facial dysmorphism, notably a tall broad forehead, synophrys, hypertelorism, malar hypoplasia, broad nose with thick alae nasi, low-set, small ears, long philtrum, thin upper lip and everted lower lip vermilion.

FBXL4-related encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome is a multi-system disorder characterized primarily by congenital or early-onset lactic acidosis and growth failure, feeding difficulty, hypotonia, and developmental delay. Other neurologic manifestations can include seizures, movement disorders, ataxia, autonomic dysfunction, and stroke-like episodes. All affected individuals alive at the time they were reported (median age: 3.5 years) demonstrated significant developmental delay. Other findings can involve the heart (hypertrophic cardiomyopathy, congenital heart malformations, arrhythmias), liver (mildly elevated transaminases), eyes (cataract, strabismus, nystagmus, optic atrophy), hearing (sensorineural hearing loss), and bone marrow (neutropenia, lymphopenia). Survival varies; the median age of reported deaths was two years (range 2 days – 75 months), although surviving individuals as old as 36 years have been reported. To date FBXL4-related mtDNA depletion syndrome has been reported in 50 individuals.

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.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010). NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006). In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005). For a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Developmental and epileptic encephalopathy-23 (DEE23) is an autosomal recessive neurologic disorder characterized by the onset of intractable seizures in the first months of life (range, 2-6 months). Affected individuals have severely impaired psychomotor development with poor or absent speech, cortical blindness, and dysmorphic facial features (summary by Perrault et al., 2014).

Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism (IDDMOH) is characterized by mildly impaired intellectual development and microcephaly. Patients may also have ocular malformations, ocular apraxia, or hypogonadotropic hypogonadism. The disorder shows a unique DNA methylation signature (summary by Al-Jawahiri et al., 2022).

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.

A rare genetic neurological disorder with characteristics of congenital microcephaly, severe intellectual disability, hypertonia at birth lessening with age, ataxia and specific dysmorphic facial features including hirsutism, low anterior hairline and bitemporal narrowing arched thick and medially sparse eyebrows, long eyelashes, lateral upper eyelids swelling and a skin fold partially covering the inferior eyelids, low-set posteriorly rotated protruding ears, anteverted nares and a full lower lip. Brain imaging shows partial to almost complete agenesis of the corpus callosum and variable degrees of cerebellar hypoplasia. Caused by homozygous mutation in the FRMD4A gene on chromosome 10p13.

Impaired intellectual development and distinctive facial features with or without cardiac defects (MRFACD) is an autosomal dominant, complex syndromic neurodevelopmental disorder characterized by delayed psychomotor development, poor speech acquisition, distinctive dysmorphic facial features, including frontal bossing, upslanting palpebral fissures, depressed nasal bridge with bulbous tip, and macrostomia. There is variable penetrance of cardiac malformations, ranging from no malformations to patent foramen ovale to septal defects and/or transposition of the great arteries (summary by Adegbola et al., 2015).

Klippel-Feil syndrome-4 with nemaline myopathy and facial dysmorphism (KFS4) is an autosomal recessive disorder characterized mainly by severe hypotonia apparent from infancy. Klippel-Feil anomaly is primarily defined by fusion of the cervical spine, with associated low posterior hairline and limited neck mobility being observed in about half of patients (summary by Alazami et al., 2015). For a general description and a discussion of genetic heterogeneity of Klippel-Feil syndrome, see KFS1 (118100).

Basel-Vanagaite-Smirin-Yosef syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by severely delayed psychomotor development resulting in mental retardation, as well as variable eye, brain, cardiac, and palatal abnormalities (summary by Basel-Vanagaite et al., 2015).

Any autosomal dominant non-syndromic intellectual disability in which the cause of the disease is a mutation in the EEF1A2 gene.

A rare mandibulofacial dysostosis with the association with scalp alopecia and sparse eyebrows and eyelashes. Craniofacial dysmorphic features include zygomatic and mandibular dysplasia or hypoplasia, cleft palate, micrognathia, dental anomalies, auricular dysmorphism and eyelid anomalies among others. Patients may experience limited jaw mobility, glossoptosis, upper airway obstruction and conductive hearing loss.

White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females.

A recently described syndrome with characteristics of developmental delay, short stature and facial dysmorphism. Dysmorphic features include bi-temporal narrowing, smooth philtrum, pointed chin and dysmorphic ears. All reported patients had a cleft palate, whereas congenital heart defects or epilepsy are observed in patients with large deletions. Deletions are located within chromosome band 15q14, distal to the Prader-Willi/Angelman region. They have a variable size with the smallest deletion being 1.6 Mb in length.

