title: Severe craniosynostosis with Noonan syndrome phenotype associated with SHOC2 mutation: clinical evidence of crosslink between FGFR and RAS signaling pathways.
abstract: Dysregulation in the RAS signaling cascade results in a family of malformation syndromes called RASopathies. Meanwhile, alterations in FGFR signaling cascade are responsible for various syndromic forms of craniosynostosis. In general, the phenotypic spectra of RASopathies and craniosynostosis syndromes do not overlap. Recently, however, mutations in ERF, a downstream molecule of the RAS signaling cascade, have been identified as a cause of complex craniosynostosis, suggesting that the RAS and FGFR signaling pathways can interact in the pathogenesis of malformation syndromes. Here, we document a boy with short stature, developmental delay, and severe craniosynostosis involving right coronal, bilateral lambdoid, and sagittal sutures with a de novo mutation in exon1 of SHOC2 (c.4A>G p.Ser2Gly). This observation further supports the existence of a crosslink between the RAS signaling cascade and craniosynostosis. In retrospect, the propositus had physical features suggestive of a dysregulated RAS signaling cascade, such as fetal pleural effusion, fetal hydrops, and atrial tachycardia. In addition to an abnormal cranial shape, which has been reported for this specific mutation, craniosynostosis might be a novel associated phenotype. In conclusion, the phenotypic combination of severe craniosynostosis and RASopathy features observed in the propositus suggests an interaction between the RAS and FGFR signaling cascades. Patients with craniosynostosis in combination with any RASopathy feature may require mutation screening for molecules in the FGFR-RAS signaling cascade.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takenouchi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Tomoru
authors.initials: T
authors.lastname: Miwa
authors.forename: Chiharu
authors.initials: C
authors.lastname: Torii
authors.forename: Rika
authors.initials: R
authors.lastname: Kosaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kishi
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kosaki
mesh_terms: D002675:Child, Preschool; D003398:Craniosynostoses / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D019066:Facies; D056973:Four-Dimensional Computed Tomography; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009154:Mutation; D009634:Noonan Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D012886:Skull / Q000002:abnormalities
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017468:Receptors, Fibroblast Growth Factor; C112913:SHOC2 protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: FGFR; RAS; SHOC2; craniosynostosis