Erika K. S. M. Leenders, Vera C. van den Brink, Lotte E. R. Kleimeier, Danielle T. J. Woutersen, Catelijne H. Coppens, Jeroen den Hertog, Willemijn M. Klein, Tuula Rinne, Sabine L. Vrancken, Saskia N. de Wildt, Jos M. T. Draaisma, Joris Fuijkschot
Radboud University Medical Center and Amalia Children’s Hospital. University Medical Center Utrecht. Leiden University.
Netherlands
International Journal of Molecular Sciences
Int J Mol Sci 2025; 26:
DOI: 10.3390/ijms26136126
Abstract
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.
Category
Primary Pulmonary Lymphatic Disease
Genetic Factors Associated with Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes