Leenders Erika K S M, van den Brink Vera C, Kleimeier Lotte E R, Woutersen Danielle T J, Coppens Catelijne H, den Hertog Jeroen, Klein Willemijn M, Rinne Tuula, Vrancken Sabine L, de Wildt Saskia N, Draaisma Jos M T, Fuijkschot Joris
Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.
Int J Mol Sci. 2025 Jun 26;26(13):6126. doi: 10.3390/ijms26136126.
Recent diagnostic advances reveal that lymphatic disease in Noonan syndrome (NS) and other NS-like RASopathies often stems from central conducting lymphatic anomalies (CCLAs). The RAS/MAPK-ERK pathway plays a central role in lymphangiogenesis. Targeting this pathway with MEK-inhibitor trametinib has emerged as a promising therapeutic strategy for managing CCLAs in patients with NS-like RASopathies. This case series assessed the clinical outcomes of trametinib therapy in eight patients with NS-like RASopathies and CCLA, each offering unique insights into the therapeutic efficacy of MEK inhibition. In infants, a lower dose of 0.01 mg/kg/day and earlier discontinuation of trametinib therapy effectively alleviated the symptoms of congenital chylothorax and rescued the lymphatic phenotype, compared to similar published cases. Moreover, four patients aged >11 y showed a slower response and did not achieve complete symptomatic recovery. In conclusion, it is advised to consider trametinib therapy for patients with severe, therapy-refractory CCLA in patients with NS-like RASopathies. However, individual responses to trametinib therapy may vary, with some patients demonstrating more favorable outcomes than others. Further investigation into potential enhancers and suppressors of the lymphatic phenotype is necessary for more accurate treatment predictions. While these factors are likely genetic, we cannot rule out other intrinsic or physiological factors.
近期的诊断进展表明，努南综合征（NS）及其他类NS型RAS病中的淋巴疾病通常源于中央传导性淋巴管异常（CCLA）。RAS/MAPK-ERK信号通路在淋巴管生成中起核心作用。使用MEK抑制剂曲美替尼靶向该信号通路已成为治疗类NS型RAS病患者CCLA的一种有前景的治疗策略。本病例系列评估了曲美替尼治疗8例类NS型RAS病和CCLA患者的临床结局，每例患者都为MEK抑制的治疗效果提供了独特见解。与已发表的类似病例相比，婴儿使用较低剂量0.01 mg/kg/天并更早停用曲美替尼治疗可有效缓解先天性乳糜胸症状并挽救淋巴管表型。此外，4例年龄大于11岁的患者反应较慢，未实现症状完全缓解。总之，对于类NS型RAS病中患有严重、难治性CCLA的患者，建议考虑使用曲美替尼治疗。然而，患者对曲美替尼治疗的个体反应可能不同，部分患者的预后比其他患者更好。为了进行更准确的治疗预测，有必要进一步研究淋巴管表型的潜在增强剂和抑制剂。虽然这些因素可能是遗传性的，但我们不能排除其他内在或生理因素。
