Congenital lipoid adrenal
hyperplasia is the most severe form of
congenital adrenal hyperplasia. Affected individuals can synthesize no
steroid hormones, and hence are all phenotypic females 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 enzyme (P450scc), which converts
cholesterol to
pregnenolone. A newborn patient was diagnosed by the lack of significant concentrations 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 heterozygosity 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
peptide). These studies show that lipoid CAH is not caused by lesions in the P450scc gene, and suggest that another unidentified factor is required for the conversion of
cholesterol to
pregnenolone, and is disordered in congenital lipoid adrenal
hyperplasia.