ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 S9.2

The expanding spectrum of DAX1 and SF1 mutations

John Achermann


UCL Institute of Child Health, London, UK.


DAX1 (NR0B1) and steroidogenic factor-1 (SF1, NR5A1) are two nuclear receptors that play a central role in adrenal development and disease. DAX1 was discovered as the cause of X-linked adrenal hypoplasia congenita in 1994 and, to date, more than 250 individuals and families with this condition have been reported. Boys tend to present with salt-losing adrenal failure in the neonatal period or with signs and symptoms of glucocorticoid insufficiency throughout childhood. Hypogonadotropic hypogonadism or pubertal arrest occurs at adolescence and impaired spermatogenesis is usually seen. More recently, the phenotypic spectrum associated with DAX1 mutations has been expanded to include apparent isolated mineralocorticoid deficiency, premature sexual maturation in childhood, or delayed-onset milder adrenal failure and partial hypogonadotropic hypogonadism first presenting in adulthood. Furthermore, female heterozygous carriers of DAX1 mutations may show adrenal failure or pubertal delay due to skewed X-inactivation. Thus, DAX1 mutations are a common cause of adrenal hypoplasia in boys, and an almost invariable cause when a family history of X-linked adrenal disease and hypogonadism are present. In contrast, although SF1 is a key regulator of adrenal and development and function in in vivo and in vitro studies, SF1 mutations are not a common cause of severe adrenal dysfunction in humans. To date, three patients with primary adrenal failure (two 46,XY females; one 46,XX female) due to SF1 mutations have been reported. However, haploinsufficiency of SF1 is emerging as a relatively frequent cause of 46,XY DSD (variable testicular dysgenesis and impaired androgenization) or vanishing testis syndrome, and polymorphisms in SF1 have been associated with micropenis or undescended testes. Long-term follow up of adrenal function will be needed in these individuals. Furthermore, somatic copy number changes resulting in overexpression in SF1 are reported in a proportion of paediatric adrenal tumors. Taken together, DAX1 and SF1 play important and diverse roles in human adrenal and reproductive function and variations in these genes can present with a spectrum of endocrine disorders in adulthood as well as in childhood.

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