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

New prospectives on treatment opportunities in RASopathies

“…A total of six patients with NS and severe lymphovascular disease have now been reported as well in addition to a report of two patients with ARAF pathogenic variants and central conducting lymphatic anomaly (this latter condition is extremely rare and has not usually been categorized as a RASopathy) (Dori et al, 2020;D. Li et al, 2019;Lioncino et al, 2022;Nakano et al, 2022). In all of these patients, significant improvement or resolution of lymphovascular disease was reported, with initial response starting at around 2 days to 1 month after treatment initiation to sustained response at 12 months after treatment initiation (example in Figure 5).…”

“…Subsequent to the publication of the mechanistic treatment of two infants with NS‐related HCM with trametinib, several other publications described experiences with MEKi for severe manifestations in RASopathies (Dori et al, 2020; D. Li et al, 2019; Meisner, Bradley, & Russell, 2021; Mussa et al, 2021; Nakano et al, 2022). Excluding our initial study, the published evidence now reports amelioration in three additional cases with cardiovascular issues (Lioncino et al, 2022; Meisner et al, 2021; Mussa et al, 2021).…”

Narrative review of pediatric heart failure in the age of precision medicine

“…Three groups have now described cases of four patients with observed improvement in patients with NS and HCM after use of trametinib (36)(37)(38). Additionally, studies have described resolution of arrhythmia and lymphatic abnormalities after initiation of MEK inhibition therapy (38)(39)(40). More investigation is needed in this domain, though there are some encouraging early reports of this medical therapy for a patient population commonly thought to only have cardiac transplantation as a therapeutic option (33).…”

The heart in RASopathies

“…F I G U R E 3 Determinants and management of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy associated with RASopathies conditions (Dori et al, 2020;Meisner, Bradley, & Russell, 2021;Nakano et al, 2022). However, the absence of clinical trials or large studies evaluating the risk and benefits of these drugs limits their use in clinical practice.…”

“…Treatment of RASopathies with therapies targeting the RAS/MAPK cascade (in Noonan syndrome) or the PI3K/AKT/mTor pathway (in NSML) are limited to case reports suggesting a beneficial effect of these therapeutic approaches in improving clinical status and resulting in LVH regression (Andelfinger et al, 2019; Marin et al, 2011; Mussa et al, 2021; Nakano et al, 2022). MEK inhibition, specifically, has also been reported as a treatment for arrythmia and for lymphatic dysplasia, each of which can be isolated or comorbid conditions in children with RASopathies and cardiomyopathy, further supporting the efficacy of targeted therapy in RASopathy‐associated conditions (Dori et al, 2020; Meisner, Bradley, & Russell, 2021; Nakano et al, 2022). However, the absence of clinical trials or large studies evaluating the risk and benefits of these drugs limits their use in clinical practice.…”