Developmental and epileptic encephalopathy-49 (DEE49) is a severe autosomal recessive neurologic disorder characterized by onset of seizures in the neonatal period, global developmental delay with intellectual disability and lack of speech, hypotonia, spasticity, and coarse facial features. Some patients may have brain calcifications on imaging (summary by Han et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Heart and brain malformation syndrome (HBMS) is a severe autosomal recessive multiple congenital anomaly syndrome characterized by profoundly delayed psychomotor development, dysmorphic facial features, microphthalmia, cardiac malformations, mainly septal defects, and brain malformations, including Dandy-Walker malformation (summary by Shaheen et al., 2016). Homozygous mutation in the SMG9 gene can also cause neurodevelopmental disorder with intention tremor, pyramidal signs, dyspraxia, and ocular anomalies (NEDITPDO; 619995), a less severe neurodevelopmental disorder.

BCL11A-related intellectual disability (BCL11A-ID) is characterized by developmental delay / intellectual disability of variable degree, neonatal hypotonia, microcephaly, distinctive but variable facial characteristics, behavior problems, and asymptomatic persistence of fetal hemoglobin. Growth delay, seizures, and autism spectrum disorder have also been reported in some affected individuals.

Kleefstra syndrome-2 (KLEFS2) is an autosomal dominant neurodevelopmental disorder characterized by delayed psychomotor development, variably impaired intellectual development, and mild dysmorphic features (summary by Koemans et al., 2017). For a discussion of genetic heterogeneity of Kleefstra syndrome, see KLEFS1 (610253).

NEDMIAL is a neurodevelopmental disorder characterized by delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, delayed or absent speech development, and impaired intellectual development, sometimes with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017 and Mannucci et al., 2021).

Any autosomal recessive congenital ichthyosis in which the cause of the disease is a mutation in the TGM1 gene.

Feingold syndrome 1 (referred to as FS1 in this GeneReview) is characterized by digital anomalies (shortening of the 2nd and 5th middle phalanx of the hand, clinodactyly of the 5th finger, syndactyly of toes 2-3 and/or 4-5, thumb hypoplasia), microcephaly, facial dysmorphism (short palpebral fissures and micrognathia), gastrointestinal atresias (primarily esophageal and/or duodenal), and mild-to-moderate learning disability.

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).

Ververi-Brady syndrome (VEBRAS) is characterized by mild developmental delay, mildly impaired intellectual development and speech delay, and mild dysmorphic facial features. Affected individuals can usually attend mainstream schools with support, and may also show autistic features (summary by Ververi et al., 2018).

Developmental and epileptic encephalopathy-66 (DEE66) is a neurologic disorder characterized by the onset of various types of seizures in the first days or weeks of life. Most seizures have focal origins; secondary generalization is common. Seizure control is difficult at first, but may become easier with time. Affected individuals show global developmental delay with hypotonia, behavioral abnormalities, and dysmorphic features or ophthalmologic defects. Brain imaging often shows cerebellar dysgenesis. A subset of patients have extraneurologic manifestations, including hematologic and distal limb abnormalities (summary by Olson et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

ASXL3-related disorder is characterized by developmental delay or intellectual disability, typically in the moderate to severe range, with speech and language delay and/or absent speech. Affected individuals may also display autistic features. There may be issues with feeding. While dysmorphic facial features have been described, they are typically nonspecific. Affected individuals may also have hypotonia that can transition to spasticity resulting in unusual posture with flexion contractions of the elbows, wrists, and fingers. Other findings may include poor postnatal growth, strabismus, seizures, sleep disturbance, and dental anomalies.

Liang-Wang syndrome (LIWAS) is a polymalformation syndrome apparent from birth that shows large phenotypic variability and severity. However, all patients have some degree of neurologic dysfunction. The most severely affected individuals have severe global developmental delay with impaired intellectual development and poor or absent speech, marked craniofacial dysmorphism, and visceral and connective tissue abnormalities affecting the bones and vessels. The least severely affected individuals lack seizures, significant dysmorphism, and visceral involvement; they come to attention for neurologic signs and symptoms, including developmental delay with speech delay, strabismus, and/or ataxia. About half of patients have brain imaging anomalies, notably cerebral and cerebellar atrophy and thin corpus callosum, whereas the other half have normal brain imaging (summary by Liang et al., 2019).

Nizon-Isidor syndrome (NIZIDS) is a neurodevelopmental disorder characterized by global developmental delay, mildly delayed walking, poor speech and language, variably impaired intellectual development, and behavioral abnormalities, such as autistic features or attention deficit-hyperactivity disorder (ADHD). Some patients may have additional features, including nonspecific facial dysmorphism, gastrointestinal difficulties, distal hand anomalies, and thin corpus callosum on brain imaging (summary by Nizon et al., 2019).

Developmental and epileptic encephalopathy-88 (DEE88) is an autosomal recessive severe neurologic disorder characterized by global developmental delay, early-onset epilepsy, and progressive microcephaly. Brain MRI findings may include corpus callosum abnormalities, prominent ventricles, and mild hypoplasia of the inferior vermis and pons (Broeks et al., 2019). For a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350.

X-linked syndromic intellectual developmental disorder with pigmentary mosaicism and coarse facies (MRXSPF) is characterized by a phenotypic triad of severe developmental delay, coarse facial dysmorphisms, and Blaschkoid pigmentary mosaicism. Additional clinical features may include epilepsy, orthopedic abnormalities, hypotonia, and growth abnormalities. The disorder affects both males and females (Villegas et al., 2019; Diaz et al., 2020).

Biliary, renal, neurologic, and skeletal syndrome (BRENS) is an autosomal recessive complex ciliopathy with multisystemic manifestations. The most common presentation is severe neonatal cholestasis that progresses to liver fibrosis and cirrhosis. Most patients have additional clinical features suggestive of a ciliopathy, including postaxial polydactyly, hydrocephalus, retinal abnormalities, and situs inversus. Additional features of the syndrome may include congenital cardiac defects, echogenic kidneys with renal failure, ocular abnormalities, joint hyperextensibility, and dysmorphic facial features. Some patients have global developmental delay. Brain imaging typically shows dilated ventricles, hypomyelination, and white matter abnormalities, although some patients have been described with abnormal pituitary development (summary by Shaheen et al., 2020 and David et al., 2020).

Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies (IDDHISD) is characterized by global developmental delay with impaired intellectual development and poor or absent speech, hypotonia, ophthalmologic abnormalities, and nonspecific dysmorphic features. Some affected individuals have seizures, and a few have involvement of other organ systems (Goodman et al., 2021).

Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (DEHMBA) is an early-onset neurodevelopmental disorder characterized by these features. Affected individuals also have nonspecific and variable dysmorphic facial features that do not constitute a recognizable gestalt. Although the disorder is caused by truncating mutations in the SRCAP gene as is FLHS, the DEHMBA phenotype is clinically distinguishable from FLHS by the lack of short stature, brachydactyly, and delayed bone age, as well as absence of a specific facial appearance. There are some overlapping features between the 2 disorders, mainly impaired intellectual development and speech delay (summary by Rots et al., 2021).

Hengel-Maroofian-Schols syndrome (HEMARS) is an autosomal recessive neurodevelopmental disorder characterized by severe global developmental delay apparent from infancy or early childhood. Affected individuals have delayed walking or inability to walk, impaired intellectual development with poor or absent speech, pyramidal signs manifest as lower limb spasticity, poor overall growth often with short stature and microcephaly, and dysmorphic facial features. Some patients develop seizures. Brain imaging shows thinning of the posterior part of the corpus callosum, delayed myelination, and cerebral and cerebellar atrophy (Hengel et al., 2021).

Neurodevelopmental disorder with hypotonia, impaired language, and dysmorphic features (NEDHILD) is a rare neurodevelopmental disorder associated with impaired intellectual development, speech and language impairment, microcephaly, seizures, hypotonia, ophthalmologic issues, constipation/gastroesophageal reflux, and behavioral problems, including autism and sleep disturbances (summary by Garrity et al., 2021).

Bryant-Li-Bhoj neurodevelopmental syndrome-1 (BRYLIB1) is a highly variable phenotype characterized predominantly by moderate to severe global developmental delay with impaired intellectual development, poor or absent speech, and delayed motor milestones. Most patients have hypotonia, although some have peripheral hypertonia. Common features include abnormal head shape, variable dysmorphic facial features, oculomotor abnormalities, feeding problems, and nonspecific brain imaging abnormalities. Additional features may include hearing loss, seizures, short stature, and mild skeletal defects (summary by Bryant et al., 2020). Genetic Heterogeneity of Bryant-Li-Bhoj Neurodevelopmental Syndrome See also BRYLIB2 (619721), caused by heterozygous mutation in the H3F3B gene (601058).

