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Follow-Up of 68 Children with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Relevance of Genotype for Management

Pediatric Endocrinology Unit (G.P., C.Th.), Physiology Laboratory (C.Tr.), and Université René Descartes and Pediatric Surgery Department (S.L.-J., C.N.-F.), Hôpital Necker-Enfants Malades, Assistance Publique-Hopitaux de Paris, 75743 Paris, France; Biochimie Endocrinienne et Moléculaire, Hôpital Debrousse, INSERM, U-329 (V.T., Y.M.), 69322 Lyon, France; and Université René Descartes and Pediatric Endocrinology Unit, Fondation-Hôpital Saint Joseph (R.B.), 75674 Paris, France

Address all correspondence and requests for reprints to: Dr. R. Brauner, 211 avenue Daumesnil, 75012 Paris, France. E-mail: raja.brauner{at}wanadoo.fr.

The phenotype of congenital adrenal hyperplasia (CAH) varies greatly. The purpose of this study was to optimize diagnosis and follow-up by comparing phenotype with genotype. Sixty-eight patients with CAH due to 21-hydroxylase deficiency were studied by clinical, hormonal, and molecular genetic methods. Patients were classified according to predicted mutation severity: group 0, null mutation (17.6%); group A, homozygous for IVS2 splice mutation or compound heterozygous for IVS2 and null mutations (33.8%); group B, homozygous or compound heterozygous for I172N mutation (14.7%); group C, homozygous or compound heterozygous for V281L or P30L mutations (26.5%); and group D, mutations with unknown enzyme activity (7.4%). All group 0 and A patients had the salt-wasting form, and group C had nonclassical forms. Group B included five salt-wasting and five simple virilizing forms. Groups 0 and A were younger at diagnosis (P < 0.02), and females were more virilized than those in group B. Group B had higher basal plasma 17-hydroxyprogesterone (564 ± 162 nmol/liter) and testosterone (11 ± 3 nmol/liter) levels than group C [59 ± 13 nmol/liter (P < 0.001) and 1.4 ± 0.2 nmol/liter (P < 0.005), respectively]. Hydrocortisone doses given to groups 0, A, and B were similar at all ages, but lower in group C (P < 0.01). Final height was below target height in classical (n = 16; -2 ± 0.2 SD score; P < 0.02) and nonclassical (n = 11; -1.2 ± 0.4 SD score; P < 0.03) forms.

The severity of the genetic defects and the clinical-laboratory features are well correlated. Genotyping, combined with neonatal screening and optimal medical and surgical treatment, can help in the management of CAH.

G.P. and V.T. contributed equally to this work and should both be viewed as first authors of this paper.

Abbreviations: CAH, Congenital adrenal hyperplasia; 17OHP, 17-hydroxyprogesterone; SDS, SD score; SV, simple virilizing; SW, salt wasting; T, testosterone.

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