title: Costello and cardio-facio-cutaneous syndromes: Moving toward clinical trials in RASopathies.
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.
authors.affiliation: Division of Medical Genetics at the University of California at San Francisco, USA. rauenk@peds.ucsf.edu
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.forename: Anuradha
authors.initials: A
authors.lastname: Banerjee
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Lauchle
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.forename: Teri
authors.initials: T
authors.lastname: Melese
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
authors.forename: Sorena
authors.initials: S
authors.lastname: Nadaf
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
authors.forename: Judith
authors.initials: J
authors.lastname: Sebolt-Leopold
authors.forename: David H
authors.initials: DH
authors.lastname: Viskochil
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D056685:Costello Syndrome / Q000188:drug therapy / Q000235:genetics*; D004476:Ectodermal Dysplasia / Q000188:drug therapy / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000188:drug therapy / Q000235:genetics; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006330:Heart Defects, Congenital / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D009456:Neurofibromatosis 1 / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D055818:Public-Private Sector Partnerships; D012107:Research Design; D015398:Signal Transduction / Q000235:genetics*; D048490:raf Kinases / Q000037:antagonists & inhibitors
chemical_list: D051231:Farnesyltranstransferase; D048490:raf Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D016283:Proto-Oncogene Proteins p21(ras)