Overview: This article described the case of a preterm infant with severe Noonan syndrome (genetic disorder that prevents normal development in various parts of the body; NS), progressive hypertrophic cardiomyopathy (disease in which the heart muscle becomes abnormally thick; HCM), and pulmonary hypertension (type of high blood pressure that affects the arteries in the lungs and the right side of the heart), treated with trametinib.
Conclusion: Trametinib appeared a promising therapeutic option for hypertrophic cardiomyopathy (disease in which the heart muscle becomes abnormally thick), however, it appeared insufficient to revert pulmonary hypertension (type of high blood pressure that affects the arteries in the lungs and the right side of the heart).
The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was introduced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension contributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.