Trametinib for Refractory Chylous Effusions and Systemic Complications in Children with Noonan Syndrome

Objective To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome. Study design Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstreamMEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures. Results Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject. Conclusions Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety. (J Pediatr 2022;248:81-8).

Automated summary

This study evaluated the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in patients with Noonan syndrome. The results showed that trametinib improved lymphatic leak and normalized growth, cardiac, and hematologic measurements. Trametinib was safely administered, but larger studies are needed to confirm efficacy and assess long-term safety.