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.

KRAS-driven model of Gorham-Stout disease effectively treated with trametinib

“…Mutations in RASA1 ( 26 ), EPHB4 ( 27 ), ARAF ( 28 ), NRAS ( 29 , 30 ), and CBL ( 31 ) have been identified in complex lymphatic anomaly patients. Additionally, patients with Noonan syndrome with RAS signaling pathway mutations can have lymphatic dysplasia, lymphedema, and retrograde lymph flow ( 32 – 34 ). Thus, GSD seems to be part of this wide spectrum of lymphatic dysplasias caused by abnormal RAS signaling.…”

Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review

“…This is increasingly important because the activation of the RAS/MAPK pathway can be inhibited by RAS/ MAPK inhibitors. Recently, this led to the successful use of a MEK inhibitor in patients with NS and severe lymphatic abnormalities [Li et al, 2019;Dori et al, 2020].…”

50 Years Ago in T J P

“…An individual with Noonan syndrome due to a pathogenic variant in SOS1 was diagnosed with a central conducting lymphatic anomaly leading to transfusion-dependent upper gastrointestinal bleeding and protein-losing enteropathy. 9 Trametinib treatment led to a resolution of her symptoms within three months and remodeling of the lymphatic system. 9 In summary, since this first report by Vallet et al, lymphatic complications have become a well-established clinical feature of Noonan syndrome which can be diagnosed by dynamic contrast magnetic resonance lymphangiography and treated by a combination of medical and surgical therapies.…”

“…9 Trametinib treatment led to a resolution of her symptoms within three months and remodeling of the lymphatic system. 9 In summary, since this first report by Vallet et al, lymphatic complications have become a well-established clinical feature of Noonan syndrome which can be diagnosed by dynamic contrast magnetic resonance lymphangiography and treated by a combination of medical and surgical therapies. Further work is needed to understand the natural history of the lymphatic complications in Noonan syndrome and evaluate the utility of trametinib therapy to treat them.…”

“…These include lymphatic embolization, lymphovenous anastomosis, and pharmacologic inhibitors. [7][8][9] Although Noonan syndrome can be caused by monoallelic pathogenic variants in multiple genes, all function to activate signaling through the RAS-MAPK signaling pathway. Trametinib is a MEK1/MEK2 reversible, selective, allosteric inhibitor used in single patient cases to treat lymphatic anomalies caused by activating variants in the RAS-MAPK pathway.…”