Split-Hand/foot Malformation 5

Description

Split-hand/split-foot malformation (SHFM) is a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals. Some patients with SHFM5 have been found to have mental retardation, ectodermal and craniofacial findings, and orofacial clefting (Elliott and Evans, 2006).

For additional phenotypic information and a discussion of genetic heterogeneity in this disorder, see SHFM1 (183600).

Clinical Features

Del Campo et al. (1999) reported 2 unrelated boys with deletions on chromosome 2 who showed a single bone in the zeugopod and monodactyly in the autopod of all 4 limbs, as well as penoscrotal hypoplasia and multiple other anomalies, including severe growth retardation, microcephaly, hypertelorism, microphthalmia, cleft palate, and low-set ears.

Garcia-Ortiz et al. (2005) described 2 brothers, born of nonconsanguineous parents, with intrauterine growth retardation, short stature, distinctive facies, microphthalmia, unilateral split-hand malformation, hypoplastic fifth ray in both hands, small penis and testes, and hypospadias. Molecular analyses of the TP63 (603273), HOXA13 (142959), and HOXD13 (142989) genes were normal.

In a literature review including 48 SHFM1 patients, 40 SHFM3 (246560) patients, 45 SHFM4 (605289) patients, and 20 SHFM5 patients, Elliott et al. (2005) found that preaxial involvement of the upper extremities was a significant locus discriminator, most commonly seen in patients with SHFM3 (60% of patients). Preaxial involvement occurred in approximately 40% of SHFM5, 4% of SHFM4, and 2% of SHFM1 patients. In further analysis of the previously studied SHFM patients, Elliott and Evans (2006) identified phenotypic patterns involving mental retardation, ectodermal and craniofacial findings, and orofacial clefting associated with the mapped genetic SHFM loci.

Mapping

The deletions at chromosome 2q24.1-q31 and 2q31.1-q32.2 in the 2 unrelated boys reported by Del Campo et al. (1999) with split-hand/foot and other anomalies removed the entire HOXD cluster (see HOXD1; 142987). Del Campo et al. (1999) proposed that the limb and genital abnormalities in these boys were due, at least in part, to haploinsufficiency for the 5-prime HOXD genes. On the other hand, deletions involving band 2q31.1 had also been associated with limb abnormalities ranging from a wide cleft between toes 1 and 2 and brachysyndactyly of toes 2 to 5, to split-hand, split-foot, and monodactyly (reviewed by Boles et al. (1995) and Maas et al. (2000)). Boles et al. (1995) suggested that these abnormalities probably represent milder and more severe forms, respectively, of split-hand/foot malformation. The monodactyly described by Del Campo et al. (1999) in association with deletions in 2q would fit well into the severe end of this spectrum (Goodman et al., 2002).

Goodman et al. (2002) presented evidence for the existence of a locus for SHFM in the interval between the EVX2 gene (142991), located on chromosome 2q31-q32, and marker D2S294, located approximately 5 Mb centromeric to the EVX2 gene. They identified a father and daughter with synpolydactyly (SPD; 186000) who had a deletion that removed only HOXD9 (142982) through EVX2. They also identified a girl with bilateral split foot and a chromosome deletion that included the entire HOXD cluster and extended approximately 5-Mb centromeric to it. These findings indicated that haploinsufficiency of the 5-prime HOXD genes causes not SHFM but SPD and suggested that a novel locus for SHFM, designated SHFM5, must lie centromeric to EVX2 on 2q31.