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Alromaihi M, Alrumaihi F, Alwanian WM, Alharbi HO, AlDuayji NN, Alfifi SM, Al-Doaiss AA, Alshabrmi FM, Thornbury W, Khan SU. A Multidimensional Approach to Understanding Genetic Diversity, Risk Stratification, and Personalized Interventions in Pediatric Hypertrophic Cardiomyopathy. Curr Probl Cardiol 2025; 50:103040. [PMID: 40157517 DOI: 10.1016/j.cpcardiol.2025.103040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025]
Abstract
Hypertrophic cardiomyopathy (HCM) in children presents unique challenges distinct from adult manifestations, with potentially devastating consequences, including sudden cardiac death. This comprehensive review synthesizes current evidence on the pathophysiology, clinical presentation, and management of pediatric HCM, highlighting critical differences from adult populations. While affecting approximately 1 in 500 individuals, pediatric HCM demonstrates more significant etiological heterogeneity, with up to 35% of cases stemming from non-sarcomeric causes, including RASopathies, metabolic disorders, and syndromic conditions. This etiological diversity contributes to variable disease trajectories and treatment responses, creating a significant research gap in pediatric-specific management protocols. Current pharmacological approaches primarily employ beta-blockers as first-line therapy, with calcium channel blockers serving as alternatives for intolerant patients. However, these conventional medications manage symptoms without addressing underlying pathophysiology or preventing disease progression. Emerging investigational therapies, including angiotensin receptor blockers and myosin inhibitors like mavacamten, show promise in preliminary studies but lack robust pediatric-specific evidence. Surgical interventions, including septal myectomy and the modified Konno procedure, demonstrate efficacy in medication-refractory cases but carry higher complication risks in younger patients. The critical research gap lies in developing targeted therapeutic approaches for pediatric-specific HCM subtypes, particularly those associated with syndromic and metabolic disorders. Additionally, risk stratification models for sudden cardiac death prevention remain inadequately validated in pediatric populations. This review identifies the urgent need for pediatric-focused clinical trials investigating both conventional and novel therapies alongside the development of age-appropriate risk assessment tools to guide personalized management strategies for this vulnerable population.
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Affiliation(s)
- Mona Alromaihi
- Department of Pediatrics, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Wanian M Alwanian
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Hajed Obaid Alharbi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Nouf Nasser AlDuayji
- Department of Physical Therapy, College of Applied Medical Sciences, Qassim University, Buraydah 51451, Saudi Arabia
| | - Somayah Mohammad Alfifi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 47713, Saudi Arabia
| | - Amin A Al-Doaiss
- Biology Department, College of Science, King Khalid University, Abha, Saudi Arabia
| | - Fahad M Alshabrmi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - William Thornbury
- William Harvey Research Institute, Queen Mary University of London, London EC1A 7BE, UK.
| | - Shahid Ullah Khan
- Department of Biomedical Sciences, Dubai Medical College for Girls, Dubai Medical University, Dubai 19099, United Arab Emirates.
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Zenker M, Wolf CM. Cardiovascular aspects of Noonan syndrome and related disorders. MED GENET-BERLIN 2025; 37:113-124. [PMID: 40207038 PMCID: PMC11976402 DOI: 10.1515/medgen-2025-2010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2025]
Abstract
Noonan syndrome and other RASopathies constitute an important group of disorders to be considered in the differential diagnosis in individuals with congenital heart defects and hypertrophic cardiomyopathy. The cardiovascular phenotype of RASopathies is complex and comprises a spectrum of abnormalities, including not only congenital defects but also abnormalities affecting the lymphovascular system and other anomalies of the vascular system, which may emerge over the course of an individual's lifetime. Affected individuals typically present with a syndromic phenotype, exhibiting additional physical symptoms outside of the cardiovascular system and neuropsychological deficits. Genetic testing of the established disease genes for RASopathies is an effective method for identifying the underlying genetic variant in the majority of cases. This approach is strongly recommended to facilitate a more precise prognosis and the potential for personalized targeted therapies. Screening for RASopathy-associated gene variants in individuals with isolated CHDs, HCM, or other isolated cardiovascular features outside the NS spectrum appears to have limited clinical utility. However, it should be noted that the RASopathy phenotype may be challenging to discern in cases of mild or oligosymptomatic involvement, or it may be obscured by the presence of severe medical conditions, particularly in very young children.
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Affiliation(s)
- Martin Zenker
- University Hospital MagdeburgInstitute of Human GeneticsLeipziger Str. 4439120MagdeburgGermany
| | - Cordula M. Wolf
- German Centre for Cardiovascular ResearchLazarettstr. 3680636MünchenGermany
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Qie D, Zhai Y, Yang F, Li Y, Xu R. A de novo TNNI3K variant aggravates the pathogenicity of DMD-associated early-onset cardiomyopathy: a case report. Front Genet 2025; 16:1525941. [PMID: 40134720 PMCID: PMC11933015 DOI: 10.3389/fgene.2025.1525941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 02/19/2025] [Indexed: 03/27/2025] Open
Abstract
Background Dystrophin is a DMD coding protein that serves as a connector maintaining the structural formation and functional hemostasis of myofilaments, which regulate the contraction of cardiomyocytes. However, early-onset heart failure or cardiomyopathy is closely associated with adverse clinical outcomes in Duchenne muscular dystrophy (DMD)-affected patients. Pathogenicity screening and identification of the potential combined variants are thus critical for the management of such patients. Herein, we report a rare case of a patient with early-onset DMD attributed to a compound genetic variant in the DMD and TNNI3K genes. Case presentation The proband, a 15-month-old male patient, presented with severe heart failure, enlarged ventricles, and diffuse fibrosis. Whole-exome sequencing was used to identify a compound missense variant as c.1540G>T (p.V514L) of the DMD gene and c.1633G>T of the TNNI3K gene, resulting in disease. The protein structures of the mutant dystrophin and TNNI3K were built using AlphaFold3. The amino acid residues around site 514 had changed in DMD p.V514L, and the altered surrounding structures resulted in protein dysfunction. Furthermore, the amino acid residues around site 545 had changed in TNNI3K p.G545C, causing significant alterations to the hydrogen bonding. As both of these mutations contribute to regulating the myofilaments, potential interactions are suspected. Then, the binding structure was established using AlphaFold3, and the structural changes were identified based on the compound variants. Conclusion We present a rare case of a compound genetic variant that induces severe and very-early-onset heart failure in DMD patients. The compound variant attenuates the interactions between DMD and TNNI3K, leading to functional collapse of the myofilaments. This finding emphasizes the importance of comprehensive genetic analysis in DMD patients. Identification of additional variants can significantly aggravate the pathological process and disease prognosis, and such patients always require swift and careful clinical management to obtain desirable outcomes.
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Affiliation(s)
- Di Qie
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Zhai
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Emergency, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Fan Yang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Emergency, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yifei Li
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Rong Xu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Radiology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
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Schmitt W, Diedrich C, Hamza TH, Meyer M, Eissing T, Breitenstein S, Rossano JW, Lipshultz SE. NT-proBNP for Predicting All-Cause Death and Heart Transplant in Children and Adults with Heart Failure. Pediatr Cardiol 2025; 46:694-703. [PMID: 38722325 PMCID: PMC11842395 DOI: 10.1007/s00246-024-03489-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 04/01/2024] [Indexed: 02/21/2025]
Abstract
Plasma N-terminal prohormone B-type natriuretic peptide (NT-proBNP) concentration is a heart failure (HF) biomarker in adults and children. Its prognostic value for HF-related events has been established only in adults. Therefore, we aimed to test the hypothesis that plasma NT-proBNP concentrations predicted the risk of heart transplantation or death in children with HF. We studied the medical records of 109 children with HF enrolled in the IBM Watson Explorys database and from 150 children enrolled in the Pediatric Cardiomyopathy Registry (PCMR). Nonlinear regression was used to assess the relationship between plasma NT-proBNP concentrations and the risk of events in the two cohorts. All children in the PCMR cohort had dilated cardiomyopathy. The Explorys cohort also included children with congenital cardiovascular malformations. Median plasma NT-proBNP concentrations were 1250 pg/mL and 184 pg/mL in the Explorys and PCMR cohorts, respectively. The percentage of deaths/heart transplantations was 7%/22%, over 2 years in the Explorys cohort and 3%/16% over 5 years in the PCMR cohort. Mean estimates of plasma NT-proBNP concentration indicative of half-maximum relative risk for events (EC50 values) at 2 and 5 years were 3730 pg/mL and 4199 pg/mL, respectively, values both close to the mean of 3880 pg/mL established for adults with HF. The plasma NT-proBNP concentration is suitable for estimating relative risk of mortality and heart transplantation in children with HF, independent of etiology and shows similar relations to clinical outcomes as in adults, indicating its likely value as a surrogate marker both for adult and pediatric HF.ClinicalTrials.gov Identifiers: NCT00005391 (May 26, 2000), NCT01873976 (June 10, 2013).
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Affiliation(s)
| | | | | | | | | | | | - Joseph W Rossano
- Division of Cardiology, Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
| | - Steven E Lipshultz
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, Clinical and Translational Research Center, University at Buffalo, 875 Ellicott Street, Suite 5018, Buffalo, NY, 14203, USA.
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De Brouchoven I, Lorand J, Bofferding L, Sorlin A, Van Damme A, Danhaive O. Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome. Front Pediatr 2025; 13:1475143. [PMID: 40041314 PMCID: PMC11876372 DOI: 10.3389/fped.2025.1475143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 01/28/2025] [Indexed: 03/06/2025] Open
Abstract
Introduction Rare pathogenic variants in the PTPN11, KRAS, SOS1 and RAF1 genes are the main molecular causes of Noonan syndrome (NS). Most are dominant gain-of-function variants that cause an overactivation of the RAS/MAPK signaling pathway leading to uncontrolled cell proliferation in many organs and systems. Albeit phenotypically heterogeneous, NS can be associated with severe cardiovascular and lymphatic anomalies, potentially lethal during infancy, neonatal and fetal periods. MEK inhibitors, a class of drugs targeting the final steps of the RAS/MAPK pathway and originally developed for cancer therapy, have been tested in preclinical studies as a targeted treatment for NS. These studies led to the occasional off-label use of MEK inhibitors in patients with RASopathies. Methods We report the case of a preterm infant with congenital pulmonary lymphangiectasis, chylothorax and hypoxic respiratory failure refractory to conventional management, who was treated with trametinib after identification of a NS PTPN11 class 5 variant. We performed a systematic review of the current published evidence on trametinib efficacy and safety for severe respiratory and/or cardiac manifestations in infants and children with Noonan syndrome, querying PubMed, Embase, Cochrane and Scopus databases, following the PRISMA guideline for systematic reviews, and using the Joanna Briggs Institute (JBI) Critical Appraisal tool for quality assessment of published evidence. Results In our patient, a five-week trametinib course, maximum dose 0.025 mg/kg/day, led to chylothorax resolution and gradual pulmonary function improvement, allowing extubation to non-invasive support, discharge home at a corrected age of 4 months, and weaning off home oxygen therapy by 10 months. No formal clinical trial of trametinib in neonatal/pediatric Noonan syndrome has been published to our knowledge. We collected 16 published cases, and added this case for reviewing trametinib regimen, efficacy and safety. A short-term improvement of symptoms was reported in all cases, with three deaths presumably unrelated to trametinib. Moderate side effects were reported in a subset of patients. Long-term follow-up data were not available. Discussion Trametinib is a promising drug in NS. Clinical trials are warranted to establish safety, efficacy, and standardized protocols for the use of trametinib as a rescue therapy in critically ill children and explore its potential place in the treatment of various NS comorbidities. Systematic Review Registration clinicaltrials.gov, identifier [NCT06555237].
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Affiliation(s)
- Isabel De Brouchoven
- Division of Neonatology, Saint-Luc University Hospital, UCLouvain, Brussels, Belgium
| | - Juan Lorand
- Division of Neonatology, Saint-Luc University Hospital, UCLouvain, Brussels, Belgium
| | - Léon Bofferding
- Division of Neonatology, Kannerklinik, Luxembourg Hospital Center, Luxembourg, Luxembourg
| | - Arthur Sorlin
- National Center of Genetics (NCG), Laboratoire National de Santé (LNS), Dudelange, Luxembourg
| | - An Van Damme
- Division of Pediatric Haemato-Oncology and Centre for Vascular Anomalies, Saint-Luc University Hospital, UCLouvain, Brussels, Belgium
| | - Olivier Danhaive
- Division of Neonatology, Saint-Luc University Hospital, UCLouvain, Brussels, Belgium
- Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
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6
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Santoro M, Barisic I, Coi A, Tan J, Garne E, Loane M, Odak L, Abate MV, Ballardini E, Cavero-Carbonell C, Gatt M, Gissler M, Klungsøyr K, Lelong N, Tucker D, Wellesley D, Morris JK. Health outcomes and drug utilisation in children with Noonan syndrome: a European cohort study. Orphanet J Rare Dis 2025; 20:76. [PMID: 39962527 PMCID: PMC11834245 DOI: 10.1186/s13023-025-03594-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 02/03/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Noonan Syndrome (NS) is a rare multisystemic disorder with heterogeneous phenotypic manifestations. The aim of this study was to analyse rates of survival, hospitalisation, surgeries and prescriptions in children born with NS in the first 10 years of life. METHODS This is a multi-centre population-based cohort study. Data on 175 liveborn children diagnosed with NS from 11 EUROCAT congenital anomaly registries were linked to healthcare databases. Each registry applied a common data model to standardise data and run common syntax scripts to produce aggregated results which were pooled using random effects meta-analyses. RESULTS Mortality rates were high in the first year of life with 5.4% (95%CI 1.5%-10.1%) of children dying before the age of 1 year with a further 2% dying up to age 5. In the first year, 87.9% (95%CI 75.3%-94.3%) of children were hospitalized and the median Length Of hospital Stay (LOS) was 15.3 days (95%CI 9.3-21.2). After the first year, the proportion of children hospitalized remained higher than 70%, but the LOS decreased to 1.3 days per year. In the first 5 years, 65.2% of children underwent a median of two surgical procedures. The median age at first surgery was 29 weeks. The proportion of children with an antibiotic prescription increased from 53.6% at age 1 to 62.4% yearly until 4 years of age. CONCLUSIONS Children with NS have high mortality and morbidity not only in the first year of life but also up to five years of age. This study evaluated the health burden of NS and provided information for clinicians, health-care providers and families.
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Affiliation(s)
- Michele Santoro
- Unit of Epidemiology of Rare Diseases and Congenital Anomalies, Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, 56124, Pisa, Italy.
| | - Ingeborg Barisic
- Children's Hospital Zagreb, Centre of Excellence for Reproductive and Regenerative Medicine, Medical School University of Zagreb, Zagreb, Croatia
| | - Alessio Coi
- Unit of Epidemiology of Rare Diseases and Congenital Anomalies, Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, 56124, Pisa, Italy
| | - Joachim Tan
- NIHR Great Ormond Street Hospital Biomedical Research Centre, UCL GOS Institute of Child Health, London, UK
- School of Health and Medical Sciences, City St George's University of London, London, UK
| | - Ester Garne
- Department of Paediatrics and Adolescent Medicine, Lillebaelt Hospital, University Hospital of Southern Denmark, Kolding, Denmark
| | - Maria Loane
- Faculty of Life and Health Sciences, Ulster University, Northern Ireland, UK
| | - Ljubica Odak
- Department of Medical and Laboratory Genetics, Endocrinology and Diabetology with Daily Care Unit, Children's Hospital Zagreb, Zagreb, Croatia
| | - Maria Valentina Abate
- Unit of Epidemiology of Rare Diseases and Congenital Anomalies, Institute of Clinical Physiology, National Research Council, Via Moruzzi 1, 56124, Pisa, Italy
| | - Elisa Ballardini
- Neonatal Intensive Care Unit, University Hospital of Ferrara IMER Registry (Emilia Romagna Registry of Birth Defects, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Clara Cavero-Carbonell
- Rare Diseases Research Unit, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region, Valencia, Spain
| | - Miriam Gatt
- Directorate for Health Information and Research, G'Mangia, Pietà, Malta
| | - Mika Gissler
- Department of Knowledge Brokers, THL Finnish Institute for Health and Welfare, Helsinki, Finland
- Region Stockholm, Academic Primary Health Care Centre, Stockholm, Sweden
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Kari Klungsøyr
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
- Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway
| | - Nathalie Lelong
- Université de Paris, CRESS-Epopé, INSERM, INRA, Paris, France
| | | | - Diana Wellesley
- Wessex Clinical Genetics Service, University Hospital Southampton, Southampton, SO16 5YA, UK
| | - Joan K Morris
- School of Health and Medical Sciences, City St George's University of London, London, UK
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Zhou Y, Yang K, Ma K, Lu M. LEOPARD syndrome with PTPN11 gene mutation in monozygotic twins: A case description and literature review. ESC Heart Fail 2025; 12:664-667. [PMID: 39145467 PMCID: PMC11769602 DOI: 10.1002/ehf2.15014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/08/2024] [Accepted: 07/16/2024] [Indexed: 08/16/2024] Open
Affiliation(s)
- Yingwen Zhou
- Department of Magnetic Resonance ImagingFuwai Hospital and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of Magnetic Resonance ImagingCangzhou Central HospitalCangzhouChina
| | - Kai Yang
- Department of Magnetic Resonance ImagingCangzhou Central HospitalCangzhouChina
| | - Kai Ma
- Department of Pediatric SurgeryFuwai Hospital and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Minjie Lu
- Department of Magnetic Resonance ImagingFuwai Hospital and National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Wolf CM, Zenker M, Boleti O, Norrish G, Russell M, Meisner JK, Peng DM, Prendiville T, Kleinmahon J, Kantor PF, Gottlieb Sen D, Human DG, Ewert P, Krueger M, Reber D, Donner B, Hart C, Odri Komazec I, Rupp S, Hahn A, Hanser A, Hofbeck M, Draaisma JMT, Udink Ten Cate FEA, Mussa A, Ferrero GB, Vaujois L, Raboisson MJ, Delrue MA, Marquis C, Théoret Y, Bogarapu S, Dancea A, Handrup MM, Kemna M, Ojala T, Dham N, Dicke F, Friede T, Kaski JP, Gelb BD, Andelfinger G. Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. JACC Basic Transl Sci 2025; 10:152-166. [PMID: 40131150 PMCID: PMC11897442 DOI: 10.1016/j.jacbts.2024.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/03/2024] [Accepted: 10/01/2024] [Indexed: 03/26/2025]
Abstract
There is an unmet medical need to treat patients with severe hypertrophic cardiomyopathy leading to heart failure and death in children carrying pathogenic activating variants in the RAS/mitogen-activated protein kinase pathway. A retrospective analysis of 61 patients provides evidence for decreased mortality and morbidity with improved cardiac status in patients with RASopathy with severe hypertrophic cardiomyopathy receiving mitogen-activated protein kinase kinase inhibition (n = 30) vs those with standard-of-care treatment (n = 31). Side effects were not life threatening and were manageable. The data presented suggest that personalized therapies targeting underlying signaling pathway abnormalities might be effective in critically ill patients with RASopathy warranting clinical investigation.
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Affiliation(s)
- Cordula M Wolf
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, School of Medicine and Health, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
| | - Martin Zenker
- Institute of Human Genetics, University Hospital Magdeburg, Otto-von-Guericke-University, Magdeburg, Germany
| | - Olga Boleti
- Centre for Inherited Cardiovascular Diseases, Institute of Cardiovascular Science, University College London and Great Ormond Street Hospital, London, United Kingdom
| | - Gabrielle Norrish
- Centre for Inherited Cardiovascular Diseases, Institute of Cardiovascular Science, University College London and Great Ormond Street Hospital, London, United Kingdom
| | - Mark Russell
- University of Michigan, Ann Arbor, Michigan, USA
| | | | - David M Peng
- University of Michigan, Ann Arbor, Michigan, USA
| | | | | | - Paul F Kantor
- Children's Hospital Los Angeles, Los Angeles, California, USA
| | | | - Derek G Human
- British Columbia's Children's Hospital, Vancouver, British Columbia, Canada
| | - Peter Ewert
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, School of Medicine and Health, Technical University of Munich, Munich, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart
| | - Marcus Krueger
- Department of Neonatology, Municipal Hospital Munich Schwabing, Munich, Germany
| | - Daniela Reber
- Department of Neonatology, Municipal Hospital Munich Schwabing, Munich, Germany
| | - Birgit Donner
- Pediatric Cardiology, University Children's Hospital of Basel, University of Basel, Basel, Switzerland
| | - Christopher Hart
- Department of Pediatric Cardiology, Pediatric Heart Center, Children's Hospital, University of Bonn, Bonn, Germany
| | - Irena Odri Komazec
- Department of Child and Adolescent Health (Pediatrics III, Pediatric Cardiology), Medical University of Innsbruck, Innsbruck, Austria
| | - Stefan Rupp
- Pediatric Heart Center, University of Giessen and Marburg, Giessen, Germany
| | - Andreas Hahn
- Department of Child Neurology, University of Giessen, Giessen, Germany
| | - Anja Hanser
- Department of Pediatric Cardiology and Intensive Medicine, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| | - Michael Hofbeck
- Department of Pediatric Cardiology and Intensive Medicine, University Hospital Tübingen, Eberhard-Karls-University, Tübingen, Germany
| | - Jos M T Draaisma
- Radboud University Medical Center, Radboud Institute for Health Sciences, Amalia Children's Hospital, Department of Pediatrics, Nijmegen, the Netherlands
| | - Floris E A Udink Ten Cate
- Radboud University Medical Center, Radboud Institute for Health Sciences, Amalia Children's Hospital, Department of Pediatrics, Nijmegen, the Netherlands
| | - Alessandro Mussa
- Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy
| | - Giovanni B Ferrero
- Department of Clinical and Biological Sciences, School of Medicine, University of Turin, Turin, Italy
| | - Laurence Vaujois
- Centre Mère-Enfant Soleil, Université de Laval, Quebec City, Quebec, Canada
| | - Marie-Josée Raboisson
- CHU Sainte Justine, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
| | - Marie-Ange Delrue
- CHU Sainte Justine, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
| | - Christopher Marquis
- CHU Sainte Justine, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
| | - Yves Théoret
- CHU Sainte Justine, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
| | - Soujanya Bogarapu
- Children's Hospital of Illinois, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Adrian Dancea
- Montreal Children's Hospital, McGill University Health Center, Montréal, Quebec, Canada
| | - Mette Moller Handrup
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; Center for Rare Diseases, Aarhus University Hospital, Copenhagen, Denmark
| | - Mariska Kemna
- Seattle Children's Hospital, Seattle, Washington, USA
| | - Tiina Ojala
- Member of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart; New Children's Hospital Pediatric Research Center, Helsinki University Hospital, Helsinki, Finland
| | - Niti Dham
- George Washington University and Children's National Hospital, Washington, District of Columbia, USA
| | - Frank Dicke
- Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada
| | - Tim Friede
- University Medical Center Göttingen, Department of Medical Statistics, Göttingen, Germany; Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research), partner site Lower Saxony, Göttingen, Germany; Deutsches Zentrum für Kinder- und Jugendgesundheit (German Center for Child and Adolescent Health), partner site Göttingen, Göttingen, Germany
| | - Juan Pablo Kaski
- Centre for Inherited Cardiovascular Diseases, Institute of Cardiovascular Science, University College London and Great Ormond Street Hospital, London, United Kingdom
| | - Bruce D Gelb
- Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Gregor Andelfinger
- CHU Sainte Justine, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada.
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9
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Wang S, Peng D. Biventricular outflow tract obstruction due to hypertrophy related to compound heterozygous variants in LZTR1. ESC Heart Fail 2024; 11:4450-4455. [PMID: 38982897 PMCID: PMC11631276 DOI: 10.1002/ehf2.14944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 05/06/2024] [Accepted: 06/20/2024] [Indexed: 07/11/2024] Open
Affiliation(s)
- Shuai Wang
- Department of Cardiovascular MedicineSecond Xiangya Hospital of Central South UniversityChangshaChina
| | - Daoquan Peng
- Department of Cardiovascular MedicineSecond Xiangya Hospital of Central South UniversityChangshaChina
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10
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Chan RH, van der Wal L, Liberato G, Rowin E, Soslow J, Maskatia S, Chan S, Shah A, Fogel M, Hernandez L, Anwar S, Voges I, Carlsson M, Buddhe S, Laser KT, Greil G, Valsangiacomo-Buechel E, Olivotto I, Wong D, Wolf C, Grotenhuis H, Rickers C, Hor K, Rutz T, Kutty S, Samyn M, Johnson T, Hasbani K, Moore JP, Sieverding L, Detterich J, Parra R, Chungsomprasong P, Toro-Salazar O, Roest AAW, Dittrich S, Brun H, Spinner J, Lai W, Dyer A, Jablonowsk R, Meierhofer C, Gabbert D, Prsa M, Patel JK, Hornung A, Diab SG, House AV, Rakowski H, Benson L, Maron MS, Grosse-Wortmann L. Myocardial Scarring and Sudden Cardiac Death in Young Patients With Hypertrophic Cardiomyopathy: A Multicenter Cohort Study. JAMA Cardiol 2024; 9:1001-1008. [PMID: 39320884 PMCID: PMC11425184 DOI: 10.1001/jamacardio.2024.2824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 07/15/2024] [Indexed: 09/26/2024]
Abstract
Importance The ability to predict sudden cardiac death (SCD) in children and adolescents with hypertrophic cardiomyopathy (HCM) is currently inadequate. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) imaging is associated with SCD events in adults with HCM. Objective To examine the prognostic significance of LGE in patients with HCM who are younger than 21 years. Design, Setting, and Participants This multicenter, retrospective cohort study was conducted from April 8, 2015, to September 12, 2022, in patients with HCM who were younger than 21 years and had undergone CMR imaging across multiple sites in the US, Europe, and South America. Observers of CMR studies were masked toward outcomes and demographic characteristics. Exposure Natural history of HCM. Main Outcome and Measures The primary outcome was SCD and surrogate events, including resuscitated cardiac arrest and appropriate discharges from an implantable defibrillator. Continuous and categorical data are expressed as mean (SD), median (IQR), or number (percentage), respectively. Survivor curves comparing patients with and without LGE were constructed by the Kaplan-Meier method, and likelihood of subsequent clinical events was further evaluated using univariate and multivariable Cox proportional hazards models. Results Among 700 patients from 37 international centers, median (IQR) age was 14.8 (11.9-17.4) years, and 518 participants (74.0%) were male. During a median (IQR) [range] follow-up period of 1.9 (0.5-4.1) [0.1-14.8] years, 35 patients (5.0%) experienced SCD or equivalent events. LGE was present in 230 patients (32.9%), which constituted an mean (SD) burden of 5.9% (7.3%) of left ventricular myocardium. The LGE amount was higher in older patients and those with greater left ventricular mass and maximal wall thickness; patients with LGE had lower left ventricular ejection fractions and larger left atrial diameters. The presence and burden of LGE was associated with SCD, even after correcting for existing risk stratification tools. Patients with 10% or more LGE, relative to total myocardium, had a higher risk of SCD (unadjusted hazard ratio [HR], 2.19; 95% CI, 1.59-3.02; P < .001). Furthermore, the addition of LGE burden improved the performance of the HCM Risk-Kids score (before LGE addition: 0.66; 95% CI, 0.58-0.75; after LGE addition: 0.73; 95% CI, 0.66-0.81) and Precision Medicine in Cardiomyopathy score (before LGE addition: 0.68; 95% CI, 0.49-0.77; after LGE addition: 0.73; 95% CI, 0.64-0.82) SCD predictive models. Conclusions and Relevance In this retrospective cohort study, quantitative LGE was a risk factor for SCD in patients younger than 21 years with HCM and improved risk stratification.
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Affiliation(s)
- Raymond H. Chan
- Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Laurine van der Wal
- Department of Primary and Long-term Care, University of Groningen, Groningen, the Netherlands
| | - Gabriela Liberato
- Heart Institute, University of São Paulo Medical School, São Paulo, Brazil
| | - Ethan Rowin
- Hypertrophic Cardiomyopathy Center, Lahey Hospital and Medical Center, Burlington, Massachusetts
| | | | - Shiraz Maskatia
- Lucile Packard Children’s Hospital, Stanford University, Palo Alto, California
- Texas Children’s Hospital, Baylor College of Medicine, Houston
| | - Sherwin Chan
- Children’s Mercy Hospital, Kansas City, Missouri
| | - Amee Shah
- Columbia University Irving Medical Center, New York, New York
| | - Mark Fogel
- Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Shafkat Anwar
- University of California, San Francisco, School of Medicine
- Benioff Children’s Hospital, University of California, San Francisco
| | - Inga Voges
- Department of Congenital Heart Disease and Pediatric Cardiology, University of Schleswig-Holstein, Kiel, Germany
- Pediatric Heart Centre, University Children’s Hospital, Giessen, Germany
| | - Marcus Carlsson
- Centre for Mathematical Sciences, Lund University, Lund, Sweden
| | - Sujatha Buddhe
- Seattle Children’s Hospital, University of Washington, Seattle
| | - Kai Thorsten Laser
- Heart and Diabetes Center, Ruhr University Bochum, Bad Oeynhausen, Germany
| | - Gerald Greil
- University of Texas Southwestern Medical Center, Dallas
| | | | - Iacopo Olivotto
- Careggi University Hospital, Florence, Italy
- Meyer Children’s Hospital IRCCS, Florence, Italy
| | - Derek Wong
- Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Cordula Wolf
- German Heart Center Munich, Department of Congenital Heart Defects and Pediatric Cardiology, Technical University of Munich, Munich, Germany
| | - Heynric Grotenhuis
- Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Kan Hor
- Nationwide Children’s Hospital, Columbus, Ohio
| | - Tobias Rutz
- Service of Cardiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Shelby Kutty
- Division of Cardiology, Department of Pediatrics, Children’s Hospital and Medical Center, University of Nebraska Medical Center, Omaha
- Taussig Heart Center, Department of Pediatrics, Johns Hopkins Hospital, Baltimore, Maryland
| | - Margaret Samyn
- Herma Heart Institute, Children’s Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee
| | | | - Keren Hasbani
- Texas Center for Pediatric and Congenital Heart Disease, Dell Children’s Medical Center, University of Texas at Austin, Austin
| | - Jeremy P. Moore
- Division of Cardiology, Department of Pediatrics, University of California, Los Angeles, Medical Center
| | | | - Jon Detterich
- Keck School of Medicine, University of Southern California, Los Angeles
- Heart Institute, Children’s Hospital Los Angeles, Los Angeles, California
| | - Rodrigo Parra
- Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Paweena Chungsomprasong
- Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | | | - Arno A. W. Roest
- Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Sven Dittrich
- Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Henrik Brun
- Department of Pediatric Cardiology, Oslo University Hospital, Oslo, Norway
| | - Joseph Spinner
- Texas Children’s Hospital, Baylor College of Medicine, Houston
| | - Wyman Lai
- Children’s Hospital of Orange County, Orange, California
| | - Adrian Dyer
- University of Texas Southwestern Medical Center, Dallas
- Cook Children’s Medical Center, Fort Worth, Texas
| | - Robert Jablonowsk
- Clinical Physiology, Department of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden
| | - Christian Meierhofer
- German Heart Center Munich, Department of Congenital Heart Defects and Pediatric Cardiology, Technical University of Munich, Munich, Germany
| | - Dominik Gabbert
- Department of Congenital Heart Disease and Pediatric Cardiology, University of Schleswig-Holstein, Kiel, Germany
| | - Milan Prsa
- Service of Cardiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | | | - Andreas Hornung
- University Children’s Hospital Tuebingen, Tuebingen, Germany
| | - Simone Goa Diab
- Department of Pediatric Cardiology, Oslo University Hospital, Oslo, Norway
| | | | - Harry Rakowski
- Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Lee Benson
- Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Martin S. Maron
- Hypertrophic Cardiomyopathy Center, Lahey Hospital and Medical Center, Burlington, Massachusetts
| | - Lars Grosse-Wortmann
- Department of Pediatrics, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland
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11
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Busley AV, Gutiérrez-Gutiérrez Ó, Hammer E, Koitka F, Mirzaiebadizi A, Steinegger M, Pape C, Böhmer L, Schroeder H, Kleinsorge M, Engler M, Cirstea IC, Gremer L, Willbold D, Altmüller J, Marbach F, Hasenfuss G, Zimmermann WH, Ahmadian MR, Wollnik B, Cyganek L. Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome. Cell Rep 2024; 43:114448. [PMID: 39003740 DOI: 10.1016/j.celrep.2024.114448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Revised: 04/03/2024] [Accepted: 06/20/2024] [Indexed: 07/16/2024] Open
Abstract
Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1L580P by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1L580P-specific disease mechanism provoking cardiac hypertrophy. The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers. LZTR1 complex dysfunction results in the accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data show that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Uni- or biallelic genetic correction of the LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies.
