title: FGFR-associated craniosynostosis syndromes and gastrointestinal defects.
abstract: Craniosynostosis is a relatively common birth defect characterized by the premature fusion of one or more cranial sutures. Examples of craniosynostosis syndromes include Crouzon (CS), Pfeiffer (PS), and Apert (AS) syndrome, with clinical characteristics such as midface hypoplasia, hypertelorism, and in some cases, limb defects. Mutations in Fibroblast Growth Factor Receptor-2 comprise the majority of known mutations in syndromic forms of craniosynostosis. A number of clinical reports of FGFR-associated craniosynostosis patients and mouse mutants have been linked to gastrointestinal tract (GIT) disorders, leading to the hypothesis of a direct link between FGFR-associated craniosynostosis syndromes and GIT malformations. We conducted an investigation to determine GIT symptoms in a sample of FGFR-associated craniosynostosis syndrome patients and a mouse model of CS containing a mutation (W290R) in Fgfr2. We found that, compared to the general population, the incidence of intestinal/bowel malrotation (IM) was present at a higher level in our sample population of patients with FGFR-associated craniosynostosis syndromes. We also showed that the mouse model of CS had an increased incidence of cecal displacement, suggestive of IM. These findings suggest a direct relationship between FGFR-related craniosynostosis syndromes and GIT malformations. Our study may shed further light on the potential widespread impact FGFR mutations on different developmental systems. Based on reports of GIT malformations in children with craniosynostosis syndromes and substantiation with our animal model, GIT malformations should be considered in any child with an FGFR2-associated craniosynostosis syndrome. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Faculty of Dentistry, University of Toronto, Toronto, Canada.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Hibberd
authors.affiliation: Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bowdin
authors.affiliation: Faculty of Dentistry, University of Toronto, Toronto, Canada.
authors.forename: Yamini
authors.initials: Y
authors.lastname: Arudchelvan
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Forrest
authors.affiliation: Department of Orthopaedic Surgery, San Francisco General Hospital, Trauma Institute, School of Medicine, The University of California at San Francisco, San Francisco, California.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Brakora
authors.affiliation: Department of Orthopaedic Surgery, San Francisco General Hospital, Trauma Institute, School of Medicine, The University of California at San Francisco, San Francisco, California.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Marcucio
authors.affiliation: Faculty of Dentistry, University of Toronto, Toronto, Canada.
authors.forename: Siew-Ging
authors.initials: SG
authors.lastname: Gong
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D001706:Biopsy; D003398:Craniosynostoses / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D041981:Gastrointestinal Tract / Q000002:abnormalities*; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D012189:Retrospective Studies; D013577:Syndrome
chemical_list: D017468:Receptors, Fibroblast Growth Factor
keywords: Apert syndrome; Crouzon syndrome; FGFR2 mutations; Pfeiffer syndrome; intestinal malrotation