{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T03:16:07Z","timestamp":1792811767752,"version":"4.5.0"},"reference-count":19,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2007,6,5]],"date-time":"2007-06-05T00:00:00Z","timestamp":1181001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2007,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Because Cardio\u2010facio\u2010cutaneous (CFC) syndrome has significant phenotypic overlap with Costello syndrome, it may be difficult to establish the diagnosis on a clinical basis. The recent discoveries of germline <jats:italic>HRAS<\/jats:italic> mutations in patients with Costello syndrome and mutations in <jats:italic>BRAF<\/jats:italic>, <jats:italic>MEK1<\/jats:italic>, and <jats:italic>MEK2<\/jats:italic> in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close interaction of the affected gene products within the MAP kinase pathway. We evaluated a series of patients who were either clinically diagnosed with Costello syndrome, or in whom the diagnoses of both Costello and CFC syndromes were considered. After excluding mutations in <jats:italic>HRAS<\/jats:italic>, we identified eight changes in <jats:italic>BRAF<\/jats:italic> and five in <jats:italic>MEK1<\/jats:italic>. Five mutations are novel, and all changes occurred de novo among those triads tested. A review of the clinical abnormalities showed important differences between patients with either a <jats:italic>BRAF<\/jats:italic> or <jats:italic>MEK1<\/jats:italic> mutation, and those previously reported with an <jats:italic>HRAS<\/jats:italic> mutation. Statistical significance was achieved, despite the relatively small number of patients with <jats:italic>BRAF<\/jats:italic> and <jats:italic>MEK1<\/jats:italic> mutations reported here, for polyhydramnios, growth hormone deficiency and the presence of more than one papilloma, which were less common in CFC compared to <jats:italic>HRAS<\/jats:italic> mutation positive patients. Although both CFC and Costello syndrome are characterized by cardiac abnormalities in about three\u2010fourths of patients, the pattern of congenital heart defects (CHD), hypertrophic cardiomyopathy (HCM), and tachycardia differs somewhat. CHD, especially pulmonic stenosis associated with a secundum\u2010type atrial septal defect, are more common in CFC than Costello syndrome (<jats:italic>P<\/jats:italic>\u2009=\u20090.02). Atrial tachycardia is less frequent in CFC patients with <jats:italic>BRAF<\/jats:italic> or <jats:italic>MEK1<\/jats:italic> mutations, compared to Costello syndrome patients with <jats:italic>HRAS<\/jats:italic> mutation (<jats:italic>P<\/jats:italic>\u2009=\u20090.04). Chaotic atrial rhythm or multifocal atrial tachycardia was observed only in Costello syndrome. Malignant tumors have been viewed as characteristic for Costello syndrome due to <jats:italic>HRAS<\/jats:italic> mutations, however, we report here on a <jats:italic>MEK1<\/jats:italic> mutation in a patient with a malignant tumor, a hepatoblastoma. Although this indicates that the presence of a tumor is not specific for Costello syndrome with <jats:italic>HRAS<\/jats:italic> mutation, it is noteworthy that the tumor histology differs from those commonly seen in Costello syndrome. Based on these clinical differences we suggest that patients with <jats:italic>BRAF<\/jats:italic> and <jats:italic>MEK<\/jats:italic> mutations should be diagnosed with CFC syndrome, and the diagnosis of Costello syndrome be reserved for patients with <jats:italic>HRAS<\/jats:italic> mutations. \u00a9 2007 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.a.31815","type":"journal-article","created":{"date-parts":[[2007,6,5]],"date-time":"2007-06-05T17:46:32Z","timestamp":1181065592000},"page":"1472-1480","source":"Crossref","is-referenced-by-count":78,"title":["Further delineation of the phenotype resulting from <i>BRAF<\/i> or <i>MEK1<\/i> germline mutations helps differentiate cardio\u2010facio\u2010cutaneous syndrome from Costello syndrome"],"prefix":"10.1002","volume":"143A","author":[{"given":"Karen W.","family":"Gripp","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela E.","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Allen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cramer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth L.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Kutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Peck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Rebolledo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia G.","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad M.","family":"Al\u2010Rahawan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L.","family":"Stabley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Sol\u2010Church","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,6,5]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31819"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1641"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0306-283"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20330"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31078"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.30065"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30100"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31047"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2005.040352"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.10558"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471695998.mgs014"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1749"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31315"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1124642"},{"key":"e_1_2_6_16_1","author":"Sanger 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