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Affiliation(s)
- Alexandra Viktoria Busley
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany
| | - Óscar Gutiérrez-Gutiérrez
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany
| | - Elke Hammer
- DZHK (German Center for Cardiovascular Research), Greifswald, Germany; Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany
| | - Fabian Koitka
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany
| | - Amin Mirzaiebadizi
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Martin Steinegger
- School of Biological Sciences, Seoul National University, Seoul, South Korea
| | - Constantin Pape
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany; Institute of Computer Science, Georg-August University Göttingen, Göttingen, Germany
| | - Linda Böhmer
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany
| | - Henning Schroeder
- NMR Signal Enhancement Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Mandy Kleinsorge
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany
| | - Melanie Engler
- Institute of Applied Physiology, University of Ulm, Ulm, Germany
| | | | - Lothar Gremer
- Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich GmbH, Jülich, Germany
| | - Dieter Willbold
- Institute of Physical Biology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Biological Information Processing, Structural Biochemistry (IBI-7), Forschungszentrum Jülich GmbH, Jülich, Germany
| | - Janine Altmüller
- Cologne Center for Genomics, University of Cologne, Faculty of Medicine, and University Hospital Cologne, Cologne, Germany; Genomics Platform, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine-Berlin, Berlin, Germany
| | - Felix Marbach
- Institute of Human Genetics, University Hospital Cologne, Cologne, Germany; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany
| | - Gerd Hasenfuss
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany
| | - Wolfram-Hubertus Zimmermann
- DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany; Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany; Translational Neuroinflammation and Automated Microscopy, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Göttingen, Germany
| | - Mohammad Reza Ahmadian
- Institute of Biochemistry and Molecular Biology II, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Bernd Wollnik
- DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany; Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany
| | - Lukas Cyganek
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany; DZHK (German Center for Cardiovascular Research), Göttingen, Germany; Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Göttingen, Germany; Translational Neuroinflammation and Automated Microscopy, Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Göttingen, Germany.
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12
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Amdani S, Conway J, George K, Martinez HR, Asante-Korang A, Goldberg CS, Davies RR, Miyamoto SD, Hsu DT. Evaluation and Management of Chronic Heart Failure in Children and Adolescents With Congenital Heart Disease: A Scientific Statement From the American Heart Association. Circulation 2024; 150:e33-e50. [PMID: 38808502 DOI: 10.1161/cir.0000000000001245] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/30/2024]
Abstract
With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort.
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13
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Chaput D, Andelfinger G. MEK Inhibition for RASopathy-Associated Hypertrophic Cardiomyopathy: Clinical Application of a Basic Concept. Can J Cardiol 2024; 40:789-799. [PMID: 38432396 DOI: 10.1016/j.cjca.2024.02.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 02/13/2024] [Accepted: 02/15/2024] [Indexed: 03/05/2024] Open
Abstract
The term "RASopathies" designates a group of developmental syndromes that are caused by activating variants of the rat sarcoma virus protein (RAS)/mitogen-activated protein kinase (MAPK) cascade. The most prevalent clinical diagnosis is Noonan syndrome, and other, less prevalent conditions include Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and others. Hypertrophic cardiomyopathy occurs in 10% of these patients and can be severe and life-threating. Recently, repurposing of medications inhibiting the RAS/MAPK on a compassionate use basis has emerged as a promising concept to improve the outcome of these patients. Herein, we specifically review the role of the RAS/MAPK pathway in RASopathy-associated cardiomyopathy, and discuss the role of small-molecule inhibition in the treatment of this condition. We describe how drug repurposing of trametinib (mitogen-activated protein/extracellular signal-regulated kinase inhibition) and sirolimus/everolimus (mammalian target of rapamycin inhibition) was performed, how genotype-specific therapies are chosen and followed, as well as initial outcomes from early case series. Finally, we lay out the challenges and opportunities for trials that aim to quantify the benefits of this approach.
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Affiliation(s)
- Dominic Chaput
- Cardiovascular Genetics Research Laboratory, CHU Sainte Justine Research Center, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
| | - Gregor Andelfinger
- Cardiovascular Genetics Research Laboratory, CHU Sainte Justine Research Center, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada.
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14
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Townsend M, Jeewa A, Khoury M, Cunningham C, George K, Conway J. Unique Aspects of Hypertrophic Cardiomyopathy in Children. Can J Cardiol 2024; 40:907-920. [PMID: 38244986 DOI: 10.1016/j.cjca.2024.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/03/2024] [Accepted: 01/14/2024] [Indexed: 01/22/2024] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is a primary heart muscle disease characterized by left ventricular hypertrophy that can be asymptomatic or with presentations that vary from left ventricular outflow tract obstruction, heart failure from diastolic dysfunction, arrhythmias, and/or sudden cardiac death. Children younger than 1 year of age tend to have worse outcomes and often have HCM secondary to inborn errors of metabolism or syndromes such as RASopathies. For children who survive or are diagnosed after 1 year of age, HCM outcomes are often favourable and similar to those seen in adults. This is because of sudden cardiac death risk stratification and medical and surgical innovations. Genetic testing and timely cardiac screening are paving the way for disease-modifying treatment as gene-specific therapies are being developed.
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Affiliation(s)
- Madeleine Townsend
- Department of Cardiology, Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA
| | - Aamir Jeewa
- Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Michael Khoury
- Division of Pediatric Cardiology, Stollery Children's Hospital, Edmonton, Alberta, Canada
| | | | - Kristen George
- Division of Cardiology, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Jennifer Conway
- Division of Pediatric Cardiology, Stollery Children's Hospital, Edmonton, Alberta, Canada.
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15
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Kaski JP, Norrish G, Gimeno Blanes JR, Charron P, Elliott P, Tavazzi L, Tendera M, Laroche C, Maggioni AP, Baban A, Khraiche D, Ziolkowska L, Limongelli G, Ojala T, Gorenflo M, Anastasakis A, Mostafa S, Caforio ALP. Cardiomyopathies in children and adolescents: aetiology, management, and outcomes in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis Registry. Eur Heart J 2024; 45:1443-1454. [PMID: 38427064 PMCID: PMC11448693 DOI: 10.1093/eurheartj/ehae109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/05/2024] [Accepted: 02/08/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND AND AIMS Childhood-onset cardiomyopathies are rare and poorly characterized. This study examined the baseline characteristics and 1-year follow-up of children with cardiomyopathy in the first European Cardiomyopathy Registry. METHODS Prospective data were collected on individuals aged 1-<18 years enrolled in the European Society of Cardiology EURObservational Research Programme Cardiomyopathy and Myocarditis long-term registry (June 2014-December 2016). RESULTS A total of 633 individuals aged ≤18 years with hypertrophic [HCM; n = 388 (61.3%)], dilated [DCM; n = 206 (32.5%)], restrictive [RCM; n = 28 (4.4%)], and arrhythmogenic right ventricular cardiomyopathy [ARVC; n = 11 (1.7%)] were enrolled by 23 referral centres in 14 countries. Median age at diagnosis was 4.0 [interquartile range (IQR) 0-10] years, and there was a male predominance [n = 372 (58.8%)] across all subtypes, with the exception of DCM diagnosed <10 years of age; 621 (98.1%) patients were receiving cardiac medication and 80 (12.6%) had an implantable cardioverter-defibrillator. A total of 253 patients (253/535, 47.3%) had familial disease. Genetic testing was performed in 414 (67.8%) patients with a pathogenic or likely pathogenic variant reported in 250 (60.4%). Rare disease phenocopies were reported in 177 patients (28.0%) and were most frequent in patients under 10 years [142 (30.9%) vs. 35 (19.6%); P = .003]. Over a median follow-up of 12.5 months (IQR 11.3-15.3 months), 18 patients (3.3%) died [HCM n = 9 (2.6%), DCM n = 5 (3.0%), RCM n = 4 (16.0%)]. Heart failure events were most frequent in RCM patients (36.0%). CONCLUSIONS The findings confirm the heterogeneous aetiology of childhood cardiomyopathies and show a high frequency of familial disease. Outcomes differed by cardiomyopathy subtype, highlighting a need for disease-specific evaluation and treatment.
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Affiliation(s)
- Juan Pablo Kaski
- Centre for Paediatric Inherited and Rare Cardiovascular Disease, University College London Institute of Cardiovascular Science and Great Ormond Street Hospital NHS Foundation Trust, 20 Guilford Street, WC1N 1DZ London, United Kingdom
| | - Gabrielle Norrish
- Centre for Paediatric Inherited and Rare Cardiovascular Disease, University College London Institute of Cardiovascular Science and Great Ormond Street Hospital NHS Foundation Trust, 20 Guilford Street, WC1N 1DZ London, United Kingdom
| | | | - Philippe Charron
- Assistance Publique-Hôpitaux de Paris, ICAN, Inserm UMR1166, Sorbonne Université, Centre de Référence des Maladies Cardiaques Héréditaires ou Rares, Hôpital Pitié-Salpêtrière, Paris, France
| | - Perry Elliott
- Centre for Inherited Cardiovascular Diseases, University College London and St. Bartholomew's Hospital, London, United Kingdom
| | - Luigi Tavazzi
- Department of Cardiology, Maria Cecilia Hospital, GVM Care&Research, Cotignola, Italy
| | - Michal Tendera
- Department of Cardiology and Structural Heart Disease, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Cécile Laroche
- EURObservational Research Programme, European Society of Cardiology, Sophia-Antipolis, France
| | - Aldo P Maggioni
- EURObservational Research Programme, European Society of Cardiology, Sophia-Antipolis, France
- Department of Cardiology, ANMCO Research Center, Florence, Italy
| | - Anwar Baban
- Cardiogenetic Centre, Medical and Surgical Department of Pediatric Cardiology, IRCCS, Bambino Gesù Children's Hospital, Rome, Italy
| | - Diala Khraiche
- Pediatric and Congenital Cardiology Unit, Hôpital Necker Enfants Malades, M3C-Necker, Paris, France
| | - Lidia Ziolkowska
- Pediatric Cardiology, The Children's Memorial Health Institute, Warsaw, Poland
| | - Giuseppe Limongelli
- Inherited and Heart Disease Unit, Monaldi Hospital, A.O. Colli (University of Campania 'Luigi Vanvitelli'), Naples, Italy
| | - Tiina Ojala
- Pediatric Cardiology, University of Helsinki and Helsinki University Hospital, Hospital for Children and Adolescents, Helsinki, Finland
| | - Matthias Gorenflo
- Pediatric Cardiology and Congenital Heart Diseases, University of Heidelberg, Heidelberg, Germany
| | - Aris Anastasakis
- Unit of Rare and Inherited CVD-Department of Cardiology, Kappa Unit, Onassis Cardiac Surgery Centre, Athens, Greece
| | - Shaimaa Mostafa
- Benha Faculty of Medicine, Cardiovascular Department, Benha University, Benha, Egypt
| | - Alida L P Caforio
- Cardiology, Department of Cardiological, Thoracic and Vascular Sciences and Public Health, University of Padua, Padua, Italy
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16
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Boleti O, Norrish G, Field E, Dady K, Summers K, Nepali G, Bhole V, Uzun O, Wong A, Daubeney PEF, Stuart G, Fernandes P, McLeod K, Ilina M, Ali MNL, Bharucha T, Donne GD, Brown E, Linter K, Jones CB, Searle J, Regan W, Mathur S, Boyd N, Reinhardt Z, Duignan S, Prendiville T, Adwani S, Kaski JP. Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy. ESC Heart Fail 2024; 11:923-936. [PMID: 38217456 PMCID: PMC10966228 DOI: 10.1002/ehf2.14637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/24/2023] [Accepted: 11/23/2023] [Indexed: 01/15/2024] Open
Abstract
AIMS This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P = 0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. CONCLUSIONS These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.
