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Phenotype-Genotype Correlation in 56 Women with Nonclassical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

Service d’Endocrinologie et Médecine de la Reproduction, Hopital Necker (C.D., A.D., L.B., F.K.), 75015 Paris; Service de Biochimie Endocrinienne et Moléculaire-INSERM, U-329, Hopital Debrousse (V.T., Y.M.), 69005 Lyon; Laboratoire SESEP, Université de Versailles-Saint Quentin (E.M.), 78000 Versailles; Laboratoire d’Immunologie et d’Histocompatibilité, Hopital St. Louis (D.C.), 75010 Paris, France

Address all correspondence and requests for reprints to: Dr. Frédérique Kuttenn, Service d’Endocrinologie et Médecine de la Reproduction-Hopital Necker, 149 rue de Sèvres 75015 Paris, France.

Complete analysis of the CYP21 gene was performed in 56 unrelated French women with symptomatic nonclassical congenital adrenal hyperplasia. The mutational spectrum and the phenotype-genotype correlation were examined. The overall predominant mutation was V281L, which was present on 51% of alleles and in 80% of women. Three novel mutations were found: L317M, R435C, and a 5'-end gene conversion. Sixty-three percent of the women were carrying a severe mutation of the CYP21 gene, and hence risk giving birth to children with a classical form of the disease. In such cases, screening for heterozygosity in the partner is crucial. Potential genotype/phenotype correlations were examined by classifying the patients into three groups according to the CYP21 allelic combinations: A (mild/mild), B (mild/severe), and C (severe/severe). Primary amenorrhea was more frequent, and mean basal and stimulated 17-hydroxyprogesterone levels were higher in compound heterozygotes for mild and severe mutations (group B) compared with women with two mild mutations (group A), but there was a considerable overlap for individual values. Surprisingly, in two women, a severe mutation was found on both alleles (group C). Therefore, the phenotype cannot be accurately predicted from the genotype. Variability in phenotypic expression may be conditioned by mechanisms other than genetic heterogeneity at the CYP21 locus.

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