Background

Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD.

Objective

The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes.

Methods

PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing.

Results

Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients.

Conclusions

PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

中文翻译：

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免疫遗传错误区分小儿非恶性淋巴组织增生性疾病

背景

儿科非恶性淋巴组织增生性疾病 (PLPD) 在临床和遗传上具有异质性。儿童长期存在的免疫失调和淋巴增殖可能会危及生命，并且缺乏数据来指导儿童 PLPD 的评估和治疗。

客观的

本研究的主要目的是确定 PLPD 的基因组免疫缺陷谱。次要目标包括临床结果的表征以及基因诊断与这些结果之间的关联。

方法

PLPD 定义为持续性淋巴结肿大、淋巴器官受累或淋巴细胞浸润超过 3 个月，伴有或不伴有慢性或显着的 Epstein-Barr 病毒 (EBV) 感染。使用全外显子组测序分析了来自 47 个不同家族的 51 名 PLPD 受试者。

结果

全外显子组测序在 51% 至 62% 的家庭（受影响儿童的 53% 至 65%）中发现了可能的免疫遗传错误。遗传病因的存在与年龄较小和噬血细胞性淋巴组织细胞增多症有关。该队列的 10 年生存率为 72.4%，与没有遗传解释的儿童（48%， P  = .03）相比，具有可行遗传诊断的患者的生存率更高（82% ）。患有 EBV 相关疾病且没有遗传解释的个体的生存结果比患有 EBV 相关疾病和遗传解释的受试者的结果特别差（17% 对 90%；P  = .002）。分子诊断的确定为多达 18 名患者提供了有针对性的治疗选择，并为 12 名患者带来了积极的管理变化。

结论

PLPD 定义了死亡风险高的儿童，全外显子组测序为该诊断提供了临床风险和治疗机会。