Genetic defects in pediatric-onset adrenal insufficiency in Japan
Genetic defects in pediatric-onset adrenal insufficiency in Japan
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DOI：
10.1530/eje-17-0027
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发表时间：
2017-08-01
影响因子：
5.8
通讯作者：
Hasegawa, Tomonobu
中科院分区：
文献类型：
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作者：
Amano, Naoko;Narumi, Satoshi;Hasegawa, Tomonobu
背景：大多数儿科发病的原发性肾上腺功能不全（PAI）患者，如21-羟化酶缺乏症，可以通过测量尿液或血清类固醇代谢物水平来诊断。然而，在缺乏特征性生化结果的患者中，病因往往难以确定。目的：了解日本PAI生物化学特征不明确的儿童遗传缺陷发生率，并对携带突变的患者进行表型分析。方法：我们招募了63名日本儿童（59个家庭），他们患有生化未表征的PAI，并对12个PAI相关基因进行了测序。基于计算机分析和结构建模对罕见变异的致病性进行了评估。我们根据人口学特征计算携带突变的患者比例。结果：我们在50个（85%）家族中发现了遗传缺陷：19个是STAR， 18个是NR0B1, 7个是SAMD9, 2个是AAAS， 2个是NNT， 1个是MC2R， 1个是CDKN1C。在接受糖皮质激素和矿皮质激素替代治疗且男性外生殖器正常的男性患者中，有78%的患者发现NR0B1缺陷。在67%的女性和9%的男性患者中发现了STAR缺陷。19例STAR缺陷患者中有7例在2岁或更大时发生PAI，其中5例没有矿皮质激素缺乏症。结论：分子检测阐明了大多数生物化学特征不明的PAI患者的病因。遗传缺陷如NR0B1缺陷是基于表型推定的，而其他具有广泛表型变异性的遗传缺陷，如STAR缺陷，则难以诊断。分子检测是生物化学特征不明确的PAI患者的合理诊断方法。
Context: Most patients with pediatric-onset primary adrenal insufficiency (PAI), such as 21-hydroxylase deficiency, can be diagnosed by measuring the urine or serum levels of steroid metabolites. However, the etiology is often difficult to determine in a subset of patients lacking characteristic biochemical findings.Objective: To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients.Methods: We enrolled 63 Japanese children (59 families) with biochemically uncharacterized PAI, and sequenced 12 PAI-associated genes. The pathogenicities of rare variants were assessed based on in silico analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics.Results: We identified genetic defects in 50 (85%) families: STAR in 19, NR0B1 in 18, SAMD9 in seven, AAAS in two, NNT in two, MC2R in one and CDKN1C in one. NR0B1 defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. STAR defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with STAR defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency.Conclusions: Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as NR0B1 defects are presumed based on phenotypes, while others with broad phenotypic variability, such as STAR defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.