title: 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.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Reproductive Endocrinology, Centre de References des Maladies Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris Pitié-Salpêtrière, 75013 Paris, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Bidet
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Marie-Béatrice
authors.initials: MB
authors.lastname: Galand-Portier
authors.forename: Véronique
authors.initials: V
authors.lastname: Tardy
authors.forename: Line
authors.initials: L
authors.lastname: Billaud
authors.forename: Kathleen
authors.initials: K
authors.lastname: Laborde
authors.forename: Christiane
authors.initials: C
authors.lastname: Coussieu
authors.forename: Yves
authors.initials: Y
authors.lastname: Morel
authors.forename: Christelle
authors.initials: C
authors.lastname: Vaury
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Golmard
authors.forename: Aurélie
authors.initials: A
authors.lastname: Claustre
authors.forename: Etienne
authors.initials: E
authors.lastname: Mornet
authors.forename: Zeina
authors.initials: Z
authors.lastname: Chakhtoura
authors.forename: Irene
authors.initials: I
authors.lastname: Mowszowicz
authors.forename: Anne
authors.initials: A
authors.lastname: Bachelot
authors.forename: Philippe
authors.initials: P
authors.lastname: Touraine
authors.forename: Frédérique
authors.initials: F
authors.lastname: Kuttenn
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics*; D000328:Adult; D002648:Child; D015331:Cohort Studies; D005260:Female; D005823:Genetics; D005838:Genotype; D006579:Heterozygote; D006650:Histocompatibility Testing; D006720:Homozygote; D006728:Hormones / Q000097:blood; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D013255:Steroid 21-Hydroxylase / Q000235:genetics*; D055815:Young Adult
chemical_list: D006728:Hormones; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase