title: X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females.
abstract: 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 alpha-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 alpha-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.
authors.affiliation: Reproductive Endocrine Unit, Massachusetts General Hospital, Boston 02114, USA. seminara.stephanie@mgh.harvard.edu
authors.forename: S B
authors.initials: SB
authors.lastname: Seminara
authors.forename: J C
authors.initials: JC
authors.lastname: Achermann
authors.forename: M
authors.initials: M
authors.lastname: Genel
authors.forename: J L
authors.initials: JL
authors.lastname: Jameson
authors.forename: W F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism; D008040:Genetic Linkage; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000627:therapeutic use; D006801:Humans; D007986:Luteinizing Hormone / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D010507:Periodicity; D010641:Phenotype; D011628:Puberty, Delayed / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D012097:Repressor Proteins; D013091:Spermatogenesis; D013737:Testis / Q000473:pathology; D013739:Testosterone / Q000097:blood; D014157:Transcription Factors / Q000235:genetics*; D014960:X Chromosome
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D014157:Transcription Factors; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone