ESPE Abstracts (2014) 82 P-D-2-1-263

Genotype and Phenotype Characteristics of Patients with Nonclassical Congenital Adrenal Hyperplasia due to 21-hydroxylase Deficiency

Nese Akcan Tombalaka, Oya Uygunerb, Guven Toksoyb, Esin Karakilica, Banu Aydina, Firdevs Basa, Nurcin Sakaa, Sukran Poyrazoglua, Ruveyde Bundaka, Hulya Kayserilib & Feyza Darendelilera

aPediatric Endocrine Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; bDepartment of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

Background: Nonclassical congenital adrenal hyperplasia (NCAH), which is generally presented with symptoms of androgen excess, is inherited autosomal recessive due to different kind of mutations in the CYP21A2. Recently, high frequency of copy number variations at CYP21A2 gene and predisposition of heterozygous duplicated CYP21A2 for de novo gene aberrations has been reported.

Objective and hypotheses: To evaluate clinical and moleculer characteristics of the patients with NCAH.

Method: Twenty-one patients (19F, 2M), diagnosed as NCAH according to their clinical, hormonal, and molecular (biallelic or monoallelic mutations) findings, were included. Sequencing and multiplex ligation-dependent probe amplification (MLPA) were used for moleculer analysis.

Results: Mean age of the patients at presentation was 10.5±4.1 (3.1–17.2) years. The presenting symptoms were clinical hyperandrogenemia (hirsutism, acne, and hair loss) (n=10), premature adrenarche (n=6), precocious puberty (n=5), menstrual irregularity (n=2), and cliteromegaly (n=2). Mean of basal and peak 17-OH progesterone levels to ACTH stimulation were 12.8±13.0 and 27.2±19.5 ng/ml respectively. Cortisol responses to ACTH stimulation were normal. Nine different mutations, including one novel were detected in patients. Eight patients carried mutation in a single allele. Two had heterozygous p.Q319X mutation with active gene duplication. One patient carried two different (p.V282L and p.P454S) mutations in a single allele. The p.454S was de novo in cis position according to parental analysis and her father had active gene duplication with p.Q319X mutation which wasn’t inherited. Other patient with homozygous p.V282L also had novel de novo heterozygous p.P214L mutation.

Conclusion: As a result of complex structure of CYP21A2 locus, not only sequencing but also MLPA or southern blood methods should be performed to both patients and parents. Much more comprehensive studies with new genetic methods, including both offsprings and parents, should be designed to exhibit clinical effects of variety of mutations in NCAH.