Abstract Body (Do not enter title and authors here): Backgound: The RASopathies are developmental syndromes resulting from variants in the RAS/mitogen-activated protein (MAPK) cascade. The vast majority of RASopathy-causing variants lead to a gain of function in RAS-MAPK signaling. This has motivated compassionate use of MEK inhibition (MEKi) for rare, but potentially lethal complications such as hypertrophic cardiomyopathy and lymphatic disease. However, the most recurrent cardiac complication in RASopathies is pulmonary valve stenosis (PVS). PVS may require balloon valvuloplasty (BV) and can recur over time.

Research question: Can MEKi be successfully used for recurrent PVS in RASopathy-patients?

Aim: To report compassionate use of MEKi (trametinib) in recurring RASopathy-associated PVS.

Method: Retrospective, single-center study at CHU Sainte Justine, Montreal, from 2021 to 2024.

Results: After informed parental consent for off-label compassionate use of trametinib, four patients with recurrence of severe PVS after balloon valvuloplasty (>= 80 mmHg) had a total of 5 treatment episodes. Three patients were female, and one patient was male. The following genotypes were represented: Case 1, RIT1 A77V; case 2, PTPN11 N308D; case 3, RIT1 F82V, del22q11dist; case 4, PTPN11 Q110G, dup Xp22.13 (VUS), dup 16p11.2. Initial BV was carried out between three weeks and 10 months of age. Recurrence of PVS was noted between 4 days and 6 months after BV. Peak gradients at recurrence measured 72 -96 mmHg, and decreased to 40 – 64 mmHg (Dp -10 to -40 mmHg) at one to three months after treatment. Treatment had to be stopped in three cases for cutaneous side effects, with a rapid second recurrence in one case, which again responded to MEKi. PVS residual gradients at latest follow-up ranged from 30 – 69 mmHg. In all four patients, repeat catheter intervention or surgery could be avoided. In three out of four RASopathy patients with severe recurrent PVS after initial BV, we observe mild or moderate residual PVS. The patient with residual severe PS also carries a del22q11.2dist, which renders her haploinsufficient for LZTR1, a potential disease/treatment modifier within the RAS-MAPK cascade.

Conclusion: Our results potentially expand the indications for MEKi in selected cases of RASopathy-associated recurrence of PVS and suggest an alternative to surgery or repeat catheterization. However, this case series is limited by the lack of an adequate contemporaneous, genotyped control cohort and its retrospective nature.