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

Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain and occurs after failed or abbreviated midline cleavage of the developing brain during the third and fourth weeks of gestation. HPE occurs in up to 1 in 250 gestations, but only 1 in 8,000 live births (Lacbawan et al., 2009). Classically, 3 degrees of severity defined by the extent of brain malformation have been described. In the most severe form, 'alobar HPE,' there is a single ventricle and no interhemispheric fissure. The olfactory bulbs and tracts and the corpus callosum are typically absent. In 'semilobar HPE,' the most common type of HPE in neonates who survive, there is partial cortical separation with rudimentary cerebral hemispheres and a single ventricle. In 'lobar HPE,' the ventricles are separated, but there is incomplete frontal cortical separation (Corsello et al., 1990). An additional milder form, called 'middle interhemispheric variant' (MIHV) has also been delineated, in which the posterior frontal and parietal lobes are incompletely separated and the corpus callosum may be hypoplastic (Lacbawan et al., 2009). Finally, microforms of HPE include a single maxillary median incisor or hypotelorism without the typical brain malformations (summary by Mercier et al., 2011). Cohen (2001) discussed problems in the definition of holoprosencephaly, which can be viewed from 2 different perspectives: anatomic (fixed) and genetic (broad). When the main interest is description, the anatomic perspective is appropriate. In genetic perspective, a fixed definition of holoprosencephaly is not appropriate because the same mutational cause may result in either holoprosencephaly or some microform of holoprosencephaly. Cohen (2001) concluded that both fixed and broad definitions are equally valid and depend on context. Munke (1989) provided an extensive review of the etiology and pathogenesis of holoprosencephaly, emphasizing heterogeneity. See also schizencephaly (269160), which may be part of the phenotypic spectrum of HPE. Genetic Heterogeneity of Holoprosencephaly Several loci for holoprosencephaly have been mapped to specific chromosomal sites and the molecular defects in some cases of HPE have been identified. Holoprosencephaly-1 (HPE1) maps to chromosome 21q22. See also HPE2 (157170), caused by mutation in the SIX3 gene (603714) on 2p21; HPE3 (142945), caused by mutation in the SHH gene (600725) on 7q36; HPE4 (142946), caused by mutation in the TGIF gene (602630) on 18p11; HPE5 (609637), caused by mutation in the ZIC2 gene (603073) on 13q32; HPE6 (605934), mapped to 2q37; HPE7 (610828), caused by mutation in the PTCH1 gene (601309) on 9q22; HPE8 (609408), mapped to 14q13; HPE9 (610829), caused by mutation in the GLI2 gene (165230) on 2q14; HPE10 (612530), mapped to 1q41-q42; HPE11 (614226), caused by mutation in the CDON gene (608707) on 11q24; HPE12 (618500), caused by mutation in the CNOT1 gene (604917) on 16q21; HPE13 (301043), caused by mutation in the STAG2 gene (300826) on Xq25; and HPE14 (619895), caused by mutation in the PLCH1 gene (612835) on 3q25. Wallis and Muenke (2000) gave an overview of mutations in holoprosencephaly. They indicated that at least 12 different loci had been associated with HPE. Mutations in genes involved in the multiprotein cohesin complex, including STAG2, have been shown to be involved in midline brain defects such as HPE. Mutations in some of those genes cause Cornelia de Lange syndrome (CDLS; see 122470), and some patients with severe forms of CDLS may have midline brain defects. See, for example, CDLS2 (300590), CDLS3 (610759), and CDLS4 (614701).

Level of glutathione in the urine above the upper limit of normal.

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).

Individuals with trigonocephaly have a keel-shaped forehead with wide biparietal diameter, resulting in a triangular shape of the head. Trigonocephaly results from premature closure of the metopic sutures and usually occurs sporadically (summary by Frydman et al., 1984). Genetic Heterogeneity of Isolated Trigonocephaly Also see trigonocephaly-2 (TRIGNO2; 614485), caused by mutation in the FREM1 gene (608944) on chromosome 9p22.

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.

Weyers acrofacial dysostosis (WAD) is an autosomal dominant disorder with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar disorder, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease (summary by Howard et al., 1997).

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).

Schilbach-Rott syndrome (SBRS) is an autosomal dominant disorder characterized by hypotelorism, epicanthal folds, cleft palate, dysmorphic facies, and hypospadias in males. The phenotype is variable; mild mental retardation has been reported (summary by Shkalim et al., 2009).

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant form of recurrent focal neuropathy characterized clinically by acute, recurrent episodes of brachial plexus neuropathy with muscle weakness and atrophy preceded by severe pain in the affected arm.

