Genotype-phenotype associations in non-classical steroid 21-hydroxylase deficiency

Objective: To evaluate whether genotype differences can explain the clinica l variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin. Design: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC 21-OHD (60 min 17-hydroxyprogesterone (17-OHP), 45-386 nmol/l) who were ref erred for evaluation of postnatal virilization or true precocious/ early pu berty. Eleven siblings diagnosed through family screening were genotyped as well. Methods: Patients were divided by genotype into three groups: (A) homozygou s or compound heterozygous for the mild mutations (V281L or P30L) (n=29; ei ght males); (B) compound heterozygous for one mild and one severe mutation (Q318X, 12 splice, I172N) (n=12; no males): (C) mild mutation detected on o ne allele only (n=4; one male; peak 17-OHP 58-151 nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Si nce group C was very small, comparisons were made between groups A and B on ly. Results: At diagnosis, group B tended to be younger (5.8+/-3.0 vs 8.1+/-4.3 years, P = 0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P = 0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62 nmol/l, P<0.01). Gro up B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/ -2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P < 0.001, respectivel y) and a higher rate of precocious puberty (50 vs 17%, P = 0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a posit ive predictive value of 86% for a cut-off of 7.5 years. Conclusions: The findings suggest that genotype might explain some of the v ariability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the t iming and pattern of puberty.