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

Taizo A Nakano; Alexander W Rankin; Aparna Annam; Ann M Kulungowski; Leslie M McCallen; Lauren R Hill; Kathryn C Chatfield

doi:10.1016/j.jpeds.2022.05.030

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

J Pediatr. 2022 Sep:248:81-88.e1. doi: 10.1016/j.jpeds.2022.05.030. Epub 2022 May 20.

Authors

Taizo A Nakano¹, Alexander W Rankin², Aparna Annam³, Ann M Kulungowski⁴, Leslie M McCallen⁵, Lauren R Hill⁶, Kathryn C Chatfield⁷

Affiliations

¹ Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Center for Cancer and Blood Disorders, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO.
² Center for Cancer and Blood Disorders, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO.
³ Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatric Radiology, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO.
⁴ Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatric Surgery, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO.
⁵ Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO.
⁶ Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO.
⁷ Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO. Electronic address: [email protected].

PMID: 35605646
DOI: 10.1016/j.jpeds.2022.05.030

Abstract

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 downstream MEK 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.

Keywords: MEK inhibition; Noonan syndrome; case series; chylous ascites; chylous effusion.

Published by Elsevier Inc.

MeSH terms

Antineoplastic Agents*
Child
Humans
Mitogen-Activated Protein Kinase Kinases
Noonan Syndrome* / complications
Noonan Syndrome* / drug therapy
Noonan Syndrome* / genetics
Pyridones / therapeutic use
Pyrimidinones / therapeutic use

Substances

Antineoplastic Agents
Pyridones
Pyrimidinones
trametinib
Mitogen-Activated Protein Kinase Kinases