Pediatric Urology Association of Hypospadias with Hypoplastic Synpolydactyly and Role of HOXD13 Gene Mutations Emre Tüzel, Hale S ¸ amlı, ˙ Ilhami Kuru, Seval Türkmen, Yavuz Demir, Gökhan Maralcan, and Cem Güler 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 unaf- fected 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. UROLOGY 70: 161–164, 2007. © 2007 Elsevier Inc. S ynpolydactyly (SPD) is a rare limb malformation that mainly affects the third and fourth fingers of the hands and the fifth toes of the feet. The mal- formation is inherited as an autosomal dominant trait, with variable expressivity and incomplete penetrance. 1 A large remarkable kindred from an isolated village in rural Turkey with 182 affected individuals having varying forms of SPD phenotype was first described in 1995. 1,2 The skeletal anomalies detected in the kindred were investigated in detail and published in recent years. 1–5 Of the affected individuals, some had more severe hand and feet deformities with less phenotypic variation than did others affected within the same kindred. 1,3 That severe form of deformity was described as a homozygote pheno- type. 1 This is an extremely rare condition that resulted from the marriage of two affected heterozygote parents. Such marriages produced homozygous offspring with SPD who inherit the deformity from both of their affected parents. Those homozygote children’s deformities were always very different from those of heterozygotes or those of the parents’ and has been termed hypoplastic SPD. 3 Along with the first description, the interesting kin- dred has been enlarging and developing different pheno- types with new affected members. The kindred has re- cently been reinvestigated by our physician team when the high incidence of hypospadias among affected males, especially in the homozygous individuals, was observed. The aim of this study was to present the interesting association of hypospadias with hypoplastic SPD and discuss the molecular genetic basis of this condition. MATERIAL AND METHODS The village in which the affected people have been living for the past 140 years was visited, and the large kindred was reinvestigated by our physician team. The affected and unaf- fected subjects were interviewed, and the pedigrees of the most From the Departments of Urology, Medical Biology and Genetics, Orthopedics, and Plastic Surgery, Afyon Kocatepe University School of Medicine, Afyon, Turkey; and Institute for Medical Genetics, Humboldt University, Berlin, Germany Reprint requests: Emre Tüzel, M.D., Department of Urology, Afyon Kocatepe University School of Medicine, Ordu Bulvarı Bereket Apt. No17/5 Kat. 2, Afyon 03200, Turkey. E-mail: emretuzel@aku.edu.tr Submitted: October 22, 2006; accepted (with revisions): March 5, 2007 © 2007 Elsevier Inc. 0090-4295/07/$32.00 161 All Rights Reserved doi:10.1016/j.urology.2007.03.013