Endocrine Abstracts

Congenital adrenal hyperplasia (CAH) comprises autosomal recessive disorders mainly due to defects in the 21-hydroxylase (CYP21) gene. We aimed to perform a genotype-phenotype analysis in Romanian patients with classical 21-hydroxylase deficiency.

Patients and methods: We included 42 patients (13 males, 29 females, 19 with the salt wasting (SW) form, 29 with the simple virilizing (SV) form. Molecular analysis was performed by direct sequencing of PCR amplified products of the CYP21A2 gene.

Results: Age at diagnosis in SW patients was 23±5 days in females, 30±11 days in males. Female SV patients were diagnosed at 28.5±43 months, males with SV were diagnosed at 8±9.6 years. The most frequent mutation in Romanian patients with 21-hydroxylase deficiency was a splice site mutation in intron 2 (IVS2-13A/C>G) (43.2%), followed by deletions and large conversions and the I172N mutation in exon 4, accounting for 14.9% each, a triple mutation (P30L+ IVS2-13A/C>G+ deletion of 8 bp in exon 3) (13.5%), P30L (6.8%), different double mutations (5.4%) and R356W (1.4%). Genotypes were divided in 3 mutation groups (0, A, B), according to their predicted functional consequences and compared to clinical phenotype. Positive predictive values were 100%, 76.5% and 78.3% for group 0, A and B respectively. Overall genotype-phenotype correlation was 88.1%. In female patients we observed in genotype group 0 only severe virilization (Prader-IV), in group A there was a tendency to severe virilization (5 patients with Prader-IV, 3 with Prader-III and 2 with Prader-II), while in group B all Prader stages were encountered (2 patients with Prader-I, 4 with Prader-II and III, respectively and 6 with Prader-IV).

Conclusions: Genotype-phenotype correlation in our patients with 21-hydroxylase deficiency was high, with an overall value of 88.1%. Severe genotypes resulted in more pronounced clinical virilization, expressed as higher Prader stages.