Objective: It has been hypothesized that carriers of CYP21 mutations are at increased risk of developing clinically evident hyperandrogenism. In the present study, we assessed the risk for symptoms of androgen excess in carriers of CYP21 gene mutations and the effect of different mutations on phenotype.
Design: All subjects underwent clinical evaluation, ACTH stimulation testing, and molecular analysis of the CYP21 gene.
Patients: One hundred and eighty-seven subjects were included in the study. Five groups were defined according to genotype: A, 38 patients with classical-congenital adrenal hyperplasia (CAH); B, 16 patients with non classical CAH; C, 66 family member carriers; D, 24 children and adolescents with symptoms suggestive of hyperandrogenism who were found to be heterozygous and E, 43 subjects with androgen excess symptoms who had normal genotype.
Measurements: Cortisol and 17-hydroxyprogesterone (17OHP) were measured basally and 60 min after ACTH stimulation. Analysis of seven common mutations of the CYP21 gene, which collectively cover 95% of the mutations in the Israeli population, was performed. The hormonal results were correlated with the genotype.
Results: The symptomatic carriers had a significantly higher rate of the mild mutation V281L compared with the family members (58% vs. 22%) and significantly higher levels of ACTH-stimulated 17OHP (mean 37.2 and 21 nmol/l, respectively; P = 0.025). Higher values of peak 17OHP levels were found in the carriers of the V281L mutation compared with carriers of other mutations (P = 0.025). Stimulated 17OHP levels were significantly higher in carriers compared with normal genotype subjects (P < 0.0001).
Conclusions: Our findings are the first to show that there is increased risk of androgen excess in carriers of CYP21 mutations and that the risk is related to genotype. Carriers for the mild, V281L mutation, are at higher risk of symptoms of androgen excess than carriers of the severe mutations. It appears that the variable phenotypes can be at least partially attributed to the degree of impairment of enzyme activity in different mutations. The severe consequences of hyperandrogenism in some of the carrier subjects indicate the need for long-term follow-up in these patients.