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Molecular Genotyping in Brazilian Patients with the Classical and Nonclassical Forms of 21-Hydroxylase Deficiency¹

Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular da Disciplina de Endocrinologia (T.A.S.S.B., A.E.C.B., G.M., J.A.M.M., I.J.P.A., B.B.M.), Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01060–970, Brazil; Serviço de Endocrinologia Pediátrica (C.A.L.), Departamento de Pediatria da Santa Casa, São Paulo, Brazil; Departamento de Clínica Médica I (M.V.L.), Universidade Federal do Rio Grande do Norte, Natal, Brazil 59010-180

Address all correspondence and requests for reprints to: Berenice B. Mendonca, M.D., Hospital das Clínicas, FMUSP, Divisão de Endocrinologia, Caixa Postal 3671, São Paulo, 01060–970, Brazil. E-mail: beremen{at}usp.br

The aim of our study was to determine, by allele-specific PCR, the frequency of point mutations in 130 Brazilian patients with the classical and nonclassical forms of 21-hydroxylase deficiency and to correlate genotype with phenotype. The most frequent mutations were I2 splice (41.8% in salt wasting), I172N (32.6% in simple virilizing), and V281L (40.2% in late onset form). The frequency of the 9 most common point mutations was similar to that reported for other countries, except for Del 8 nt and Cluster, which were less frequent in the classical form. Rarer mutations such as P453S, G291S, I7 splice, W405X, R483P, and R483frameshift were rarely found or were absent. The 93 fully genotyped patients were classified into 3 mutation groups, based on the degree of enzymatic activity (group A, <2%; group B, 2%, and group C, >18%). In group A, 62% of the cases presented the salt wasting form; in group B, 96% the simple virilizing form; and in group C, 88% the late onset form. We diagnosed 80% of the affected alleles after screening for large rearrangements and 15 point mutations. The absence of previously described mutations in 20% of the affected alleles suggests the presence of new mutations in our population.

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