Genotype and hormonal phenotype in nonclassical 21-hydroxylase deficiency

In nonclassical steroid 21-hydroxylase deficiency, the genotype may be represented as a homozygous mild (nonclassical) form of the 21-hydroxylase defect or as a compound heterozygote, with one severe (classical) and one mild (nonclassical) 21-hydroxylase deficiency allele. We examined hormone levels in patients with nonclassical 21-hydroxylase deficiency in whom pedigree analysis and/or HLA linkage disequilibrium allowed unequivocal identification of the respective haplotypes as either classical or nonclassical. The results indicated that compound heterozygotes (21-OH defsevere/21-OH defmild) have an ACTH-stimulated 17-hydroxyprogesterone (17-OHP) response significantly greater than that of mild homozygotes (21-OH defmild/21-OH defmild): at 60 min, 8,131 +/- 4,205 (+/-SD) (n = 17) vs. 4,468 +/- 2,123 ng/dl (n = 31) for the respective groups (P less than or equal to 0.01); at 360 min, 11,067 +/- 5,582 (n = 17) vs. 5746 +/- 1565 (n = 8, P less than or equal to 0.01). Since serum cortisol levels were the same in both groups, the ratio of 17-OHP to cortisol was higher in the former group. Sixty minute ACTH-stimulated serum delta 4-androstenedione levels also were significantly higher in compound heterozygotes than in mild homozygotes. Serum dehydroepiandrosterone and its sulfate were not significantly different between the two groups. Notably, compound heterozygotes were no more likely to have signs of androgen excess than were homozygotes for the mild gene defect. Stimulated levels of serum 17-OHP, 17-OHP/cortisol, delta 4-androstenedione and dehydroepiandrosterone and its sulfate did not differ significantly between heterozygotes for the classical (21-OH defsevere/21-OHnormal) and nonclassical (21-OH defmild/21-OHnormal) 21-hydroxylase deficiency alleles. Thus, the presence of a single normal 21-hydroxylase allele is sufficient to obscure the difference between a severe and a mild 21-hydroxylase deficiency allele on the opposite haplotype. We conclude that the compound heterozygous patients as a group have a significantly higher response of 21-hydroxylase precursors to ACTH stimulation than do patients with the homozygous mild 21-hydroxylase deficiency state.