Background: Nonclassical congenital adrenal hyperplasia (NCCAH) due to mild 21-hydroxylase deficiency is caused by mutations of the CYP21A2 gene located on chromosome 6p21.3.
Objective and hypotheses: To determine cut-off for basal and stimulated 17-hydroxyprogesterone (17-OHP) levels, to evaluate CYP21A2 gene mutations frequency among Croatian NCCAH patients, to determine correlation between 17-OHP levels and genotype and to evaluate correlation between 17-OHP levels, CYP21A2 gene mutations and phenotype.
Method: A cohort of 49 patients (38 unrelated) with NCCAH (31 females/18 males) was studied (eight female/14 male patients discovered through family studies). The subjects were evaluated for signs of hyperandrogenism, basal and ACTH-stimulated 17-OHP levels were measured and CYP21A2 gene molecular analysis were performed.
Results: The 17-OHP cut-off levels of best sensitivity and specificity are 8.8 nmol/l for baseline and 39.2 nmol/l for ACTH stimulated 17-OHP levels. Only one patient had baseline 17-OHP levels below 6 nmol/l. Among 40 fully genotyped patients, 12 carried two mild CYP21A2 mutations, 27 were compound heterozygotes for one mild and one severe mutation, and one had two severe mutations (I172N/ I2G). The commonest mutation in our study group is pV281L (83.87%) and 70.87% patients carry one moderate/severe mutation. Genotype severity did not correlate with 17-OHP levels. No correlation was found between phenotype and 17-OHP levels or grading of genotype.
Conclusion: Patients with basal 17-OHP levels above 8.8 nmol/l should be further evaluated for NCCAH. Phenotype and 17-OHP levels do not correlate with severity of genotype suggesting that modifier factors my modulate phenotypic expression. Thus molecular analysis of CYP21A2 gene should be done in all patients, especially due to high frequency of patients with one moderate/severe mutation. Considering the high incidence of heterozygotes in the general population, it is important to genotype the partners of the patients with one severe mutation to offer genetic counselling.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology