{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:21:22Z","timestamp":1788182482671,"version":"build-2803163510"},"reference-count":15,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:p>In this report, we describe the case of a 4-month-old infant diagnosed after birth with severe pulmonary stenosis and Noonan syndrome (NS) carrying a heterozygous pathogenic variant in the RAF1 gene. The patient was admitted for surgical correction, and during preoperative evaluation, severe biventricular hypertrophic cardiomyopathy, severe valvular pulmonary stenosis, and a bifid cardiac apex (BCA) were identified. The surgical procedure was performed without complications; however, due to postoperative hemodynamic instability, extracorporeal membrane oxygenation (ECMO) support was initiated. The patient initially showed satisfactory clinical evolution, allowing ECMO weaning; nevertheless, the patient subsequently developed cardiac arrest and died. It is known that the right ventricle and left ventricle develop independently and later fuse during embryogenesis. Disruption of this developmental process may result in a bifid apex. The GTPase Rac1 plays a regulatory role in embryonic cardiac development and cardiomyocyte differentiation. Cardiomyocyte-specific deletion of Rac1 (Rac1^Nkx2.5^) during cardiac development has been shown to result in a bifid apex, in addition to hypertrabeculation and a thin compact myocardium. NS caused by RAF1 mutations, as observed in this case, is associated with cardiac malformations in approximately 5%\u201310% of cases. Hypertrophic cardiomyopathy has an incidence of up to 95%, which may significantly worsen prognosis. Although this morphological finding is rare, when isolated it is usually associated with a favorable prognosis. However, BCA has been described in association with congenital heart disease, requiring careful evaluation. When associated with congenital cardiac malformations and genetic syndromes, particularly hypertrophic cardiomyopathy, the prognosis may be guarded.<\/jats:p>","DOI":"10.4103\/jcecho.jcecho_26_26","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:04:39Z","timestamp":1778144679000},"page":"481-484","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":0,"title":["Bifid Cardiac Apex in Noonan Syndrome: An Unusual Cardiac Morphology Associated with a RAF1 Pathogenic Variant"],"prefix":"10.4103","volume":"36","author":[{"given":"Maria Elisa Martini","family":"Albrecht","sequence":"first","affiliation":[{"name":"Service of Pediatric Cardiology and Cardiac Surgery, Rede D\u2019Or S\u00e3o Luiz, S\u00e3o Paulo, Brazil"},{"name":"Department of Obstetrics, Paulista School of Medicine, Federal University of S\u00e3o Paulo (EPM-UNIFESP), S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elssi Espinosa","family":"Quintero","sequence":"additional","affiliation":[{"name":"Service of Pediatric Cardiology and Cardiac Surgery, Rede D\u2019Or S\u00e3o Luiz, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia Miagusuku","family":"Samos","sequence":"additional","affiliation":[{"name":"Service of Pediatric Cardiology and Cardiac Surgery, Rede D\u2019Or S\u00e3o Luiz, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana Torres","family":"Pacheco","sequence":"additional","affiliation":[{"name":"Service of Pediatric Cardiology and Cardiac Surgery, Rede D\u2019Or S\u00e3o Luiz, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio Leonardo","family":"da Silva Paiva","sequence":"additional","affiliation":[{"name":"Service of Genetics, Rede D\u2019Or S\u00e3o Luiz, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo Yano","family":"Callado","sequence":"additional","affiliation":[{"name":"Discipline of Woman Health, Albert Einstein Israelite College of Health Sciences (FICSAE), Albert Einstein Israelite Hospital, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward Araujo","family":"J\u00fanior","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Paulista School of Medicine, Federal University of S\u00e3o Paulo (EPM-UNIFESP), S\u00e3o Paulo, Brazil"},{"name":"Discipline of Woman Health, Municipal University of S\u00e3o Caetano do Sul (USCS), S\u00e3o Caetano do Sul, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stevan Krieger","family":"Martins","sequence":"additional","affiliation":[{"name":"Service of Pediatric Cardiology and Cardiac Surgery, Rede D\u2019Or S\u00e3o Luiz, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"R2-20260831","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1136\/archdischild-2021-322858","article-title":"Noonan