A rare disorder characterized by the partial separation of the cerebral hemispheres. It is associated with mutations in the SIX3 gene.

Holoprosencephaly-9 refers to a disorder characterized by a wide phenotypic spectrum of brain developmental defects, with or without overt forebrain cleavage abnormalities. It usually includes midline craniofacial anomalies involving the first branchial arch and/or orbits, pituitary hypoplasia with panhypopituitarism, and postaxial polydactyly. The disorder shows incomplete penetrance and variable expressivity (summary by Roessler et al., 2003 and Bertolacini et al., 2012). For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. Considerable heterogeneity in the genetic causes of HPE has been demonstrated (Ming et al., 2002). For general phenotypic information and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Syndrome with characteristics of short stature, trigonocephaly and developmental delay. It has been described in three males. Moderate intellectual deficit was reported in one of the males and the other two patients displayed psychomotor retardation. X-linked transmission has been suggested but autosomal recessive inheritance cannot be ruled out.

A single maxillary central incisor positioned in the midline with morphological symmetry of the crown and bordered by lateral incisors.

A rare disorder caused by mutations in the TGIF gene mapped to chromosome 18p11.3. It is characterized by semilobar holoprosencephaly, hypotelorism, and ptosis.

Any holoprosencephaly in which the cause of the disease is a mutation in the SHH gene.

FGFR1-related Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorder and ectrodactyly spectrum disorder. HPE spectrum disorder, resulting from failed or incomplete forebrain division early in gestation, includes alobar, semilobar, or lobar HPE. Other observed midline brain malformations include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Other findings associated with the HPE spectrum such as craniofacial dysmorphism, neurologic issues (developmental delay, spasticity, seizures, hypothalamic dysfunction), feeding problems, and endocrine issues (hypogonadotropic hypogonadism and central insipidus diabetes) are common. Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays (also called split-hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen.

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.

LIG4 syndrome is an autosomal recessive severe combined immunodeficiency with features of radiosensitivity, chromosomal instability, pancytopenia, and developmental and growth delay. Leukemia and dysmorphic facial features have been reported in some patients (summary by van der Burg et al., 2006).

Holoprosencephaly-postaxial polydactyly syndrome associates, in chromosomally normal neonates, holoprosencephaly, severe facial dysmorphism, postaxial polydactyly and other congenital abnormalities, suggestive of trisomy 13. Incidence is unknown. Dysmorphic features include hypotelorism, severe eye anomalies such as microphthalmia or anophthalmia, premaxillary region aplasia and cleft lip and palate. Congenital cardiac anomalies are common. The condition seems to be inherited as an autosomal recessive trait. Prognosis is poor.

With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of EPG5-related disorder represents a continuum. At the most severe end of the spectrum is classic Vici syndrome (defined as a neurodevelopmental disorder with multisystem involvement characterized by the combination of agenesis of the corpus callosum, cataracts, hypopigmentation, cardiomyopathy, combined immunodeficiency, microcephaly, and failure to thrive); at the milder end of the spectrum are attenuated neurodevelopmental phenotypes with variable multisystem involvement. Median survival in classic Vici syndrome appears to be 24 months, with only 10% of children surviving longer than age five years; the most common causes of death are respiratory infections as a result of primary immunodeficiency and/or cardiac insufficiency resulting from progressive cardiac failure. No data are available on life span in individuals at the milder end of the spectrum.

Characterised by frontal encephalocoele, craniosynostosis, and developmental delay.

Craniosynostosis is a primary abnormality of skull growth involving premature fusion of the cranial sutures such that the growth velocity of the skull often cannot match that of the developing brain. This produces skull deformity and, in some cases, raises intracranial pressure, which must be treated promptly to avoid permanent neurodevelopmental disability (summary by Fitzpatrick, 2013). For a discussion of genetic heterogeneity of craniosynostosis, see CRS1 (123100).

Stormorken syndrome is an autosomal dominant disorder characterized by mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate myopathy, congenital miosis, and ichthyosis. Additional features may include headache or recurrent stroke-like episodes (summary by Misceo et al., 2014).

Holoprosencephaly associated with mutations in the ZIC2 gene.

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

Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is an autosomal recessive multiple congenital anomaly syndrome with features of a first and second branchial arch syndrome. Craniofacial abnormalities can lead to conductive hearing loss, respiratory insufficiency, and feeding difficulties. Additional features include rhizomelic skeletal anomalies as well as abnormalities of the shoulder and pelvic joints. Affected individuals may also have some features of a neurocristopathy or abnormal mesoderm development, such as urogenital anomalies, that are distinct from other branchial arch syndromes (summary by Parry et al., 2013).

