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21-Hydroxylase and 11ß-Hydroxylase Mutations in Romanian Patients with Classic Congenital Adrenal Hyperplasia

Endocrinology Clinic (A.G.S.), First Pediatric Clinic (P.G.S.), Iuliu Hatieganu University of Medicine and Pharmacy, 400476 Cluj, Romania; First Clinic of Internal Medicine (A.G.S., M.M.W.), Department of Endocrinology, Johannes Gutenberg University, 55131 Mainz, Germany; Laboratory of Molecular Genetics (S.C., E.S.), 69121 Heidelberg, Germany; and University Children’s Hospital (U.H.), Ruprecht-Karls University, 69120 Heidelberg, Germany

Address all correspondence and requests for reprints to: Anca Grigorescu Sido, M.D., First Clinic of Internal Medicine, Department of Endocrinology, Johannes Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany. E-mail: agsido{at}yahoo.co.uk.

Context: Congenital adrenal hyperplasia (CAH) comprises autosomal recessive disorders mainly due to defects in the 21-hydroxylase (CYP21) gene.

Objective: The study aimed to perform molecular characterization in 43 Romanian patients with classical CAH forms diagnosed at the Center for Genetic Diseases of the Pediatric Clinic/University Cluj (38 with 21-hydroxylase deficiency, five with 11ß-hydroxylase deficiency), to determine the frequency of mutations in the CYP21A2 gene and attempt a genotype-phenotype correlation in patients with 21-hydroxylase deficiency.

Design: Molecular analysis was performed by direct sequencing of PCR amplified products of the CYP21A2 and CYP11B1 genes.

Results: The most frequent mutation in Romanian patients with 21-hydroxylase deficiency was I2G (43.9%), followed by deletions and large conversions (16.7%), I172N and the triple mutation (P30L+I2G+del8bp), accounting for 12.1% each, P30L (7.6%) and R356W (1.5%). Genotypes were categorized in three mutation groups (0, A, and B), according to their predicted functional consequences, and compared with clinical phenotype. Positive predictive values were 100, 75, and 100% for groups 0, A, and B, respectively. Overall genotype-phenotype correlation was 87.88%. In the five patients with 11ß-hydroxylase deficiency, the following homozygous mutations were identified: T318R in two related patients; R448H in two unrelated patients; and P94L, a new, yet-undescribed mutation.

Conclusion: The present study is the first countrywide report of mutational analysis in a Romanian patient population with 21-hydroxylase deficiency. Molecular diagnosis was performed in a small number of CAH patients proved not to suffer from 21-hydroxylase deficiency but from 11ß-hydroxylase deficiency, and a new mutation was identified.

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