Teebi hypertelorism syndrome-2 (TBHS2) is characterized primarily by hypertelorism, prominent forehead, thick and broad eyebrows, and short nose with depressed nasal root and broad nasal tip. Other features include thin upper lip, small chin with horizontal crease, and high or cleft palate. Developmental delay and/or impaired intellectual development have been observed in some patients (Li et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of Teebi hypertelorism syndrome, see TBHS1 (145420).

Neurodevelopmental disorder with poor growth and skeletal anomalies (NEDGS) is an autosomal recessive disorder characterized by global developmental delay and impaired intellectual development apparent from infancy. Affected individuals have hypotonia, delayed walking, poor or absent speech, and variable skeletal anomalies. More variable features include seizures, nonspecific dysmorphic facial features, oculomotor apraxia, and nonspecific brain imaging abnormalities (Iqbal et al., 2021).

Braddock-Carey syndrome (BRDCS) is characterized by Pierre-Robin sequence, persistent congenital thrombocytopenia, agenesis of the corpus callosum, severe developmental delay, microcephaly, high forehead, sparse curly hair, downslanting palpebral fissures, telecanthus, inverted U-shaped upper vermilion, enamel hypoplasia, large posteriorly rotated ears, clinodactyly, and camptodactyly (Braddock et al., 2016). Genetic Heterogeneity of Braddock-Carey Syndrome BRDCS2 (619981) is caused by mutation in the KIF15 gene (617569) on chromosome 3p21.

Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-Pelger-Huet anomaly (NEDFLPH) is an autosomal recessive disorder characterized by global developmental delay with severely impaired intellectual development. Affected individuals often have behavioral abnormalities and may have variable findings on brain imaging, such as thin corpus callosum. Laboratory studies show nuclear lobulation defects in a subset of neutrophils, indicating a pseudo-Pelger-Huet anomaly (see 169400) and suggesting defects in the integrity of the nuclear envelope, where TMEM147 localizes (Thomas et al., 2022).

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).

Autosomal dominant intellectual developmental disorder-73 (MRD73) is a highly variable neurodevelopmental disorder characterized by impaired intellectual development that ranges from mild to severe, speech delay, behavioral abnormalities, and nonspecific dysmorphic facial features (Janssen et al., 2022).

Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies (NEDLBF) is characterized by global developmental delay, speech delay, variably impaired intellectual development, behavioral abnormalities, and dysmorphic facial features. The phenotype and severity of the disorder is heterogeneous, ranging from borderline to severe. Brain imaging is usually normal. More variable additional features include early feeding difficulties, failure to thrive, short stature, mild visual impairment, hypotonia, seizures (particularly febrile), and distal skeletal defects of the hands and feet (Jia et al., 2022).

Tan-Almurshedi syndrome (TANALS) is an autosomal recessive neurodevelopmental disorder characterized by intrauterine growth retardation, poor overall growth with short stature and microcephaly, hypotonia, global developmental delay with impaired intellectual development, poor or absent speech, spasticity, and dysmorphic facial features (Westrip et al., 2023).

Neurodevelopmental disorder with progressive movement abnormalities (NEDPM) is an autosomal recessive complex neurologic disorder characterized by global developmental delay apparent from infancy, moderately to severely impaired intellectual development, poor or absent speech, behavioral abnormalities, and various hyperkinetic movement disorders, including dystonia, spasticity, and cerebellar ataxia, that interfere with gait and cause a stooped posture. The disorder appears to be progressive with age-related deterioration of cognitive and motor function; parkinsonism may develop in older patients. Additional more variable features include seizures, dysmorphic facial features, oculomotor defects, and brain imaging abnormalities (Kaiyrzhanov et al., 2024).

ReNU syndrome (RENU), also known as neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA), is characterized by hypotonia, global developmental delay, severely impaired intellectual development with poor or absent speech, delayed walking or inability to walk, feeding difficulties with poor overall growth, seizures (in most), dysmorphic facial features, and brain anomalies, including ventriculomegaly, thin corpus callosum, and progressive white matter loss (Greene et al., 2024; Schot et al., 2024; Chen et al., 2024).