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
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
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DOI：
10.1210/jc.2008-1582
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发表时间：
2009-05-01
影响因子：
5.8
通讯作者：
Kuttenn, Frederique
中科院分区：
文献类型：
--
作者：
Bidet, Maud;Bellanne-Chantelot, Christine;Kuttenn, Frederique
内容：非经典先天性肾上腺皮质增生症（nonclassical congenital adrenal hyperplasia，NC-CAH）是一种常见的常染色体隐性遗传病，由21-羟化酶（21-hydroxylase，2共有161名NC-CAH无关的女性被诊断为迟发性症状，主要是多毛症，ACTH后17-羟孕酮超过10 ng/ml，他们的330个亲戚被调查了。结果：CYP 21 A2基因突变频率最高的是V281 L。在63.7%的先证者中发现了一个严重的突变，令人惊讶的是，在四个先证者中发现了两个严重的突变。与无临床差异相比，携带至少一个重度突变的先证者的基础睾酮、雄烯二酮、基础和ACTH后17-羟孕酮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名为纯合子或复合杂合子，42名无临床症状; 242名为杂合子，37名未受影响。后ACTH 21-脱氧皮质醇（21 dF）是显着高于杂合子比未受影响的，但是，存在重叠。在12个杂合子，后ACTH 21 dF低于0.55 ng/ml，通常接受的截止值为建议杂zygosity.Conclusions：家庭成员的研究强调了NC-CAH的可变表达，即使在一个家庭，这表明修饰因子可能调节表型表达。ACTH后21 dF不能可靠地检测杂合子受试者。考虑到杂合子在普通人群中的高频率，有必要对具有一个严重突变的患者的伴侣进行基因分型，以提供遗传咨询。（临床内分泌代谢杂志94：1570-1578，2009）
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 pro-bands 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. (J Clin Endocrinol Metab 94: 1570-1578, 2009)