Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes
Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes
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DOI：
10.1182/blood-2018-11-887141
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发表时间：
2019-07-04
期刊：
影响因子：
20.3
通讯作者：
Rieux-Laucat, Frederic
中科院分区：
文献类型：
--
作者：
Hadjadj, Jerome;Aladjidi, Nathalie;Rieux-Laucat, Frederic
Evans综合征（ES）是一种罕见的严重自身免疫性疾病，其特征是自身免疫性溶血性贫血和免疫性血小板减少症的组合。在大多数情况下，根本原因不明。我们试图确定在儿科ES（pES）的遗传缺陷，强遗传决定论的假设的基础上。在2004年开始的一项由203名早发性ES患者组成的全国性前瞻性队列研究中（末次随访时的中位[范围]年龄：16.3岁（[1.2-41.0岁]），80名非选择的连续个体接受了基因检测。临床数据作为遗传发现的函数进行分析。52例患者（65%）接受了基因诊断（M+组）：49例携带生殖系突变，3例携带体细胞变异。32例（40%）患者在9个已知参与原发性免疫缺陷的基因（TNFRSF 6、CTLA 4、STAT 3、PIK 3CD、CBL、ADAR 1、LRBA、RAG 1和KRAS）中的1个中存在致病性突变，而20例患者（25%）在16个基因中携带可能的致病性变异，这些基因以前在自身免疫性疾病的背景下未报道过。最后，在其余28例患者（35%，M组）中未发现遗传异常。M+组显示出比M-组更严重的疾病，具有更高的额外免疫病理学表现频率和更大的治疗线中位数。6例患者（均来自M+组）在研究期间死亡。总之，pES在至少65%的病例中可能由遗传决定。系统的，广泛的遗传筛查应提供pES;遗传学的结果具有预后意义，并可能指导靶向治疗的选择。
Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M- group). The M+ group displayed more severe disease than the M- group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.