Mutations of SRY are the cause of complete pure
gonadal dysgenesis (
PGD) in 10-15% of patients. In the remaining individuals, it has been suggested that mutations in other genes involved in the testis-determining pathway could be causative. We describe the first report in which three cases of 46,XY complete
PGD are attributed to mutations of the Desert hedgehog (DHH) gene. DHH was sequenced using genomic
DNA from
paraffin-embedded gonadal tissue from six patients with complete 46,XY
PGD. Mutations were found in three patients: a homozygous mutation in exon 2, responsible for a L162P, and a homozygous 1086delG in exon 3. Mutated individuals displayed 46,XY complete
PGD, differentiating from the only previously described patient with a homozygous DHH mutation, who exhibited a partial form of
PGD with
polyneuropathy, suggesting that localization of mutations influence phenotypic expression. This constitutes the first report where mutations of DHH are associated with the presence of 46,XY complete
PGD, demonstrating that the genetic origin of this entity is heterogeneous and that disorders in other genes, different from SRY, involved in the testis-determining pathway are implicated in abnormal testicular differentiation in humans. These data extend previous reports demonstrating DHH is a key gene in gonadal differentiation.