Penttinen syndrome (PENTT) is characterized by a prematurely aged appearance involving lipoatrophy and epidermal and dermal atrophy, as well as hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acroosteolysis (Johnston et al., 2015).

Scalp-ear-nipple syndrome is characterized by aplasia cutis congenita of the scalp, breast anomalies that range from hypothelia or athelia to amastia, and minor anomalies of the external ears. Less frequent clinical characteristics include nail dystrophy, dental anomalies, cutaneous syndactyly of the digits, and renal malformations. Penetrance appears to be high, although there is substantial variable expressivity within families (Marneros et al., 2013).

Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the NSUN2 gene.

An extremely rare form of carbohydrate deficient glycoprotein syndrome characterized clinically in the single reported case by repeated hemorrhagic incidents, including severe pulmonary hemorrhage.

Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria. The mild phenotype (~75% of affected males) with onset in the second or third decade of life is typically limited to these biochemical findings, whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia. In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled.

Endocrine-cerebro-osteodysplasia (ECO) syndrome is characterized by various anomalies of the endocrine, cerebral, and skeletal systems resulting in neonatal mortality.

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

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

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

Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the TRAPPC9 gene.

A rare partial autosomal trisomy/tetrasomy characterized by global developmental delay, intellectual disability, autistic behavior, muscular hypotonia, macrocephaly and facial dysmorphism (frontal bossing, short palpebral fissures, low set, dysplastic ears, short or shallow philtrum, high arched or narrow palate, micrognathia). Other associated clinical features include sleep disturbances, seizures, aplasia/hypoplasia of the corpus callosum, skeletal abnormalities (large hands and feet, long fingers and toes, talipes).

A rare syndrome with characteristics of pre-natal onset growth retardation (low birth weight and short stature), hypotonia, developmental delay and intellectual disability associated with microcephaly and craniofacial (low anterior hairline, hypotelorism, thick lips with carp-shaped mouth, high-arched palate, low-set ears), cardiac (conotruncal heart malformations such as tetralogy of Fallot) and skeletal (hypoplastic thumbs and first metacarpals) abnormalities.

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

The cardinal features of chromosome 6q11-q14 interstitial deletions include hypotonia, short stature, skeletal/limb anomalies, umbilical hernia, and urinary tract anomalies, as well as characteristic facial features including upslanting palpebral fissures, low-set and/or dysplastic ears, and high-arched palate (summary by Wang et al., 2009).

The chromosome 16p12.2-p11.2 deletion syndrome is characterized phenotypically by dysmorphic facial features, feeding difficulties, recurrent ear infections, developmental delay, and cognitive impairment. Additional features, such as heart defects and short stature, are variable (Ballif et al., 2007; Battaglia et al., 2009). The pericentric region of chromosome 16, specifically involving 16p12-p11, is a structurally complex region enriched in repetitive sequence elements, rendering this region susceptible to deletion or rearrangement (Ballif et al., 2007). There are several phenotypes associated with variation in this region: see 611913 for a deletion or duplication at 16p11.2 associated with autism; see 136570 for discussion of a recurrent 520-kb deletion at 16p12.1 associated with developmental delay and craniofacial dysmorphism; and see 613444 for a 220-kb deletion at 16p11.2 associated with isolated severe early-onset obesity and obesity with developmental delay. Battaglia et al. (2009) emphasized that the region at chromosome 16p11.2 that confers susceptibility to autism (AUTS14; see 611913) is located more centromeric to and is distinct from the 16p12.2-p11.2 region involved in the multiple congenital anomalies and intellectual disability phenotype.

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).

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA.

A heterozygous deletion of chromosome 15q11.2 may increase the susceptibility to neuropsychiatric or neurodevelopmental problems, including delayed psychomotor development, speech delay, autism spectrum disorder, attention deficit-hyperactivity disorder, obsessive-compulsive disorder, and possibly seizures (summary by Doornbos et al., 2009 and Burnside et al., 2011). See also chromosome 15q11.2 duplication syndrome (608636).

Primary lymphedema with myelodysplasia, also known as Emberger syndrome, is a rare disorder characterized by childhood-onset lymphedema of the lower limbs, with lymphoscintigraphy suggestive of lymphatic vessel hypoplasia, and genital lymphatic abnormalities. Myelodysplasia is usually with monosomy 7. Multiple warts, deafness, and minor anomalies (mild hypotelorism, neck webbing, and slender fingers) may also be present (summary by Mansour et al., 2010).

Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (summary by Snape et al., 2011). See also MVA1 (257300), caused by mutation in the BUB1B gene (602860) on chromosome 15q15.

Any holoprosencephaly in which the cause of the disease is a mutation in the CDON gene.

FKBP14 kyphoscoliotic Ehlers-Danlos syndrome (FKBP14-kEDS) is characterized by congenital muscle hypotonia and weakness (typically improving during childhood), progressive scoliosis, joint hypermobility, hyperelastic skin, gross motor developmental delay, myopathy, and hearing impairment. Most affected children achieve independent walking between ages two and four years. A decline of motor function in adulthood may be seen, but affected individuals are likely to be able to participate in activities of daily living in adulthood and maintain independent walking. Occasional features underlying systemic connective tissue involvement include aortic rupture and arterial dissection, subdural hygroma, insufficiency of cardiac valves, bluish sclerae, bladder diverticula, inguinal or umbilical herniae, and premature rupture of membranes during pregnancy. Rarer findings may include bifid uvula with submucous or frank cleft palate, speech/language delay without true cognitive impairment, and rectal prolapse.

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

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

Cornelia de Lange syndrome (CdLS) encompasses a spectrum of findings from mild to severe. Severe (classic) CdLS is characterized by distinctive facial features, growth restriction (prenatal onset; <5th centile throughout life), hypertrichosis, and upper-limb reduction defects that range from subtle phalangeal abnormalities to oligodactyly (missing digits). Craniofacial features include synophrys, highly arched and/or thick eyebrows, long eyelashes, short nasal bridge with anteverted nares, small widely spaced teeth, and microcephaly. Individuals with a milder phenotype have less severe growth, cognitive, and limb involvement, but often have facial features consistent with CdLS. Across the CdLS spectrum IQ ranges from below 30 to 102 (mean: 53). Many individuals demonstrate autistic and self-destructive tendencies. Other frequent findings include cardiac septal defects, gastrointestinal dysfunction, hearing loss, myopia, and cryptorchidism or hypoplastic genitalia.

Microcephalic primordial dwarfism, Dauber type is a rare, genetic developmental defect during embryogenesis characterized by severe pre- and postnatal growth retardation, severe microcephaly, severe developmental delay and intelletual disability, severe adult short stature and facial dysmorphism (incl. hypotelorism, small ears, prominent nose). Other reported features include skeletal anomalies (Madelung deformity, clinodactyly, mild lumbar scoliosis, bilateral hip dysplasia) and seizures. Absence of thelarche and menarche is also associated.

Meckel syndrome, also known as Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis. There is extensive clinical variability and controversy as to the minimum diagnostic criteria. Early reports, including that of Opitz and Howe (1969) and Wright et al. (1994), stated that the classic triad of Meckel syndrome comprises (1) cystic renal disease; (2) a central nervous system malformation, most commonly occipital encephalocele; and (3) polydactyly, most often postaxial. However, based on a study of 67 patients, Salonen (1984) concluded that the minimum diagnostic criteria are (1) cystic renal disease; (2) CNS malformation, and (3) hepatic abnormalities, including portal fibrosis or ductal proliferation. In a review of Meckel syndrome, Logan et al. (2011) stated that the classic triad first described by Meckel (1822) included occipital encephalocele, cystic kidneys, and fibrotic changes to the liver. Genetic Heterogeneity of Meckel Syndrome See also MKS2 (603194), caused by mutation in the TMEM216 gene (613277) on chromosome 11q12; MKS3 (607361), caused by mutation in the TMEM67 gene (609884) on chromosome 8q; MKS4 (611134), caused by mutation in the CEP290 gene (610142) on chromosome 12q; MKS5 (611561), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12; MKS6 (612284), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15; MKS7 (267010), caused by mutation in the NPHP3 (608002) gene on chromosome 3q22; MKS8 (613885), caused by mutation in the TCTN2 gene (613846) on chromosome 12q24; MKS9 (614209), caused by mutation in the B9D1 gene (614144) on chromosome 17p11; MKS10 (614175), caused by mutation in the B9D2 gene (611951) on chromosome 19q13; MKS11 (615397), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; MKS12 (616258), caused by mutation in the KIF14 gene (611279) on chromosome 1q32; MKS13 (617562), caused by mutation in the TMEM107 gene (616183) on chromosome 17p13; and MKS14 (619879), caused by mutation in the TXNDC15 gene (617778) on chromosome 5q31.

Progressive microcephaly with seizures and cerebral and cerebellar atrophy is a severe autosomal recessive neurodevelopmental and neurodegenerative disorder with onset in the first days or months of life. Patients are born with microcephaly and soon develop intractable seizures, resulting in profoundly delayed development and hypotonia (summary by Zhang et al., 2014).

Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome is a rare, genetic developmental defect during embryogenesis disorder characterized primarily by congenital hypopituitarism and/or postaxial polydactyly. It can be associated with short stature, delayed bone age, hypogonadotropic hypogonadism, and/or midline facial defects (e.g. hypotelorism, mild midface hypoplasia, flat nasal bridge, and cleft lip and/or palate). Hypoplastic anterior pituitary and ectopic posterior pituitary lobe are frequent findings on MRI examination.

Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). For a discussion of genetic heterogeneity of TTD, see 601675.

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

In patients with SSMED, short stature and microcephaly are apparent at birth, and there is progressive postnatal growth failure. Endocrine dysfunction, including hypergonadotropic hypogonadism, multinodular goiter, and diabetes mellitus, is present in affected adults. Progressive ataxia has been reported in some patients, with onset ranging from the second to fifth decade of life. In addition, a few patients have developed tumors, suggesting that there may be a predisposition to tumorigenesis. In contrast to syndromes involving defects in other components of the nonhomologous end-joining (NHEJ) complex (see, e.g., 606593), no clinically overt immunodeficiency has been observed in SSMED, although laboratory analysis has revealed lymphopenia or borderline leukopenia in some patients (Murray et al., 2015; Bee et al., 2015; de Bruin et al., 2015; Guo et al., 2015).

Neurodevelopmental disorder with spastic paraplegia and microcephaly (NEDSPM) is an autosomal recessive neurologic syndrome characterized by delayed psychomotor development with delayed walking, moderately to severely impaired intellectual development, and poor or absent speech. More severely affected individuals show poor overall growth with progressive microcephaly, axial hypotonia, oromotor dysfunction with drooling, joint contractures, and spastic paraplegia resulting in walking difficulties. Some patients may develop seizures; nonspecific dysmorphic features have also been reported (summary by Hengel et al., 2018 and Ouyang et al., 2019).

Female-restricted X-linked syndromic intellectual developmental disorder-99 (MRXS99F) is an X-linked dominant neurodevelopmental disorder characterized by delayed psychomotor development and mild to moderate intellectual disability. Affected females can have a wide range of additional congenital anomalies, including scoliosis, postaxial polydactyly, mild cardiac or urogenital anomalies, dysmorphic facial features, and mild structural brain abnormalities (summary by Reijnders et al., 2016).

Tonne-Kalscheuer syndrome (TOKAS) is an X-linked recessive multiple congenital anomaly disorder with 2 main presentations. Most patients exhibit global developmental delay apparent from early infancy, impaired intellectual development, speech delay, behavioral abnormalities, and abnormal gait. Affected individuals also have dysmorphic facial features that evolve with age, anomalies of the hands, feet, and nails, and urogenital abnormalities with hypogenitalism. A subset of more severely affected males develop congenital diaphragmatic hernia in utero, which may result in perinatal or premature death. Carrier females may have very mild skeletal or hormonal abnormalities (summary by Frints et al., 2019). Also see Fryns syndrome (229850), an autosomal recessive disorder with overlapping features.

The core features of short stature-micrognathia syndrome (SSMG) are intrauterine growth restriction (IUGR), postnatal short stature that is often rhizomelic, and micrognathia. Other common features include preterm birth, microcephaly, developmental delay, and genitourinary malformations in males. Transient liver dysfunction and glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, and cataracts have also been observed. Inter- and intrafamilial phenotypic severity varies greatly, from a relatively mild disorder to intrauterine death or stillbirth (Ritter et al., 2022).

Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, a bleeding diathesis, and, in some individuals, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. Ocular findings include reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. The bleeding diathesis can result in variable bruising, epistaxis, gingival bleeding, postpartum hemorrhage, colonic bleeding, and prolonged bleeding with menses or after tooth extraction, circumcision, and other surgeries. Pulmonary fibrosis, a restrictive lung disease, typically causes symptoms in the early thirties and can progress to death within a decade. Granulomatous colitis is severe in about 15% of affected individuals. Neutropenia and/or immune defects occur primarily in individuals with pathogenic variants in AP3B1 and AP3D1.

