ESPE Abstracts (2015) 84 P-2-174

Clinical, Biochemical and Molecular Characteristics of the Patients with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency in Croatia

Miroslav Dumica, Nevena Krnicb, Vesna Kusecc, Zorana Grubicd, Katarina Stingld, Tony Yuene, Katja Dumic Kubatb, Veselin Skrabicf & Maria I Newe

aUniversity of Zagreb Medical School, Zagreb, Croatia; bDepartment of Pediatric Endocrinology and Diabetes, Clinical Hospital Centre Zagreb, Zagreb, Croatia; cDepartment of Laboratory Medicine, Endocrinological Laboratory, Clinical Hospital Centre Zagreb, Zagreb, Croatia; dDepartment of Laboratory Medicine, Tissue Typing Centre, Clinical Hospital Centre Zagreb, Zagreb, Croatia; eSteroid Disorder Program, Department od Pediatric Endocrinology, Mount Sinai School of Medicine, New York, NY, USA; fDepartment of Pediatrics, Clinical Hospital Centre Split, Split, Croatia

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.