SPONTANEOUS FEMINIZATION IN A 46,XX FEMALE-PATIENT WITH CONGENITAL LIPOID ADRENAL-HYPERPLASIA DUE TO A HOMOZYGOUS FRAMESHIFT MUTATION IN THE STEROIDOGENIC ACUTE REGULATORY PROTEIN

The most severe form of congenital adrenal hyperplasia (CAH) is lipoid CAH. It was once thought that this disease was due to mutations in th e cholesterol side-chain cleavage enzyme system, thus eliminating the ability to convert cholesterol to pregnenolone, causing a complete abs ence of steroid hormone production. We recently showed that lipoid CAH is due to mutations in the steroidogenic acute regulatory (StAR) prot ein, thus preventing acutely stimulated adrenal and gonadal responses to tropic stimulation. However, this lesion may permit low levels of S tAR-independent steroidogenesis to persist until the accumulation of i ntracellular lipid deposits destroys steroidogenic capacity. This mode l would predict that the steroidogenic cells of the ovaries of affecte d 46,XX females should remain undamaged until puberty, at which time l ow levels of StAR-independent estrogen biosynthesis should be detectab le. We describe a 15.5-yr-old 46,XX female with a classic history of l ipoid CAH who underwent spontaneous feminization and cyclical vaginal bleeding beginning at age 13. Genetic analysis of the patient and her parents showed that she was homozygous for the novel StAR frameshift m utation 261delT. This is the first adolescent female with lipoid CAH w ho has undergone spontaneous feminization and who has been analyzed ge netically. Finding an inactive StAR gene in this patient confirms our two-hit model of the pathogenesis of lipoid CAH, in which loss of StAR activity initially preserves StAR-independent steroidogenesis, which is lost only after cells undergo chronic tropic stimulation and subseq uent damage from accumulation of cholesterol esters.