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

N. Weintrob*, C. Brautbar, A. Pertzelan, Z. Josefsberg, Z. Dickerman, A. Kauschansky, P. Lilos, D. Peled, M. Phillip, S. Israel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


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.

Original languageEnglish
Pages (from-to)397-403
Number of pages7
JournalEuropean Journal of Endocrinology
Issue number3
StatePublished - 2000
Externally publishedYes


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