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

Abstract

Objective: To evaluate whether genotype differences can explain the clinical 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 NC21-OHD (60 min 17-hydroxyprogesterone (17-OHP), 45-386 nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well. Methods: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P3OL) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one 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. Since group C was very small, comparisons were made between groups A and B only. 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). Group 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, respectively) 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 positive predictive value of 86% for a cut-off of 7.5 years. Conclusions: The findings suggest that genotype might explain some of the variability 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 timing and pattern of puberty.