This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bidet, M. Articles by Kuttenn, F. Search for Related Content PubMed PubMed Citation Articles by Bidet, M. Articles by Kuttenn, F. Related Collections Adrenal and Hypertension Female Endocrinology

Clinical and Molecular Characterization of a Cohort of 161 Unrelated Women with Nonclassical Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency and 330 Family Members

Departments of Reproductive Endocrinology (M.B., M.-B.G.-P., A.C., Z.C., I.M., A.B., P.T., F.K.), and Genetics (C.B.-C., C.V.), Hormonal Biochemistry (C.C.), Statistical Unit (J.-L.G.), and Centre de References des Maladies Endocriniennes Rares de la Croissance (M.B., Z.C., A.B., P.T., F.K.), Assistance Publique-Hôpitaux de Paris Pitié-Salpêtrière, 75013 Paris, France; Endocrine and Molecular Biochemistry, Biology and Pathology East Center (V.T., Y.M.), 69 677 Bron Cedex, France; Endocrinology (L.B.), Assistance Publique-Hôpitaux de Paris Cochin, 75014 Paris, France; Laboratory of Hormonal Investigations (K.L.), Assistance Publique-Hôpitaux de Paris Necker, 75015 Paris, France; Laboratoire Société d'Etudes et de Soins pour les Enfants Polymalformés (E.M.), Central Hospitalier de Versailles, 78150 Versailles, France; University of Paris V, René Descartes, Faculty of Medicine, INSERM U845 (K.L., F.K.), 75015 Paris, France; University Pierre et Marie Curie (M.B., C.B.C., C.C., J.L.G., A.B., P.T.), 75005 Paris, France; and University Claude Bernard Lyon II (V.T.,Y.M.), Lyon, France; and University of Versailles (E.M.), Versailles, France

Address all correspondence and requests for reprints to: Frédérique Kuttenn, Department of Reproductive Endocrinology, Hôpital Pitié- Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France. E-mail: frederique.kuttenn{at}psl.aphp.fr.

Context: Nonclassical congenital adrenal hyperplasia (NC-CAH) due to partial 21-hydroxylase deficiency is one of the most frequent autosomal recessive diseases.

Objective: The aim of this study was to determine the genotype/phenotype relationship in probands and family members.

Patients and Methods: A total of 161 NC-CAH unrelated women diagnosed on late-onset symptoms, mainly hirsutism, and post-ACTH 17-hydroxyprogesterone more than 10 ng/ml, and 330 of their relatives was explored. CYP21A2 was genotyped in 124 probands.

Results: The most frequent mutation was V281L. One severe mutation was found in 63.7% of probands, and surprisingly two severe mutations in four probands. Contrasting with the absence of clinical differences, basal testosterone, and androstenedione, basal and post-ACTH 17-hydroxyprogesterone were significantly higher in probands carrying at least one severe mutation than in those with two mild mutations (P < 0.01). Among the 330 family members, 51 were homozygotes or compound heterozygotes, and 42 were clinically asymptomatic; 242 were heterozygotes and 37 unaffected. Post-ACTH 21-deoxycortisol (21dF) was significantly higher in heterozygotes than in unaffected, however, an overlap existed. In 12 heterozygotes, post-ACTH 21dF was below 0.55 ng/ml, the cutoff value usually accepted for suggesting heterozygosity.

Conclusions: The study of family members underlines the variable expression of NC-CAH even within a family, suggesting that modifier factors may modulate phenotype expression. Post-ACTH 21dF cannot reliably detect heterozygous subjects. Considering the high frequency of heterozygotes in the general population, it is essential to genotype the partner(s) of the patients with one severe mutation to offer genetic counseling.