Nimet Melis BİLEN, Gönül ÇATLI, Cemil KOÇYİĞİT, Bumin Nuri DÜNDAR
The Journal of Pediatric Research - 2026;13(3):209-219
Aim: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by pathogenic variants in the CYP21A2 gene. Although genotype is generally predictive of clinical phenotype, genotype-phenotype discordance may occur. This study aimed to evaluate genotype-phenotype correlations and to characterize the molecular spectrum of CYP21A2 variants in children with CAH. Materials and Methods: In this retrospective single-center study, 22 patients with CAH due to 21-hydroxylase deficiency were included. The patients were classified as salt-wasting (SW), simple-virilizing (SV), or non-classical (NC) according to clinical and hormonal findings. The detected variants were grouped according to their predicted residual enzyme activity, and genotype-phenotype concordance was evaluated. Results: Eight patients (36.4%) had the SW phenotype, six (27.3%) had the SV phenotype, and eight (36.4%) had the NC phenotype. The most frequent variant was I2 splice (c.293-13C>G) (25%), followed by I172N (c.515T>A; p.Ile172Asn) (14.2%). Overall genotype-phenotype concordance was observed in 20 of the 22 patients (90%), and genotype severity groups were significantly associated with the clinical phenotype (p=0.001). One homozygous I172N patient exhibited an unexpectedly mild NC phenotype despite an anticipated SV phenotype. A previously unreported compound heterozygous variant, P30L(c.92C>T)/p.E321Afs*60 (c.961_962delGA), was identified in one patient with the NC phenotype. Conclusion: Our findings demonstrate a strong overall genotype-phenotype correlation in CAH, while also highlighting that patients carrying moderate-severity or novel variants may present with unexpectedly mild or variable clinical phenotypes. Integration of molecular findings with detailed clinical, hormonal, and longitudinal follow-up data remains essential for accurate phenotypic prediction.
