Endocrine Abstracts

In humans, the adrenal gland develops from the intermediate mesoderm at around 4 weeks gestation and undergoes a series of distinct morphological and functional changes throughout pre- and post-natal life. Two key transcriptional regulators of adrenal development are the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1, Ad4BP). Mutations or deletions of DAX-1 result in X-linked adrenal hypoplasia congenita (AHC). Boys with this condition typically present with salt-losing adrenal failure in early infancy or throughout childhood and show evidence of hypogonadotropic hypogonadism (HH) and impaired spermatogenesis in adolescence. DAX-1 mutations are a relatively frequent cause of adrenal hypoplasia in males, especially with a family history of X-linked adrenal failure or when HH is present. Alternative presentations of X-linked AHC include isolated mineralocorticoid insufficiency, premature sexual maturation, adrenal hypoplasia in girls with skewed X-inactivation and adult-onset adrenal failure/HH. Despite this clinical insight, the molecular aetiology of X-linked AHC remains poorly understood. The related nuclear receptor SF-1 regulates transcription of many key target genes involved in adrenal development and function. Partial loss of SF-1 function more frequently results in 46,XY DSD or primary ovarian insufficiency, but in most cases adrenal reserve is normal. Syndromic causes of adrenal hypoplasia include changes in sonic hedgehog (SHH), WNT4 (causing SERKAL syndrome), and IMAGe syndrome (IUGR, skeletal anomalies, adrenal hypoplasia and mild genital features). Pbx1 and Cited2 are implicated in adrenal development in mice, but no significant changes in these factors have been found in humans with adrenal hypoplasia. The search continues, therefore, for new transcriptional regulators and networks that account for adrenal hypoplasia where the cause is currently unknown.