Normal genes for the cholesterol side chain cleavage enzyme, P450scc, in congenital lipoid adrenal hyperplasia

Congenital lipoid adrenal hyperplasia is the most severe form of congenital adrenal hyperplasia. Affected individuals can syn-thesize no steroid hormones, and hence are all phenotypic fe-males with a severe salt-losing syndrome that is fatal if not treated in early infancy. All previous studies have suggested that the disorder is in the cholesterol side chain cleavage en-zyme (P450scc), which converts cholesterol to pregnenolone. A newborn patient was diagnosed by the lack of significant con-centrations of adrenal or gonadal steroids either before or after stimulation with corticotropin (ACTH) or gonadotropin (hCG). The P450scc gene in this patient and in a previously described patient were grossly intact, as evidenced by Southern blotting patterns. Enzymatic (polymerase chain reaction) amplification and sequencing of the coding regions of their P450scc genes showed these were identical to the previously cloned human P450scc cDNA and gene sequences. Undetected compound he-terozygosity was ruled out in the new patient by sequencing P450scc cDNA enzymatically amplified from gonadal RNA. Northern blots of gonadal RNA from this patient contained normal sized mRNAs for P450scc and also for adrenodoxin reductase, adrenodoxin, sterol carrier protein 2, endozepine, and GRP-78 (the precursor to steroidogenesis activator pep-tide). These studies show that lipoid CAH is not caused by lesions in the P450scc gene, and suggest that another unidenti-fied factor is required for the conversion of cholesterol to preg-nenolone, and is disordered in congenital lipoid adrenal hyper-plasia. (J. Clin. Invest. 1991.88:1955-1962.) Key words: preg-nenolone- pseudohermaphroditism * cholesterol desmolase-polymerase chain reaction * sex steroid