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Mutations in the Desert hedgehog (DHH) Gene in Patients with 46,XY Complete Pure Gonadal Dysgenesis

Research Unit in Developmental Biology (P.C., D.S., J.P.M.), Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México, Distrito Federal 06725, México; and Department of Pathology (E.R.), Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", México, Distrito Federal 14000, México

Address all correspondence and requests for reprints to: Juan Pablo Méndez, M.D., Unidad de Investigación Médica en Biología del Desarrollo, Coordinación de Investigación en Salud, Coahuila 5, Apartado Postal A-047, Colonia Roma, C.P. 06703, México, D.F., México. E-mail: jpmb{at}servidor.unam.mx.

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 paraffinembedded 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.

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