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Affiliation(s)
- Olga Boleti
- Centre for Inherited Cardiovascular Diseases, Department of CardiologyGreat Ormond Street HospitalLondonUK
- Institute of Cardiovascular ScienceUniversity College LondonLondonUK
| | - Gabrielle Norrish
- Centre for Inherited Cardiovascular Diseases, Department of CardiologyGreat Ormond Street HospitalLondonUK
- Institute of Cardiovascular ScienceUniversity College LondonLondonUK
| | - Ella Field
- Centre for Inherited Cardiovascular Diseases, Department of CardiologyGreat Ormond Street HospitalLondonUK
- Institute of Cardiovascular ScienceUniversity College LondonLondonUK
| | - Kathleen Dady
- Centre for Inherited Cardiovascular Diseases, Department of CardiologyGreat Ormond Street HospitalLondonUK
| | - Kim Summers
- Institute of Cardiovascular ScienceUniversity College LondonLondonUK
| | - Gauri Nepali
- The Heart UnitBirmingham Children's HospitalBirminghamUK
| | - Vinay Bhole
- The Heart UnitBirmingham Children's HospitalBirminghamUK
| | - Orhan Uzun
- Children's Heart UnitUniversity Hospital of WalesCardiffUK
| | - Amos Wong
- Children's Heart UnitUniversity Hospital of WalesCardiffUK
| | - Piers E. F. Daubeney
- Department of Paediatric CardiologyRoyal Brompton and Harefield NHS TrustLondonUK
| | - Graham Stuart
- Department of Paediatric CardiologyBristol Royal Hospital for ChildrenBristolUK
| | | | - Karen McLeod
- Department of Paediatric CardiologyRoyal Hospital for ChildrenGlasgowUK
| | - Maria Ilina
- Department of Paediatric CardiologyRoyal Hospital for ChildrenGlasgowUK
| | | | - Tara Bharucha
- Department of Paediatric CardiologySouthampton General HospitalSouthamptonUK
| | | | - Elspeth Brown
- Department of Paediatric CardiologyLeeds General InfirmaryLeedsUK
| | - Katie Linter
- Department of Paediatric CardiologyGlenfield HospitalLeicesterUK
| | | | - Jonathan Searle
- Children's Heart ServiceEvelina Children's HospitalLondonUK
- Department of Paediatric CardiologyJohn Radcliffe HospitalOxfordUK
| | - William Regan
- Children's Heart ServiceEvelina Children's HospitalLondonUK
| | - Sujeev Mathur
- Children's Heart ServiceEvelina Children's HospitalLondonUK
| | - Nicola Boyd
- Department of Paediatric CardiologyThe Freeman HospitalNewcastleUK
| | - Zdenka Reinhardt
- Department of Paediatric CardiologyThe Freeman HospitalNewcastleUK
| | - Sophie Duignan
- The Children's Heart CentreOur Lady's Children's HospitalDublinIreland
| | | | - Satish Adwani
- Department of Paediatric CardiologyJohn Radcliffe HospitalOxfordUK
| | - Juan Pablo Kaski
- Centre for Inherited Cardiovascular Diseases, Department of CardiologyGreat Ormond Street HospitalLondonUK
- Institute of Cardiovascular ScienceUniversity College LondonLondonUK
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Knauer C, Haltern H, Schoger E, Kügler S, Roos L, Zelarayán LC, Hasenfuss G, Zimmermann WH, Wollnik B, Cyganek L. Preclinical evaluation of CRISPR-based therapies for Noonan syndrome caused by deep-intronic LZTR1 variants. MOLECULAR THERAPY. NUCLEIC ACIDS 2024; 35:102123. [PMID: 38333672 PMCID: PMC10851011 DOI: 10.1016/j.omtn.2024.102123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 01/18/2024] [Indexed: 02/10/2024]
Abstract
Gene variants in LZTR1 are implicated to cause Noonan syndrome associated with a severe and early-onset hypertrophic cardiomyopathy. Mechanistically, LZTR1 deficiency results in accumulation of RAS GTPases and, as a consequence, in RAS-MAPK signaling hyperactivity, thereby causing the Noonan syndrome-associated phenotype. Despite its epidemiological relevance, pharmacological as well as invasive therapies remain limited. Here, personalized CRISPR-Cas9 gene therapies might offer a novel alternative for a curative treatment in this patient cohort. In this study, by utilizing a patient-specific screening platform based on iPSC-derived cardiomyocytes from two Noonan syndrome patients, we evaluated different clinically translatable therapeutic approaches using small Cas9 orthologs targeting a deep-intronic LZTR1 variant to cure the disease-associated molecular pathology. Despite high editing efficiencies in cardiomyocyte cultures transduced with lentivirus or all-in-one adeno-associated viruses, we observed crucial differences in editing outcomes in proliferative iPSCs vs. non-proliferative cardiomyocytes. While editing in iPSCs rescued the phenotype, the same editing approaches did not robustly restore LZTR1 function in cardiomyocytes, indicating critical differences in the activity of DNA double-strand break repair mechanisms between proliferative and non-proliferative cell types and highlighting the importance of cell type-specific screens for testing CRISPR-Cas9 gene therapies.
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Affiliation(s)
- Carolin Knauer
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
| | - Henrike Haltern
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
| | - Eric Schoger
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Sebastian Kügler
- Department of Neurology, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Lennart Roos
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany
| | - Laura C. Zelarayán
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, 37075 Göttingen, Germany
- Department of Cardiology and Angiology, University of Giessen, 35390 Giessen, Germany
| | - Gerd Hasenfuss
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany
| | - Wolfram-Hubertus Zimmermann
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany
- Institute of Pharmacology and Toxicology, University Medical Center Göttingen, 37075 Göttingen, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 37075 Göttingen, Germany
- DZNE (German Center for Neurodegenerative Diseases), 37075 Göttingen, Germany
| | - Bernd Wollnik
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany
- Institute of Human Genetics, University Medical Center Göttingen, 37075 Göttingen, Germany
| | - Lukas Cyganek
- Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, 37075 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), partner site Göttingen, 37075 Göttingen, Germany
- Cluster of Excellence "Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, 37075 Göttingen, Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 37075 Göttingen, Germany
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18
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Hauptmeijer RWL, Lippert L, Ten Cate FEAU, Fejzic Z, Leenders E, Wolf CM, Draaisma JMT. Differentiating primary sarcomeric hypertrophic cardiomyopathy from Noonan syndrome: can the electrocardiogram be of use? Cardiol Young 2024; 34:597-603. [PMID: 37649442 DOI: 10.1017/s1047951123003177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Noonan syndrome is a multi-system genetic disorder and patients may suffer from hypertrophic cardiomyopathy. Previous studies have identified electrocardiographic features that may support a diagnosis of Noonan syndrome. In this two-centre retrospective study, we analysed typical Noonan syndrome-related electrocardiographic features in 30 patients with Noonan syndrome with hypertrophic cardiomyopathy and compared these with the electrocardiographic features in 15 children with sarcomeric hypertrophic cardiomyopathy. Typical Noonan syndrome-related electrocardiographic features are a negative aVF, small left precordial R-waves, large right precordial S-waves, and abnormal Q-wave. We also analysed electrocardiographic features of hypertrophic cardiomyopathy: ST-segment abnormalities and T-wave abnormalities. A negative aVF was seen in 83% of patients with Noonan syndrome-related hypertrophic cardiomyopathy in contrast to 27% of patients with primary sarcomeric hypertrophic cardiomyopathy (p < 0.001). An extreme QRS axis in the north-west was seen only in patients with Noonan syndrome-related hypertrophic cardiomyopathy. This QRS axis deviation is likely to be determined by the Noonan syndrome-related hypertrophic cardiomyopathy and not by the type of hypertrophic cardiomyopathy. There were no differences between the two groups in the frequency of large right precordial S-waves and small R-waves in the left precordial leads V5 and V6. However, an abnormal R/S ratio was more often seen in patients with Noonan syndrome-related hypertrophic cardiomyopathy (p < 0.001). Pathologic Q-waves were seen statistically more frequently in patients with sarcomeric hypertrophic cardiomyopathy (p = 0.009). The occurrence of ST-segment and T-wave pathology did not statistically differ between the two groups. Electrography can be of use in differentiating sarcomeric hypertrophic cardiomyopathy from Noonan syndrome-related hypertrophic cardiomyopathy.
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Affiliation(s)
- Robert W L Hauptmeijer
- Department of Pediatrics, Radboud Institute for Health Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lea Lippert
- Department of Congenital Heart Disease and Pediatric Cardiology, Technical University of Munich, School of Medicine & Health, Munich, Germany
| | - Floris E A Udink Ten Cate
- Department of Pediatric Cardiology, Radboud Institute for Health Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Zina Fejzic
- Department of Pediatric Cardiology, Radboud Institute for Health Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Erika Leenders
- Department of Human genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Cordula M Wolf
- Department of Congenital Heart Disease and Pediatric Cardiology, Technical University of Munich, School of Medicine & Health, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Jos M T Draaisma
- Department of Pediatrics, Radboud Institute for Health Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
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19
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Zheng J, Peng L, Cheng R, Li Z, Xie J, Huang E, Cheng J, Zhao Q. RAF1 mutation leading to hypertrophic cardiomyopathy in a Chinese family with a history of sudden cardiac death: A diagnostic insight into Noonan syndrome. Mol Genet Genomic Med 2024; 12:e2290. [PMID: 37787490 PMCID: PMC10767430 DOI: 10.1002/mgg3.2290] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 09/10/2023] [Accepted: 09/19/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in sarcomeric genes. However, a subset of cases is attributed to genetic disorders unrelated to sarcomeric genes, such as Noonan syndrome (NS) and other RASopathies. In this study, we present a family with a history of sudden cardiac death (SCD) and focus on two adults with syndromic left ventricular hypertrophy (LVH). METHODS Clinical evaluations, including echocardiography, were conducted to assess cardiac manifestations. Whole-exome sequencing was performed to identify potential genetic variants underlying syndromic LVH in the study participants. RESULTS Whole-exome sequencing revealed a missense variant in the RAF1 gene, c.782C>T (p.Pro261Leu). This variant confirmed the diagnosis of NS in the affected individuals. CONCLUSION The findings of this study underscore the importance of family history investigation and genetic testing in diagnosing syndromic LVH. By identifying the underlying genetic cause, clinicians can better understand the etiology of RAS-HCM and its association with SCD in young adults.
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Affiliation(s)
- Jingjing Zheng
- Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat‐Sen UniversityGuangzhouChina
| | - Longyun Peng
- Department of CardiologyThe First Affiliated Hospital, Sun Yat‐Sen UniversityGuangzhouChina
| | - Ruofei Cheng
- Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat‐Sen UniversityGuangzhouChina
| | - Zhiyan Li
- Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat‐Sen UniversityGuangzhouChina
| | - Jianjie Xie
- Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat‐Sen UniversityGuangzhouChina
| | - Erwen Huang
- Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat‐Sen UniversityGuangzhouChina
| | - Jianding Cheng
- Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat‐Sen UniversityGuangzhouChina
| | - Qianhao Zhao
- Faculty of Forensic Medicine, Zhongshan School of MedicineSun Yat‐Sen UniversityGuangzhouChina
- Guangdong Province Translational Forensic Medicine Engineering Technology Research CenterSun Yat‐Sen UniversityGuangzhouChina
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20
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Yi JS, Perla S, Bennett AM. An Assessment of the Therapeutic Landscape for the Treatment of Heart Disease in the RASopathies. Cardiovasc Drugs Ther 2023; 37:1193-1204. [PMID: 35156148 PMCID: PMC11726350 DOI: 10.1007/s10557-022-07324-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/03/2022] [Indexed: 12/14/2022]
Abstract
The RAS/mitogen-activated protein kinase (MAPK) pathway controls a plethora of developmental and post-developmental processes. It is now clear that mutations in the RAS-MAPK pathway cause developmental diseases collectively referred to as the RASopathies. The RASopathies include Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome, neurofibromatosis type 1, and Costello syndrome. RASopathy patients exhibit a wide spectrum of congenital heart defects (CHD), such as valvular abnormalities and hypertrophic cardiomyopathy (HCM). Since the cardiovascular defects are the most serious and recurrent cause of mortality in RASopathy patients, it is critical to understand the pathological signaling mechanisms that drive the disease. Therapies for the treatment of HCM and other RASopathy-associated comorbidities have yet to be fully realized. Recent developments have shown promise for the use of repurposed antineoplastic drugs that target the RAS-MAPK pathway for the treatment of RASopathy-associated HCM. However, given the impact of the RAS-MAPK pathway in post-developmental physiology, establishing safety and evaluating risk when treating children will be paramount. As such insight provided by preclinical and clinical information will be critical. This review will highlight the cardiovascular manifestations caused by the RASopathies and will discuss the emerging therapies for treatment.
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Affiliation(s)
- Jae-Sung Yi
- Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA
| | - Sravan Perla
- Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA
| | - Anton M Bennett
- Department of Pharmacology, Yale University School of Medicine, SHM B226D, 333 Cedar Street, New Haven, CT, 06520-8066, USA.
- Yale Center for Molecular and Systems Metabolism, Yale University, New Haven, CT, 06520, USA.
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21
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Nguyen SN, Chung MM, Vinogradsky AV, Richmond ME, Zuckerman WA, Goldstone AB, Bacha EA. Long-term outcomes of surgery for obstructive hypertrophic cardiomyopathy in a pediatric cohort. JTCVS OPEN 2023; 16:726-738. [PMID: 38204697 PMCID: PMC10775098 DOI: 10.1016/j.xjon.2023.09.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 01/12/2024]
Abstract
Background Septal reduction therapy via septal myectomy or a modified Konno procedure is the mainstay of therapy for drug-refractory obstructive hypertrophic cardiomyopathy (HCM), although outcomes data on septal myectomy in pediatric patients are limited. We evaluated long-term outcomes following surgery for obstructive HCM in a pediatric cohort. Methods We retrospectively reviewed patients age ≤18 years with obstructive HCM who underwent a left and/or right ventricular septal myectomy at our institution between 1992 and 2022. Primary endpoints were transplantation-free survival, freedom from HCM-related death, and cumulative probability of HCM-related reintervention. We further evaluated outcomes in patients with and without Noonan syndrome or other RASopathies. Results Thirty-seven patients (median age, 7.4 years; interquartile range [IQR], 3.4-12.9 years) underwent transaortic septal myectomy. A combined modified Konno procedure was performed in 5 patients (13.9%). Sixteen patients (43.2%) had a RASopathy. A concomitant right ventricular outflow tract resection was performed in 9 patients (24.3%). There was 1 (2.7%) in-hospital death and 4 late deaths at a median follow-up of 10.5 years (IQR, 0.1-29.3). Twenty-year transplant-free survival and freedom from HCM-related death were 80.6% (95% confidence interval [CI], 64.2%-100%) and 87.1% (95% CI, 71.8%-100%), respectively. The 20-year cumulative probability of HCM-related reintervention was 34.2% (95% CI, 12.8%-57.1%). Seven patients required a septal reintervention. There was no difference in any primary endpoints between patients with and without a RASopathy. Conclusions Surgery for obstructive HCM, including septal myectomy with and without a modified Konno procedure, may be performed with low morbidity and good long-term outcomes in pediatric patients. Recurrent outflow tract obstruction is not uncommon.
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Affiliation(s)
- Stephanie N. Nguyen
- Section of Pediatric and Congenital Cardiac Surgery, New York Presbyterian/Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, NY
| | - Megan M. Chung
- Section of Pediatric and Congenital Cardiac Surgery, New York Presbyterian/Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, NY
| | - Alice V. Vinogradsky
- Section of Pediatric and Congenital Cardiac Surgery, New York Presbyterian/Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, NY
| | - Marc E. Richmond
- Division of Pediatric Cardiology, New York Presbyterian/Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, NY
| | - Warren A. Zuckerman
- Division of Pediatric Cardiology, New York Presbyterian/Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, NY
| | - Andrew B. Goldstone
- Section of Pediatric and Congenital Cardiac Surgery, New York Presbyterian/Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, NY
| | - Emile A. Bacha
- Section of Pediatric and Congenital Cardiac Surgery, New York Presbyterian/Morgan Stanley Children's Hospital, Columbia University Irving Medical Center, New York, NY
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22
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Kim ST, Lee SY, Kim GB, Bae EJ, Ko JM, Song MK. Cardiovascular Characteristics and Progressions of Hypertrophic Cardiomyopathy and Pulmonary Stenosis in RASopathy Syndrome in the Genomic Era. J Pediatr 2023; 262:113351. [PMID: 36806754 DOI: 10.1016/j.jpeds.2022.12.045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 11/07/2022] [Accepted: 12/25/2022] [Indexed: 02/19/2023]
Abstract
INTRODUCTION To investigate cardiovascular characteristics and progressions of hypertrophic cardiomyopathy (HCM) and pulmonary stenosis (PS) and determine whether any genotype-phenotype correlations exist in patients with gene-confirmed RASopathy syndrome. STUDY DESIGN Eighty patients (male, 55%) confirmed as having RASopathy syndrome by genetic testing at a single tertiary center were enrolled. Subjects' medical and echocardiography records were reviewed and the changes in the z scores of left ventricular wall thickness (LVWT) and the degree of PS over time were examined during follow-up of 5.7 ± 3.1 and 7.5 ± 5.2 years, respectively. RESULTS The most common RASopathy gene identified was PTPN11 (56%), followed by RAF1 (10%). Eighty-five percent of patients had cardiovascular diseases, wherein 42% had HCM, and 38% PS. Mean maximal LVWT z score on the initial echocardiography (mean age 5.0 ± 6.0 years) was 3.4 ± 1.3 (median 2.8, range 2.1-6.6) in the HCM group. Overall, the maximal LVWT increased with time, especially in the HCM group (z = 3.4 ± 1.3 to 3.7 ± 1.6, P = .008) and RAF1-variant group (z = 3.7 ± 1.7 to 4.6 ± 1.8, P = .031). Five patients newly developed HCM during the study period. Genotype-phenotype correlation was significant for HCM (P = .002); 31% of patients with PTPN11 and 88% with RAF1 variants had HCM. PS did not progress in this study cohort. CONCLUSIONS In this study, progression of ventricular hypertrophy was seen in a significant number of patients with genotype correlation. Thus, long-term follow up of cardiovascular problems in patients with RASopathy is necessary.
