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.
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.
Bidet
Maud
M
Department of Reproductive Endocrinology, Centre de References des Maladies Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris Pitié-Salpêtrière, 75013 Paris, France.
Bellanné-Chantelot
Christine
C
Galand-Portier
Marie-Béatrice
MB
Tardy
Véronique
V
Billaud
Line
L
Laborde
Kathleen
K
Coussieu
Christiane
C
Morel
Yves
Y
Vaury
Christelle
C
Golmard
Jean-Louis
JL
Claustre
Aurélie
A
Mornet
Etienne
E
Chakhtoura
Zeina
Z
Mowszowicz
Irene
I
Bachelot
Anne
A
Touraine
Philippe
P
Kuttenn
Frédérique
F
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
D006728:Hormones; C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase