Background Refractory chylous effusions due to lymphatic dysplasia related to Noonan syndrome cause significant morbidity and mortality due to protein and immunoglobulin losses. Very few cases have been published reporting successful treatment of patients with trametinib where all conventional treatments had failed. Case Summary We present a girl with Noonan syndrome and hypertrophic cardiomyopathy who presented with life threatening refractory chylothorax where all conventional treatment options failed. She was successfully treated with mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib. Discussion MEK inhibition with trametinib is emerging as a possible salvage treatment option for a subset of patients with Noonan syndrome and severe pulmonary lymphangiectasia. More experience is required to establish optimal treatment regimen and long term outcomes.
IntroductionTrametinib is a novel medicine that inhibits the mitogen-activated protein kinase enzyme (MEK), part of the mitogen-activated protein kinases (MAPK) signalling pathway. MAPKs regulates cell behaviour by controlling DNA transcription and subsequent protein production. It was developed to inhibit growth of cancers with an up-regulated MAPK signalling pathway. However, its role is expanding to other conditions which also have a link to MAPK pathways. Noonan syndrome is a genetic multisystem disorder which is linked to dysregulation of MAPK pathway.1Lymphatic abnormalities, most commonly peripheral lymphoedema, are estimated to be present in up to 20% of individuals. There had been one case report in literature whereby a patient with Noonan’s syndrome was treated with MEK inhibitor (trametinib) with remodelling of lymphatic vasculature and complete resolution of symptoms.2SituationA 3-year-old girl with previous intensive care admissions for chylothorax. Background issues included Noonan syndrome (RIT1 mutation), hypertrophic obstructive cardiomyopathy (HOCM), multiple congenital cardiac abnormalities, and spontaneous bowel perforation with a history of high output ileostomy. Previous failed treatments for the chylothoraces using conventional methods included medium-chained triglyceride (MCT) diet, parenteral nutrition (PN) and octreotide. Trametinib was accessed through Novartis’ compassionate scheme as a rescue treatment. Patients treated with MEK inhibitors are likely to encounter adverse effects including skin irritation, diarrhoea, hypertension, vision changes and pneumonitis. Dosage adjustment or withholding treatment is required if renal, hepatic or worsening cardiovascular impairment occurs. It was felt that this child needed a bespoke side effect management protocol due to their comorbidities. The protocol was devised by the pharmacist in consultation with the mother of the child, dietitian, cardiologist and general surgeon. It was important to particularly target the management of skin rashes, increased stoma losses, pneumonitis, hypertension and cardiac impairment. Tolerability and side effects were monitored and the protocol was followed and adjusted as clinically appropriate based on multidisciplinary team (MDT) and family discussions.Lessons LearntThis medication is only routinely used in oncology patients in an outpatient setting. Therefore, the side effect management is based on practice within this patient cohort.3In this situation the treatment was novel, using a theoretical pathway to guide its use. In addition, this child had comorbidities which complicated assessment of side effects. The side effects seen were skin irritation, increased stoma output and nausea, despite proactive management. Skin irritation was managed with short courses of steroid cream and regular emollients under guidance from a dermatologist. High stoma losses (>20 mL/kg) occurred despite maximum dose of loperamide and withholding most enteral nutrition, allowing small bites of fat-free food for comfort, and drinks of rehydration solution as part of a stoma losses replacement plan. In total, 12 weeks of treatment was given, with no chylothorax reoccurrence seen at 10 weeks post-treatment. In conclusion, our experience has demonstrated that it is possible to manage the side effects of trametinib in a patient with multiple comorbidities using a patient centred and MDT approach.ReferencesRoberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome.Lancet2013;381(9863):333–342.Dori Y, Smith C, Pinto E, Snyder K, March ME, Hakonarson H, Belasco J. Severe lymphatic disorder resolved with MEK inhibition in a patient with Noonan syndrome and SOS1 mutation.Pediatrics2020;146(6):e20200167. doi: 10.1542/peds.2020-0167. PMID: 33219052.O’Hare P, Ahmed M, Samrin-Balch L. Guideline for the prescribing of the MEK inhibitor trametinib for the treatment of oncology indications. Great Ormond Street Hospital for Children NHS Foundation Trust. Dec 2017.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.