Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation

Pediatrics. 2020 Dec;146(6):e20200167. doi: 10.1542/peds.2020-0167.


Noonan syndrome is a multiorgan system disorder mediated by genetic defects along the RASknown as RASopathies. It is the second most common syndromic cause of congenital heart disease and, in ∼20% of the cases, is associated with severe lymphatic disorders, including chylothorax and protein-losing enteropathy. Recently, we reported on the use of mitogen-activated protein kinase inhibition in a patient with an ARAF mutation and severe lymphatic disorder leading to an abrupt improvement in symptoms and complete remodeling of the central lymphatic system. Here, we present a patient with Noonan syndrome and severe lymphatic abnormality, leading to transfusion-dependent upper gastrointestinal bleeding and protein-losing enteropathy. The patient stopped responding to medical therapy and underwent several lymphatic interventional procedures, which led only to a temporary improvement in symptoms. Because of a lack of other treatment options, an expanded access approval was obtained, and the patient initiated treatment by mitogen-activated protein kinase inhibition using trametinib. This led to resolution of her symptoms, with complete normalization of her electrolyte levels, hemoglobin, and albumin within 3 months of starting the drug. Similar to the previously reported case, she also had complete and generalized remodeling of her lymphatic system. In patients with RAS pathway defects complicated by a severe lymphatic disorder, inhibition of the RAS-MAPK pathway should be considered as a possible treatment option in patients who failed conventional treatment and might be a first-line treatment in the future.

MeSH terms

  • DNA / genetics*
  • DNA Mutational Analysis
  • Female
  • Humans
  • Infant, Newborn
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mutation*
  • Noonan Syndrome / drug therapy*
  • Noonan Syndrome / genetics
  • Noonan Syndrome / metabolism
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology
  • Pyridones / pharmacology*
  • Pyrimidinones / pharmacology*
  • SOS1 Protein / genetics*
  • SOS1 Protein / metabolism


  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • SOS1 Protein
  • SOS1 protein, human
  • trametinib
  • DNA
  • Mitogen-Activated Protein Kinase Kinases