Identification of point mutations in the 21-hydroxylase gene in patients affected with congenital adrenal hyperplasia

INTRODUCTION: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder due to impaired cortisol secretion. Approximately 95% of CAH cases are caused by defects in the 21-hydrodylase2 (CYPA2) gene. The spectrum of clinical manifestations includes a severe and mild form of expression. The frequency of the following point mutations was determined: P30L, IVS2-12A/C-G splice, Del 8pb, I172N, cluster Ex6, V281L, Q318X, R356W and P453S. MATERIALS AND METHODS: The 58 patients consisted of 48 with the severe form of CAH and 10 with the mild form. Point mutations in the hydroxylase gene were isolated by allele-specific PCR and PCR-ACRS (amplification created restriction site), and their frequency was determined. RESULTS: Alternate alleles were identified in 82.8% of the samples. The most frequent mutations were IVS2-12A/C-G splice (26.7%), Q318X (21.5%), V281L (12.1%) and I172N (12.1%). DISCUSSION: The most frequent mutations were similar to those observed in other countries, except for Q318X. Although its frequency was higher but similar to that observed in Latin American countries, it contrasted with those of other continents and indicated the possible influence of genetic background in its expression. Several of the mutations were associated with specific clinical forms related to the enzyme activity. In the milder forms of CAH, several alleles were detected. These were important because these patients can have children with the virilizing and salt wasting forms. Recognition of the allelic forms of CAH will permit more specific genetic counseling and prenatal diagnosis.