Craniosynostosis in patients with noonan syndrome caused by germline KRAS mutations

Christian P. Kratz, Giuseppe Zampino, Marjolein Kriek, Sarina G. Kant, Chiara Leoni, Francesca Pantaleoni, Anne Marie Oudesluys-Murphy, Concezio D. Rocco, Stephan P. Kloska, Marco Tartaglia, Martin Zenker

Research output: Contribution to journalArticlepeer-review

Abstract

Craniosynostosis, the premature fusion of one or more cranial sutures, is a developmental defect that disrupts the cranial morphogenetic program, leading to variable dysmorphic craniofacial features and associated functional abnormalities. Cranio- synostosis is frequently observed as an associated feature in a number of clinically and genetically heterogeneous syndromic conditions, including a group of disorders caused by activating mutations in genes coding for the fibroblast growth factor receptor family members FGFR1, FGFR2, and FGFR3. In these disorders, dysregulation of intracellular signaling promoted by the aberrant FGFR function is mediated, at least in part, by the RAS-MAPK transduction pathway. Mutations in KRAS, HRAS, and other genes coding for proteins participating in this signaling cascade have recently been identified as underlying Noonan syndrome (NS) and related disorders. While cardinal features of these syndromes include distinctive dysmorphic facial features, reduced growth, congenital heart defects, and variable ectoder- mal anomalies and cognitive impairment, craniosynostosis is not a recognized feature. Here, we report on the occurrence of premature closure of cranial sutures in subjects with NS, and their specific association with mutations in the KRAS gene. These findings highlight the pathogenetic significance of aberrant signaling mediated by the RAS signaling pathway in other known forms of craniosynostosis, and suggest that, even in the absence of radiologically demonstrable synostosis of the calvarian sutures, dysregulated growth and/or suture closure at specific craniofacial sites might contribute to the craniofacial anomalies occurring in NS.

Original languageEnglish
Pages (from-to)1036-1040
Number of pages5
JournalAmerican Journal of Medical Genetics, Part A
Volume149
Issue number5
DOIs
Publication statusPublished - May 2009

Keywords

  • Craniosynostosis
  • KRAS
  • Noonan syndrome

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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