The RASopathies are a group of syndromes caused by genetic variants that affect the RAS-MAPK signaling pathway, which is essential for cell response to diverse stimuli. These variants functionally converge towards the overactivation of the pathway, leading to various constitutional and mosaic conditions. These syndromes show overlapping though distinct clinical presentations and share congenital heart defects, hypertrophic cardiomyopathy (HCM), and lymphatic dysplasia as major clinical features, with highly variable prevalence and severity. Available treatments have mainly been directed to target the symptoms. However, repurposing MEK inhibitors (MEKis), which were originally developed for cancer treatment, to target evolutive aspects occurring in these disorders is a promising option. Animal models have shown encouraging results in treating various RASopathy manifestations, including HCM and lymphatic abnormalities. Clinical reports have also provided first evidence supporting the effectiveness of MEKi, especially trametinib, in treating life-threatening conditions associated with these disorders. Nevertheless, despite notable improvements, there are adverse events that occur, necessitating careful monitoring. Moreover, there is evidence indicating that multiple pathways can contribute to these disorders, indicating a current need to more accurate understand of the underlying mechanism of the disease to apply an effective targeted therapy. In conclusion, while MEKi holds promise in managing life-threatening complications of RASopathies, dedicated clinical trials are required to establish standardized treatment protocols tailored to take into account the individual needs of each patient and favor a personalized treatment.

Acute myocarditis (AM) is an inflammation of the myocardium with a rapid onset of typically <1 month. The use of anakinra (ANK) for treating inflammatory AM in adults has been recently described; however, while some reports are promising, its efficacy remains debated. Here, we present a case of severe AM with concomitant systemic symptoms [fever, elevated C-reactive protein (CRP)] in a pediatric patient who was successfully treated with high-dose ANK. A literature review of similar published cases is also presented. A 14-year-old boy was admitted for AM with concomitant pericarditis. At disease onset, the patient presented with high fever and elevated CRP (163 mg/L) and troponin I (14,816 ng/L). Treatment with ibuprofen (30 mg/kg/day), intravenous immunoglobulin (80 g in 24 h), and colchicine (0.5 mg per day) were initiated without benefit and with further worsening of contractile function [Ejection Fraction (EF) 26%]. Consequently, inotropic support and intravenous methylprednisolone were started, leading to a partial improvement of EF (45%). Due to the inability to reduce inotropic support, a rescue treatment with ANK (7 mg/kg/day) in continuous intravenous infusion was started, resulting in progressive improvement and normalization of left ventricular systolic function. Our literature review identified five case reports of pediatric AM successfully treated with ANK. Most cases presented elevated inflammatory markers (ferritin and CRP) and/or concomitant pericarditis. We conclude that ANK, especially at high doses, may be useful for treating severe pediatric AM, particularly when associated with severe inflammation and/or pericarditis.