Clin Genet 2012 Printed in Singapore. All rights reserved  2012 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/cge.12005 Original Article Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis Goodwin AF, Oberoi S, Landan M, Charles C, Groth J, Martinez A, Fairley C, Weiss LA, Tidyman WE, Klein OD, Rauen KA. Craniofacial and dental development in cardio-facio-cutaneous syndrome: the importance of Ras signaling homeostasis. Clin Genet 2012.  John Wiley & Sons A/S, 2012 Cardio-facio-cutaneous syndrome (CFC) is a RASopathy that is characterized by craniofacial, dermatologic, gastrointestinal, ocular, cardiac, and neurologic anomalies. CFC is caused by activating mutations in the Ras/mitogen-activated protein kinase (MAPK) signaling pathway that is downstream of receptor tyrosine kinase (RTK) signaling. RTK signaling is known to play a central role in craniofacial and dental development, but to date, no studies have systematically examined individuals with CFC to define key craniofacial and dental features. To fill this critical gap in our knowledge, we evaluated the craniofacial and dental phenotype of a large cohort (n = 32) of CFC individuals who attended the 2009 and 2011 CFC International Family Conferences. We quantified common craniofacial features in CFC which include macrocephaly, bitemporal narrowing, convex facial profile, and hypoplastic supraorbital ridges. In addition, there is a characteristic dental phenotype in CFC syndrome that includes malocclusion with open bite, posterior crossbite, and a high-arched palate. This thorough evaluation of the craniofacial and dental phenotype in CFC individuals provides a step forward in our understanding of the role of RTK/MAPK signaling in human craniofacial development and will aid clinicians who treat patients with CFC. Conflict of interest The authors declare no conflict of interest. AF Goodwin a,b , S Oberoi a,b , M Landan a,b , C Charles a,b,f , J Groth a,b , A Martinez c , C Fairley a,b , LA Weiss d,e , WE Tidyman a,b , OD Klein a,b,c,e and KA Rauen c,e a Department of Orofacial Sciences, b Program in Craniofacial and Mesenchymal Biology, c Department of Pediatrics, Division of Medical Genetics, d Department of Psychiatry, e Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA, and f Current address: Team ‘‘Evo-Devo of Vertebrate Dentition’’, Institut de G´ enomique Fonctionnelle de Lyon, Ecole Normale Sup ´ erieure de Lyon, Universit ´ e de Lyon, CNRS UMR 5242, Lyon, France Key words: cardio-facio-cutaneous syndrome – craniofacial development – malocclusion – MAPK pathway – occlusion – Ras – RASopathy – receptor tyrosine kinase – signal transduction – tooth development Corresponding author: Katherine Rauen, MD, PhD Associate Professor, UCSF Helen Diller Family Comprehensive Cancer Center, 2340 Sutter Street, Room S429, 94115 San Francisco, CA, USA. Tel.: +1 415 514 3513; fax: +1 415 476 9305; e-mail: rauenk@peds.ucsf.edu [PO BOX 0808] Received 5 July 2012, revised and accepted for publication 27 August 2012 Cardio-facio-cutaneous syndrome (CFC) is a mul- tiple congenital anomaly disorder characterized by craniofacial malformation, ectodermal abnormalities, congenital heart defects, growth delays, and neurocog- nitive deficits. CFC is one of the RASopathies, which also include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), NS with multiple lentigines, capillary malformation-AV malformation syndrome, Legius syn- drome, and Costello syndrome (CS). The common feature of the RASopathies is that they are caused by germline mutations that result in dysregulation of the Ras/mitogen-activated protein kinase (MAPK) pathway (1). CFC is caused by heterozygous, activat- ing, germline mutations in KRAS , BRAF , MAP2K1 1