syndrome: Improving recognition and diagnosis","volume":"107","author":"Zenker","year":"2022","journal-title":"Arch Dis Child"},{"key":"R3-20260831","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"Lancet"},{"key":"R4-20260831","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.3390\/ijms26083515","article-title":"Update on the clinical and molecular characterization of Noonan syndrome and other RASopathies: A retrospective study and systematic review","volume":"26","author":"Reynolds","year":"2025","journal-title":"Int J Mol Sci"},{"key":"R5-20260831","doi-asserted-by":"crossref","first-page":"5735","DOI":"10.3390\/jcm13195735","article-title":"Prenatal sonographic features of Noonan syndrome: Case series and literature review","volume":"13","author":"Tangshewinsirikul","year":"2024","journal-title":"J Clin Med"},{"key":"R6-20260831","doi-asserted-by":"crossref","first-page":"3973","DOI":"10.3390\/jcm14113973","article-title":"Second trimester ultrasound diagnosis of external hydrocephalus in two fetuses with Noonan syndrome-case report series","volume":"14","author":"Elekes","year":"2025","journal-title":"J Clin Med"},{"key":"R7-20260831","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/pd.2782","article-title":"Targeted ultrasound examination and DNA testing for Noonan syndrome, in fetuses with increased nuchal translucency and normal karyotype","volume":"31","author":"Bakker","year":"2011","journal-title":"Prenat Diagn"},{"key":"R8-20260831","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/archdischild-2013-305047","article-title":"Cardiovascular disease in Noonan syndrome","volume":"99","author":"Prendiville","year":"2014","journal-title":"Arch Dis Child"},{"key":"R9-20260831","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1097\/MOP.0000000000000669","article-title":"Cardiovascular disease in Noonan syndrome","volume":"30","author":"Pierpont","year":"2018","journal-title":"Curr Opin Pediatr"},{"key":"R10-20260831","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.carpath.2013.06.003","article-title":"Bifid cardiac apex in a 25-year-old male with sudden cardiac death","volume":"23","author":"Wu","year":"2014","journal-title":"Cardiovasc Pathol"},{"key":"R11-20260831","doi-asserted-by":"crossref","first-page":"70","DOI":"10.4250\/jcu.2017.25.2.70","article-title":"Bifid cardiac apex in an old woman","volume":"25","author":"Masoura","year":"2017","journal-title":"J Cardiovasc Ultrasound"},{"key":"R12-20260831","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3390\/jcdd8030029","article-title":"Myocardium-specific deletion of rac1 causes ventricular noncompaction and outflow tract defects","volume":"8","author":"Leung","year":"2021","journal-title":"J Cardiovasc Dev Dis"},{"key":"R13-20260831","first-page":"158","article-title":"A rare case of congenital heart disease with bifid cardiac apex: A unique finding in left ventricle","volume":"8","author":"Maleki","year":"2013","journal-title":"J Tehran Heart Cent"},{"key":"R14-20260831","first-page":"e82066","article-title":"Multimodal management of complex congenital heart disease: A case of atrial and ventricular septal defects with a bifid apex","volume":"17","author":"I\u015fik","year":"2025","journal-title":"Cureus"},{"key":"R15-20260831","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/ajmg.c.31765","article-title":"Congenital heart defects in Noonan syndrome: Diagnosis, management, and treatment","volume":"184","author":"Linglart","year":"2020","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"R16-20260831","first-page":"61","article-title":"Noonan syndrome: Genetic and clinical update and treatment options","volume":"93","author":"Carcavilla","year":"2020","journal-title":"An Pediatr (Engl Ed)"}],"container-title":["Journal of Cardiovascular Echography"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ovid.com\/10.4103\/jcecho.jcecho_26_26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T13:01:10Z","timestamp":1788181270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ovid.com\/10.4103\/jcecho.jcecho_26_26"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":15,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.4103\/jcecho.jcecho_26_26","relation":{},"ISSN":["2211-4122","2347-193X"],"issn-type":[{"value":"2211-4122","type":"print"},{"value":"2347-193X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,6]]},"assertion":[{"value":"2026-02-21","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-29","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}