成人噬血细胞综合征基因型特点及家系调查

Genetic features of adult onset hemophagocytic lymphohistiocytosis with family survey

目的对存在噬血细胞综合征(HLH)相关基因缺陷的成人患者进行基因特点的分析和家系调查,为研究HLH的发病机制进一步提供基础。方法以2016年1月至2018年12月北京HLH协作组在册登记的272例成人HLH患者为研究对象,对存在HLH相关基因缺陷的成人患者及其家属成员的基因特点、细胞毒功能进行检测和分析。结果成人原发性HLH的遗传学特点表现为错义突变和不典型位点突变。具有纯合突变或复杂杂合突变的成人原发性HLH患者NK细胞活性较存在单等位基因SNP的患者略低,但携带单等位基因SNP的健康家属成员的NK细胞活性明显高于原发性HLH患者以及HLH发病的单等位基因杂合突变患者。部分患者尽管在HLH相关致病基因上存在突变,但在缺少强烈外界刺激条件的情况下可以不出现HLH的临床表现。结论成人原发性HLH患者的突变位点、突变方式多见于错义突变和不典型位点,残存的细胞毒功能可能在一定程度维持基本的机体免疫功能,当外界刺激因素达到一定强度后导致HLH的临床表现。

Objective To investigate the genetic features of adult onset primary hemophagocytic lymphohistiocytosis( HLH) and carry out family survey in order to search for the reason of " late onset". Methods The data were collected from adult onset HLH patients who were registered in Beijing HLH Group. We did analysis of genetic features and cytotoxicity function of the patients and their family member who carried mutation on the known genes associated with HLH. Results The genetic features of adult onset primary HLH manifested as missense mutation and atypical mutation sites on the susceptibility gene. The NK cell activity was slightly lower in adult primary HLH patients with homozygous mutations or complex heterozygous mutations than in patients with monoallelic mutation. However,it was higher in persons who had monoallelic mutation on the susceptibility gene but did not developed HLH. Although some patients have mutations in HLH related genes,they might have no clinical manifestations of HLH in absence of strong external stimulation. Conclusion Missense mutations and atypical sites are more common in adult primary HLH. The remaining cytotoxic function may maintain the basic immune function to a certain extent. When the external stimulus reaches a certain intensity,it leads to the clinical manifestation of HLH.