Influence of different genotypes on 17-hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

OBJECTIVE The diagnosis of the nonclassical form of 21-hydroxylase (NC-21OH) deficiency, established before molecular studies, is based on basal 17OH-progesterone (17OH-P) values >15 nmol/l or ACTH-stimulated 17OH-P values > 30 nmol/l, This disease is caused by mutations in the structural gene that can be grouped into three categories: A, B and C, according to the predicted level of enzymatic activity, So, the genotype of the nonclassical form is a combination of mutations that cause moderate impairment of enzymatic activity in one allele and mutations which cause total (A), severe (B: 3%) or moderate (C: 20-60%) impairment of enzymatic activity in the other allele, DESIGN We analysed the influence of the different genotypes on 17OH-P levels in 58 patients with the nonclassical form of 21OH deficiency. RESULTS After screening for 18 mutations through Southern blotting, allele-specific polymerase chain reaction (PCR) and enzyme restriction, mutations were identified in 73% of the alleles, Patients with mutations identified in both alleles were divided into groups AIC (n=18), B/C (n=3) and C/C (n=15), The basal and ACTH-stimulated 17OH-P levels in patients with A/C genotype ranged from 1.2 to 153 and 72-363 nmol/l, and in CIC genotype ranged from 0.9 to 72 and 51-363 nmol/l, respectively (P<0.05 for stimulated levels). The lowest value of ACTH-stimulated 17OH-P levels in fully genotyped patients was 51 nmol/l, Patients with the A/C genotype presented androgen excess symptoms earlier than patients with the C/C genotype. CONCLUSIONS These data suggest an influence of genotype on phenotype and on 17OH-P levels, The high frequency of unidentified mutant alleles in nonclassical 21-hydroxylase deficiency suggests that ACTH-stimulated values of 17OH-P between 30 and 51 nmol/l have overestimated this diagnosis. Genotyping more patients with nonclassical 21-hydroxylase deficiency will help to redefine the cut-off value for ACTH-stimulated 17OH-P for correct diagnosis of this disease.