Bidet Maud, Bellanné-Chantelot Christine, Galand-Portier Marie-Béatrice, Tardy Véronique, Billaud Line, Laborde Kathleen, Coussieu Christiane, Morel Yves, Vaury Christelle, Golmard Jean-Louis, Claustre Aurélie, Mornet Etienne, Chakhtoura Zeina, Mowszowicz Irene, Bachelot Anne, Touraine Philippe, Kuttenn Frédérique
Department of Reproductive Endocrinology, Centre de References des Maladies Endocriniennes Rares de la Croissance, Assistance Publique-Hôpitaux de Paris Pitié-Salpêtrière, 75013 Paris, France.
J Clin Endocrinol Metab. 2009 May;94(5):1570-8. doi: 10.1210/jc.2008-1582. Epub 2009 Feb 10.
Nonclassical congenital adrenal hyperplasia (NC-CAH) due to partial 21-hydroxylase deficiency is one of the most frequent autosomal recessive diseases.
The aim of this study was to determine the genotype/phenotype relationship in probands and family members.
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.
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.
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.
因21-羟化酶部分缺乏导致的非经典型先天性肾上腺皮质增生症（NC-CAH）是最常见的常染色体隐性疾病之一。
本研究旨在确定先证者及其家庭成员的基因型/表型关系。
共对161名因迟发性症状（主要为多毛症）而被诊断出的NC-CAH非亲属女性以及促肾上腺皮质激素刺激后17-羟孕酮超过10 ng/ml的女性及其330名亲属进行了研究。对124名先证者进行了CYP21A2基因分型。
最常见的突变是V281L。在63.7%的先证者中发现了一个严重突变，令人惊讶的是，有四名先证者存在两个严重突变。与临床差异、基础睾酮和雄烯二酮缺乏形成对比的是，携带至少一个严重突变的先证者的基础及促肾上腺皮质激素刺激后的17-羟孕酮水平显著高于携带两个轻度突变的先证者（P < 0.01）。在330名家庭成员中，51名是纯合子或复合杂合子，其中42名临床无症状；242名是杂合子，37名未受影响。促肾上腺皮质激素刺激后的21-脱氧皮质醇（21dF）在杂合子中显著高于未受影响者，然而，两者存在重叠。在12名杂合子中，促肾上腺皮质激素刺激后的21dF低于0.55 ng/ml，这是通常用于提示杂合性的临界值。
对家庭成员的研究强调了即使在一个家族中NC-CAH的表达也存在差异，这表明修饰因子可能会调节表型表达。促肾上腺皮质激素刺激后的21dF不能可靠地检测出杂合子个体。考虑到杂合子在普通人群中的高频率，对有一个严重突变的患者的配偶进行基因分型以提供遗传咨询至关重要。