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Affiliation(s)
- Susan Taejung Kim
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang Yun Lee
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Gi Beom Kim
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eun Jung Bae
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung Min Ko
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea; Rare Disease Center, Seoul National University Hospital, Seoul, Republic of Korea
| | - Mi Kyoung Song
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
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23
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Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales-Villa R, Basso C, Bezzina CR, Biagini E, Blom NA, de Boer RA, De Winter T, Elliott PM, Flather M, Garcia-Pavia P, Haugaa KH, Ingles J, Jurcut RO, Klaassen S, Limongelli G, Loeys B, Mogensen J, Olivotto I, Pantazis A, Sharma S, Van Tintelen JP, Ware JS, Kaski JP. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J 2023; 44:3503-3626. [PMID: 37622657 DOI: 10.1093/eurheartj/ehad194] [Citation(s) in RCA: 912] [Impact Index Per Article: 456.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/26/2023] Open
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24
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Mukhtar G, Sasidharan B, Krishnamoorthy KM, Kurup HKN, Gopalakrishnan A, SasiKumar D, P SS, Valaparambil AK, Sivasubramonian S, Sivadasanpillai H. Clinical profile and outcomes of pediatric hypertrophic cardiomyopathy in a South Indian tertiary care cardiac center: a three decade experience. BMC Pediatr 2023; 23:446. [PMID: 37679699 PMCID: PMC10483701 DOI: 10.1186/s12887-023-04255-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 08/17/2023] [Indexed: 09/09/2023] Open
Abstract
INTRODUCTION Although much research has been done on adult hypertrophic cardiomyopathy, data on pediatric hypertrophic cardiomyopathy is still limited. METHODS AND RESULTS The study enrolled all patients with cardiomyopathy who presented to us between 1990 to 2020 and were younger than 18 yrs. During the thirty-year study period, we identified 233 cases of pediatric cardiomyopathy. Sixty-three cases (27%) had hypertrophic cardiomyopathy. Out of the 63 HCM cases, 12% presented in the neonatal period and 37% presented in the first year of life. The median age of presentation was 7 yrs (Range 0.1-18 yrs). Sixteen patients had proven syndromic, metabolic, or genetic disease (25%). LV outflow obstruction was present in 30 patients (47%). Noonan syndrome was present in 9 of the 63 patients (14%). Dyspnea on exertion was the most common mode of presentation. Cardiac MRI was done in 28 patients, out of which 17 had late gadolinium enhancement (LGE). Mid myocardial enhancement was the most common pattern. Four patients had LGE of more than 15%. Over a mean follow-up period of 5.6 years (0.1-30 years), twenty-one were lost to follow-up (33%). Among the patients whose outcome was known, eleven died (26%), and thirty-one (73%) were alive. The 5-year survival rate of HCM patients was 82%, and the 10-year survival rate was 78%. Seven died of sudden cardiac death, three from heart failure, and one from ventricular arrhythmias. Sustained ventricular arrhythmias were seen in three patients and atrial arrhythmias in two. First-degree AV block was seen in 10 patients (15%) and bundle branch blocks (BBB) in five (8%). Eight patients required ICD or transplant (12.7%). Two patients underwent ICD for primary prevention, and one underwent PPI for distal AV conduction disease. Among the various clinical, echocardiographic, and radiological risk factors studied, only consanguinity showed a trend towards higher events of death or ventricular arrhythmias (P-value 0.08). CONCLUSION More than one-third of our HCM cohort presented in infancy. LV outflow tract obstruction is common (47%). Mid myocardial enhancement was the most common pattern of late gadolinium enhancement. SCD was the most common cause of death. The outcome in our HCM cohort is good and similar to other population cohorts. Only Consanguinity showed a trend towards higher events of death or ventricular arrhythmias.
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Affiliation(s)
- Gousia Mukhtar
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India.
| | - Bijulal Sasidharan
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
| | - Kavassery Mahadevan Krishnamoorthy
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
| | - Harikrishnan K N Kurup
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
| | - Arun Gopalakrishnan
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
| | - Deepa SasiKumar
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
| | - Sankara Sarma P
- Achutha Menon Center for Health Science Studies, Thiruvananthapuram, Kerala, 695011, India
| | - Ajit Kumar Valaparambil
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
| | - Sivasankaran Sivasubramonian
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
| | - Harikrishnan Sivadasanpillai
- Department of Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, SCTIMST, Thiruvananthapuram, Kerala, 695011, India
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Griffeth EM, Dearani JA, Schaff HV, Johnson JN, Ackerman MJ, Bos JM, Alzate-Aguirre M, Todd A, Cannon BC, Wackel PL, Stephens EH. Septal Myectomy Outcomes in Children and Adolescents With Obstructive Hypertrophic Cardiomyopathy. Ann Thorac Surg 2023; 116:499-507. [PMID: 37116851 PMCID: PMC10524729 DOI: 10.1016/j.athoracsur.2023.04.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 03/15/2023] [Accepted: 04/04/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND Little data exist regarding characteristics and outcomes of pediatric patients undergoing septal myectomy. We evaluated this in a large referral population. METHODS Septal myectomy was performed in 199 consecutive patients aged ≤18 years with obstructive hypertrophic cardiomyopathy from January 1, 1976, to June 30, 2021. RESULTS Median age was 13 years (interquartile range [IQR], 8-15 years). Left ventricular myectomy approaches included transaortic (163 of 198 [82%]), transapical (16 of 198 [8%]), and combined (19 of 198 [10%]). Right ventricular interventions included myectomy (13 of 199 [7%]) and patch reconstruction of the outflow tract (15 of 199 [8%]). Maximum left ventricular outflow tract gradients decreased after myectomy (prebypass: 50 mm Hg [IQR, 31-73 mm Hg] vs postbypass: 4 mm Hg [IQR, 0-9 mm Hg], P < .001), and this was sustained long-term (5 mm Hg [IQR, 5-10 mm Hg] at 10 years). Iatrogenic aortic and mitral valve injuries occurred in 13 of 199 (7%) and 1 of 199 (1%), respectively; however, all were successfully repaired. Operative mortality was 2 of 199 (1%). The cumulative incidence of redo myectomy was low, at 5.8% at 5 and 8.3% at 10 years. Redo myectomy patients had higher maximum left ventricular outflow tract gradients on echocardiography at predischarge and 1 year and were younger at the index operation (8 years [IQR, 2.5-10 years] vs 13 years [IQR, 9-16 years], P < .001). Overall survival at 10 years was 90%, relative to 47% in a previously reported pediatric nonoperative cohort. CONCLUSIONS Pediatric septal myectomy provides safe, effective, and durable relief of ventricular outflow tract obstruction. Iatrogenic valve injury remains a low but nonnegligible risk. Recurrent obstruction requiring redo myectomy is infrequent and can be identified early. Long-term survival in this pediatric septal myectomy cohort appears to fare better than pediatric hypertrophic cardiomyopathy cohorts managed nonoperatively.
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Affiliation(s)
- Elaine M Griffeth
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
| | - Joseph A Dearani
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota.
| | - Hartzell V Schaff
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
| | | | - Michael J Ackerman
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - J Martijn Bos
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Mateo Alzate-Aguirre
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Austin Todd
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Bryan C Cannon
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
| | - Philip L Wackel
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
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Cheong D, Eisenberg R, Lamour JM, Hsu DT, Choi J, Bansal N. Waitlist and Posttransplant Outcomes of Children and Young Adults With Hypertrophic Cardiomyopathy. Ann Thorac Surg 2023; 116:588-597. [PMID: 35690136 DOI: 10.1016/j.athoracsur.2022.05.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 04/20/2022] [Accepted: 05/22/2022] [Indexed: 11/01/2022]
Abstract
BACKGROUND Heart transplantation (HT) is standard therapy for end-stage hypertrophic cardiomyopathy (HCM); however, few studies have described outcomes of older children and young adults with HCM listed for HT. Our objective was to compare waitlist and post-HT outcomes among pediatric and young adult patients with HCM and dilated cardiomyopathy (DCM). METHODS The Scientific Registry of Transplant Recipients was queried for patients with HCM and DCM listed at ≤25 years of age. Patient characteristics, waitlist and post-HT survival were compared between younger (≤5 years of age) and older (>5 to ≤25 years of age) HCM patients and between HCM and DCM patients. RESULTS Among 6252 patients listed for HT at ≤25 years of age with DCM and HCM, 3926 and 250 were in the older cohort and 1944 and 132 were in the younger cohort, respectively. Older HCM patients were less likely to be critically ill at listing compared with younger HCM patients (P = .0001). Waitlist mortality was similar between HCM and DCM patients in both age cohorts. Post-HT survival in HCM patients was similar between the age cohorts. In the younger cohort, early post-HT survival was worse in HCM compared with DCM (P = .009), with no difference in long-term survival. Survival was similar between the older cohorts. CONCLUSIONS Older children and young adults with HCM are less critically ill than the younger cohort and show waitlist and post-HT survival similar to DCM patients. The young children with HCM had worse early posttransplantation survival, though long-term survival was same as DCM.
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Affiliation(s)
- Daniel Cheong
- Department of Pediatric Cardiology, Cohen Children's Medical Center/Northwell Health, New Hyde Park, New York
| | - Ruth Eisenberg
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Jacqueline M Lamour
- Division of Pediatric Cardiology, Children's Hospital at Montefiore, Bronx, New York
| | - Daphne T Hsu
- Division of Pediatric Cardiology, Children's Hospital at Montefiore, Bronx, New York
| | - Jaeun Choi
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Neha Bansal
- Division of Pediatric Cardiology, Children's Hospital at Montefiore, Bronx, New York.
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Östman-Smith I. Lessons From a Genotype-Phenotype Study About the Clinical Spectrum of Hypertrophic Cardiomyopathy Associated With Noonan Syndrome With Multiple Lentigines and PTPN11-Mutations. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2023; 16:359-362. [PMID: 37325916 DOI: 10.1161/circgen.123.004206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Affiliation(s)
- Ingegerd Östman-Smith
- Institute of Clinical Specialties, Sahlgrenska Academy, Gothenburg University & Children´s Heart Center, Queen Silvia Children´s Hospital, Sahlgrenska University Hospital, Region Västra Götaland, Gothenburg, Sweden
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28
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Monda E, Prosnitz A, Aiello R, Lioncino M, Norrish G, Caiazza M, Drago F, Beattie M, Tartaglia M, Russo MG, Colan SD, Calcagni G, Gelb BD, Kaski JP, Roberts AE, Limongelli G. Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2023; 16:350-358. [PMID: 37199218 PMCID: PMC11791648 DOI: 10.1161/circgen.122.003861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 03/10/2023] [Indexed: 05/19/2023]
Abstract
BACKGROUND We aimed to examine clinical features and outcomes of consecutive molecularly characterized patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy. METHODS A retrospective, longitudinal multicenter cohort of consecutive children and adults with a genetic diagnosis of Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy between 2002 and 2019 was assembled. We defined a priori 3 different patterns of left ventricular remodeling during follow-up: (1) an increase in ≥15% of the maximal left ventricular wall thickness (MLVWT), both in mm and z-score (progression); (2) a reduction ≥15% of the MLVWT, both in mm and z-score (absolute regression); (3) a reduction ≥15% of the MLVWT z-score with a stable MLVWT in mm (relative regression). The primary study end point was a composite of cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator-shock. RESULTS The cohort comprised 42 patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy, with a median age at diagnosis of 3.5 (interquartile range, 0.2-12.3) years. Freedom from primary end point was 92.7% (95% CI, 84.7%-100%) 1 year after presentation and 80.9% (95% CI, 70.1%-90.7%) at 5 years. Patients with MLVWT z-score >13.7 showed reduced survival compared with those with <13.7. During a median follow-up of 3.7 years (interquartile range, 2.6-7.9), absolute regression was the most common type of left ventricular remodeling (n=9, 31%), followed by progression (n=6, 21%), and relative regression (n=6, 21%). CONCLUSIONS These findings provide insights into the natural history of left ventricular hypertrophy, and can help inform clinicians regarding risk stratification and clinical outcomes in patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy.
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Affiliation(s)
- Emanuele Monda
- Inherited and Rare Cardiovascular Diseases, Dept of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Aaron Prosnitz
- Congenital Heart Center, Levine Children’s Hospital, Atrium Health, Charlotte, NC
| | - Rossella Aiello
- Inherited and Rare Cardiovascular Diseases, Dept of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Michele Lioncino
- Inherited and Rare Cardiovascular Diseases, Dept of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Gabrielle Norrish
- Centre for Paediatric Inherited & Rare Cardiovascular Disease, Institute of Cardiovascular Science, University College London
- Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, United Kingdom
| | - Martina Caiazza
- Inherited and Rare Cardiovascular Diseases, Dept of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Fabrizio Drago
- Dept of Pediatric Cardiology & Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Meaghan Beattie
- Dept of Cardiology & Division of Genetics, Dept of Pediatrics, Boston Children’s Hospital, Boston, MA
| | - Marco Tartaglia
- Genetics & Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | - Maria Giovanna Russo
- Inherited and Rare Cardiovascular Diseases, Dept of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
| | - Steven D. Colan
- Dept of Cardiology & Division of Genetics, Dept of Pediatrics, Boston Children’s Hospital, Boston, MA
| | - Giulio Calcagni
- Dept of Pediatric Cardiology & Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Bruce D. Gelb
- Mindich Child Health and Development Institute & Depts of Pediatrics & Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Juan Pablo Kaski
- Centre for Paediatric Inherited & Rare Cardiovascular Disease, Institute of Cardiovascular Science, University College London
- Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, United Kingdom
| | - Amy E. Roberts
- Dept of Cardiology & Division of Genetics, Dept of Pediatrics, Boston Children’s Hospital, Boston, MA
| | - Giuseppe Limongelli
- Inherited and Rare Cardiovascular Diseases, Dept of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy
- Institute of Cardiovascular Sciences, University College of London & St. Bartholomew’s Hospital, London, United Kingdom
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Hilal N, Chen Z, Chen MH, Choudhury S. RASopathies and cardiac manifestations. Front Cardiovasc Med 2023; 10:1176828. [PMID: 37529712 PMCID: PMC10387527 DOI: 10.3389/fcvm.2023.1176828] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/20/2023] [Indexed: 08/03/2023] Open
Abstract
As binary switches, RAS proteins switch to an ON/OFF state during signaling and are on a leash under normal conditions. However, in RAS-related diseases such as cancer and RASopathies, mutations in the genes that regulate RAS signaling or the RAS itself permanently activate the RAS protein. The structural basis of this switch is well understood; however, the exact mechanisms by which RAS proteins are regulated are less clear. RAS/MAPK syndromes are multisystem developmental disorders caused by germline mutations in genes associated with the RAS/mitogen-activated protein kinase pathway, impacting 1 in 1,000-2,500 children. These include a variety of disorders such as Noonan syndrome (NS) and NS-related disorders (NSRD), such as cardio facio cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML, also known as LEOPARD syndrome). A frequent manifestation of cardiomyopathy (CM) and hypertrophic cardiomyopathy associated with RASopathies suggest that RASopathies could be a potential causative factor for CM. However, the current supporting evidence is sporadic and unclear. RASopathy-patients also display a broad spectrum of congenital heart disease (CHD). More than 15 genes encode components of the RAS/MAPK signaling pathway that are essential for the cell cycle and play regulatory roles in proliferation, differentiation, growth, and metabolism. These genes are linked to the molecular genetic pathogenesis of these syndromes. However, genetic heterogeneity for a given syndrome on the one hand and alleles for multiple syndromes on the other make classification difficult in diagnosing RAS/MAPK-related diseases. Although there is some genetic homogeneity in most RASopathies, several RASopathies are allelic diseases. This allelism points to the role of critical signaling nodes and sheds light on the overlap between these related syndromes. Even though considerable progress has been made in understanding the pathophysiology of RASopathy with the identification of causal mutations and the functional analysis of their pathophysiological consequences, there are still unidentified causal genes for many patients diagnosed with RASopathies.
