General Medical Information

Congenital Adrenal Lipoid Hyperplasia

Joe Leigh Simpson

In congenital adrenal lipoid hyperplasia, male pseudohermaphrodites show ambiguous or female-like external genitalia and severe sodium wasting. Adrenals are characterized by foamy-appearing cells filled with cholesterol. Accumulation of cholesterol has long indicated that cholesterol cannot be converted to pregnenolone. Inheritance has been presumed to be autosomal recessive on the basis of increased parental consanguinity.

The cytochrome P450 enzyme responsible for converting cholesterol to pregnenolone is P450scc (side chain cleavage); the gene is CYP11A. P450scc converts cholesterol to pregnenolone via 20a-hydroxylase, 22a-hydroxylase, and 20,22-desmolase. A large gene located on chromosome 15, CYP11A is 20 kb long and has nine exons.

Surprisingly, perturbations of this gene have never been shown in congenital adrenal lipoid hyperplasia. Rather, congenital adrenal lipoid hyperplasia results from perturbation of the steroidogenic acute regulatory (StAR) protein. The StAR protein delivers precursors for cholesterol side chain cleavage, and predictably its perturbation would have major effects of hormone action in gonads and adrenals. Mapped to 8p11.2, the gene spans 8 kb and consists of seven exons interrupted by six introns. Mutations in StAR have been reported in congenital lipoid hyperplasia, producing a nonfunctional protein. Typically a point mutation produces stop codons or exon/intron splicing errors that yield large deletions or truncated gene products.