Split-Hand/foot Malformation 6

A number sign (#) is used with this entry because of evidence that split-hand/foot malformation-6 (SHFM6) is caused by homozygous mutation in the WNT10B gene (601906) on chromosome 12q13.

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 SHFM have been found to have mental retardation, ectodermal and craniofacial findings, and orofacial clefting (Elliott and Evans, 2006).

For a general phenotypic description and a discussion of genetic heterogeneity of split-hand/foot malformations, see SHFM1 (183600).

Clinical Features

Klein (1932) described a boy and girl with ectrodactyly who were born from the mating between a man and the daughter of his half brother.

Verma et al. (1976) reported split-hand and split-foot malformation (SHFM) in 2 sibships of a consanguineous kindred; they noted that the 2-year-old male proband had an 'atypical variety', as not only the median rays but also the rays bordering the clefts were affected by reduction anomalies; x-rays also showed bilateral fusion of the radius and ulna. Pointing to the cases of possible recessive inheritance published by Ray (1960) and Freire-Maia (1971), Verma et al. (1976) concluded that no clinical features distinguishing the autosomal recessive and autosomal dominant forms were evident.

Mufti and Wood (1987) suggested autosomal recessive inheritance to explain the occurrence of ectrodactyly in 4 half sisters from 2 different mothers. The family was Saudi and 1 of the matings was known to be consanguineous. The 2 sisters from the consanguineous sibship had anomalies of the hands only; they had 4 unaffected brothers and 1 unaffected sister. In the sibship not known to be consanguineous, 1 sister had normal hands but malformed feet and bilateral tibial aplasia, and her younger sister had malformations of both hands and feet as well as aplasia of the right tibia; they had an unaffected older brother. Hennekam and Lommen (1988) suggested that the patients reported by Mufti and Wood (1987) had the tibial aplasia with ectrodactyly syndrome (119100).

Zlotogora and Nubani (1989) reported 4 cases of 'typical' split-hand/foot malformation in 2 sibships from an inbred kindred. Although this seemed to confirm the existence of an autosomal recessive form of the disorder, the authors presented an alternative possibility, namely, that an additional locus controls the expression of the dominant mutation. According to this hypothesis, a dominant allele at the controlling locus leads to nonpenetrance of the split-hand/foot mutation and the appearance of normal carriers.

Gul and Oktenli (2002) reported a 5-generation consanguineous Turkish family in which 9 affected members had split-hand/foot malformation with highly variable expression: 4 affected individuals had involvement of both hands and feet, whereas in 4 others, only the feet were affected, and in 1, only the hands. Parental consanguinity in the reported cases and recurrence of the condition in sibs born to unaffected parents supported autosomal recessive inheritance.

Ugur and Tolun (2008) restudied the Turkish family with SHFM originally reported by Gul and Oktenli (2002), identifying 13 affected members, 12 of whom had central feet reductions with or without hand involvement, while the remaining (male) patient had the mildest phenotype, with only cutaneous syndactyly of the right hand and no foot involvement. In general, females were less severely affected than males, and hands were affected much less than feet.

Blattner et al. (2010) reported a 30-year-old pregnant Swiss woman with apparently sporadic occurrence of split-hand/foot malformation who presented for genetic counseling. The deformity was apparent at birth, and there were no other affected family members. Radiographs from age 12 years showed loss of the second, third, and fourth toes of both feet, a bifid fifth toe on the right foot, and fusion of the third and fourth metatarsal of both feet. The right hand had complete cutaneous syndactyly of the fourth and fifth finger and hypoplasia of the third finger with loss of the distal phalanx. The left hand showed proximal cutaneous syndactyly of the third and fourth finger. She had surgical correction of the hand and foot anomalies.

Mapping

By homozygosity mapping under an assumption of recessive inheritance with 80% penetrance in a consanguineous Turkish family with SHFM, originally reported by Gul and Oktenli (2002), Ugur and Tolun (2008) obtained maximum 2-point and multipoint lod scores of 3.87 and 5.47, respectively, on chromosome 12q31.11-q13. Ugur and Tolun (2008) also identified other common haplotypes in this family, including an approximately 20-Mb haplotype at chromosome 1p34.3-p32.3, delineated by D1S496 and D1S200, that was found in heterozygosity or homozygosity in all affected individuals but 1; linkage to SHFM2 (313350) on chromosome Xq26.2-q27.1 was excluded, but a common haplotype at Xq22.3-q25, between markers DXS6797 and ATCT003, was found in all affected males but 1.

Molecular Genetics

In a consanguineous Turkish family with SHFM mapping to chromosome 12q31.11-q13, originally reported by Gul and Oktenli (2002), Ugur and Tolun (2008) analyzed the candidate gene WNT10B and identified a missense mutation (R332W; 601906.0001) that was present in homozygosity in all affected members of the family except for the man with the mildest phenotype, who had no bone defect and no foot involvement. The mutation, which was not found in 200 controls, was also present in homozygosity in 1 unaffected female, whose unaffected status was confirmed by repeated radiologic examination. Ugur and Tolun (2008) proposed that either a second locus contributed to the phenotype or a suppressor locus prevented trait manifestation in the nonpenetrant female. Linkage analysis for the 5 known SHFM loci excluded 4 of them; however, a rare insertion polymorphism (rs34201045) at an alternate promoter used for transcription of an N-terminal-truncated p63 isotype (see TP63, 603273) was detected in heterozygosity or homozygosity in all but 1 affected individual.

In a 30-year-old pregnant Swiss woman with SHFM6, who presented for genetic counseling, Blattner et al. (2010) identified a homozygous truncating mutation in the WNT10B gene (601906.0001). Blattner et al. (2010) emphasized that this patient, who presented with apparent sporadic occurrence of the disorder and could have been presumed to have a de novo dominant mutation, was found to be homozygous for the WNT10B mutation, resulting in serious implications for genetic counseling.