Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry.
Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry.
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DOI：
10.1016/j.jaci.2015.06.048
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Aricò M
中科院分区：
文献类型：
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作者：
Cetica V;Sieni E;Pende D;Danesino C;De Fusco C;Locatelli F;Micalizzi C;Putti MC;Biondi A;Fagioli F;Moretta L;Griffiths GM;Luzzatto L;Aricò M
噬血细胞性淋巴组织细胞增生症（HLH）是一种罕见的危及生命的疾病，主要影响儿童，但也影响成人，其特征是高度炎症。家族性噬血细胞性淋巴组织细胞增生症（FHL）患者的一个子集，有各种潜在的遗传异常，其频率尚未系统地确定以前。这项工作旨在根据我们25年的经验分析，进一步了解这种罕见疾病的致病基础。从我们的登记研究中，我们共分析了500例HLH的患者。在171例（34%）患者中发现了定义FHL的双等位基因致病突变;在出生后第一年内诊断的患者中FHL的比例要高得多（64%）。总之，基因PRF 1（FHL 2）和UNC 13 D（FHL 3）突变占FHL病例的70%。总的来说，超过90%的FHL患者可以进行基因诊断。穿孔蛋白表达和脱粒程度对于诊断FHL比噬血细胞作用和细胞毒性测定更有用。在281例（56%）被归类为“散发性”HLH的患者中，43例在FHL定义基因之一中有单等位基因突变。鉴于这种基因剂量效应，FHL不是严格隐性的。我们认为，临床综合征HLH一般是由外源性触发和遗传易感性的综合作用。在这种组合中，外源性和遗传因素的不同权重解释了从继发于严重感染的HLH到FHL的广泛疾病谱。
Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease affecting mostly children but also adults and characterized by hyperinflammatory features. A subset of patients, referred to as having familial hemophagocytic lymphohistiocytosis (FHL), have various underlying genetic abnormalities, the frequencies of which have not been systematically determined previously. This work aims to further our understanding of the pathogenic bases of this rare condition based on an analysis of our 25 years of experience. From our registry, we have analyzed a total of 500 unselected patients with HLH. Biallelic pathogenic mutations defining FHL were found in 171 (34%) patients; the proportion of FHL was much higher (64%) in patients given a diagnosis during the first year of life. Taken together, mutations of the genes PRF1 (FHL2) and UNC13D (FHL3) accounted for 70% of cases of FHL. Overall, a genetic diagnosis was possible in more than 90% of our patients with FHL. Perforin expression and the extent of degranulation have been more useful for diagnosing FHL than hemophagocytosis and the cytotoxicity assay. Of 281 (56%) patients classified as having “sporadic” HLH, 43 had monoallelic mutations in one of the FHL-defining genes. Given this gene dosage effect, FHL is not strictly recessive. We suggest that the clinical syndrome HLH generally results from the combined effects of an exogenous trigger and genetic predisposition. Within this combination, different weights of exogenous and genetic factors account for the wide disease spectrum that ranges from HLH secondary to severe infection to FHL.