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Affiliation(s)
- Nazia Hilal
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Broad Institute of Harvard and MIT, Cambridge, MA, United States
| | - Zi Chen
- Harvard Medical School, Boston, MA, United States
- Department of Surgery, Brigham, and Women’s Hospital, Boston, MA, United States
| | - Ming Hui Chen
- Harvard Medical School, Boston, MA, United States
- Department of Cardiology, Boston Children’s Hospital, Boston, MA, United States
| | - Sangita Choudhury
- Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Broad Institute of Harvard and MIT, Cambridge, MA, United States
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30
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Bogle C, Colan SD, Miyamoto SD, Choudhry S, Baez-Hernandez N, Brickler MM, Feingold B, Lal AK, Lee TM, Canter CE, Lipshultz SE. Treatment Strategies for Cardiomyopathy in Children: A Scientific Statement From the American Heart Association. Circulation 2023; 148:174-195. [PMID: 37288568 DOI: 10.1161/cir.0000000000001151] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
This scientific statement from the American Heart Association focuses on treatment strategies and modalities for cardiomyopathy (heart muscle disease) in children and serves as a companion scientific statement for the recent statement on the classification and diagnosis of cardiomyopathy in children. We propose that the foundation of treatment of pediatric cardiomyopathies is based on these principles applied as personalized therapy for children with cardiomyopathy: (1) identification of the specific cardiac pathophysiology; (2) determination of the root cause of the cardiomyopathy so that, if applicable, cause-specific treatment can occur (precision medicine); and (3) application of therapies based on the associated clinical milieu of the patient. These clinical milieus include patients at risk for developing cardiomyopathy (cardiomyopathy phenotype negative), asymptomatic patients with cardiomyopathy (phenotype positive), patients with symptomatic cardiomyopathy, and patients with end-stage cardiomyopathy. This scientific statement focuses primarily on the most frequent phenotypes, dilated and hypertrophic, that occur in children. Other less frequent cardiomyopathies, including left ventricular noncompaction, restrictive cardiomyopathy, and arrhythmogenic cardiomyopathy, are discussed in less detail. Suggestions are based on previous clinical and investigational experience, extrapolating therapies for cardiomyopathies in adults to children and noting the problems and challenges that have arisen in this experience. These likely underscore the increasingly apparent differences in pathogenesis and even pathophysiology in childhood cardiomyopathies compared with adult disease. These differences will likely affect the utility of some adult therapy strategies. Therefore, special emphasis has been placed on cause-specific therapies in children for prevention and attenuation of their cardiomyopathy in addition to symptomatic treatments. Current investigational strategies and treatments not in wide clinical practice, including future direction for investigational management strategies, trial designs, and collaborative networks, are also discussed because they have the potential to further refine and improve the health and outcomes of children with cardiomyopathy in the future.
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31
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Tsatsopoulou A, Protonotarios I, Xylouri Z, Papagiannis I, Anastasakis A, Germanakis I, Patrianakos A, Nyktari E, Gavras C, Papadopoulos G, Meditskou S, Lazarou E, Miliou A, Lazaros G. Cardiomyopathies in children: An overview. Hellenic J Cardiol 2023; 72:43-56. [PMID: 36870438 DOI: 10.1016/j.hjc.2023.02.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 02/14/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Paediatric cardiomyopathies form a heterogeneous group of disorders characterized by structural and electrical abnormalities of the heart muscle, commonly due to a gene variant of the myocardial cell structure. Mostly inherited as a dominant or occasionally recessive trait, they might be part of a syndromic disorder of underlying metabolic or neuromuscular defects or combine early developing extracardiac abnormalities (i.e., Naxos disease). The annual incidence of 1 per 100,000 children appears higher during the first two years of life. Dilated and hypertrophic cardiomyopathy phenotypes share an incidence of 60% and 25%, respectively. Arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy, and left ventricular noncompaction are less commonly diagnosed. Adverse events such as severe heart failure, heart transplantation, or death usually appear early after the initial presentation. In ARVC patients, high-intensity aerobic exercise has been associated with worse clinical outcomes and increased penetrance in at-risk genotype-positive relatives. Acute myocarditis in children has an incidence of 1.4-2.1 cases/per 100,000 children per year, with a 6-14% mortality rate during the acute phase. A genetic defect is considered responsible for the progression to dilated cardiomyopathy phenotype. Similarly, a dilated or arrhythmogenic cardiomyopathy phenotype might emerge with an episode of acute myocarditis in childhood or adolescence. This review provides an overview of childhood cardiomyopathies focusing on clinical presentation, outcome, and pathology.
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Affiliation(s)
- Adalena Tsatsopoulou
- General Paediatrics and Clinical Research, Private Clinic, Naxos, Greece; Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece; Unit of Inherited and Rare Cardiovascular Diseases, Onassis Cardiac Surgery Centre, Athens, Greece; Laboratory of Histology and Embryology, Department of Medicine, School of Life Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Protonotarios
- University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, SO16 6YD, UK
| | - Zafeirenia Xylouri
- University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, Hampshire, SO16 6YD, UK
| | - Ioannis Papagiannis
- Department of Paediatric Cardiology and Adult Congenital Heart Disease, Onassis Cardiac Surgery Centre, Athens, Greece
| | - Aris Anastasakis
- Unit of Inherited and Rare Cardiovascular Diseases, Onassis Cardiac Surgery Centre, Athens, Greece
| | - Ioannis Germanakis
- Department of Paediatrics, University Hospital Heraklion, School of Medicine, University of Crete, Heraklion, Greece
| | | | | | | | | | - Soultana Meditskou
- Laboratory of Histology and Embryology, Department of Medicine, School of Life Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Emilia Lazarou
- Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Antigoni Miliou
- Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | - George Lazaros
- Unit of Inherited Cardiac Conditions and Sports Cardiology, 1st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece.
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Kaski JP, Kammeraad JAE, Blom NA, Happonen JM, Janousek J, Klaassen S, Limongelli G, Östman-Smith I, Sarquella Brugada G, Ziolkowska L. Indications and management of implantable cardioverter-defibrillator therapy in childhood hypertrophic cardiomyopathy. Cardiol Young 2023; 33:681-698. [PMID: 37102324 DOI: 10.1017/s1047951123000872] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/28/2023]
Abstract
Sudden cardiac death is the most common mode of death during childhood and adolescence in hypertrophic cardiomyopathy, and identifying those individuals at highest risk is a major aspect of clinical care. The mainstay of preventative therapy is the implantable cardioverter-defibrillator, which has been shown to be effective at terminating malignant ventricular arrhythmias in children with hypertrophic cardiomyopathy but can be associated with substantial morbidity. Accurate identification of those children at highest risk who would benefit most from implantable cardioverter-defibrillator implantation while minimising the risk of complications is, therefore, essential. This position statement, on behalf of the Association for European Paediatric and Congenital Cardiology (AEPC), reviews the currently available data on established and proposed risk factors for sudden cardiac death in childhood-onset hypertrophic cardiomyopathy and current approaches for risk stratification in this population. It also provides guidance on identification of individuals at risk of sudden cardiac death and optimal management of implantable cardioverter-defibrillators in children and adolescents with hypertrophic cardiomyopathy.
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Affiliation(s)
- Juan Pablo Kaski
- Centre for Paediatric Inherited and Rare Cardiovascular Disease, University College London Institute of Cardiovascular Science, London, UK
- Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital, London, UK
| | - Janneke A E Kammeraad
- Erasmus MC - Sophia Children's Hospital, Department of Paediatric Cardiology, Rotterdam, the Netherlands
| | - Nico A Blom
- Department of Pediatric Cardiology, University of Leiden, Leiden, the Netherlands
- Amsterdam University Medical Centre, Amsterdam, the Netherlands
| | - Juha-Matti Happonen
- Department of Paediatric Cardiology, Helsinki University Children's Hospital, Helsinki, Finland
| | - Jan Janousek
- Children's Heart Center, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Sabine Klaassen
- Department of Pediatric Cardiology, Charite-Universitatsmedizin Berlin, Berlin, Germany
| | - Giuseppe Limongelli
- Inherited and Rare Cardiovascular Disease Unit, AO dei Colli Monaldi Hospital, Universita della Campania "Luigi Vanvitelli", Naples, Italy
| | - Ingegerd Östman-Smith
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Sebastian SA, Panthangi V, Singh K, Rayaroth S, Gupta A, Shantharam D, Rasool BQ, Padda I, Co EL, Johal G. Hypertrophic Cardiomyopathy: Current Treatment and Future Options. Curr Probl Cardiol 2023; 48:101552. [PMID: 36529236 DOI: 10.1016/j.cpcardiol.2022.101552] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Hypertrophic cardiomyopathy (HCM) is a disease involving the cardiac sarcomere. It is associated with various disease-causing gene mutations and phenotypic expressions, managed with different therapies with variable prognoses. The heterogeneity of the disease is evident in the fact that it burdens patients of all ages. HCM is the most prevalent cause of sudden death in athletes. However, several technological advancements and therapeutic options have reduced mortality in patients with HCM to 0.5% per year. In addition, rapid advances in our knowledge of the molecular defects accountable for HCM have strengthened our awareness of the disorder and recommended new approaches to the assessment of prognosis. Despite all these evolutions, a small subgroup of patients with HCM will experience sudden cardiac death, and risk stratification remains a critical challenge. This review provides a practical guide to the updated recommendations for patients with HCM, including clinical updates for diagnosis, family screening, clinical imaging, risk stratification, and management.
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Affiliation(s)
| | | | - Karanbir Singh
- Department of Internal Medicine, Government Medical College, Amritsar, Punjab, India
| | - Swetha Rayaroth
- Department of Internal Medicine, JSS Medical College, Mysuru, Karnataka, India
| | - Aditi Gupta
- Department of Internal Medicine, Jawaharlal Nehru Medical College, Belgaum, Karnataka, India
| | - Darshan Shantharam
- Department of Internal Medicine, Yenepoya Medical college, Mangalore, India
| | | | - Inderbir Padda
- Department of Internal Medicine, Richmond University Medical Center, Staten Island, New York
| | - Edzel Lorraine Co
- Department of Internal Medicine, University of Santo Tomas, Manila, Philippines
| | - Gurpreet Johal
- Department of Cardiology, Valley Medical Center, University of Washington, Seattle, Washington
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Ackerman MJ, Garmany R. RASopathy-Associated Cardiac Hypertrophy: A Shocking Gap in Care. J Am Coll Cardiol 2023; 81:1046-1048. [PMID: 36922090 DOI: 10.1016/j.jacc.2023.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 01/12/2023] [Indexed: 03/18/2023]
Affiliation(s)
- Michael J Ackerman
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Pediatric and Adolescent Medicine/Division of Pediatric Cardiology, Windland Smith Rice Genetic Heart Rhythm Clinic, Mayo Clinic, Rochester, Minnesota, USA; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA.
| | - Ramin Garmany
- Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA; Mayo Clinic Medical Scientist Training Program, Rochester, Minnesota, USA. https://twitter.com/GarmanyRamin
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Lynch A, Tatangelo M, Ahuja S, Steve Fan CP, Min S, Lafreniere-Roula M, Papaz T, Zhou V, Armstrong K, Aziz PF, Benson LN, Butts R, Dragulescu A, Gardin L, Godown J, Jeewa A, Kantor PF, Kaufman BD, Lal AK, Parent JJ, Richmond M, Russell MW, Balaji S, Stephenson EA, Villa C, Jefferies JL, Whitehill R, Conway J, Howard TS, Nakano SJ, Rossano J, Weintraub RG, Mital S. Risk of Sudden Death in Patients With RASopathy Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2023; 81:1035-1045. [PMID: 36922089 DOI: 10.1016/j.jacc.2023.01.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/29/2022] [Accepted: 01/09/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Genetic defects in the RAS/mitogen-activated protein kinase pathway are an important cause of hypertrophic cardiomyopathy (RAS-HCM). Unlike primary HCM (P-HCM), the risk of sudden cardiac death (SCD) and long-term survival in RAS-HCM are poorly understood. OBJECTIVES The study's objective was to compare transplant-free survival, incidence of SCD, and implantable cardioverter-defibrillator (ICD) use between RAS-HCM and P-HCM patients. METHODS In an international, 21-center cohort study, we analyzed phenotype-positive pediatric RAS-HCM (n = 188) and P-HCM (n = 567) patients. The between-group differences in cumulative incidence of all outcomes from first evaluation were compared using Gray's tests, and age-related hazard of all-cause mortality was determined. RESULTS RAS-HCM patients had a lower median age at diagnosis compared to P-HCM (0.9 years [IQR: 0.2-5.0 years] vs 9.8 years [IQR: 2.0-13.9 years], respectively) (P < 0.001). The 10-year cumulative incidence of SCD from first evaluation was not different between RAS-HCM and P-HCM (4.7% vs 4.2%, respectively; P = 0.59). The 10-year cumulative incidence of nonarrhythmic deaths or transplant was higher in RAS-HCM compared with P-HCM (11.0% vs 5.4%, respectively; P = 0.011). The 10-year cumulative incidence of ICD insertions, however, was 5-fold lower in RAS-HCM compared with P-HCM (6.9% vs 36.6%; P < 0.001). Nonarrhythmic deaths occurred primarily in infancy and SCD primarily in adolescence. CONCLUSIONS RAS-HCM was associated with a higher incidence of nonarrhythmic death or transplant but similar incidence of SCD as P-HCM. However, ICDs were used less frequently in RAS-HCM compared to P-HCM. In addition to monitoring for heart failure and timely consideration of advanced heart failure therapies, better risk stratification is needed to guide ICD practices in RAS-HCM.
