title: Craniofacial and dental development in Costello syndrome.
abstract: Costello syndrome (CS) is a RASopathy characterized by a wide range of cardiac, musculoskeletal, dermatological, and developmental abnormalities. The RASopathies are defined as a group of syndromes caused by activated Ras/mitogen-activated protein kinase (MAPK) signaling. Specifically, CS is caused by activating mutations in HRAS. Although receptor tyrosine kinase (RTK) signaling, which is upstream of Ras/MAPK, is known to play a critical role in craniofacial and dental development, the craniofacial and dental features of CS have not been systematically defined in a large group of individuals. In order to address this gap in our understanding and fully characterize the CS phenotype, we evaluated the craniofacial and dental phenotype in a large cohort (n = 41) of CS individuals. We confirmed that the craniofacial features common in CS include macrocephaly, bitemporal narrowing, convex facial profile, full cheeks, and large mouth. Additionally, CS patients have a characteristic dental phenotype that includes malocclusion with anterior open bite and posterior crossbite, enamel hypo-mineralization, delayed tooth development and eruption, gingival hyperplasia, thickening of the alveolar ridge, and high palate. Comparison of the craniofacial and dental phenotype in CS with other RASopathies, such as cardio-facio-cutaneous syndrome (CFC), provides insight into the complexities of Ras/MAPK signaling in human craniofacial and dental development.
authors.affiliation: Program in Craniofacial and Mesenchymal Biology, and Division of Craniofacial Anomalies, Department of Orofacial Sciences, University of California San Francisco, San Francisco, California.
authors.forename: Alice F
authors.initials: AF
authors.lastname: Goodwin
authors.forename: Snehlata
authors.initials: S
authors.lastname: Oberoi
authors.forename: Maya
authors.initials: M
authors.lastname: Landan
authors.forename: Cyril
authors.initials: C
authors.lastname: Charles
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Massie
authors.forename: Cecilia
authors.initials: C
authors.lastname: Fairley
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.forename: Ophir D
authors.initials: OD
authors.lastname: Klein
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D056685:Costello Syndrome / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000196:embryology* / Q000235:genetics*; D003744:Dental Enamel Hypoplasia / Q000196:embryology / Q000235:genetics; D004476:Ectodermal Dysplasia / Q000196:embryology / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000196:embryology / Q000235:genetics; D005260:Female; D005885:Gingival Hyperplasia / Q000196:embryology / Q000235:genetics; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D008297:Male; D008310:Malocclusion / Q000196:embryology / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D014070:Tooth / Q000196:embryology; D014071:Tooth Abnormalities / Q000196:embryology / Q000235:genetics; D055815:Young Adult
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: CS; Costello syndrome; MAPK pathway; RASopathy; Ras; craniofacial development; enamel; gingival hyperplasia; malocclusion; occlusion; receptor tyrosine kinase; signal transduction; tooth development