title: Neonatal pulmonary arterial hypertension and Noonan syndrome: two fatal cases with a specific RAF1 mutation.
abstract: Mutations in RAF1 are associated with Noonan syndrome and hypertrophic cardiomyopathy. We present two infants with Noonan syndrome and an identical RAF1 mutation, p.Ser257Leu (c.770C>T), who developed severe pulmonary arterial hypertension (PAH) that proved to be fatal. The RAF1 gene encodes Raf-1 kinase, part of the Ras/mitogen-activated kinase (MAPK) signaling pathway, which has been linked to the development of PAH. This specific mutation has been associated with dephosphorylation of a critical serine residue and constitutive activation of the Raf-1 kinase. These two cases suggest that abnormal activation of the Ras/MAPK pathway may play a significant role in the development of pulmonary vascular disease in the subset of patients with Noonan syndrome and a specific RAF1 mutation.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Hopper
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Feinstein
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Manning
authors.forename: William
authors.initials: W
authors.lastname: Benitz
authors.forename: Louanne
authors.initials: L
authors.lastname: Hudgins
mesh_terms: D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000235:genetics; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000175:diagnosis* / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*
chemical_list: D019908:Proto-Oncogene Proteins c-raf
keywords: Noonan syndrome; Raf-1; pulmonary arterial hypertension