Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome

Eur J Med Genet. 2022 Nov;65(11):104630. doi: 10.1016/j.ejmg.2022.104630. Epub 2022 Sep 30.

Abstract

Infants with Noonan Syndrome and hypertrophic cardiomyopathy have a poor prognosis and a high mortality especially when diagnosed before six months of age. As for the majority of the RASopathies, no medical treatment has been approved for Noonan Syndrome. Meanwhile, several approved agents targeting the same RAS/MAPK signaling pathway are used in cancer treatment. In this case report we describe a child with Noonan Syndrome caused by a pathogenic RIT1 variant, who developed severe early-onset hypertrophic cardiomyopathy and pulmonary valve stenosis. She received off-label treatment with the MEK-inhibitor trametinib which resulted in complete remission of the cardiac hypertrophy and a significant improvement of the pulmonary valve stenosis. Our case emphasizes the potential of existing cancer agents targeting the RAS/MAPK signaling pathway as successful treatment for RASopathy manifestations.

Keywords: Hypertrophic cardiomyopathy; Noonan syndrome; Pulmonary valve stenosis.

Publication types

  • Case Reports

MeSH terms

  • Cardiomyopathy, Hypertrophic* / drug therapy
  • Cardiomyopathy, Hypertrophic* / genetics
  • Cardiomyopathy, Hypertrophic* / pathology
  • Child
  • Female
  • Humans
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation
  • Noonan Syndrome* / drug therapy
  • Noonan Syndrome* / genetics
  • Pulmonary Valve Stenosis*
  • ras Proteins / genetics

Substances

  • Mitogen-Activated Protein Kinase Kinases
  • ras Proteins
  • RIT1 protein, human