In Children and Adolescents From Brugada Syndrome–Families, Only SCN5A Mutation Carriers Develop a Type-1 ECG Pattern Induced By Fever
2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 1 Linguagem: Inglês
10.1161/circulationaha.120.045720
ISSN1524-4539
AutoresPuck J. Peltenburg, Nico A. Blom, Arja S. Vink, Janneke A.E. Kammeraad, Hans J.M.P.J. Breur, Lukas Rammeloo, Arthur A.M. Wilde, Sally-Ann B. Clur,
Tópico(s)ECG Monitoring and Analysis
ResumoHomeCirculationVol. 142, No. 1In Children and Adolescents From Brugada Syndrome–Families, Only SCN5A Mutation Carriers Develop a Type-1 ECG Pattern Induced By Fever Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBIn Children and Adolescents From Brugada Syndrome–Families, Only SCN5A Mutation Carriers Develop a Type-1 ECG Pattern Induced By Fever Puck J. Peltenburg, MD, Nico A. Blom, MD, PhD, Arja S. Vink, MD, Msc(EBP), Janneke A.E. Kammeraad, MD, PhD, Hans J.M.P.J. Breur, MD, PhD, Lukas A.J. Rammeloo, MD, Arthur A.M. Wilde, MD, PhD and Sally-Ann B. Clur, MBBCh, FCP(SA)Paed, MSc(Med), PhD Puck J. PeltenburgPuck J. Peltenburg Department of Pediatric Cardiology, Emma Children's Hospital (P.J.P, N.A.B., A.S.V., S.-A.B.C.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands. Heart Center (P.J.P., A.S.V., A.A.M.W.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands. , Nico A. BlomNico A. Blom Department of Pediatric Cardiology, Emma Children's Hospital (P.J.P, N.A.B., A.S.V., S.-A.B.C.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands. Department of Pediatric Cardiology, Willem-Alexander Children's Hospital, Leiden University Medical Centre, The Netherlands (N.A.B.). , Arja S. VinkArja S. Vink Department of Pediatric Cardiology, Emma Children's Hospital (P.J.P, N.A.B., A.S.V., S.-A.B.C.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands. Heart Center (P.J.P., A.S.V., A.A.M.W.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands. , Janneke A.E. KammeraadJanneke A.E. Kammeraad Department of Pediatric Cardiology, Sophia Children's Hospital, Erasmus University, Rotterdam, The Netherlands (J.A.E.K.). , Hans J.M.P.J. BreurHans J.M.P.J. Breur Department of Pediatric Cardiology, Wilhelmina Children's Hospital, UMC Utrecht, The Netherlands (H.J.M.P.J.B.). , Lukas A.J. RammelooLukas A.J. Rammeloo Department of Pediatric Cardiology, Amsterdam UMC, location Vrije Universiteit Medical Centre, The Netherlands (L.A.J.R.). , Arthur A.M. WildeArthur A.M. Wilde Heart Center (P.J.P., A.S.V., A.A.M.W.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands. and Sally-Ann B. ClurSally-Ann B. Clur Sally-Ann B. Clur, MBBCh, FCP(SA)Paed, MSc(Med), PhD, Department of Cardiology and Pediatric Cardiology, Amsterdam University Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands. Email E-mail Address: [email protected] Department of Pediatric Cardiology, Emma Children's Hospital (P.J.P, N.A.B., A.S.V., S.-A.B.C.), Amsterdam University Medical Center, location Academic Medical Center (AMC), The Netherlands. Originally published6 Jul 2020https://doi.org/10.1161/CIRCULATIONAHA.120.045720Circulation. 2020;142:89–91is corrected byCorrection to: In Children and Adolescents From Brugada Syndrome–Families, Only SCN5A Mutation Carriers Develop a Type-1 ECG Pattern Induced By FeverOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 6, 2020: Previous Version of Record Brugada syndrome (BrS) is a rare inherited condition in which ventricular arrhythmias may cause syncope, aborted cardiac arrest, or sudden cardiac death. Although BrS is associated with mutations in the SCN5A gene, most adult patients are SCN5A-mutation negative.1 Fever can unmask the diagnostic Brugada type-1 pattern on the ECG2 and precede arrhythmic symptoms, especially in children.3 All children considered at risk for BrS, based on a family history of BrS or a BrS genotype are currently advised to record an ECG during fever (≥38.5°C/101.3°Fahrenheit) for diagnosis and risk stratification. This is stressful and time consuming for both patients and parents. We hypothesized that a type-1 fever-ECG and symptoms only occur in children with a familial SCN5A mutation.One hundred eleven pediatric patients aged <19 years were eligible because they had ≥1 fever-ECG recorded and were at-risk for BrS, by having a BrS genotype, a first-degree family member with BrS, or a first-degree family member with a BrS genotype. After exclusion of probands, carriers of overlap syndrome mutations or multiple SCN5A variants, and those with structural cardiac abnormalities, 97 children were included. Fever-ECGs and nonfever-ECGs recorded during outpatient visits closest to the date of the fever-ECGs were analyzed for a type-1 pattern by a blinded expert (A.A.M.W.) and patient characteristics were collected. Patients with ≥1 type-1 fever-ECG during follow-up were compared with those without. Categorical variables were compared using a χ2 test or Fisher exact test, and Bonferroni correction for multiple comparisons was applied where appropriate. Continuous variables were compared using a Wilcoxon rank-sum test for not-normal distributions. The study was approved by the Institutional Review Board. Informed consent was waived because the study used retrospective data from regular care.A total of 309 ECGs from 97 patients were analyzed (193 fever-ECGs and 116 nonfever-ECGs). A type-1 pattern was seen on 22 (11.4%) fever-ECGs from 14 different patients and on none of the nonfever-ECGs. The median age at first episode of a fever-induced type-1 was 7.1 (2.8–10.6) years. In 7 patients the type-1 pattern was not apparent on the first recorded fever-ECG, but on a subsequent fever-ECG recorded after a median of 0.7 (0.1–4.9) years. A positive family history for sudden cardiac death, sex, first-degree family member with phenotypic BrS, median age at first presentation, and follow-up duration were similar in the 2 groups (Table). All patients with ≥1 type-1 fever-ECG were carriers of a (likely) pathogenic SCN5A variant (13 [92.9%]) or had a 50% likelihood of being a carrier (1 [7.1%]). This genetic background differed significantly from the group without type-1 fever-ECG (P<0.001), where 31 patients (37.3%) were carriers of a (likely) pathogenic SCN5A variant and 38 (45.8%) were from a genotype-elusive family (Table). In the child with ≥1 type-1 fever-ECG and a 50% likelihood of being a carrier, no genetic diagnostic testing had been performed. His father was diagnosed with BrS after an aborted cardiac arrest at age 31 and was found to carry a SCN5A variant of unknown significance/likely pathogenic variant.In this cohort only 1 child had an episode of ventricular arrhythmia, namely nonsustained ventricular tachycardia during fever. He had ≥1 type-1 fever-ECG and carried a SCN5A mutation. No patients in this cohort were symptomatic.We show that, with the exception of 1 child who had not yet been tested for the familial variant, only pediatric patients from BrS-families with a SCN5A mutation developed a type-1 ECG during fever. The occurrence of symptoms in this population was low. The molecular and cellular mechanisms underlying the fever-dependent manifestations of BrS are complex. Fever may augment dysfunction of the mutated sodium cardiac channels, which could lead to an increased susceptibility to develop a type-1 ECG and arrhythmias.4 The group without type-1 fever-ECG was genetically heterogeneous. According to our study results, a BrS-phenotype without a SCN5A-mutation seems to be absent or concealed during childhood and fever. This apparent difference in genetic background in children with BrS compared with adults is in agreement with recent large cohort studies, in which the proportion of SCN5A mutation carriers in young patients appears to be higher compared with adults (62% to 77% versus 23% to 27%).3,5This study describes a relatively large cohort of pediatric patients from BrS families with numerous fever- and nonfever-ECGs. Limitations are the heterogeneous cohort and retrospective study design, which are inevitable in studying this disease. Sensitivity analyses including only those patients with a first-degree family member with a clear BrS phenotype did not change our results.We conclude that, if future cohort studies support our findings, recording of fever-ECGs may not be mandatory in pediatric patients from BrS families without a SCN5A-mutation because their risk for a fever-induced Brugada type-1 