Endocrine Abstracts

Transcription factors play an important role in the development and function of the hypothalamic-pituitary adrenal (HPA) axis at multiple levels. Mutations in several of these factors have now been described in patients with primary and secondary forms of congenital adrenal hypoplasia. Secondary adrenal hypoplasia results from defective ACTH release and action. This condition can occur as part of a combined pituitary hormone deficiency due to mutations in the homeobox transcription factor, HESX1, or as isolated ACTH deficiency following mutations in the T-box factor, Tpit. Primary adrenal hypoplasia congenita (AHC) occurs in X-linked and autosomal forms. X-linked AHC results from mutations in the atypical orphan nuclear receptor, DAX1 (NR0B1). More than 100 DAX1 mutations have been identified. Affected boys usually present with primary adrenal failure in early infancy or childhood. Hypogonadotropic hypogonadism is an integral part of this condition and studies of the Dax1 (Ahch) knockout mouse have revealed impaired spermatogenesis. Variant adult-onset forms of X-linked AHC have been recognized recently, which result from milder disturbances of DAX1 function. The related orphan nuclear receptor steroidogenic factor-1 (SF1, NR5A1) regulates the transcription of many target genes involved in adrenal development, steroidogenesis and reproduction. Recently, mutations in the gene encoding SF1 have been described in patients with 46XY sex-reversal, primary adrenal insufficiency and Mullerian structures, and in a girl with isolated primary adrenal insufficiency. The study of naturally-occurring mutations is providing insight into critical domains of these transcription factors, as well as the importance of functional gene dosage effects in developmental endocrinology.