A novel duplication in the HOXA13 gene in a family with atypical hand-foot-genital syndrome.

Hypospadias, when the urethral opening is located on the ventral side of the penis, is one of the most common congenital malformations with an incidence of 3 per 1000 males. Hypospadias is considered a complex trait caused by several genetic and environmental factors; low birth weight, for example, is associated with an increased risk for hypospadias. Most cases of hypospadias are sporadic but about 10% of the boys have a relative with the malformation. 6–9 There are families with an autosomal dominant inheritance pattern of hypospadias. 10 Hypospadias is also a manifestation in some rare single gene traits affecting sex differentiation, for example, the X linked partial androgen insensitivity syndrome and the recessive 5-alpha-reductase deficiency. However, these syndromes are characterised by severe hypospadias in association with other genital malformations such as cryptorchidism, bifid scrotum, and penoscrotal transposition. Hand-foot-genital syndrome (HFGS) is an autosomal dominant syndrome that may include hypospadias. 15 HFGS is characterised by skeletal anomalies and urogenital malformations. The skeletal manifestations affect the distal limbs and include short, proximally placed thumbs with hypoplastic thenar eminences, ulnar deviation of the second finger, clinodactyly of the fifth finger, short, medially deviated halluces, brachydactyly of the second to fifth toes, and shortening of the carpals and tarsals. Typical urogenital abnormalities in females are bicornuate uterus, vaginal septum, and ectopic localisation of ureteric and urethral orifices. Vesicoureteral reflux and ureteropelvic obstruction has been observed in females as well as in males. The syndrome was initially called hand-foot-uterus syndrome by Stern et al, but the observation of hypospadias in some affected males prompted the change of nomenclature. 19 The most specific finding in HFGS is the typical radiographic pattern described by Poznanski et al. In the hands, this includes a shortened metacarpal, a pointed distal phalanx, and pseudoepiphysis of the metacarpal bones in the thumb. In the feet, metatarsal 1 and proximal phalanx 1 are short and the big toe deviates medially or, less commonly, laterally. Incomplete ossification and fusion of tarsal bones are also seen. Overall, the skeletal manifestations are invariable and highly penetrant, whereas the urogenital abnormalities show reduced penetrance and variable expression. Eight families and four sporadic cases with characteristic features of HFGS have been described so far. 20–28 The phenotype varies both within and between these families. In 1997, it was reported that HFGS is caused by mutations in the HOXA13 gene. The following mutations in HOXA13 have been found in seven HFGS families: four different nonsense mutations (W369X, S136X, Q196X, and Q365X), one missense mutation (N372H), and two in frame insertions of 24 and 18 bp respectively. 23 26 29 In addition, an interstitial deletion removing the entire HOXA cluster was found in the family reported by Devriendt et al. The insertions are both located in the last of three polyalanine tracts in the first exon and result in additional polyalanines. Similar polyalanine tract expansions have been described in HOXD13 in several families with synpolydactyly. The insertions in HOXA13 and HOXD13 consist of cryptic expansions (GCA, GCC, GCG, GCT) rather than trinucleotide repeats, are stable through generations, and are believed to have originated through unequal crossing over. Three additional families with atypical features of HFGS have been described. However, there are divergences from the classical description making the diagnosis less probable, as pointed out by Utsch et al. Nevertheless, in the family reported as Guttmacher syndrome also including polydactyly, both a missense mutation in the homeobox region of the HOXA13 gene and a dinucleotide deletion in the promoter was found. In the family with Müllerian duct fusion defects and ear malformations reported by Goodman et al, no mutation in the HOXA13 gene was found. The genetic basis for the syndrome described by Longmuir et al with mainly distal skeletal malformations has not been addressed. The mutations in HOXA13 and HOXD13, together with a mutation in HOXA11 resulting in amegakaryocytic thrombocytopenia and radioulnar synostosis, are the only mutations in HOX genes described in man to date. Characteristically, these abnormalities are discrete and may easily escape medical attention. We report the identification of a novel mutation in the HOXA13 gene in a six generation family originally ascertained Key points