Syndactyly, Type Iii

A number sign (#) is used with this entry because of evidence that isolated syndactyly type III is caused by heterozygous mutation in the GJA1 gene (121014) on chromosome 6q22. Syndactyly type III is the characteristic digital anomaly in oculodentodigital dysplasia (ODDD; 164200, 257850), which is also caused by mutation in the GJA1 gene.

Clinical Features

In syndactyly type III, there is usually complete and bilateral syndactyly between the fourth and fifth fingers. Usually it is soft tissue syndactyly but occasionally the distal phalanges are fused. The fifth finger is short with absent or rudimentary middle phalanx. The feet are not affected. The family reported by Johnston and Kirby (1955) was one of the largest fully described pedigrees, involving 7 affected males and 7 affected females over 5 generations in a pattern compatible with autosomal dominant inheritance (Temtamy and McKusick, 1978).

McKusick (1986) observed soft-tissue syndactyly of fingers IV and V in a mother and syndactyly with some bony fusion of fingers III, IV, and V bilaterally in her son. In the Johnston and Kirby (1955) pedigree, 1 person had syndactyly of all 3 fingers.

McKiernan and McCann (1993) reported a 4-generation family with 14 affected members and several instances of male-to-male transmission.

De Smet et al. (1994) reported 5 patients with syndactyly of the ring and small fingers as an isolated malformation; 3 of the patients had affected relatives in a pattern consistent with autosomal dominant inheritance. In 2 instances, a person who seemed to represent a skipped generation showed clinodactyly of the fifth finger with no syndactyly. There was 1 instance of male-to-male transmission.

Brueton et al. (1990) described a family with type III syndactyly and a facial phenotype resembling that of oculodentodigital dysplasia but without any of the other characteristic ocular and dental features. They noted that Temtamy and McKusick (1978) had reported an isolated patient who had a peculiar facies with small, widely spaced eyes, raising the possibility of ODDD even in the absence of ocular or dental abnormalities. Gladwin et al. (1997) included the family of Brueton et al. (1990) in their linkage study which yielded results consistent with location of the gene in 6q22-q24 where the gene for ODDD syndrome was assigned. They raised the possibility that isolated type III syndactyly and the ODDD syndrome may be caused by mutation in the same gene.

Molecular Genetics

Paznekas et al. (2003) screened 17 families with oculodentodigital dysplasia and found mutations in the GJA1 gene (see 121014.0003-121014.0007) in all. All of their probands had syndactyly of at least the fourth and fifth fingers. In 4 individuals with sporadic disease, there was syndactyly type III (involvement of only the fourth and fifth fingers) and different missense mutations in the first transmembrane domain, including gly21 to arg (121014.0005) and gly22 to glu (121014.0006). Two of the multiplex families studied by them had a proband with syndactyly type III but had other affected family members with additional digital involvement and mutations in domains beyond the first transmembrane. The data were taken to support the view that ODDD and 'isolated' syndactyly type III represent a disease spectrum rather than separate genetic conditions (Schrander-Stumpel et al., 1993). Paznekas et al. (2003) noted that connexin-43 is strongly expressed in the distal part of early limb buds and has an expression pattern restricted to the developing digits and regions of precartilage condensation, as shown by studies in Xenopus, mouse, and chick.

In affected members of the family reported by Brueton et al. (1990) with type III syndactyly and a facial phenotype resembling that of ODDD but without any of the usual ophthalmologic, dental, or skeletal features commonly reported in that disorder, Richardson et al. (2004) identified a 427G-A transition in the GJA1 gene, resulting in a gly143-to-ser mutation (121014.0008) in the cytoplasmic loop of the protein.