Goldman A S, Van Dyke D C, Gupta C, Katsumata M
Center for Craniofacial Anomalies, University of Illinois, College of Medicine at Chicago 60612.
Am J Med Genet. 1987 Nov;28(3):607-18. doi: 10.1002/ajmg.1320280308.
Our recent studies of the teratogenic mechanisms of phenytoin (DPH) and glucocorticoids in mice have indicated that DPH utilizes the anti-inflammatory pathway of glucocorticoids in producing congenital defects, such as cleft palate. This pathway is influenced by H-2 and H-3 histocompatibility-linked genes in the mouse, such that congenic strains have H-2 or H-3 alleles that confer susceptibility to DPH-induced congenital defects, and susceptible H-2 congenic strains have high glucocorticoid receptor levels. However, other H-2 or H-3 alleles confer resistance to these defects in their otherwise genetically identical congenic partner strains, and "resistant" H-2 alleles are associated with low levels of these receptors. To determine whether this animal work is applicable to the human, we have sought to investigate whether the level of glucocorticoid receptors in circulating lymphocytes of children with the fetal hydantoin syndrome (FHS) is as it is in the animals. We found that children with FHS had glucocorticoid receptor levels significantly elevated above those of unaffected children with similar DPH exposure in control families. The receptor level of affected children was also significantly elevated above that of fathers of children with the FHS and of fathers and mothers of control children. These findings are consistent with those documented in the animal models and suggest that an elevated level of glucocorticoid receptors in lymphocytes may be a marker for susceptibility to the FHS syndrome.
我们最近对苯妥英（DPH）和糖皮质激素在小鼠体内致畸机制的研究表明，DPH在产生先天性缺陷（如腭裂）时利用了糖皮质激素的抗炎途径。该途径受小鼠中H-2和H-3组织相容性连锁基因的影响，使得同源近交系具有赋予对DPH诱导的先天性缺陷易感性的H-2或H-3等位基因，且易感性H-2同源近交系具有高糖皮质激素受体水平。然而，其他H-2或H-3等位基因在其基因相同的同源近交系伙伴品系中赋予对这些缺陷的抗性，并且“抗性”H-2等位基因与这些受体的低水平相关。为了确定这项动物研究是否适用于人类，我们试图研究胎儿苯妥英综合征（FHS）患儿循环淋巴细胞中糖皮质激素受体水平是否与动物相同。我们发现，FHS患儿的糖皮质激素受体水平显著高于对照家庭中接触类似DPH的未受影响儿童。受影响儿童的受体水平也显著高于FHS患儿的父亲以及对照儿童的父亲和母亲。这些发现与动物模型中的记录一致，并表明淋巴细胞中糖皮质激素受体水平升高可能是FHS综合征易感性的一个标志。
