The most basic description of Moebius syndrome is a congenital facial palsy with impairment of ocular abduction. The facial nerve (cranial nerve VII) and abducens nerve (CN VI) are most frequently involved, but other cranial nerves may be involved as well. Other variable features include orofacial dysmorphism and limb malformations. Mental retardation has been reported in a subset of patients. Most cases of Moebius syndrome are sporadic, but familial occurrence has been reported (Verzijl et al., 2003). The definition of and diagnostic criteria for Moebius syndrome have been controversial and problematic. The syndrome has most frequently been confused with hereditary congenital facial paresis (HCFP; see 601471), which is restricted to involvement of the facial nerve and no other abnormalities. Verzijl et al. (2003) and Verzijl et al. (2005) concluded that HCFP and Moebius syndrome are distinct disorders, and that Moebius syndrome is a complex developmental disorder of the brainstem. Moebius syndrome was defined at the Moebius Syndrome Foundation Research Conference in 2007 as congenital, nonprogressive facial weakness with limited abduction of one or both eyes. Additional features can include hearing loss and other cranial nerve dysfunction, as well as motor, orofacial, musculoskeletal, neurodevelopmental, and social problems (summary by Webb et al., 2012). Kumar (1990) provided a review of Moebius syndrome, which was critiqued by Lipson et al. (1990). Briegel (2006) provided a review of Moebius sequence with special emphasis on neuropsychiatric findings.

Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment. Other findings can include poor weight gain often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance. Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain. Anomalies of the liver, spleen, and/or pancreas are less common. Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection. To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot. The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date.

SALL4-related disorders include Duane-radial ray syndrome (DRRS, Okihiro syndrome), acro-renal-ocular syndrome (AROS), and SALL4-related Holt-Oram syndrome (HOS) – three phenotypes previously thought to be distinct entities. DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in SALL4 may cause clinically typical HOS (i.e., radial ray malformations and cardiac malformations without additional features).

Solitary median maxillary central incisor (SMMCI) may occur as an isolated anomaly or with various associated features, primarily short stature, choanal atresia, midnasal stenosis, and holoprosencephaly (Hall et al., 1997).

An EEC syndrome characterized by autosomal dominant inheritance that has material basis in variation in the chromosome region 7q11.2-q21.3.

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

Craniometaphyseal dysplasia is an osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial palsy (summary by Nurnberg et al., 1997). The delineation of separate autosomal dominant (CMDD; 123000) and autosomal recessive forms of CMD by Gorlin et al. (1969) was confirmed by reports that made it evident that the dominant form is relatively mild and comparatively common, whereas the recessive form is rare, severe, and possibly heterogeneous.

MID1-related Opitz G/BBB syndrome (MID1-OS) is characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 30% of affected males. Cleft lip and/or palate are present in approximately half of affected males. Other malformations (present in <50% of affected males) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only.

VATER is a mnemonically useful acronym for the nonrandom association of vertebral defects (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R). This combination of associated defects was pointed out by Quan and Smith (1972). Nearly all cases have been sporadic. VACTERL is an acronym for an expanded definition of the association that includes cardiac malformations (C) and limb anomalies (L). The VACTERL association is a spectrum of various combinations of its 6 components, which can be a manifestation of several recognized disorders rather than a distinct anatomic or etiologic entity (Khoury et al., 1983). Also see VATER/VACTERL association with hydrocephalus (VACTERL-H; 276950) and VACTERL with or without hydrocephalus (VACTERLX; 314390).