Diagnosis of X-linked adrenal hypoplasia congenita by mutation analysis of the DAX1 gene.

OBJECTIVE: To develop a rapid diagnostic approach to individuals with the X-linked cytomegalic form of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to mutations in DAX1, a new member of the nuclear hormone receptor gene superfamily.
DESIGN: Molecular genetic diagnostic investigations of individuals with AHC and their relatives included polymerase chain reaction amplification of DAX1 for identification of intragenic mutations and fluorescence in situ hybridization with a cosmid containing the DAX1 gene for evaluation of larger deletions. PARTICIPANTS: Families that had males affected with AHC were evaluated for mutations involving the DAX1 gene.
RESULTS: DAX1 mutations were identified in four families that had males affected with AHC. Two apparently independent pedigrees had an identical frame-shift mutation due to a single base pair deletion, and a third had a larger deletion involving the entire DAX1 locus. The fourth family was evaluated by fluorescence in situ hybridization for prenatal diagnosis, and both the DAX1 locus and the contiguous glycerol kinase region were deleted.
CONCLUSIONS: Molecular genetic and molecular cytogenetic techniques represent rapid and complementary approaches to the diagnosis of mutations in the DAX1 gene responsible for AHC and the associated HH. Specific diagnosis of the cause of adrenal insufficiency in these boys permits anticipatory management of the HH and prenatal counseling for parents of the affected child and other members of their families.