Mild brachydactyly type A1 maps to chromosome 2q35-q36 and is caused by a novel IHH mutation in a three generation family.

The brachydactylies are a heterogeneous group of inherited digital abnormalities originally classified into five types, on the basis of malformation of the digits. Among them, brachydactyly type A1 (BDA-1, MIM 112500), also referred to as Farrabee or Fitch type 9, is mainly characterised by short middle phalanges, which may be fused to the terminal ones. 2 All the small tubular bones tend to be reduced in size, but the middle phalanges are the most severely shortened. Several phenotypes have been described for this disease. BDA-1 may occur as an isolated condition or maybe associated with other manifestations. Patients often have short stature and additional features, such as radial and/or ulnar clinodactyly, malformed or absent epiphyses, scoliosis, abnormal menisci, and club feet. 4 Some patients also showed mental retardation, nystagmus, squint, and sixth nerve palsy. 6 Despite the fact that BDA-1 has been identified as a Mendelian disorder since 1903, until recently few molecular genetic studies on this malformation have been performed. Several candidate genes including MSX1, MSX2, FGF1, FGF2, and the HOXD gene cluster have been excluded for this autosomal dominant disease. In 2000, a linkage study performed in two large Chinese families mapped the locus for BDA-1 to chromosome 2q35-q36 and subsequent analysis in the same families identified mutations in the Indian hedgehog gene (IHH) in affected subjects. The IHH gene lies within the critical region on chromosome 2q35-q36, and codes for a signalling molecule that is known to mediate condensation, growth, and differentiation of cartilage. To date, there have been no other reports linking IHH mutations to BDA-1. Moreover, the affected subjects who showed a mutation in the IHH gene had physical manifestations beyond those described in BDA-1 by Fitch, and a recent study in a family with typical features of BDA-1 identified the presence of a novel locus on chromosome 5p13.3-p13.2. Thus, the different BDA-1 phenotypes might be the result of locus heterogeneity. In this study we report a family affected by a mild form of BDA-1 with a novel mutation in the IHH gene.