A Case Report of Using MEK Inhibition, Trametinib for Treatment of Noonan Syndrome

Noonan syndrome is an autosomal-dominant disorder associated with mutations in the gene encoding of RAS/MAPK pathway, leading to specific cardiac consequences. Patients with RASopathies, such as those with hypertrophic cardiomyopathy, often have a worse prognosis. The present case study involved a 1-year-8-month-old patient with biventricular hypertrophy, who was treated with an allosteric MEK1 inhibitor due to the severity of their condition.

The patient, a newborn, was admitted on day five of life with respiratory distress and a detected heart murmur. Additional symptoms included trial ectopic tachycardia, hyperinsulinism, facial dysmorphia, and cryptorchidism. Genetic sequencing panel revealed missense mutation in the RAF1 gene. Echocardiography performed upon admission showed aortic coarctation and dysplastic atrioventricular valves with discrete turbulent flow across the left ventricular outflow tract. Surgical correction for coarctation occurred at two months, but the patient experienced rapid progression in cardiac hypertrophy.

The patient was then treated with trametinib, which was initiated at a starting dosage of 0.02 mg/kg/d. Initial echocardiography indicated severe hypertrophy, but after starting trametinib, there was significant improvement, including reduced septal thickness and decreased proBNP levels.

Thus, this case highlights the role of understanding molecular basis of genetically determined disorders in developing targeted therapies, indicating that trametinib is effective and safe for treating cardiac manifestations in children with Noonan syndrome.

Source: Krasic S, Đuric I, Ilic N, Sarajlija A, Nesic D, Vukomanovic V. Treatment of RAF1-Related Biventricular Hypertrophy and Double Chamber Right Ventricle by MEK Inhibition Using Trametinib. Indian J Pediatr. 2024 Oct 28. doi: 10.1007/s12098-024-05305-9. Epub ahead of print. PMID: 39466569.