RERE-related disorders are characterized by neurodevelopmental problems with or without structural anomalies of the eyes, heart, kidneys, and genitourinary tract and mild sensorineural hearing loss. Hypotonia and feeding problems are common among affected individuals. Developmental delay and intellectual disability range from mild to profound. Behavior problems may include attention-deficit/hyperactivity disorder, self-injurious behavior, and autism spectrum disorder. A variety of eye anomalies (coloboma, optic nerve anomalies, microphthalmia, and/or Peter's anomaly) and vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia) have been reported. Congenital heart defects, most commonly septal defects, have also been described. Genitourinary abnormalities include vesicoureteral reflux, and cryptorchidism and hypospadias in males. Sensorineural hearing loss can be unilateral or bilateral.

Thrombocytopenia-6 is an autosomal dominant hematologic disorder characterized by increased bleeding episodes due to reduced platelet count and abnormal platelet morphology resulting from defective megakaryopoiesis. Patients may also have bone abnormalities, including osteoporosis or tooth loss, as well as an increased risk for myelofibrosis (summary by Turro et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of thrombocytopenia, see 313900.

Most individuals with HNRNPH2-related neurodevelopmental disorder (HNRNPH2-NDD) have symptoms early in life, before age 12 months. The major features of HNRNPH2-NDD are developmental delay / intellectual disability, motor and language delays, behavioral and psychiatric disorders, and growth and musculoskeletal abnormalities. Minor features include dysmorphic facies, gastrointestinal disturbances, epilepsy, and visual defects. Although HNRNPH2-NDD is an X-linked condition, there is not enough information on affected females versus affected males to make any generalizations about phenotypic differences between the two sexes.

Immunodeficiency-47 (IMD47) is an X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Some patients also have neurologic abnormalities (summary by Jansen et al., 2016).

ALKKUCS is an autosomal recessive severe neurodevelopmental disorder characterized by arthrogryposis, brain abnormalities associated with cerebral parenchymal underdevelopment, and global developmental delay. Most affected individuals die in utero or soon after birth. Additional abnormalities may include hypotonia, dysmorphic facial features, and involvement of other organ systems, such as cardiac or renal. The few patients who survive have variable intellectual disability and may have seizures (summary by Gueneau et al., 2018).

A rare fatal inborn error of metabolism disorder with characteristics of respiratory distress and severe hypotonia at birth, severe global developmental delay, early-onset intractable seizures, myopathic facies with craniofacial dysmorphism (trigonocephaly/progressive microcephaly, low anterior hairline, arched eyebrows, hypotelorism, strabismus, small nose, prominent philtrum, thin upper lip, high-arched palate, micrognathia, malocclusion), severe, congenital flexion joint contractures and elevated serum creatine kinase levels. Scoliosis, optic atrophy, mild hepatomegaly, and hypoplastic genitalia may also be associated. There is evidence the disease is caused by homozygous or compound heterozygous mutation in the DPM2 gene on chromosome 9q34.

Developmental delay with or without dysmorphic facies and autism (DEDDFA) is a complex neurodevelopmental disorder apparent from infancy or early childhood and associated with variably impaired intellectual development. Some patients may be severely affected with no speech and inability to walk, whereas others may be able to attend special schools or have normal intellectual function associated with autism spectrum disorder and mild speech delay. Genetic analysis has suggested that the phenotype can be broadly categorized into 2 main groups. Patients with TRRAP mutations affecting residues 1031-1159 have a more severe disorder, often with multisystem involvement, including renal, cardiac, and genitourinary systems, as well as structural brain abnormalities. Patients with mutations outside of that region tend to have a less severe phenotype with a higher incidence of autism and usually no systemic involvement. Patients in both groups usually have somewhat similar dysmorphic facial features, such as upslanting palpebral fissures, hypertelorism, low-set ears, and broad or depressed nasal bridge, although these features are highly variable (summary by Cogne et al., 2019).

Holoprosencephaly-12 with or without pancreatic agenesis (HPE12) is a developmental disorder characterized by abnormal separation of the embryonic forebrain (HPE) resulting in dysmorphic facial features and often, but not always, impaired neurologic development. Most patients with this form of HPE also have congenital absence of the pancreas, resulting in early-onset type 1 diabetes mellitus and requiring pancreatic enzyme replacement. Other features may include hearing loss and absence of the gallbladder (summary by De Franco et al., 2019 and Kruszka et al., 2019). For a phenotypic description and a discussion of genetic heterogeneity of holoprosencephaly, see HPE1 (236100).

Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (NEDMABA) is an autosomal recessive disorder characterized by severe global developmental delay, usually with hypotonia and absence of spontaneous movements other than head control, impaired intellectual development with absent speech, distal contractures, progressive microcephaly, dysmorphic features, and distal skeletal abnormalities, such as rocker-bottom feet and clenched hands with camptodactyly. Brain imaging tends to show a simplified gyral pattern of the cerebral cortex, delayed myelination, thin corpus callosum, and hypoplasia of the brainstem and cerebellum. The disorder may be complicated by feeding and/or breathing difficulties, often resulting in death in infancy (summary by Magini et al., 2019).

Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotonia (NEDBASH) is an autosomal recessive disorder characterized by severely impaired intellectual and motor development, axial and peripheral hypotonia usually with inability to walk, and significant behavioral abnormalities consistent with autism spectrum disorder and reminiscent of Rett syndrome (RTT; 312750), such as poor communication, stereotypic or repetitive behaviors, hand-wringing, bruxism, and sleep disturbances. Other features include poor overall growth, and joint hypermobility. Rare features include seizures, dystonia, spasticity, and nonspecific brain abnormalities (summary by Abu-Libdeh et al., 2019 and Dias et al., 2019).

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

Developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85) is an X-linked neurologic disorder characterized by onset of severe refractory seizures in the first year of life, global developmental delay with impaired intellectual development and poor or absent speech, and dysmorphic facial features. The seizures tend to show a cyclic pattern with clustering. Many patients have midline brain defects on brain imaging, including thin corpus callosum and/or variable forms of holoprosencephaly (HPE). The severity and clinical manifestations are variable. Almost all reported patients are females with de novo mutations predicted to result in a loss of function (LOF). However, some patients may show skewed X inactivation, and the pathogenic mechanism may be due to a dominant-negative effect. The SMC1A protein is part of the multiprotein cohesin complex involved in chromatid cohesion during DNA replication and transcriptional regulation; DEE85 can thus be classified as a 'cohesinopathy' (summary by Symonds et al., 2017 and Kruszka et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Retinal dystrophy and leukodystrophy (RDLKD) is a peroxisomal enzyme deficiency caused by impaired very long chain fatty acid (VLCFA) metabolism. Patients exhibit ataxia and spastic paraparesis as well as developmental delay, and may show facial dysmorphism (Ferdinandusse et al., 2017).

Developmental and epileptic encephalopathy-87 (DEE87) is a neurologic disorder characterized by global developmental delay, hypotonia, and onset of frequent refractory seizures or infantile spasms between 6 and 15 months of age. Affected individuals have severely impaired motor and cognitive development with little or absent speech and poor visual tracking. More variable features include facial dysmorphisms, joint laxity, and nonspecific brain imaging findings (summary by Chung et al., 2020).

Rajab interstitial lung disease with brain calcifications-1 (RILCBC1) is an autosomal recessive multisystem disorder with a highly variable phenotype. Most patients present in infancy or early childhood with poor growth and interstitial lung disease, which may lead to death. Some may also have liver, skeletal, and renal abnormalities, and most have intracranial calcifications on brain imaging. Some may have early impaired motor development, but most have normal cognitive development (summary by Xu et al., 2018). Genetic Heterogeneity of Rajab Interstitial Lung Disease with Brain Calcifications Also see Rajab interstitial disease with brain calcifications-2 (RILDBC2; 619013), caused by mutation in the FARSA gene (602918).

Li-Ghorbani-Weisz-Hubshman syndrome (LIGOWS) is a neurodevelopmental disorder characterized by global developmental delay, mild to moderately impaired intellectual development with language delay, and mild dysmorphic features. Affected individuals may have behavioral abnormalities and difficulties with numbers and understanding certain concepts, such as money. Some patients have seizures. Brain imaging often shows enlarged ventricles, thin corpus callosum, and gray matter nodular heterotopia, suggesting abnormal cortical brain development. More variable additional features may be present (summary by Li et al., 2020).

Mitochondrial complex IV deficiency nuclear type 10 (MC4DN10) is an autosomal recessive multisystem metabolic disorder characterized by the onset of severe symptoms soon after birth. Affected infants have respiratory and neurologic distress, metabolic lactic acidosis, and dysmorphic features, including microphthalmia. Death occurs in early infancy. Postmortem examination has demonstrated systemic involvement with hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal hyperplasia. There is also abnormal brain myelination and cavitating brain lesions. Patient tissues show decreased levels and activity of mitochondrial respiratory complex IV (summary by Weraarpachai et al., 2012). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.

Neurodevelopmental disorder with microcephaly, language delay, and gait abnormalities (NEDMILG) is an autosomal recessive disorder characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. More variable features include hypotonia, early-onset seizures, and a peripheral demyelinating or axonal peripheral sensorimotor neuropathy. The disease follows a neurodegenerative course in many patients; clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).

