Extract

The development of the steroidogenic axis represents a complex system involving multiple, intricately related steps that function in an exquisitely well-timed manner (1). The high frequency with which the networked steps produce a normally formed and functioning hypothalamic-pituitary-adrenal/gonadal axis is a tribute to the robust nature of this complex system. Diseases, such as the adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HHG) associated with DAX-1 mutations (2–5), demonstrate specific sites of vulnerability within the robust network. The complexity of this system also explains the difficulty in precisely predicting phenotype from genotype among DAX-1 mutations, as is true for many other disorders (6–9).

DAX-1 mutations disrupt steroidogenic axis development

AHC may be caused by deletion of the Xp21 DAX-1 gene as part of a contiguous gene syndrome or by intragenic mutations (1, 10). Mutations within the DAX-1 gene showed that AHC and HHG are both caused by alterations in this same gene (2), consistent with the observed expression of DAX-1 throughout the steroidogenic axis (11, 12). Subsequent investigations demonstrated that HHG was due to defects in both hypothalamic and pituitary function (13). DAX-1 may also have a role in spermatogenesis (14–16).

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