Pediatrics B, Edmond and Lili Safra Children's Hospital, Chaim Sheba Medical Center at Tel Hashomer, Ramat-Gan, Israel.
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Pediatr Res. 2023 Dec;94(6):1911-1915. doi: 10.1038/s41390-022-01986-0. Epub 2022 Mar 4.
Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy.
The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay.
Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib.
Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies.
This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.
卡波西样淋巴管瘤病（KLA）是一种复杂的淋巴异常，最常累及纵隔、肺、皮肤和骨骼，目前治疗方法有限。近年来，RAS-MAPK 通路突变被认为是几种复杂淋巴异常发病机制的基础。具体来说，大多数 KLA 患者存在激活型NRAS 突变（p.Q61R）。最近的报告表明，MEK 抑制剂曲美替尼治疗携带 ARAF 和 SOS1 功能获得性突变以及 CBL 基因（RAS-MAPK 通路的负调控因子）功能丧失性突变的复杂淋巴异常患者具有良好的疗效。我们报告了一例 9 岁儿童，患有严重的 KLA，通过血浆衍生的无细胞 DNA 检测到典型的 NRAS（p.Q61R）突变，对曲美替尼治疗有反应。
使用液滴数字 PCR 从血浆 cfDNA 中检测 NRAS 体细胞突变。使用三维球体发芽测定法对曲美替尼对突变型 NRAS 影响的淋巴内皮细胞的体外活性进行了同时的研究。
曲美替尼治疗导致终身血小板减少症得到缓解，肺功能测试和整体健康状况得到改善，同时停止了长期的全身皮质类固醇治疗。对表达突变型 NRAS 的细胞进行的同时研究表明，淋巴管生成能力增强，同时 RAS-MAPK 和 PI3K-AKT-mTOR 通路过度激活，这两种作用均被曲美替尼逆转。
曲美替尼治疗可显著改变 RAS 通路相关淋巴异常患者的预后。
这是首例成功应用曲美替尼治疗携带最典型 NRAS p.Q61R 突变的 KLA 患者的描述。治疗可以显著改变 RAS 通路相关淋巴异常患者的预后。我们设计了 KLA 的体外模型，为疾病发病机制的进一步研究提供了一种可重复的方法。突变型 NRAS p.Q61R 细胞表现出增强的淋巴管生成能力。
