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

Abstract

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.

• Authors: Yoav Dori, Chris Smith, Erin Pinto, Kristen Snyder, Michael E March, Hakon Hakonarson, Jean Belasco
• Journal: Pediatrics (Pediatrics) Vol. 146 Issue 6 (12 2020) ISSN: 1098-4275 [Electronic] United States
• PMID: 33219052 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 by the American Academy of Pediatrics.

Chemical References

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

Topics

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