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X-Linked Adrenal Hypoplasia Congenita: A Mutation in DAX1Expands the Phenotypic Spectrum in Males and Females¹

Reproductive Endocrine Unit, Massachusetts General Hospital (S.B.S., W.F.C.), Boston, Massachusetts 02114; the Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School (J.C.A., J.L.J.), Chicago, Illinois 60611; and the Section of Pediatric Endocrinology, Yale University School of Medicine (M.G.), New Haven, Connecticut 06520

Address all correspondence and requests for reprints to: Stephanie B. Seminara, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 505, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114. E-mail: seminara.stephanie{at}mgh.harvard.edu

X-linked adrenal hypoplasia congenita (AHC) is a disorder associated with primary adrenal insufficiency and hypogonadotropic hypogonadism (HH). The gene responsible for X-linked AHC, DAX1, encodes a member of the nuclear hormone receptor superfamily. We studied an extended kindred with AHC and HH in which two males (the proband and his nephew) were affected with a nucleotide deletion (501delA). The proband’s mother, sister, and niece were heterozygous for this frameshift mutation. At age 27 yr, after 7 yr of low dose hCG therapy, the proband underwent a testicular biopsy revealing rare spermatogonia and Leydig cell hyperplasia. Despite steadily progressive doses of hCG and Pergonal administered over a 3-yr period, the proband remained azoospermic. The proband’s mother, sister (obligate carrier), and niece all had a history of delayed puberty, with menarche occurring at ages 17–18 yr.

Baseline patterns of pulsatile gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the affected males. LH, FSH, and free -subunit were determined during 12.5–24 h of frequent blood sampling (every 10 min). Both patients then received pulsatile GnRH (25 ng/kg) sc every 2 h for 6–7 days. Gonadotropin responses to a single GnRH pulse iv were monitored daily to assess the pituitary responsiveness to exogenous GnRH. In the proband, FSH and LH levels demonstrated a subtle, but significant, response to GnRH over the week of pulsatile GnRH therapy. Free -subunit levels demonstrated an erratic pattern of secretion at baseline and no significant response to pulsatile GnRH.

We conclude that 1) affected males with AHC/HH may have an intrinsic defect in spermatogenesis that is not responsive to gonadotropin therapy; 2) female carriers of DAX1 mutations may express the phenotype of delayed puberty; and 3) although affected individuals display minimal responses to pulsatile GnRH, as observed in other AHC kindreds, subtle differences in gonadotropin patterns may nevertheless exist between affected individuals within a kindred.

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