Effects of MEK-inhibitor treatment in infants with lymphatic abnormalities in noonan syndrome.

Noonan syndrome (NS) is a genetic disorder associated with dysregulation of the RAS/MAPK signaling pathway and is frequently accompanied by lymphatic abnormalities. These lymphatic complications can lead to severe clinical manifestations, including chylous effusions and respiratory compromise, particularly in infants. Management of such complications is often challenging, and conventional therapies may be insufficient in severe cases. Recently, targeted therapies affecting the RAS/MAPK pathway, such as MEK inhibitors, have emerged as a potential treatment option for patients with refractory lymphatic disease. In this context, the present study describes our initial clinical experience with MEK inhibitor therapy using Trametinib in infants with Noonan syndrome and lymphatic abnormalities. Six infants with genetically confirmed NS (3 female, 3 male; mean age 0.5 ± 0.72 years) presenting with lymphatic abnormalities and intractable chylous effusions were treated with Trametinib. Clinical presentation was assessed at baseline as well as at 6-week and 1-year follow-up. Dedicated MR lymphangiography was performed at baseline and after one year, and lymphatic abnormalities were rated using a 6-point Likert scale. Possible adverse events were documented. After one year of therapy, considerable clinical improvement was observed in all patients. None of the patients required chest drainage and no clinical signs of chylothorax were present. Follow-up MR lymphangiography demonstrated a decrease in pleural effusions in all cases, with no residual fluid in three patients and only minimal residual fluid in the remaining three. Pathologic pulmonary and pleural lymphatic perfusion decreased in all cases (median 3 vs. 1). However, lymphatic imaging did not demonstrate normalization of lymphatic anatomy or flow in any patient. Overall, in this exploratory analysis Trametinib therapy resulted in considerable clinical improvement in infants with lymphatic abnormalities associated with Noonan syndrome, while MR lymphangiography showed only limited remodeling of the central lymphatic system over one year of treatment without normalization of lymphatic anatomy or lymphatic flow.