Table_2_Genetics and clinical phenotype of Erdheim–Chester disease: A case report of constrictive pericarditis and a systematic review of the literature.pdf

BackgroundErdheim–Chester disease (ECD) is a rare form of histiocytosis. An increasing number of genetic mutations have been associated with this syndrome, confirming its possible neoplastic origin. Recently, a connection between the BRAF mutational status and a specific phenotype was described; however, no studies have yet evaluated the correlations between other mutations and the clinical features of the disease.
ObjectivesThis study aims to clarify the association between the clinical phenotype and genetic mutations identified in the neoplastic cell lines of ECD.
MethodsWe describe a case of ECD characterized by pericardial involvement and a KRAS mutation shared with chronic myelomonocytic leukemia. Hence, through a meta-analysis of individual participant data of all genetically and clinically described cases of ECD in the literature, we aimed to elucidate the association between its clinical phenotype and baseline genetic mutations.
ResultsOf the 760 studies screened, our review included 133 articles published from 2012 to April 2021. We identified 311 ECD patients whose genotype and phenotype were described. We found five main genes (BRAF, KRAS, NRAS, PIK3CA, and MAP2K1) whose mutation was reported at least three times. Mutation of BRAF led to a neurological disease (183 of 273 patients, 67%; p < 0.001); KRAS- and NRAS-mutated patients mainly showed cutaneous (five of six patients, 83.3%, p < 0.004) and pleural (four of nine patients, 44%, p = 0.002) involvement, respectively; PIK3CA was not associated with specific organ involvement; and MAP2K1 mutations caused the disease to primarily involve the peritoneum and retroperitoneum (4 of 11, 36.4%, p = 0.01).
ConclusionThis work implies a possible influence of baseline mutation over the natural history of ECD, underscoring the importance of a thorough genetic analysis in all cases with the ultimate goal of identifying a possible targeted therapy for each patient.

研究背景：埃德海姆-切斯特病（Erdheim–Chester disease, ECD）是一种罕见的组织细胞增生症（histiocytosis）。目前已有越来越多的基因突变（genetic mutations）被证实与该综合征相关，这也印证了其可能具有肿瘤源性（neoplastic origin）。此前已有研究报道BRAF突变状态（BRAF mutational status）与特定表型（clinical phenotype）之间存在关联，但尚未有研究探讨其他基因突变与ECD临床特征（clinical features）之间的相关性。

研究目的：本研究旨在阐明埃德海姆-切斯特病（ECD）肿瘤细胞系中检出的基因突变与临床表型之间的关联。

研究方法：本研究首先报道1例以心包受累（pericardial involvement）为特征、且存在与慢性粒单核细胞白血病（chronic myelomonocytic leukemia）共享的KRAS突变（KRAS mutation）的ECD病例。随后，我们对文献中所有已完成基因及临床特征描述的ECD病例的个体参与者数据进行荟萃分析（meta-analysis of individual participant data），以期阐明其临床表型与基线基因突变之间的关联。

研究结果：在筛选的760项研究中，本综述纳入了2012年至2021年4月发表的133篇文献，共纳入311例明确记载基因型（genotype）与表型（phenotype）的ECD患者。我们共识别出5个主要基因（BRAF、KRAS、NRAS、PIK3CA及MAP2K1），其突变报道次数均至少达3次。其中，BRAF突变患者中67%（183/273）出现神经系统病变（neurological disease）（p < 0.001）；KRAS突变与NRAS突变患者分别主要表现为皮肤受累（cutaneous involvement）（6例中5例，83.3%，p < 0.004）与胸膜受累（pleural involvement）（9例中4例，44%，p = 0.002）；PIK3CA突变未与特定器官受累相关联；而MAP2K1突变则主要导致腹膜（peritoneum）与腹膜后（retroperitoneum）受累（11例中4例，36.4%，p = 0.01）。

研究结论：本研究提示基线基因突变可能对ECD的自然病程（natural history）存在影响，强调了对所有患者开展全面基因分析的重要性，最终目标是为每位患者探索潜在的靶向治疗（targeted therapy）方案。