21-Hydroxylase and 11beta-hydroxylase mutations in Romanian patients with classic congenital adrenal hyperplasia.
BACKGROUND
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 11beta-hydroxylase deficiency), to determine the frequency of mutations in the CYP21A2 gene and attempt a genotype-phenotype correlation in patients with 21-hydroxylase deficiency.


METHODS
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 11beta-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.


CONCLUSIONS
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 11beta-hydroxylase deficiency, and a new mutation was identified.
Grigorescu Sido
Anca
A
Endocrinology Clinic, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj, Romania. agsido@yahoo.co.uk
Weber
Matthias M
MM
Grigorescu Sido
Paula
P
Clausmeyer
Susanne
S
Heinrich
Udo
U
Schulze
Egbert
E
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000453:epidemiology / Q000235:genetics*; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000502:physiology*; D012383:Romania / Q000453:epidemiology; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics*; D013255:Steroid 21-Hydroxylase / Q000235:genetics*
D013255:Steroid 21-Hydroxylase; D013252:Steroid 11-beta-Hydroxylase