Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies

Katherine A Rauen, Anuradha Banerjee, W. Robert Bishop, Jennifer O. Lauchle, Frank Mccormick, Martin Mcmahon, Teri Melese, Pamela N. Munster, Sorena Nadaf, Roger J. Packer, Judith Sebolt-Leopold, David H. Viskochil

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


The RASopathies, one of the largest groups of multiple congenital anomaly syndromes known, are caused by germline mutations in various genes encoding components of the Ras/mitogen-activated protein kinase (MAPK) pathway. The RASopathies have many overlapping characteristics, including craniofacial manifestations, cardiac malformations, cutaneous, musculoskeletal, gastrointestinal, and ocular abnormalities, neurocognitive impairment, hypotonia, and an increased risk of developing cancer. Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome are two of the more rare RASopathies. CS is caused by activating mutations in HRAS, and CFC is caused by dysregulation of signaling in the Ras/MAPK pathway due to mutations in BRAF, MEK1, or MEK2. The Ras/MAPK pathway, which has been well-studied in cancer, is an attractive target for inhibition in the treatment of various malignancies utilizing small molecule therapeutics that specifically inhibit the pathway. With many inhibitors of the Ras/MAPK pathway in clinical trials, the notion of using these molecules to ameliorate developmental defects in CS and CFC is under consideration. CS and CFC, like other syndromes in their class, have a progressive phenotype and may be amenable to inhibition or normalization of signaling.

Original languageEnglish (US)
Pages (from-to)136-146
Number of pages11
JournalAmerican Journal of Medical Genetics, Part C: Seminars in Medical Genetics
Issue number2
StatePublished - May 15 2011
Externally publishedYes


  • BRAF inhibitor
  • Cardio-facio-cutaneous syndrome
  • Clinical trial
  • Costello syndrome
  • Farnesyl transferase inhibitor
  • MEK inhibitor
  • Neurofibromatosis type 1
  • Ras/MAPK
  • RASopathy
  • Signal transduction pathway
  • Therapy

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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