Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present.

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

The pseudoaminopterin syndrome (aminopterin syndrome sine aminopterin; ASSA) is a multiple congenital anomaly disorder characterized by ossification defects of the skull, dysmorphic facial features, delayed development, and variable limb defects. The clinical features resemble the embryopathy caused by maternal treatment with the folic acid antagonist aminopterin, which has been recognized since 1952 (Thiersch, 1952) when aminopterin was used as an abortifacient. The characteristic phenotype of the children who survived infancy after having been exposed to aminopterin or its methyl derivative, methotrexate, in early pregnancy included a very unusual facies, skull anomalies, and skeletal defects (summary by Fraser et al., 1987).

A very rare syndrome described in two siblings with manifestation of prenatal onset of growth deficiency, microcephaly, hypoplastic genitalia, and birth onset of convulsions.

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).

X-linked reticulate pigmentary disorder shows more severe manifestations in hemizygous males compared to heterozygous females. Affected males have early onset of recurrent respiratory infections and failure to thrive resulting from inflammatory gastroenteritis or colitis. Patients also show reticular pigmentation abnormalities of the skin and may develop corneal scarring. Carrier females may be unaffected or have only pigmentary abnormalities along the lines of Blaschko (summary by Starokadomskyy et al., 2016).

Although the phenotypic spectrum and severity of FG syndrome is wide, the cardinal features include congenital hypotonia, delayed speech development, relative macrocephaly, dysmorphic facies, and anal anomalies or severe constipation (Unger et al., 2007). For a general phenotypic description and a discussion of genetic heterogeneity of FG syndrome, see FGS1 (305450).

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500).

Pitt-Hopkins syndrome (PTHS) is characterized by significant developmental delays with moderate-to-severe intellectual disability and behavioral differences, characteristic facial features, and episodic hyperventilation and/or breath-holding while awake. Speech is significantly delayed and most individuals are nonverbal with receptive language often stronger than expressive language. Other common findings are autism spectrum disorder symptoms, sleep disturbance, stereotypic hand movements, seizures, constipation, and severe myopia.

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.

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). 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 nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA) is an autosomal dominant neurologic disorder with significant phenotypic heterogeneity, even within families. The disorder is most often diagnosed through genetic analysis with retrospective clinical phenotyping. Symptom onset is usually in early childhood, although later onset, even in adulthood, has been reported. Most affected individuals show global developmental delay from early childhood, particularly of motor and language skills. Many have mild intellectual disability; behavioral and psychiatric abnormalities such as autism and obsessive-compulsive disorder are also often observed. The movement disorder is prominent and may include cerebellar signs such as ataxia, tremor, dysmetria, poor coordination, and dysarthria. Other abnormal movements including spasticity, myoclonus, and dystonia have been reported, thus widening the phenotypic spectrum. Brain imaging is usually normal, but may show cerebellar atrophy or nonspecific white matter lesions. Variable dysmorphic facial features may also be present (summary by Thevenon et al., 2012; Jacobs et al., 2021; Wijnen et al., 2020).

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.

Any non-syndromic X-linked intellectual disability in which the cause of the disease is a mutation in the FRMPD4 gene.

Gabriele-de Vries syndrome is characterized by mild-to-profound developmental delay / intellectual disability (DD/ID) in all affected individuals and a wide spectrum of functional and morphologic abnormalities. Intrauterine growth restriction or low birth weight and feeding difficulties are common. Congenital brain, eye, heart, kidney, genital, and/or skeletal system anomalies have also been reported. About half of affected individuals have neurologic manifestations, including hypotonia and gait abnormalities. Behavioral issues can include attention-deficit/hyperactivity disorder, anxiety, autism or autistic behavior, and schizoaffective disorder.

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.

Myoectodermal gonadal dysgenesis syndrome (MEGD) is characterized by 46,XY complete or partial gonadal dysgenesis, or 46,XX gonadal dysgenesis, in association with extragonadal anomalies, including low birth weight, typical facies, rod and cone dystrophy, sensorineural hearing loss, omphalocele, anal atresia, renal agenesis, skeletal abnormalities, dry and scaly skin, severe myopathy, and neuromotor delay. Dysmorphic facial features along with muscular habitus are the hallmarks of the syndrome. Abnormal hair patterning with frontal upsweep and additional whorls, eyebrow abnormalities comprising broad, arched, and sparse or thick eyebrows, underdeveloped alae nasi, smooth philtrum, and low-set ears with overfolded helices facilitate a gestalt diagnosis. (Guran et al., 2019; Altunoglu et al., 2022).

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.

Neurodevelopmental disorder with spasticity, cataracts, and cerebellar hypoplasia (NEDSCAC) is an autosomal recessive disorder characterized by global developmental delay with variably impaired intellectual development. More severely affected individuals are nonverbal and do not achieve independent ambulation, whereas others develop some speech and can walk, or show regression later in childhood. Common features include axial hypotonia, peripheral spasticity, dystonia, cataracts, and seizures. Brain imaging usually shows cerebellar hypoplasia with variable additional abnormalities, such as thin corpus callosum, cerebral atrophy, and hypomyelination (summary by Meng et al., 2021).

Neurodevelopmental disorder with central hypotonia and dysmorphic facies (NEDCHF) is an autosomal dominant disorder characterized by global developmental delay, impaired intellectual development, seizures, distinctive facial features, scoliosis, delayed closure of the anterior fontanel, and nonspecific brain abnormalities (Wakeling et al., 2021).

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).

Cornelia de Lange syndrome (CDLS) is a genetically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 60% of patients have mutations in the NIPBL gene (608667) (summary by Musio et al., 2006 and Hoppman-Chaney et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of Cornelia de Lange syndrome, see CDLS1 (122470).