Molecular analysis and genotype-phenotype correlations in patients with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency from southern Poland — experience of a clinical center

Abstract

Purpose The prevalence of CYP21A2 gene variants and genotype-phenotype correlations are variable among populations. The aim of this study was to characterize CYP21A2 gene variants in adult patients with classical congenital adrenal hyperplasia (CCAH) from southern Poland and to analyze genotype-phenotype correlations. Materials/Methods A total of 48 patients (30 women and 18 men) with CCAH were included in the study. Patients were divided into two clinical subgroups, namely, salt-wasting (SW) — 38 patients and simple virilizing (SV) — 10 patients. A genetic analysis MLPA (multiplex ligation-dependent probe amplification) was performed in all of them. In dubious cases, the analysis was complemented by Sanger sequencing. Genotypes were classified into five groups (depending on the residual in vitro enzymatic activity), namely, null, A, B, C, and D, and correlated with the clinical picture. Results Molecular defects were investigated and identified in 48 patients. The most common variant in the studied group was I2G, followed by whole or partial gene copy deletion, and I172N. One novel variant c.[878G>T] (p.Gly293Val) was found. In nine patients, a non-concordance between genotype and phenotype was observed. Genotype-phenotype correlations measured by positive predictive value (PPV) were as follows: 100% in group null, 90.5% in group A, and 66.7% in group B. Conclusions CYP21A2 variants in the studied cohort were similar to values previously reported in other countries of the region. There was a good correlation between genotype and phenotype in the null and A groups, the correlation being considerably lower in group B.

Genetic and clinical characteristics including occurrence of testicular adrenal rest tumors in Slovak and Slovenian patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

“…A higher concordance was observed for group C genotypes (70.83%) compared to 2 European studies. In comparison (Table 4), previous studies reported 97-100% concordance for null, 79-96% for A, 46-87% for B, and 58-100% for C genotypes (3)(4)(5)(6)9). One-third of the patients (33.33%) with genotype B were classified as SW-CAH.…”

“…A complete loss of 21-OH function results in the most severe salt-wasting (SW-CAH) phenotypes, whereas a minimal residual 21-OH production is sufficient to maintain aldosterone homeostasis, resulting in moderate simple virilizing phenotypes (SV-CAH) or mild less-symptomatic nonclassical CAH phenotypes (NC-CAH) (1,2). Numerous studies have examined large nation-based or population-based cohorts of patients around the world to establish genotype-phenotype associations (3)(4)(5)(6)(7)(8)(9). CYP21A2 is located near its pseudogene (CYP21A2P), which is 96% homologous to it.…”