Background: Mutations in the 21-hydroxylase gene (CYP21A2) accounts for 9095% of all congenital adrenal hyperplasia (CAH) cases. There is a strong relationship between genotype and disease severity.
Objective: The aim of the study was to investigate the most frequent known mutations in CYP21A2 and to describe the genotype-phenotype correlation in Turkish children with CAH due to 21-hydroxylase deficiency.
Methods: Based on clinical and hormonal criteria, patients were classified according to phenotype as salt-wasting (SW), simple-virilising (SV) or nonclassical (NC). Genetic analysis was performed using a reverse-hybridisation strip-based assay (the CAH StripAssay) that explored the presence of the 11 CYP21A2 mutations most prevalent in European populations: P30L, I2 splice (IVS2), Del 8 bp E3 (G110del8nt), I172N, Cluster E6 (I236N, V237E, M239K), V281L, L307 frameshift (F306+T), Q318X, R356W, P453S and R483P.
Results: Of the 46 patients included in the study, the disease-causing CYP21A2 gene mutations were found in 25 (54%) across all three forms of CAH. The most frequent mutations were point mutations (84%), followed by splice site mutations (24%) and deletions (4%). In the SW group, three patients were homozygous and one heterozygous for I2 splice, one was homozygous for P30L+I2splice+del 8bp+E3 del, one was homozygous for I2splice+Q318X and one was heterozygous for I2splice+V281L. In the SV group, one patient was homozygous for I172N and one was heterozygous for I172N+Q318X. In the NC group, seven patients were heterozygous for Q318X, seven were heterozygous for V281L, one was heterozygous for V281L+P453S and one was heterozygous for I172N.
Conclusion: Hormonal assays can diagnose CAH, but they are unable to discriminate heterozygotes from normal individuals or detect disease severity. This study showed a good correlation between genotype and phenotype in patients with 21-hydroxylase deficiency. The results suggest that well-known mutations can predict disease severity.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology