Schreiner Felix, Tozakidou Magdalini, Maslak Rita, Holtkamp Ute, Peter Michael, Gohlke Bettina, Woelfle Joachim
Pediatric Endocrinology Division, Children's Hospital, University of Bonn, Bonn, Germany.
Eur J Endocrinol. 2009 Apr;160(4):667-73. doi: 10.1530/EJE-08-0639. Epub 2009 Jan 27.
17-Hydroxyprogesterone (17-OHP) screening for classical congenital adrenal hyperplasia (CAH) is part of many newborn screening programs worldwide. Cut-off values are relatively high, and screening sensitivity does not reach 100%. Recently, the glucocorticoid receptor (GR) N363S-variant has been linked to relatively low degree of virilization and comparatively lower 17-OHP serum concentrations in clinically diagnosed female CAH patients. We sought to determine whether functional GR gene variants, either increasing (N363S, BclI) or decreasing GR sensitivity (R23K), underlie the variable 17-OHP screening levels in healthy newborns.
GR genotypes were compared with 17-OHP screening values in 1000 random samples from routine screening. 17-OHP was measured by conventional immunoassay (TRFIA) and a liquid chromatography-tandem mass spectrometry method (LC-MS/MS), which has been shown to increase screening specificity by steroid profiling and avoiding cross-reactions of the 17-OHP-antibody.
There was no significant association of 17-OHP with GR genotypes, even after inclusion of gestational and postnatal age as covariates. However, among LC-MS/MS steroid measurements, we observed some unexpected trends, including lower 11-deoxycortisol concentrations in both 363S- and 23K-carriers. For carriers of the frequent BclI variant, linear regression analysis revealed a significant increase of 4-androstenedione levels with every mutant allele inherited.
Functional GR variants do not underlie the variation of 17-OHP values observed in healthy individuals. However, whether and to which extent genetically determined differences in individual GR sensitivity influence 17-OHP screening levels in conditions of a pathological hypothalamus-pituitary-adrenal gland-axis stimulation and thus may explain false-negative screening results in those affected by CAH remains to be investigated.
对经典型先天性肾上腺皮质增生症（CAH）进行17-羟孕酮（17-OHP）筛查是全球许多新生儿筛查项目的一部分。截断值相对较高，且筛查敏感性未达到100%。最近，糖皮质激素受体（GR）N363S变异与临床诊断的女性CAH患者相对较低的男性化程度和相对较低的血清17-OHP浓度有关。我们试图确定功能性GR基因变异，无论是增加（N363S、BclI）还是降低GR敏感性（R23K），是否是健康新生儿中17-OHP筛查水平变化的基础。
将GR基因型与来自常规筛查的1000个随机样本中的17-OHP筛查值进行比较。17-OHP通过传统免疫测定法（时间分辨荧光免疫分析法）和液相色谱-串联质谱法（LC-MS/MS）进行测量，后者已被证明可通过类固醇谱分析提高筛查特异性并避免17-OHP抗体的交叉反应。
即使将孕周和出生后年龄作为协变量纳入，17-OHP与GR基因型之间也没有显著关联。然而，在LC-MS/MS类固醇测量中，我们观察到一些意外趋势，包括363S和23K携带者中11-脱氧皮质醇浓度较低。对于常见BclI变异的携带者，线性回归分析显示，每继承一个突变等位基因，4-雄烯二酮水平显著升高。
功能性GR变异不是健康个体中观察到的17-OHP值变化的基础。然而，在病理性下丘脑-垂体-肾上腺轴刺激的情况下，个体GR敏感性的遗传决定差异是否以及在何种程度上影响17-OHP筛查水平，从而可能解释CAH患者的假阴性筛查结果，仍有待研究。
