title: Craniosynostosis and Noonan syndrome with KRAS mutations: Expanding the phenotype with a case report and review of the literature.
abstract: Noonan syndrome (NS) is a multiple congenital anomaly syndrome caused by germline mutations in genes coding for components of the Ras-mitogen-activated protein kinase (RAS-MAPK) pathway. Features include short stature, characteristic facies, congenital heart anomalies, and developmental delay. While there is considerable clinical heterogeneity in NS, craniosynostosis is not a common feature of the condition. Here, we report on a 2 month-old girl with Noonan syndrome associated with a de novo mutation in KRAS (p.P34Q) and premature closure of the sagittal suture. We provide a review of the literature of germline KRAS mutations and find that approximately 10% of published cases have craniosynostosis. Our findings expand on the NS phenotype and suggest that germline mutations in the KRAS gene are causally involved in craniosynostosis, supporting the role of the RAS-MAPK pathway as a mediator of aberrant bone growth in cranial sutures. The inclusion of craniosynostosis as a possible phenotype in KRAS-associated Noonan Syndrome has implications in the differential diagnosis and surgical management of individuals with craniosynostosis.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yonit A
authors.initials: YA
authors.lastname: Addissie
authors.affiliation: Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi, India.
authors.forename: Udhaya
authors.initials: U
authors.lastname: Kotecha
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Hart
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Ariel F
authors.initials: AF
authors.lastname: Martinez
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Paul
authors.initials: P
authors.lastname: Kruszka
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D003398:Craniosynostoses / Q000150:complications* / Q000235:genetics*; D059472:Exome / Q000235:genetics; D019066:Facies; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D007231:Infant, Newborn; D009154:Mutation / Q000235:genetics*; D009634:Noonan Syndrome / Q000150:complications* / Q000235:genetics*; D010641:Phenotype; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012886:Skull / Q000000981:diagnostic imaging; D014057:Tomography, X-Ray Computed
chemical_list: C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: KRAS; Noonan syndrome; RAS-MAPK; RASopathy; craniosynostosis