Erdheim–Chester disease (ECD) is a histiocytic neoplasm that predominantly harbors mitogen-activated protein kinase (MAPK) pathway variants. MAPK inhibitors typically are effective treatments, but mutations outside the MAPK pathway, such as CSF1R variants, may cause refractory ECD. We describe a patient with a novel somatic mutation in CSF1R (CSF1R^{R549_E554delinsQ}) that resulted in refractory ECD affecting the central nervous system. Cell model studies, RNA sequencing analysis, and in silico protein modeling suggested that she had a gain-of-function mutation occurring in a region critical for autoinhibition. The patient was treated with pexidartinib, a CSF1R inhibitor, and has had a complete clinical and metabolic response lasting more than 1.5 years to date. To our knowledge, this is the first report to describe successful treatment of a patient with ECD by using an agent that specifically targets CSF1R. This case also highlights the critical role of individualized molecular profiling to identify novel therapeutic targets in ECD.

中文翻译：

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CSF1R 突变 Erdheim–Chester 病患者对 pexidartinib 的持续、完全反应

Erdheim-Chester 病 (ECD) 是一种组织细胞肿瘤，主要含有丝裂原活化蛋白激酶 (MAPK) 通路变异。MAPK 抑制剂通常是有效的治疗方法，但 MAPK 通路外的突变（例如CSF1R变体）可能会导致难治性 ECD。我们描述了一名在CSF1R ( CSF1R ^{R549_E554delinsQ} )中出现新型体细胞突变的患者，该突变导致难治性 ECD 影响中枢神经系统。细胞模型研究、RNA 测序分析和电子计算机蛋白质模型表明，她在对自身抑制至关重要的区域发生了功能获得性突变。该患者接受了一种 CSF1R 抑制剂 pexidartinib 治疗，迄今已获得持续超过 1.5 年的完整临床和代谢反应。据我们所知，这是第一份描述使用专门针对 CSF1R 的药物成功治疗 ECD 患者的报告。该案例还强调了个体化分子谱分析在 ECD 中识别新治疗靶点的关键作用。