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Affiliation(s)
- Aine Lynch
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada
| | - Mark Tatangelo
- Ted Rogers Computational Program, Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Sachin Ahuja
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Chun-Po Steve Fan
- Ted Rogers Computational Program, Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Sandar Min
- Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Myriam Lafreniere-Roula
- Applied Health Research Centre, St Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
| | - Tanya Papaz
- Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada
| | - Vivian Zhou
- Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Kathryn Armstrong
- Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada
| | - Peter F Aziz
- Department of Pediatrics, Cleveland Clinic Children's Hospital, Cleveland, Ohio, USA
| | - Lee N Benson
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada
| | - Ryan Butts
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Andreea Dragulescu
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada
| | - Letizia Gardin
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
| | - Justin Godown
- Department of Pediatrics, Monroe Carrell Jr Children's Hospital at Vanderbilt University, Nashville, Tennessee, USA
| | - Aamir Jeewa
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada
| | - Paul F Kantor
- Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Beth D Kaufman
- Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Palo Alto, California, USA
| | - Ashwin K Lal
- Department of Pediatrics, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA
| | - John J Parent
- Department of Pediatrics, Riley Children's Hospital, Indianapolis, Indiana, USA
| | - Marc Richmond
- Department of Pediatrics, Morgan Stanley Children's Hospital, Columbia University Medical Center, New York, New York, USA
| | - Mark W Russell
- Department of Pediatrics, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Seshadri Balaji
- Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA
| | - Elizabeth A Stephenson
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada
| | - Chet Villa
- Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, Ohio, USA
| | - John L Jefferies
- Department of Pediatrics, University of Tennessee Health Sciences Centre, Memphis, Tennessee, USA
| | - Robert Whitehill
- Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Jennifer Conway
- Department of Pediatrics, Stollery Children's Hospital, Edmonton, Alberta, Canada
| | - Taylor S Howard
- Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA
| | - Stephanie J Nakano
- Department of Pediatrics, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Joseph Rossano
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Robert G Weintraub
- Department of Cardiology, The Royal Children's Hospital of Melbourne, Melbourne, Victoria, Australia
| | - Seema Mital
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto Ontario, Canada; Ted Rogers Computational Program, Ted Rogers Centre for Heart Research, Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada.
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Thakkar K, Karajgi AR, Kallamvalappil AM, Avanthika C, Jhaveri S, Shandilya A, Anusheel, Al-Masri R. Sudden cardiac death in childhood hypertrophic cardiomyopathy. Dis Mon 2023; 69:101548. [PMID: 36931945 DOI: 10.1016/j.disamonth.2023.101548] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/17/2023]
Abstract
The most prevalent cause of mortality in children with hypertrophic cardiomyopathy (HCM) is sudden cardiac death (SCD), which happens more frequently than in adult patients. Risk stratification tactics have generally been drawn from adult practice, however emerging data has revealed significant disparities between children and adult cohorts, implying the need for pediatric-specific risk stratification methodologies. We conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until October 2021. The following search strings and Medical Subject Heading (MeSH) terms were used: "HCM," "SCD," "Sudden Cardiac Death," and "Childhood Onset HCM." We explored the literature on the risk of SCD in HCM for its epidemiology, pathophysiology, the role of various genes and their influence, associated complications leading to SCD and preventive and treatment modalities. Childhood-onset HCM is linked to significant life-long morbidity and mortality, including a higher SCD rate in children than in adults. The present focus is on symptom relief and avoiding illness-related consequences, but the prospect of future disease-modifying medicines offers an intriguing opportunity to alter disease expression and outcomes in these young individuals. Current preventive recommendations promote implantable cardioverter defibrillator placement based on cumulative risk factor thresholds, although they have been demonstrated to have weak discriminating capacity. This article addresses questions and discusses the etiology, risk factors, and method to risk stratification for SCD in children with HCM.
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Affiliation(s)
- Keval Thakkar
- G.M.E.R.S. Medical College and General Hospital, Gandhinagar, India
| | | | | | - Chaithanya Avanthika
- Karnataka Institute of Medical /Sciences, PB Rd, Vidya Nagar, Hubli, Karnataka, India.
| | | | | | - Anusheel
- Ryazan State I P Pavlov Medical Institute, Ryazan, Russia
| | - Rayan Al-Masri
- Jordan University of Science and technology, Irbid, Jordan
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Gelb BD, Yohe ME, Wolf C, Andelfinger G. New prospectives on treatment opportunities in RASopathies. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2022; 190:541-560. [PMID: 36533679 PMCID: PMC10150944 DOI: 10.1002/ajmg.c.32024] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 11/18/2022] [Accepted: 11/25/2022] [Indexed: 12/24/2022]
Abstract
The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.
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Affiliation(s)
- Bruce D. Gelb
- Mindich Child Health and Development Institute and Departments of Pediatrics and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Marielle E. Yohe
- Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Cordula Wolf
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, School of Medicine & Health, Technical University of Munich, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Gregor Andelfinger
- CHU Sainte Justine, Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
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Helenius K, Parkkola R, Arola A, Peltola V, Haanpää MK. Detailed prenatal and postnatal MRI findings and clinical analysis of RAF1 in Noonan syndrome. Eur J Med Genet 2022; 65:104626. [PMID: 36155125 DOI: 10.1016/j.ejmg.2022.104626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 07/26/2022] [Accepted: 09/19/2022] [Indexed: 11/25/2022]
Abstract
Noonan syndrome is a genetically heterogeneous developmental disorder, which usually includes findings such as short stature, facial dysmorphia, cardiac abnormalities and a varying degree of intellectual disability. We present a unique case of a rare variant of Noonan syndrome in a very preterm female infant born at 28 + 4 gestational weeks, with abnormal radiological findings visible at fetal magnetic resonance imaging (MRI) and evolution of the brain lesions during infancy.
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Affiliation(s)
- Kjell Helenius
- Department of Paediatrics and Adolescent Medicine, Finland; University of Turku, Turku, Finland.
| | | | - Anita Arola
- Department of Paediatrics and Adolescent Medicine, Finland
| | - Ville Peltola
- Department of Paediatrics and Adolescent Medicine, Finland; University of Turku, Turku, Finland
| | - Maria K Haanpää
- Department of Genomics and Medical Genetics, Turku University Hospital, Finland; University of Turku, Turku, Finland
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Nakano TA, Rankin AW, Annam A, Kulungowski AM, McCallen LM, Hill LR, Chatfield KC. Trametinib for Refractory Chylous Effusions and Systemic Complications in Children with Noonan Syndrome. J Pediatr 2022; 248:81-88.e1. [PMID: 35605646 DOI: 10.1016/j.jpeds.2022.05.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/10/2022] [Accepted: 05/17/2022] [Indexed: 10/18/2022]
Abstract
OBJECTIVE To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome. STUDY DESIGN Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstream MEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures. RESULTS Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject. CONCLUSIONS Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety.
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Affiliation(s)
- Taizo A Nakano
- Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Center for Cancer and Blood Disorders, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO
| | - Alexander W Rankin
- Center for Cancer and Blood Disorders, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO
| | - Aparna Annam
- Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatric Radiology, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO
| | - Ann M Kulungowski
- Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatric Surgery, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO
| | - Leslie M McCallen
- Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO
| | - Lauren R Hill
- Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO
| | - Kathryn C Chatfield
- Vascular Anomalies Center, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO; Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children's Hospital Colorado, Aurora, CO.
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Leegaard A, Gregersen PA, Nielsen TØ, Bjerre JV, Handrup MM. Succesful MEK-inhibition of severe hypertrophic cardiomyopathy in RIT1-related Noonan Syndrome. Eur J Med Genet 2022; 65:104630. [DOI: 10.1016/j.ejmg.2022.104630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/26/2022] [Indexed: 11/29/2022]
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Tsuda E, Ito Y, Kato Y, Sakaguchi H, Ohuchi H, Kurosaki K. Thirty-year outcome in children with hypertrophic cardiomyopathy based on the type. J Cardiol 2022; 80:557-562. [PMID: 35961804 DOI: 10.1016/j.jjcc.2022.07.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/07/2022] [Accepted: 07/11/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND We reviewed the long-term outcome of children with hypertrophic cardiomyopathy (HCM) based on the type. METHODS We reviewed the medical records of 100 patients (male 54 female 46) with HCM at our hospital between 1977 and 2015. The survival and cardiac event-free survival rates were calculated by the Kaplan-Meier method. RESULTS The age at the time of the diagnosis ranged from 0 to 15 years with a median of 8 years. The number of patients with Noonan syndrome and hypertrophic obstructive cardiomyopathy (HOCM), idiopathic HCM (i-HCM), and secondary HCM (s-HCM) was 13, 13, 65, and 9 respectively. A dilated phase of HCM occurred in 24 patients. Nineteen (79 %) of the 24 patients died of heart failure, and two underwent a heart transplantation. Eight (33 %) of the 24 patients had s-HCM. The median age when a dilated phase occurred was 15 years old, and the median interval from the initial diagnosis to the dilated phase was 8 years. The median time from the diagnosis of a dilated phase to death was 1.6 years. Sudden death and implantable cardioverter defibrillator implantations occurred in 6 and 11 patients at around 15 years old, respectively. The 20-year survival rates were as follows: Noonan syndrome 84 %; HOCM 82 %; i-HCM 71 %; and s-HCM 17 %. Overall, the survival rates at 10, 20, and 30 years were 83 % (95 % confidence interval 73-89), 69 % (58-78), and 63 % (50-74), respectively. The overall cardiac event-free survival rates at 10, 20, and 30 years were 57 % (47-67), 39 % (31-50), and 32 % (21-44), respectively. CONCLUSION The long-term outcome in children with HCM was poor, and the outcome of s-HCM was very poor. The occurrence of a dilated phase worsened the outcome in HCM patients. Sudden death and d-HCM often occurred at around 15 years old.
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Affiliation(s)
- Etsuko Tsuda
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan.
| | - Yuki Ito
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Yoshiaki Kato
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Heima Sakaguchi
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Hideo Ohuchi
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Kenichi Kurosaki
- Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan
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Sun L, Xie YM, Wang SS, Zhang ZW. Cardiovascular Abnormalities and Gene Mutations in Children With Noonan Syndrome. Front Genet 2022; 13:915129. [PMID: 35770001 PMCID: PMC9234298 DOI: 10.3389/fgene.2022.915129] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/23/2022] [Indexed: 11/20/2022] Open
Abstract
Background: Common cardiac abnormalities in Noonan syndrome (NS) include congenital heart diseases (CHD), pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Molecular diagnoses are enabling earlier and more precise diagnosis of patients who have a subtle or atypical presentation. The aims of this study were to investigate genotype-phenotype associations with respect to Noonan syndrome (NS)-associated cardiac abnormalities and catheter or surgery-based interventions conditions. Methods: From January 2019 to December 2021, 22 children with a confirmed molecular diagnosis of NS combined with cardiovascular abnormalities were consecutively enrolled into the current study. A comprehensive review was carried out of echocardiography and electrocardiogram results, second-generation whole-exome sequencing results and catheter or surgery-based interventions conditions. Results: The main manifestations of electrocardiogram abnormalities were QTc prolongation, abnormal Q wave in the precordial lead and limb lead, right ventricular hypertrophy and left or right deviation of the electrical axis. The most commonly detected abnormality was pulmonary valve dysplasia with stenosis, seen in 15 (68.2%) patients, followed by atrial septal defect in 11 (50%) patients. Seven genes (RAF1, RIT1, SOS1, PTPN11, BRAF, SOS2, and LZTR1) were found to contain disease-associated variants. The most commonly observed genetic mutations were PTPN11 (27%) and RAF1 (27%). Each genotype was associated with specific phenotypic findings. RIT1, SOS1, PTPN11, and SOS2 had common echocardiography features characterized by pulmonary valve stenosis, while RAF1 was characterized by HCM. Interestingly, patients with BRAF mutations were not only characterized by HCM, but also by pulmonary valve stenosis. In the cohort there was only one patient carrying a LZTR1 mutation characterized by left ventricle globose dilation. Ten cases underwent catheter or surgery-based interventions. All the operations had immediate results and high success rates. However, some of the cases had adverse outcomes during extended follow-up. Based on the genotype-phenotype associations observed during follow-up, BRAF and RAF1 genotypes seem to be poor prognostic factors, and multiple interventions may be required for NS patients with severe pulmonary stenosis or myectomy for HCM. Conclusions: The identification of causal genes in NS patients has enabled the evaluation of genotype-cardiac phenotype relationships and prognosis of the disease. This may be beneficial for the development of therapeutic approaches.
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Abstract
Noonan syndrome is a genetic disorder characteried by short stature, typical facial features, developmental delay, and CHD. In this single-centre retrospective study, we analysed typical Noonan syndrome-related electrocardiographic features in 95 patients with clinically and molecularly confirmed Noonan syndrome. Typical Noonan syndrome-related electrocardiographic features are left axis deviation, small left precordial R-waves, large right precordial S-waves, abnormal Q-wave, and abnormal wide QRS complex. In this representative cohort, CHD was found in 59 patients (62.1%) and typical Noonan syndrome-related electrographic features in 60 patients (63.2%). The typical Noonan syndrome-related electrographic features were also increased over baseline in patients without CHD (41.7%). Of all 95 patients, left axis deviation was seen in 46.3%, small left precordial R-waves in 30.5%, large right precordial S-waves in 5.3%, and abnormal Q-wave and wide QRS complex in 2.1%. There was no significant difference in the frequency of the individual-specific electrographic features between the group with CHD and the group without CHD. However, there were significantly more patients with a small left precordial R-wave in the subgroup with pulmonary stenosis compared to patients without pulmonary stenosis. Conclusion: Specific Noonan syndrome-related electrographic features are frequently present in patients with Noonan syndrome, also in the absence of CHD. These results suggest that there may be a continuum of cardiac anomalies from overt CHD to milder abnormalities that are only seen on electrocardiogram.
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Abstract
BACKGROUND Cardiovascular disease is one of the most important problems in long-term follow-up for Noonan syndrome. We examined cardiovascular issues and clinical manifestations, with a focus on the cardiovascular disease and prognosis of patients with Noonan syndrome. METHODS This single-centre study evaluated patients who were clinically and genetically diagnosed with Noonan syndrome. RESULTS Forty-three patients diagnosed with Noonan syndrome were analysed. The most prevalent responsible mutation was found in PTPN11 (25/43). The second and third most prevalent causative genes were SOS1 (6/43) and RIT1 (5/43), respectively, and 67.4% of genetically diagnosed patients with Noonan syndrome had structural cardiovascular abnormalities. Pulmonary valve stenosis was prevalent in patients with mutations in PTPN11 (8/25), SOS1 (4/6), and RIT1 (4/5). Hypertrophic cardiomyopathy was found in two of three patients with mutations in RAF1. There was no difference in the cardiovascular events or cardiovascular disease prevalence in patients with or without PTPN11 mutations. The proportion of RIT1 mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients with PTPN11 mutations. Patients who underwent any intervention for pulmonary valve stenosis exhibited significantly higher pulmonary flow velocity than patients who did not undergo intervention, when they visited our hospital for the first time. All patients who underwent intervention for pulmonary valve stenosis had a pulmonary flow velocity of more than 3.0 m/s at first visit. CONCLUSIONS These findings suggest that genetic information can provide a clinical prognosis for cardiovascular disease and may be part of genotype-based follow-up in Noonan syndrome.
