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.

<p>Prenatal Diagnosis of Pfeiffer Syndrome Patient with FGFR2 C.940-1G>C Variant: A Case Report</p>

“…2 We present the clinical findings of a patient with SP diagnosed inutero due to a variant in FRFR2 gene. [8][9][10][11][12][13] Although most cases are diagnosed in their neonatal stage, prenatal diagnosis is possible. Three-dimensional obstetric ultrasound is the first-line diagnostic tool for suspected PS, being useful to verify suture closure in the third trimester of pregnancy for the most severe cases 14 although the diagnosis with lower gestational ages has been reported.…”

Clinical genetics of craniosynostosis

“…Recent clinical updates have been published on prevalence of tracheal cartilaginous sleeve [15] and progressive postnatal pansynostosis [16] in syndromic craniosynostosis, both of which highlight the particularly high burden of complications arising from FGFR2 mutations. Additional FGFR2 mutation-focused phenotype studies have been published on foramen magnum size [17], ophthalmic complications [18] and intestinal malrotation [19]. Complications were found to be differentially enriched in different syndromes: tracheal sleeve, proptosis and exposure keratitis were particularly associated with Pfeiffer syndrome, whereas insidious postnatal pansynostosis was most common in Crouzon syndrome.…”

Bones, Glands, Ears and More: The Multiple Roles of FGF10 in Craniofacial Development

“…A major group of human craniosynostosis syndromes, including Apert, Crouzon, or Pfeiffer syndromes, is caused by mutations leading to overactivation of Fgf receptors. Apert and Crouzon syndromes are caused by mutations in FGFR2 that increase affinity of the receptor for the ligand, and Pfeiffer syndrome is caused by mutations in either FGFR2 or FGFR1 ( Schell et al, 1995 ; Anderson et al, 1998 ; Hibberd et al, 2016 ). The search for specific ligands involved in the process of fusion of the sutures revealed that FGF10 can play a significant role in proper formation of skull shape.…”