The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.

Original languageEnglish
Pages (from-to)541-560
Number of pages20
JournalAmerican Journal of Medical Genetics, Part C: Seminars in Medical Genetics
Issue number4
StatePublished - Dec 2022


  • MEK inhibition
  • Noonan syndrome
  • RASopathies
  • cardiofaciocutaneous syndrome
  • mTOR inhibition


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