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Trakmulkichkarn T, Ghadiry-Tavi R, Fruitman D, Niederhoffer KY, Caluseriu O, Lauzon JL, Wewala G, Hornberger LK, Urschel S, Conway J, McBrien A. Clinical presentation, genetic etiology and outcome associated with fetal cardiomyopathy: comparison of two eras. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2022; 59:325-334. [PMID: 34159662 DOI: 10.1002/uog.23713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 06/07/2021] [Accepted: 06/14/2021] [Indexed: 06/13/2023]
Abstract
OBJECTIVE To assess the rate and type of genetic diagnosis and clinical outcome of cases of fetal cardiomyopathy (CM) during two eras, in order to examine the impact of advanced genetic testing and improved perinatal management strategies. METHODS All diagnoses of fetal CM in Alberta, Canada, encountered between 2003 and 2019, were reviewed retrospectively. Genetic, cardiac and non-cardiac diagnoses and clinical outcome were documented. Cases with CM secondary to extracardiac pathology and maternal conditions were excluded. Cases diagnosed in the earlier era of the study period (2003-2012) were compared with those diagnosed in the later era (2013-2019). RESULTS Thirty-eight cases of fetal CM met the inclusion criteria. Median gestational age (GA) at diagnosis was 22.8 (range, 13.4-37.4) weeks. Associated structural heart disease was present in 39% (15/38) of cases and 24% (9/38) had arrhythmia. Hydrops was identified in 29% (11/38) of cases at presentation, and a further 18% (7/38) developed hydrops later in gestation. Twenty-six percent (10/38) of cases underwent termination of pregnancy and 24% (9/38) had intrauterine death. Of liveborn cases, neonatal death occurred in 16% (3/19), late death occurred in 21% (4/19) and 63% (12/19) were alive at the last follow-up. Excluding cases that had termination of pregnancy and those with a liveborn infant who received planned palliative care, the rate of neonatal survival was higher in the later compared with the earlier era (69% (11/16) vs 45% (5/11)), although the difference was not statistically significant (P = 0.26). A genetic etiology was confirmed in 39% (15/38) of cases and strongly suspected in 24% (9/38). A significantly higher proportion of cases had a confirmed or strongly suspected genetic etiology in the later era compared with in the earlier era (76% (19/25) vs 38% (5/13); P = 0.04). CONCLUSIONS In the recent era, a higher proportion of fetal CM cases had a confirmed or strongly suspected genetic etiology than reported previously. Based on comparison with older series, modern perinatal management strategies may not have a significant impact on neonatal survival in cases of fetal CM; however, a larger study would be better powered to detect more subtle differences. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
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Affiliation(s)
- T Trakmulkichkarn
- Fetal and Neonatal Cardiology and Heart Function and Transplant Programs, Division of Cardiology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Women's and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
- Department of Obstetrics and Gynecology, Phramongkutklao Hospital, Bangkok, Thailand
| | - R Ghadiry-Tavi
- Cumming School of Medicine, University of Calgary, Department of Pediatrics, Alberta Children's Hospital, Calgary, AB, Canada
| | - D Fruitman
- Cumming School of Medicine, University of Calgary, Department of Pediatrics, Alberta Children's Hospital, Calgary, AB, Canada
- Section of Cardiology, Alberta Children's Hospital, Calgary, AB, Canada
| | - K Y Niederhoffer
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - O Caluseriu
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - J L Lauzon
- Department of Medical Genetics, Alberta Children's Hospital, Calgary, AB, Canada
- Alberta Children's Hospital Research Institute for Child and Maternal Health, Alberta Children's Hospital, Calgary, AB, Canada
| | - G Wewala
- Fetal and Neonatal Cardiology and Heart Function and Transplant Programs, Division of Cardiology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Women's and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - L K Hornberger
- Fetal and Neonatal Cardiology and Heart Function and Transplant Programs, Division of Cardiology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Women's and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
- Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada
| | - S Urschel
- Fetal and Neonatal Cardiology and Heart Function and Transplant Programs, Division of Cardiology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Women's and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
- Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - J Conway
- Fetal and Neonatal Cardiology and Heart Function and Transplant Programs, Division of Cardiology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Women's and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
| | - A McBrien
- Fetal and Neonatal Cardiology and Heart Function and Transplant Programs, Division of Cardiology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
- Women's and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada
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46
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Leoni C, Blandino R, Delogu AB, De Rosa G, Onesimo R, Verusio V, Marino MV, Lanza GA, Rigante D, Tartaglia M, Zampino G. Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by RASopathies: Clinical implications and literature review. Am J Med Genet A 2022; 188:431-445. [PMID: 34643321 DOI: 10.1002/ajmg.a.62529] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 08/11/2021] [Accepted: 09/21/2021] [Indexed: 11/07/2022]
Abstract
Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype- phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single-center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid-shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.
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Affiliation(s)
- Chiara Leoni
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Rita Blandino
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Angelica Bibiana Delogu
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gabriella De Rosa
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Roberta Onesimo
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
| | - Valeria Verusio
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Maria Vittoria Marino
- Unit of Pediatrics, Pediatric Cardiology, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Gaetano Antonio Lanza
- Università Cattolica del Sacro Cuore, Rome, Italy
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCSS, Rome, Italy
| | - Donato Rigante
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
| | - Giuseppe Zampino
- Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
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47
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Meier AB, Raj Murthi S, Rawat H, Toepfer CN, Santamaria G, Schmid M, Mastantuono E, Schwarzmayr T, Berutti R, Cleuziou J, Ewert P, Görlach A, Klingel K, Laugwitz KL, Seidman CE, Seidman JG, Moretti A, Wolf CM. Cell cycle defects underlie childhood-onset cardiomyopathy associated with Noonan syndrome. iScience 2022; 25:103596. [PMID: 34988410 PMCID: PMC8704485 DOI: 10.1016/j.isci.2021.103596] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/10/2021] [Accepted: 12/04/2021] [Indexed: 11/06/2022] Open
Abstract
Childhood-onset myocardial hypertrophy and cardiomyopathic changes are associated with significant morbidity and mortality in early life, particularly in patients with Noonan syndrome, a multisystemic genetic disorder caused by autosomal dominant mutations in genes of the Ras-MAPK pathway. Although the cardiomyopathy associated with Noonan syndrome (NS-CM) shares certain cardiac features with the hypertrophic cardiomyopathy caused by mutations in sarcomeric proteins (HCM), such as pathological myocardial remodeling, ventricular dysfunction, and increased risk for malignant arrhythmias, the clinical course of NS-CM significantly differs from HCM. This suggests a distinct pathophysiology that remains to be elucidated. Here, through analysis of sarcomeric myosin conformational states, histopathology, and gene expression in left ventricular myocardial tissue from NS-CM, HCM, and normal hearts complemented with disease modeling in cardiomyocytes differentiated from patient-derived PTPN11 N308S/+ induced pluripotent stem cells, we demonstrate distinct disease phenotypes between NS-CM and HCM and uncover cell cycle defects as a potential driver of NS-CM.
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Affiliation(s)
- Anna B. Meier
- First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Sarala Raj Murthi
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, School of Medicine and Health, Munich 80636, Germany
| | - Hilansi Rawat
- First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Christopher N. Toepfer
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
- Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
- Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
| | - Gianluca Santamaria
- First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Manuel Schmid
- Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - Elisa Mastantuono
- Institute of Human Genetics, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Thomas Schwarzmayr
- Institute of Human Genetics, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Riccardo Berutti
- Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany
- Institute of Neurogenomics, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg 85764, Germany
| | - Julie Cleuziou
- Department of Congenital and Pediatric Heart Surgery, German Heart Center Munich, Technical University of Munich, Munich 80636, Germany
- INSURE (Institute for Translational Cardiac Surgery), Department of Cardiovascular Surgery, German Heart Center Munich, Technical University of Munich, Munich 80636, Germany
| | - Peter Ewert
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, School of Medicine and Health, Munich 80636, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Agnes Görlach
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, School of Medicine and Health, Munich 80636, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Karin Klingel
- Institute for Pathology and Neuropathology, Department of Cardiopathology, University Hospital Tuebingen, Tuebingen 72076, Germany
| | - Karl-Ludwig Laugwitz
- First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | | | | | - Alessandra Moretti
- First Department of Medicine, Cardiology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich 81675, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
| | - Cordula M. Wolf
- Department of Congenital Heart Defects and Pediatric Cardiology, German Heart Center Munich, Technical University of Munich, School of Medicine and Health, Munich 80636, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich Germany
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48
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Zha P, Kong Y, Wang L, Wang Y, Qing Q, Dai L. Noonan syndrome caused by RIT1 gene mutation: A case report and literature review. Front Pediatr 2022; 10:934808. [PMID: 36160792 PMCID: PMC9490085 DOI: 10.3389/fped.2022.934808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 08/18/2022] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE Noonan syndrome (NS), an autosomal dominant disease known as a RASopathy, is caused by germline mutations in mitogen-activated protein kinase pathway genes. A RIT1 gene mutation has been found to cause NS. The present study summarizes RIT1 gene mutation sites and associated clinical phenotypes. METHODS We retrospectively analyzed the clinical characteristics of a case of NS caused by RIT1 mutation in our hospital, and searched the PubMed database, China National Knowledge Infrastructure (CNKI) database and Wanfang database with the keywords Noonan syndrome and RIT1. Studies published between May 1, 2014 and July 1, 2021 were retrieved. By reviewing the abstracts and full text of the studies, we screened NS cases associated with RIT1 mutation in children 0-18 years of age. The clinical characteristics of these cases were summarized. RESULTS A total of 41 cases were analyzed, including 13 boys and 28 girls. There were 14 premature cases. The age at diagnosis was 4 days to 18 years, and 10 cases were diagnosed at 0-1 years of age. Common amino acid substitution positions included 57 (13/41), 95 (7/41), 82 (8/41), and 90 (4/41). A total of 63.63% cases had abnormal prenatal examination results, manifesting mainly as fetal neck edema, polyhydramnios and cardiac malformation. With respect to abnormal conditions after birth, 70-80% of patients had typical developmental malformations of the face, neck and thorax; 19/35 patients had abnormal lymphatic development; and a portion of patients had short stature and motor development disorders. A total of 87.80% (36/41) patients had cardiac dysplasia, among which hypertrophic cardiomyopathy (HCM) accounted for 58.53%. A total of 84.62% of patients carrying the p.A57G mutation had HCM, but no HCM was found in patients with the p.G95A mutation. A total of 34.15% of patients had pulmonary artery or pulmonary valve stenosis (PVS). In patients with the p.M90I mutation, 75% had PVS. Patients with concurrent HCM and PVS accounted for 19.51 and 48.78% of patients had supraventricular tachycardia. CONCLUSION A RIT1 gene mutation causing NS was associated with a high rate of abnormal prenatal examination findings. Most patients had typical NS craniofacial deformities, and some have short stature and motor development disorders. The cardiac deformity rate was high, and HCM was common. Some patients had supraventricular arrhythmias. Heart abnormalities showed high heterogeneity, given the various mutation loci.
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Affiliation(s)
- Ping Zha
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei, China
| | - Ying Kong
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei, China
| | - Lili Wang
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei, China
| | - Yujuan Wang
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei, China
| | - Qing Qing
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei, China
| | - Liying Dai
- Department of Neonatology, Anhui Provincial Children's Hospital, Hefei, China
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49
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Lioncino M, Monda E, Verrillo F, Moscarella E, Calcagni G, Drago F, Marino B, Digilio MC, Putotto C, Calabrò P, Russo MG, Roberts AE, Gelb BD, Tartaglia M, Limongelli G. Hypertrophic Cardiomyopathy in RASopathies: Diagnosis, Clinical Characteristics, Prognostic Implications, and Management. Heart Fail Clin 2022; 18:19-29. [PMID: 34776080 PMCID: PMC9674037 DOI: 10.1016/j.hfc.2021.07.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
RASopathies are multisystemic disorders caused by germline mutations in genes linked to the RAS/mitogen-activated protein kinase pathway. Diagnosis of RASopathy can be triggered by clinical clues ("red flags") which may direct the clinician toward a specific gene test. Compared with sarcomeric hypertrophic cardiomyopathy, hypertrophic cardiomyopathy in RASopathies (R-HCM) is associated with higher prevalence of congestive heart failure and shows increased prevalence and severity of left ventricular outflow tract obstruction. Biventricular involvement and the association with congenital heart disease, mainly pulmonary stenosis, have been commonly described in R-HCM. The aim of this review is to assess the prevalence and unique features of R-HCM and to define the available therapeutic options.
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Affiliation(s)
- Michele Lioncino
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples
| | - Emanuele Monda
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples
| | - Federica Verrillo
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples
| | - Elisabetta Moscarella
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Division of Cardiology, A.O.R.N. “Sant’Anna & San Sebastiano”, Caserta I-81100, Italy
| | - Giulio Calcagni
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart;,Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children’s Hospital IRCSS, Rome, Italy
| | - Fabrizio Drago
- The European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart - ERN GUARD-Heart;,Pediatric Cardiology and Arrhythmia/Syncope Units, Bambino Gesù Children’s Hospital IRCSS, Rome, Italy
| | - Bruno Marino
- Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Maria Cristina Digilio
- Genetics and Rare Disease Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Carolina Putotto
- Department of Pediatrics, Sapienza University of Rome, Rome, Italy
| | - Paolo Calabrò
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Division of Cardiology, A.O.R.N. “Sant’Anna & San Sebastiano”, Caserta I-81100, Italy
| | - Maria Giovanna Russo
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Department of Pediatric Cardiology, AORN dei Colli, Monaldi Hospital, Naples
| | - Amy E. Roberts
- Department of Cardiology, Children’s Hospital Boston, Boston, MA, USA
| | - Bruce D. Gelb
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Marco Tartaglia
- Genetics and Rare Disease Research Division, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Giuseppe Limongelli
- Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples;,Division of Cardiology, A.O.R.N. “Sant’Anna & San Sebastiano”, Caserta I-81100, Italy;,Corresponding author. Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Naples.
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50
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Butler MG, Miller BS, Romano A, Ross J, Abuzzahab MJ, Backeljauw P, Bamba V, Bhangoo A, Mauras N, Geffner M. Genetic conditions of short stature: A review of three classic examples. Front Endocrinol (Lausanne) 2022; 13:1011960. [PMID: 36339399 PMCID: PMC9634554 DOI: 10.3389/fendo.2022.1011960] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/20/2022] [Indexed: 11/30/2022] Open
Abstract
Noonan, Turner, and Prader-Willi syndromes are classical genetic disorders that are marked by short stature. Each disorder has been recognized for several decades and is backed by extensive published literature describing its features, genetic origins, and optimal treatment strategies. These disorders are accompanied by a multitude of comorbidities, including cardiovascular issues, endocrinopathies, and infertility. Diagnostic delays, syndrome-associated comorbidities, and inefficient communication among the members of a patient's health care team can affect a patient's well-being from birth through adulthood. Insufficient information is available to help patients and their multidisciplinary team of providers transition from pediatric to adult health care systems. The aim of this review is to summarize the clinical features and genetics associated with each syndrome, describe best practices for diagnosis and treatment, and emphasize the importance of multidisciplinary teams and appropriate care plans for the pediatric to adult health care transition.
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Affiliation(s)
- Merlin G. Butler
- Department of Psychiatry & Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS, United States
- Department of Pediatrics, University of Kansas Medical Center, Kansas City, KS, United States
- *Correspondence: Merlin G. Butler,
| | - Bradley S. Miller
- Pediatric Endocrinology, University of Minnesota Masonic Children’s Hospital, Minneapolis, MN, United States
| | - Alicia Romano
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States
| | - Judith Ross
- Department of Pediatrics, Nemours Children’s Health, Wilmington, DE, United States
- Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, United States
| | | | - Philippe Backeljauw
- Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Vaneeta Bamba
- Division of Endocrinology, Children’s Hospital of Philadelphia; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Amrit Bhangoo
- Pediatric Endocrinology, Children's Health of Orange County (CHOC) Children’s Hospital, Orange, CA, United States
| | - Nelly Mauras
- Division of Endocrinology, Nemours Children’s Health, Jacksonville, FL, United States
| | - Mitchell Geffner
- The Saban Research Institute, Children’s Hospital Los Angeles, Los Angeles, CA, United States
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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