MEK Inhibition in a Newborn with RAF1 -Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease

• Published in: Genes 2021-12, Vol.13 (1), p.6
• Main Authors: Mussa, Alessandro, Carli, Diana, Giorgio, Elisa, Villar, Anna Maria, Cardaropoli, Simona, Carbonara, Caterina, Campagnoli, Maria Francesca, Galletto, Paolo, Palumbo, Martina, Olivieri, Simone, Isella, Claudio, Andelfinger, Gregor, Tartaglia, Marco, Botta, Giovanni, Brusco, Alfredo, Medico, Enzo, Ferrero, Giovanni Battista
• Format: Article
• Language: English
• Subjects: Autopsy; Blood; Cardiomyopathy; Cardiomyopathy, Hypertrophic - drug therapy; Congestive heart failure; Fatal Outcome; Female; Gene expression; Humans; Hydrocephalus; Hypertension; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - prevention & control; Hypoxia; Infant, Newborn; Kinases; Lung diseases; MAP kinase; MAP Kinase Kinase Kinases - antagonists & inhibitors; Noonan Syndrome - genetics; Noonan's syndrome; Obstructive lung disease; Patients; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-raf - genetics; Pulmonary arteries; Pulmonary artery; Pulmonary hypertension; Signal transduction; Transcription; Transcriptomes; Ultrasonic imaging; Values; Vascular diseases; Veins & arteries; Ventilators; Ventriculoperitoneal shunt; Whole Exome Sequencing
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes13010006

The :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 :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 -associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.