X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females

J Clin Endocrinol Metab. 1999 Dec;84(12):4501-9. doi: 10.1210/jcem.84.12.6172.


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.

Publication types

  • Case Reports
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Adrenal Insufficiency / genetics*
  • Adrenal Insufficiency / pathology
  • Adrenal Insufficiency / physiopathology
  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins / genetics*
  • Female
  • Follicle Stimulating Hormone / metabolism
  • Genetic Linkage
  • Gonadotropin-Releasing Hormone / administration & dosage
  • Gonadotropin-Releasing Hormone / therapeutic use
  • Humans
  • Luteinizing Hormone / metabolism
  • Male
  • Mutation*
  • Pedigree
  • Periodicity
  • Phenotype*
  • Puberty, Delayed / genetics
  • Receptors, Retinoic Acid / genetics*
  • Repressor Proteins*
  • Spermatogenesis
  • Testis / pathology
  • Testosterone / blood
  • Transcription Factors / genetics*
  • X Chromosome*


  • DAX-1 Orphan Nuclear Receptor
  • DNA-Binding Proteins
  • NR0B1 protein, human
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Transcription Factors
  • Gonadotropin-Releasing Hormone
  • Testosterone
  • Luteinizing Hormone
  • Follicle Stimulating Hormone