Targeted Therapy for Complex Lymphatic Anomalies in Patients with Noonan Syndrome and Related Disorders

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.

Keywords: CCLA; Noonan syndrome; RASopathies; genetics; lymphatic anomaly; targeted therapy; trametinib.

Figure 1

Intracellular signaling pathways in lymphatic endothelial cells (LECs) mediated through the VEGFC-VEGFR-3 ligand–receptor interaction. The activation of ERK1/2 is believed to initiate the transcription of PROX1, which subsequently triggers a positive feedback loop with VEGFR-3. This loop leads to the downstream activation of the RAS/MAPK pathway, resulting in ERK phosphorylation. This signaling cascade activates nuclear transcription.

Figure 2

DCMRL imaging before treatment of patient #2. Before treatment, contrast did not reach beyond the diaphragm (1). Additionally, severe hepatic (2) and retroperitoneal (3) backflow was observed following intranodal injection.