title: Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita.
abstract: 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.
authors.affiliation: Institute of Endocrine Sciences, Inc., Ospedale Maggiore IRCCS and Istituto Auxologico Italiano, 20122 Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
authors.forename: Gokhan
authors.initials: G
authors.lastname: Ozisik
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Roberto
authors.initials: R
authors.lastname: Romoli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Borretta
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
authors.forename: Anna
authors.initials: A
authors.lastname: Spada
authors.forename: J Larry
authors.initials: JL
authors.lastname: Jameson
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
mesh_terms: D000311:Adrenal Glands / Q000002:abnormalities*; D000309:Adrenal Insufficiency / Q000150:complications; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D000595:Amino Acid Sequence; D017124:Conserved Sequence; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D005817:Genetic Counseling; D006801:Humans; D007006:Hypogonadism / Q000097:blood / Q000209:etiology* / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D018168:Receptors, Retinoic Acid / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000097:blood / Q000737:chemistry / Q000235:genetics*; D014960:X Chromosome
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; C539966:Nr0b1 protein, mouse; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D000324:Adrenocorticotropic Hormone