Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
Department of Pediatrics, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
Eur J Endocrinol. 2017 Aug;177(2):187-194. doi: 10.1530/EJE-17-0027. Epub 2017 May 25.
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.
To assess the frequency of genetic defects in Japanese children with biochemically uncharacterized PAI and characterize the phenotypes of mutation-carrying patients.
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 analyses and structural modeling. We calculated the proportion of mutation-carrying patients according to demographic characteristics.
We identified genetic defects in 50 (85%) families: in 19, in 18, in seven, in two, in two, in one and in one. defects were identified in 78% of the male patients that received both glucocorticoid and mineralocorticoid replacement therapy and had normal male external genitalia. defects were identified in 67% of female and 9% of male patients. Seven of the 19 patients with defects developed PAI at age two or older, out of whom, five did not have mineralocorticoid deficiency.
Molecular testing elucidated the etiologies of most biochemically uncharacterized PAI patients. Genetic defects such as defects are presumed based on phenotypes, while others with broad phenotypic variability, such as defects, are difficult to diagnose. Molecular testing is a rational approach to diagnosis in biochemically uncharacterized PAI patients.
大多数儿童期起病的原发性肾上腺皮质功能不全（PAI）患者，如 21-羟化酶缺乏症，通过测量尿液或血清类固醇代谢物水平即可诊断。然而，在缺乏特征性生化表现的患者亚群中，病因通常难以确定。
评估生化表现不典型的日本儿童 PAI 患者中遗传缺陷的发生频率，并对携带突变患者的表型进行特征分析。
我们纳入了 63 名生化表现不典型的日本 PAI 患儿（59 个家系），并对 12 个 PAI 相关基因进行了测序。根据分析和结构建模评估罕见变异的致病性。根据人口统计学特征计算携带突变患者的比例。
我们在 50 个（85%）家系中发现了遗传缺陷：19 个家系中为 ，18 个家系中为 ，7 个家系中为 ，2 个家系中为 ，2 个家系中为 ，1 个家系中为 ，1 个家系中为 。在接受糖皮质激素和盐皮质激素替代治疗且具有正常男性外生殖器的男性患者中，78%存在 缺陷。在女性患者中，67%存在 缺陷，而在男性患者中，9%存在 缺陷。19 例 缺陷患者中有 7 例在 2 岁或以上发病，其中 5 例无盐皮质激素缺乏。
分子检测阐明了大多数生化表现不典型 PAI 患者的病因。基于表型可推测出 缺陷等遗传缺陷，而其他表型变异性较大的，如 缺陷，则难以诊断。分子检测是诊断生化表现不典型 PAI 患者的合理方法。
