Association of hypospadias with hypoplastic synpolydactyly and role of hoxd13 gene mutations

Objectives To present the association of hypospadias with hypoplastic synpolydactyly and discuss the molecular genetic basis of these conditions. Methods A large synpolydactyly kindred first described in 1995 was reinvestigated. Affected and unaffected subjects were interviewed, and pedigrees of the most recent generations were constructed. The marriages of two affected individuals were identified. The siblings who were homozygous for the deformity were asked to attend our institution and underwent a detailed clinical evaluation. Genetic studies and mutation screening were performed using polymerase chain reaction on genomic DNA extracted from venous blood. Results Of the 245 members of the kindred, 125 individuals were affected. Of these 125 individuals, 12 were homozygotes (6 females and 6 males) with a mean age of 12 years. The remaining 113 individuals (57 females and 56 males) were heterozygotes showing milder limb deformities. No sex-related phenotypic difference was found in the extremity findings, but all the males with a homozygote pattern had hypospadias. Three had distal penile, two had mid-shaft, and one had penoscrotal hypospadias. Of the affected 56 heterozygote males, 22 were also noted to have distal hypospadias in various forms. Neither the heterozygote nor the homozygote females had any genital anomalies. The laboratory tests and karyotype profiles of these individuals were normal. Mutation screening of the homozygote subjects revealed a polyalanine duplication band of nine additional alanine residues at the human HOXD13 gene. Conclusions These findings strongly suggest that specific mutations in HOXD13 gene may cause both hypoplastic synpolydactyly and hypospadias.