Lessons from congenital lipoid adrenal hyperplasia

Congenital lipoid adrenal hyperplasia (lipoid CAH) is the most severe of the CAH syndromes, eliminating virtually all adrenal and gonadal steroid hormone synthesis. Previously regarded as a rare, esoteric condition, lipoid CAH has recently received considerable attention since the discovery that lipoid CAH was caused by mutations in the gene for the steroidogenic acute regulatory protein (StAR), and the demonstration that the disease is fairly common in Japan. Clinical studies of lipoid CAH substantially illuminated the biology of the StAR protein, as lipoid CAH constitutes a StAR gene knockout experiment of nature. Studies of lipoid CAH showed that steroidogenic cells employ both StAR-dependent and StAR-independent modes of steroidogenesis. This in turn indicated that the lipoid CAH phenotype was due to two events: first, a loss of StAR-dependent steroidogenesis led to diminished steroidogenesis and to cellular accumulation of cholesterol esters; second, cellular damage caused by this accumulation eliminated StAR-independent steroidogenesis. This two-hit model of lipoid CAH explains the variable onset of salt loss and the presence of apparently normal pubertal feminization in affected 46,XX females. However, the mechanism of StAR's action to promote the flow of cholesterol into mitochondria remains unknown.