Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation.
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.
DNA, DNA Mutational Analysis, Female, Humans, Infant, Newborn, Mitogen-Activated Protein Kinase Kinases, Mutation, Noonan Syndrome, Phenotype, Protein Kinase Inhibitors, Pyridones, Pyrimidinones, SOS1 Protein
Dori, Y., Smith, C., Pinto, E., Snyder, M., March, M., Hakonarson, H., & Belasco, J. (2020). Severe Lymphatic Disorder Resolved With MEK Inhibition in a Patient With Noonan Syndrome and SOS1 Mutation.. Pediatrics, 146 (6) https://doi.org/10.1542/peds.2020-0167