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Hypogonadotropic Hypogonadism as a Presenting Feature of Late-Onset X-Linked Adrenal Hypoplasia Congenita

Institute of Endocrine Sciences, Inc. (G.M., R.R., L.P., A.S., P.B.-P.), Ospedale Maggiore IRCCS and Istituto Auxologico Italiano, 20122 Milan, Italy; Division of Endocrinology, Metabolism, and Molecular Medicine (G.O., J.C.A., J.L.J.), Northwestern University Medical School, Chicago, Illinois 60611; Institute of Child Health and Department of Medicine (J.C.A.), University College London, London, WC1N 1EH, United Kingdom; and Endocrinologia (G.B.), Ospedale S. Croce e Carle, 12100 Cuneo, Italy

Address all correspondence and requests for reprints to: Paolo Beck-Peccoz, M.D., Ph.D., Istituto di Scienze Endocrine-Università di Milano Padiglione Granelli, Via F. Sforza, 35, 20122 Milan, Italy. E-mail: paolo.beckpeccoz{at}unimi.it

Mutations in the orphan nuclear receptor DAX-1 cause X-linked adrenal hypoplasia congenita. Affected boys usually present with primary adrenal failure in early infancy or childhood. Impaired sexual development because of hypogonadotropic hypogonadism becomes apparent at the time of puberty. We report adult-onset adrenal hypoplasia congenita in a patient who presented with hypogonadism at 28 yr of age. Although he had no clinical evidence of adrenal dysfunction, compensated primary adrenal failure was diagnosed by biochemical testing. Semen analysis showed azoospermia, and he did not achieve fertility after 8 months of treatment with gonadotropins. A novel Y380D DAX-1 missense mutation, which causes partial loss of function in transient gene expression assays, was found in this patient. This case demonstrates that partial loss-of-function mutations in DAX1 can present with hypogonadotropic hypogonadism and covert adrenal failure in adulthood. Further, an important role for DAX-1 in spermatogenesis in humans is confirmed, supporting findings in the Dax1 (Ahch) knockout mouse.

This work was partially supported by MURST-Rome (9906153187), Fondi Ricerca Corrente-IRCCS, and Research Funds of Istituto Auxologico Italiano IRCCS (project no. 05C801). This work was also performed as part of the National Cooperative Program for Infertility Research and was supported by NIH Grants U54-HD-29164 and PO1 HD-21921 and by General Clinical Research Center Grant MO1-RR-00048.

Abbreviations: AHC, Adrenal hypoplasia congenita; DBD, DNA-binding domain; Egr-1, early growth response-1; HHG, hypogonadotropic hypogonadism; LBD, ligand-like binding domain.

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