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

Am J Med Genet C Semin Med Genet. 2011 May 15;157C(2):136-46. doi: 10.1002/ajmg.c.30294. Epub 2011 Apr 14.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clinical Trials as Topic / methods*
  • Costello Syndrome / drug therapy
  • Costello Syndrome / genetics*
  • Ectodermal Dysplasia / drug therapy
  • Ectodermal Dysplasia / genetics
  • Facies
  • Failure to Thrive / drug therapy
  • Failure to Thrive / genetics
  • Farnesyltranstransferase / antagonists & inhibitors
  • Heart Defects, Congenital / drug therapy
  • Heart Defects, Congenital / genetics
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors
  • Neurofibromatosis 1 / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Public-Private Sector Partnerships
  • Research Design*
  • Signal Transduction / genetics*
  • raf Kinases / antagonists & inhibitors

Substances

  • Farnesyltranstransferase
  • raf Kinases
  • MAP Kinase Kinase 1
  • MAP2K1 protein, human
  • Proto-Oncogene Proteins p21(ras)

Supplementary concepts

  • Cardiofaciocutaneous syndrome