{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T02:26:29Z","timestamp":1772763989864,"version":"3.50.1"},"reference-count":28,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2023,9,11]],"date-time":"2023-09-11T00:00:00Z","timestamp":1694390400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cardio\u2010facio\u2010cutaneous syndrome (CFCS) is a rare genetic disorder belonging to the RASopathies, a group of developmental syndromes caused by upregulated RAS\/MAPK signaling. Pathogenic variants affecting four genes, <jats:italic>KRAS<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, <jats:italic>MAP2K1<\/jats:italic> and <jats:italic>MAP2K2<\/jats:italic>, encoding core signal transducers of the pathway, underlie the condition. Major clinical features include a distinctive facies, ectodermal and cardiac anomalies, reduced postnatal growth, intellectual disability, and musculoskeletal abnormalities. Similar to other RASopathies, reports of visual impairment, high refractive error, optic nerve pallor, and other ocular abnormalities have been anecdotally reported in the literature. The aim of our study is to report the prevalence of ophthalmologic abnormalities in a large monocentric cohort of individuals affected by CFCS and explore the occurrence of genotype\u2013endophenotype correlations in this series of patients. We observed that <jats:italic>BRAF<\/jats:italic> mutations are associated to a higher prevalence of anisometropia &gt;3D (11.8% vs. 0%) and high astigmatism (29.4% vs. 0%; both <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) while patients with mutations in other genes had a significantly higher prevalence of myopia &gt;6 D (60% vs. 5.9%; <jats:italic>p<\/jats:italic>\u2009=\u20090.012). Pale optic disc was associated with higher prevalence of inferior oblique muscle (IO) overaction (33.3% vs. 0%) and lower prevalence of ptosis (0% vs. 11.8%; both <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Combined exotropia, IO overaction and nystagmus were frequent in patients with pale optic nerve. Our findings might suggest the need for earlier ophthalmologic referral for CFCS patients due to high risk of amblyopia, especially those expressing <jats:italic>BRAF<\/jats:italic> mutations.<\/jats:p>","DOI":"10.1002\/ajmg.a.63395","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T06:59:45Z","timestamp":1694501985000},"page":"2783-2792","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Systematic ophthalmologic evaluation in cardio\u2010facio\u2010cutaneous syndrome: A genotype\u2013endophenotype correlation"],"prefix":"10.1002","volume":"191","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9996-9871","authenticated-orcid":false,"given":"Emanuele","family":"Crincoli","sequence":"first","affiliation":[{"name":"Ophthalmology Unit \u201cFondazione Policlinico Universitario A. Gemelli IRCCS\u201d  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4089-637X","authenticated-orcid":false,"given":"Chiara","family":"Leoni","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defect, Department of Woman and Child Health and Public Health Fondazione Policlinico Universitario A. Gemelli, IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1697-6337","authenticated-orcid":false,"given":"Germana","family":"Viscogliosi","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defect, Department of Woman and Child Health and Public Health Fondazione Policlinico Universitario A. Gemelli, IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-6657","authenticated-orcid":false,"given":"Roberta","family":"Onesimo","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defect, Department of Woman and Child Health and Public Health Fondazione Policlinico Universitario A. Gemelli, IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberta","family":"Mattei","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit \u201cFondazione Policlinico Universitario A. Gemelli IRCCS\u201d  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Tartaglia","sequence":"additional","affiliation":[{"name":"Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Ges\u00f9, IRCCS  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiammetta","family":"Catania","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Hopital Fondation Adolphe De Rothschild  Paris France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislao","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit \u201cFondazione Policlinico Universitario A. Gemelli IRCCS\u201d  Rome Italy"},{"name":"Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"},{"name":"\u201cConsiglio Nazionale delle Ricerche, Istituto di Neuroscienze\u201d  Pisa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Center for Rare Diseases and Birth Defect, Department of Woman and Child Health and Public Health Fondazione Policlinico Universitario A. Gemelli, IRCCS  Rome Italy"},{"name":"Universit\u00e0 Cattolica del Sacro Cuore  Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annabella","family":"Salerni","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit \u201cFondazione Policlinico Universitario A. 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