Kulle A E, Riepe F G, Hedderich J, Sippell W G, Schmitz J, Niermeyer L, Holterhus P M
Division of Pediatric Endocrinology and DiabetesDepartment of PediatricsInstitute of Medical Informatics and StatisticsUniversity Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Schwanenweg 20, D-24105 Kiel, Germany
Division of Pediatric Endocrinology and DiabetesDepartment of PediatricsInstitute of Medical Informatics and StatisticsUniversity Hospital Schleswig-Holstein, Christian-Albrechts University Kiel, Schwanenweg 20, D-24105 Kiel, Germany.
Eur J Endocrinol. 2015 Oct;173(4):517-24. doi: 10.1530/EJE-14-1084.
Heterozygosity in 21-hydroxylase deficiency (21OHD) has been associated with hyperandrogenemic symptoms in children and adults. Moreover, the carrier status is mandatory for genetic counseling. We aimed at defining a hormonal parameter for carrier detection by mass spectrometry.
Eleven basal and ACTH-stimulated steroid hormones of heterozygous carriers of CYP21A2 mutations and control individuals were compared.
Hormones were determined in plasma samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) in 58 carriers (35 males, 23 females, age range 6-78 years) and 44 random controls (25 males, 19 females, age range 8-58 years).
Heterozygotes could be identified best applying the 17-hydroxyprogesterone+21-deoxycortisol/cortisol×1000 ((17OHP+21S)/F×1000) equation 30 min after ACTH injection. An optimal cut-off value of 8.4 provided 89% sensitivity and specificity. Considering this data and a published frequency of heterozygotes of 1/50 to 1/61, the positive predictive value (PPV) of this cut-off is 12%. Of note, the negative predictive value (NPV) excluding heterozygosity in a given patient is 99.8%.
Considering only marginal biochemical effects anticipated from heterozygosity, the stimulated ((17OHP+21S)/F×1000) identifies and excludes heterozygotes remarkably well. Nevertheless, LC-MS/MS cannot replace genetic testing, since sensitivity and specificity did not reach 100%. However, due to the considerably high NPV of the optimal cut-off and to a specificity of even 100% applying a cut-off higher than 14.7, hormonal assessment of heterozygosity can be of significant aid in conditions with limited access to genetic testing, as in some health care systems. The ((17OHP+21S)/F×1000) equation can guide diagnostic considerations in the differential diagnosis of hyperandrogenism.
21-羟化酶缺乏症（21OHD）杂合子与儿童及成人的高雄激素症状有关。此外，携带者状态对于遗传咨询至关重要。我们旨在通过质谱法确定一种用于检测携带者的激素参数。
比较了CYP21A2突变杂合子携带者和对照个体的11种基础及促肾上腺皮质激素（ACTH）刺激后的类固醇激素。
采用液相色谱串联质谱法（LC-MS/MS）测定了58名携带者（35名男性，23名女性，年龄范围6 - 78岁）和44名随机对照个体（25名男性，19名女性，年龄范围8 - 58岁）血浆样本中的激素。
注射ACTH后30分钟应用17-羟孕酮 + 21-脱氧皮质醇/皮质醇×1000（(17OHP + 21S)/F×1000）公式能最佳识别杂合子。最佳截断值为8.4时，灵敏度和特异性均为89%。考虑到该数据以及已公布的杂合子频率为1/50至1/61，此截断值的阳性预测值（PPV）为12%。值得注意的是，在特定患者中排除杂合子的阴性预测值（NPV）为99.8%。
仅考虑杂合子预期的轻微生化效应，刺激后的((17OHP + 21S)/F×1000)能很好地识别和排除杂合子。然而，LC-MS/MS不能替代基因检测，因为灵敏度和特异性未达到100%。不过，由于最佳截断值的NPV相当高，且应用高于14.7的截断值时特异性甚至可达100%，在一些医疗系统中，当获取基因检测的途径有限时，杂合子的激素评估可能会有很大帮助。((17OHP + 21S)/F×1000)公式可指导高雄激素血症鉴别诊断中的诊断思考。
