Discussion

RASopathies are a family of disorders involving mutations in the Ras/mitogen activated protein kinase pathway (Ras-MAPK pathway) controlling cell-cycle arrest, apoptosis, cell survival, cell growth, cell migration, cytoskeletal remodelling, and transcription. ^{Reference Gripp, Morse and Axelrad1} These mutations increased activation of the Ras pathway and can cause increased expression of target genes cyclin D1, cMYC, BCl2 with the end result being uncontrolled cell growth. In these syndromes, common symptoms include unusual facial features, developmental delay, cardiac anomalies, skeletal anomalies, poor feeding, and growth. ^{Reference Jindal, Goyal, Burdine, Rauen and Shvartsman2} The most well-known RASopathies are Noonan syndrome and neurofibromatosis 1 and 2, but this family of disorders also includes Costello syndrome, Legius syndrome, and cardiofaciocutaneous syndrome (CFC).

In RASopathies, the highest mortality features are cardiac in nature, with studies showing only less than 34% of infants with hypertrophic cardiomyopathy in Noonan syndrome survive past one year. ^{Reference Andelfinger, Marquis and Raboisson3–Reference Geddes, Ware, Hussain and Parent4} Unfortunately, 85% of Costello patients present with cardiac disease, including hypertrophic cardiomyopathy, CHDs, and dysrhythmias. ^{Reference Andelfinger, Marquis and Raboisson3} While isolated non-reentrant atrial tachycardia has in the past been most associated specifically with Costello syndrome, more recent case reports suggest that this is seen in a variety of RASopathies as well. Ectopic and multifocal atrial tachycardias associated with RASopathies are often refractory to standard beta blocker management and can occur independently of hypertrophic cardiomyopathy. ^{Reference Levin, Saitta and Gripp5–Reference Meisner, Bradley and Russell6}

Trametinib is a selective reversible allosteric inhibitor of Mitogen-activated protein kinase kinase 1 (MEK1) and Mitogen-activated protein kinase kinase 2 (MEK2 activity), approved by the United States Federal Drug Association to treat specific cancers due to mutation in the proto-onco gene serine/threonine-protein kinase B-Raf (BRAF mutations). It acts as an inhibitor of the Ras-MAPK pathway that is downstream of upregulating RASopathy mutations, including the HRAS mutation of Costello syndrome. ^{Reference Andelfinger, Marquis and Raboisson3}

Several case reports have shown trametinib to benefit certain RASopathy patients with hypertrophic cardiomyopathy, lymphatic abnormalities, and concurrent arrhythmias. ^{Reference Andelfinger, Marquis and Raboisson3–Reference Geddes, Ware, Hussain and Parent4,Reference Hebron, Hernandez and Yohe7} These initial models suggested that inhibition of MEK1 and MEK2 acts via reversing excess cell proliferation of the myocardium thus causing alleviation of arrythmias secondary to hypertrophy. However, some studies suggest the cardiac symptoms of RASopathies are primarily due to calcium dysregulation from the Ras-MAPK pathway’s downstream impact on intracellular calcium ion channels. ^{Reference Levin, Saitta and Gripp5} Cases such as these provided the foundation for use of trametinib in this case. The patient’s response to treatment with a disease-modifying agent supports that the arrythmia was secondary to the genetic disease process and improved via downstream effects of trametinib. Knowledge of the pathophysiology behind the mechanism of action of this arrythmia and trametinib’s role in management remains limited and further study is warranted. While further study is pursued, trametinib should be considered as a disease-modifying therapy for RASopathy patients with arrhythmia who are refractory to conventional treatment.

It is worth noting that trametinib has been associated with several major side effects including dermatitis, haemorrhage, venous thrombosis, colitis, ocular toxicity, interstitial lung disease, and more. Routine monitoring for these complications is necessary. This patient was started at a low dose of 0.125 mg daily, which was not titrated due to risk of adverse events and the desired effect had been achieved. Case reports using targeted therapy for RASopathies have yet to report long-term management strategies, but due to the mechanism of action, it is likely that patients will need to continue trametinib indefinitely to maintain remission of disease.

There are additional limitations for use of trametinib in RASopathies due to the variety of possible gene mutations. If the patient also has a significant mutation in the mammalian target of rapamycin (mTOR) pathway below MEK in the signal cascade, then trametinib will likely be less effective. Likewise, the mutations causing CFC may affect the binding site of trametinib, rendering it ineffective. ^{Reference Hebron, Hernandez and Yohe7}

This case suggests that trametinib can be an effective therapeutic option for management of arrhythmias in patients with certain RASopathies, even in the absence of hypertrophic cardiomyopathy. Utilising the lowest dose necessary to achieve desired outcome may help to avoid side effects. Routine monitoring for adverse effects should be performed. Further research should include determining optimal paediatric dosing, long term treatment outcomes, and defining appropriate duration of treatment for this patient population.