Ma N, Li ZW, Liu JJ, Liu XG, Zhou X, Wang BW, Li YL, Zhang TC, Xie P. RAF1 mutation expands the cardiac phenotypic spectrum of Noonan syndrome: A case report. World J Cardiol 2025; 17(6): 106525 [DOI: 10.4330/wjc.v17.i6.106525]
Corresponding Author of This Article
Ping Xie, MD, Chief Physician, Full Professor, Department of Cardiovascular Medicine, Gansu Provincial Hospital, No. 204 Donggang West Road, Lanzhou 730000, Gansu Province, China. pingxie66@163.com
Research Domain of This Article
Cardiac & Cardiovascular Systems
Article-Type of This Article
Case Report
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Nan Ma, Zhong-Wei Li, Bo-Wen Wang, Yan-Ling Li, Tian-Cheng Zhang, Ping Xie, Department of Cardiovascular Medicine, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
Jia-Jia Liu, Department of Echocardiography Room, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
Xing-Guang Liu, Department of Cardiovascular Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
Xing Zhou, Department of Radiology, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
Author contributions: Ma N performed patient management, manuscript writing and data collection; Li ZW performed clinical diagnosis and treatment planning; Liu JJ contributed to the manuscript with serial echocardiographic assessment; Liu XG contributed to the cardiac surgical intervention; Zhou X contributed to the radiological assessment; Wang BW performed permanent pacemaker implantation; Li YL performed pacemaker programming and follow-up; Zhang TC performed intraoperative electrophysiological monitoring; Xie P revised the manuscript and provided treatment instructions; and all authors thoroughly reviewed and endorsed the final manuscript.
Supported by the Gansu Provincial Science and Technology Plan Project, No. 24JRRA886 and No. 23JRRA1287; and Gansu Provincial People’s Hospital: Excellent Doctoral Student Cultivation Program, No. 22GSSYD-14.
Informed consent statement: Written informed consent was obtained from the patient’s parents (legal guardians) for the publication of this case report, including all clinical data and anonymized medical images. Patient identity was protected through strict de-identification measures in accordance with privacy protection standards.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
CARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ping Xie, MD, Chief Physician, Full Professor, Department of Cardiovascular Medicine, Gansu Provincial Hospital, No. 204 Donggang West Road, Lanzhou 730000, Gansu Province, China. pingxie66@163.com
Received: March 7, 2025 Revised: April 13, 2025 Accepted: May 15, 2025 Published online: June 26, 2025 Processing time: 105 Days and 11.8 Hours
Abstract
BACKGROUND
Noonan syndrome is a relatively common autosomal dominant genetic disorder characterized by cardiovascular defects owing to functional abnormalities in key genes such as RAF1. Mutations in RAF1 are typically associated with hypertrophic cardiomyopathy (HCM). However, in this case, the patient exhibited atrial and ventricular septal defects (VSDs).
CASE SUMMARY
This case report describes an 11-year-old boy diagnosed with Noonan syndrome, in whom genetic testing revealed a c.770C>T (p.Ser257 Leu) mutation in RAF1. The patient presented with intermittent chest discomfort and shortness of breath, symptoms that significantly worsened after physical activity. Clinical evaluation revealed marked growth retardation and multiple physical abnormalities. Electrocardiographic and echocardiographic assessments revealed VSDs, atrial septal defects, and left ventricular outflow tract obstruction. Following multidisciplinary consultation, the patient underwent cardiac surgical intervention, which led to clinical improvement; however, they subsequently developed a third-degree atrioventricular block, necessitating the implantation of a permanent pacemaker. During follow-up, echocardiographic findings demonstrated near-complete resolution of the shunt across the atrial and ventricular septa, significant improvement in left ventricular outflow tract obstruction, and notable reduction in ventricular septal thickness. A genetic mutation at the c.770C>T (p.Ser257 Leu) locus of RAF1 is typically associated with HCM and pulmonary hypertension. However, this patient’s clinical phenotype manifested as HCM, atrial septal defect, and VSD, suggesting that this mutation may involve a different pathophysiological mechanism.
CONCLUSION
This case confirms the genotype-phenotype heterogeneity of Noonan syndrome and highlights the complex management requirements of RAF1 mutation-associated cardiac pathologies. Early surgical intervention can ameliorate structural defects, but it must be integrated with genetic counseling and lifelong monitoring to optimize patient outcomes.
Core Tip: This case report elucidates the unique clinical heterogeneity of the RAF1 c.770C>T (p.Ser257 Leu) mutation in Noonan syndrome. While this variant is classically associated with severe hypertrophic cardiomyopathy and pulmonary hypertension, our patient exhibited atypical congenital heart defects - including atrial septal defect and ventricular septal defect - coexisting with hypertrophic cardiomyopathy, suggesting potential dysregulation of alternative molecular pathways in cardiac morphogenesis. Notably, this case expands the phenotypic spectrum of RAF1 mutations, underscoring the necessity for comprehensive genetic counseling even in carriers of “classic” mutations, as genotype-phenotype correlations remain incompletely defined. Mechanistically, we propose that this mutation disrupts RAF1 protein-mediated mitogen-activated protein kinase signaling, thereby contributing to aberrant cardiac developmental pathways.
