Genotype and phenotype charasterictics of patients with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Abstract

Background: Nonclassical congenital adrenal hyperplasia(NCAH), which is generally presented with symptoms ofandrogen excess, is inherited autosomal recessive due to differentkind of mutations in the CYP21A2. Recently, high frequency ofcopy number variations at CYP21A2 gene and predisposition ofheterozygous duplicated CYP21A2 for de novo gene aberrationshas been reported. Objective and hypotheses: To evaluateclinical and moleculer characteristics of the patients with NCAH.Method: Twenty-one patients (19F, 2M), diagnosed as NCAHaccording to their clinical, hormonal, and molecular (biallelic ormonoallelic mutations) findings, were included. Sequencing andmultiplex ligation-dependent probe amplification (MLPA) wereused for moleculer analysis. Results: Mean age of the patientsat presentation was 10.5G4.1 (3.1–17.2) years. The presentingsymptoms were clinical hyperandrogenemia (hirsutism, acne, andhair loss) (nZ10), premature adrenarche (nZ6), precociouspuberty (nZ5), menstrual irregularity (nZ2), and cliteromegaly(nZ2). Mean of basal and peak 17-OH progesterone levels toACTH stimulation were 12.8G13.0 and 27.2G19.5 ng/mlrespectively. Cortisol responses to ACTH stimulation werenormal. Nine different mutations, including one novel weredetected in patients. Eight patients carried mutation in a singleallele. Two had heterozygous p.Q319X mutation with active geneduplication. One patient carried two different (p.V282L andp.P454S) mutations in a single allele. The p.454S was de novo in cisposition according to parental analysis and her father had activegene duplication with p.Q319X mutation which wasn’t inherited.Other patient with homozygous p.V282L also had novel de novoheterozygous p.P214L mutation. Conclusion: As a result ofcomplex structure of CYP21A2 locus, not only sequencing but also MLPA or southern blood methods should be performed to bothpatients and parents. Much more comprehensive studies withnew genetic methods, including both offsprings and parents,should be designed to exhibit clinical effects of variety of mutationsin NCAH.