A microdeletion within DAX-1 in X-linked adrenal hypoplasia congenita and hypogonadotrophic hypogonadism

Background: X-linked adrenal hypoplasia congenita (AHC) is a developmental disorder characterized by primary adrenal gland failure, which produces ext reme and potentially fatal endocrine deficiencies. Hypogonadotrophic hypogo nadism (HHG) also may be associated with AHC, AHC has been shown to result from a variety of mutations in the DAX-1 gene, which encodes a member of th e nuclear hormone receptor superfamily, Methods: The proband, one of the world's oldest living patients with AHC an d HHG, was diagnosed in 1955, He was on corticosteroid replacement therapy since that time and androgen replacement therapy since puberty. We sequence d his DAX-1 gene. Results: We found a 4 bp ACTC deletion between nucleotides 1464 and 1467 in the second exon of the normal DAX-1 sequence, This mutation caused a shift in the reading frame and predicted a premature stop codon at amino acid po sition 416, The mutation abolished a recognition site for DdeI, allowing fo r confirmation by restriction analysis. Conclusions: The position of the mutation confirms the functional importanc e of the COOK-terminal 10% of the DAX-1 sequence, The clinical history also reinforces the importance of early diagnosis in AHC, which can be associat ed with longevity and no obvious morbidity after more than 40 years of horm one replacement therapy.