Cardiofacioneurodevelopmental syndrome (CFNDS) is characterized by microcephaly, midline facial defects, developmental delay, and cerebellar hypoplasia. Variable cardiac defects may be present, including atrioventricular canal and ventricular septal defects. Heterotaxy has also been reported (Harel et al., 2020).

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

White-Kernohan syndrome (WHIKERS) is a neurodevelopmental disorder characterized by global developmental delay with variably impaired intellectual development, hypotonia, and characteristic facial features. Some patients may have abnormalities of other systems, including genitourinary and skeletal (summary by White et al., 2021).

Ritscher-Schinzel syndrome-4 (RTSC4) is characterized by a constellation of congenital anomalies, including dysmorphic craniofacial features and structural brain anomalies, such as Dandy-Walker malformation (220200), hindbrain malformations, or agenesis of the corpus callosum, associated with global developmental delay and impaired intellectual development. Congenital cardiac defects have been reported in 1 family (summary by Ritscher et al., 1987 and Jeanne et al., 2021). For a discussion of genetic heterogeneity of Ritscher-Schinzel syndrome, see RTSC1 (220210).

DEGCAGS syndrome is an autosomal recessive syndromic neurodevelopmental disorder characterized by global developmental delay, coarse and dysmorphic facial features, and poor growth and feeding apparent from infancy. Affected individuals have variable systemic manifestations often with significant structural defects of the cardiovascular, genitourinary, gastrointestinal, and/or skeletal systems. Additional features may include sensorineural hearing loss, hypotonia, anemia or pancytopenia, and immunodeficiency with recurrent infections. Death in childhood may occur (summary by Bertoli-Avella et al., 2021).

Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).

Neurodevelopmental disorder with hypotonia and brain abnormalities (NEDHYBA) is characterized by impaired development of motor skills, cognitive function, and speech acquisition beginning in infancy or early childhood. Some affected individuals may have feeding difficulties, seizures, behavioral abnormalities, and nonspecific dysmorphic facial features. Brain imaging shows variable abnormalities, including corpus callosum defects, cerebellar defects, and decreased white matter volume. There is significant phenotypic variability (summary by Duncan et al., 2021).

Galloway-Mowat syndrome-9 (GAMOS9) is an autosomal recessive disorder characterized by onset of nephrotic syndrome with proteinuria in infancy or early childhood. The renal disease is slowly progressive, but some affected individuals may develop end-stage renal disease in the first decade. Renal biopsy shows focal segmental glomerulosclerosis (FSGS) or diffuse mesangial sclerosis (DMS). Affected individuals also have developmental delay and secondary microcephaly. Additional features may include facial dysmorphism and gastroesophageal reflux. Early death may occur (Arrondel et al., 2019). For a discussion of genetic heterogeneity of GAMOS, see GAMOS1 (251300).

Marbach-Schaaf neurodevelopmental syndrom (MASNS) is characterized by global developmental delay with speech delay and behavioral abnormalities, including autism spectrum disorder and ADHD. Affected individuals also show movement disorders, such as dyspraxia and apraxia. More variable features include high pain tolerance, sleep disturbances, and variable nonspecific dysmorphic features (summary by Marbach et al., 2021).

Nonphotosensitive trichothiodystrophy-8 (TTD8) is characterized by brittle hair and nails and scaly skin, accompanied by failure to thrive, microcephaly, and neuromotor developmental delay. Hair analysis shows low sulfur content, and skin fibroblasts demonstrate normal DNA repair efficiency after UV irradiation (Botta et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of trichothiodystrophy, see TTD1 (601675).

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

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).

Combined oxidative phosphorylation deficiency-55 (COXPD55) is characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia phenotype has been described in 1 patient (summary by Olahova et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Autosomal recessive dyskeratosis congenita-8 (DKCB8) is characterized by progressive bone marrow failure affecting all lineages apparent from infancy or early childhood. More variable features may include poor growth, mild developmental delay, immunodeficiency, and gastrointestinal manifestations, such as esophageal stricture or inflammatory bowel disease. Some patients may have mucocutaneous features, including oral leukoplakia, nail dystrophy, or pigmentary skin abnormalities, although these features may be absent. Unlike patients with other forms of DKC, those with DKCB8 do not have shortened telomeres, although there is evidence of telomere instability. Hematopoietic stem cell transplant may be curative (Kermasson et al., 2022). For a discussion of genetic heterogeneity of dyskeratosis congenita, see DKCA1 (127550).

Complex cortical dysplasia with other brain malformations-11 (CDCBM11) is an autosomal recessive disorder characterized by dilated ventricles and reduced white matter and associated with axonal developmental defects (Qian et al., 2022). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).