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

Genes (Basel). 2021 Dec 21;13(1):6. doi: 10.3390/genes13010006.

Abstract

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.

Keywords: MEK-inhibitor; Noonan syndrome; RASopathies; hypertrophic cardiomyopathy; therapeutics; transcriptomics.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cardiomyopathy, Hypertrophic / drug therapy*
  • Exome Sequencing
  • Fatal Outcome
  • Female
  • Humans
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / prevention & control*
  • Infant, Newborn
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Noonan Syndrome / genetics*
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins c-raf / genetics*

Substances

  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-raf
  • Raf1 protein, human
  • MAP Kinase Kinase Kinases