ECG and arrhythmic events is low. A drug challenge, preferably after puberty, can finally make or reject a diagnosis of BrS in these children.Table. Baseline CharacteristicsF-type-1pos (n=14)F-type-1neg (n=83)Complete Cohort (n=97)P ValueSex, No. of males (%)11 (78.6)43 (51.8)54 (55.7)0.08Median age at first presentation in years (IQR)4.4 [1.3-6.3]3.7 [0.8-6.9]4.0 [0.9-6.8]0.86Median follow-up duration in months (IQR)39 [12-95]25 [4-41]27 [4-43]0.14First-degree family member with BrS phenotype, n (%)12 (85.7)66 (79.5)78 (80.4)0.74Family history of sudden cardiac death, n (%)5 (35.7)23 (27.7)28 (28.9)0.54Genotype (Likely) pathogenic SCN5A variant, n (%)13 (92.9)31 (37.3)44 (45.4)<0.01 First-degree family member with (likely) pathogenic SCN5A variant, n (%)1 (7.1)6 (7.2)7 (7.2) Unknown, n (%)—1 (1.2)1 (1.0) First-degree family member variant of unknown significance, n (%)—7 (8.4)7 (7.2) Genotype elusive, n (%)—38 (45.8)38 (39.2)BrS indicates Brugada syndrome; F-type-1pos, ≥1 type-1 fever-ECG; F-type-1neg, without type-1 fever-ECG; and IQR, interquartile range.Sources of FundingWe acknowledge support from the Netherlands Cardiovascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, the Royal Netherlands Academy of Sciences (PREDICT2).DisclosuresNone.FootnotesThe data will be made available to other researchers for the purpose of reproducing the results upon reasonable request.https://www.ahajournals.org/journal/circSally-Ann B. Clur, MBBCh, FCP(SA)Paed, MSc(Med), PhD, Department of Cardiology and Pediatric Cardiology, Amsterdam University Medical Centre, PO Box 22660, 1100 DD Amsterdam, The Netherlands. Email s.a.[email protected]nlReferences1. Antzelevitch C, Yan GX, Ackerman MJ, Borggrefe M, Corrado D, Guo J, Gussak I, Hasdemir C, Horie M, Huikuri H, et al. J-Wave syndromes expert consensus conference report: emerging concepts and gaps in knowledge.Heart Rhythm. 2016; 13:e295–e324. doi: 10.1016/j.hrthm.2016.05.024CrossrefMedlineGoogle Scholar2. Adler A, Topaz G, Heller K, Zeltser D, Ohayon T, Rozovski U, Halkin A, Rosso R, Ben-Shachar S, Antzelevitch C, et al. Fever-induced Brugada pattern: how common is it and what does it mean?Heart Rhythm. 2013; 10:1375–1382. doi: 10.1016/j.hrthm.2013.07.030CrossrefMedlineGoogle Scholar3. Michowitz Y, Milman A, Sarquella-Brugada G, Andorin A, Champagne J, Postema PG, Casado-Arroyo R, Leshem E, Juang JJM, Giustetto C, et al. 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Age at diagnosis of Brugada syndrome: influence on clinical characteristics and risk of arrhythmia.Heart Rhythm. 2020; 17(5 Pt A):743–749. doi: 10.1016/j.hrthm.2019.11.027CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Picconi E, Buonsenso D, De Rosa G and Morena T (2022) Brugada pattern revealed during SARS-COV-2-related multi-systemic inflammatory syndrome in a 6-year-old child, BMJ Case Reports, 10.1136/bcr-2021-248035, 15:2, (e248035), Online publication date: 1-Feb-2022. Franciosi S, Abrams D, Ingles J and Sanatani S (2022) Sudden Cardiac Arrest in the Paediatric Population, CJC Pediatric and Congenital Heart Disease, 10.1016/j.cjcpc.2022.02.001, 1:2, (45-59), Online publication date: 1-Apr-2022. Crabben S, Kowsoleea A, Clur S and Wilde A (2021) Pregnancy in women with Brugada syndrome: Is there an increased arrhythmia risk? 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Xu L and Shi R (2021) Generation of functional Na V 1.5 current by endogenous transcriptional activation of SCN5A , Biotechnology & Biotechnological Equipment, 10.1080/13102818.2021.1892524, 35:1, (469-477), Online publication date: 1-Jan-2021. Nakajima T, Tamura S, Kurabayashi M and Kaneko Y (2021) Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes, International Journal of Molecular Sciences, 10.3390/ijms22083930, 22:8, (3930) Wilde A, Semsarian C, Márquez M, Sepehri Shamloo A, Ackerman M, Ashley E, Sternick E, Barajas-Martinez H, Behr E, Bezzina C, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob M, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware J, Winlaw D, Kaufman E, Aiba T, Bollmann A, Choi J, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn A, MacIntyre C, Mackall J, Mont L, Napolitano C, Ochoa J, Peichl P, Pereira A, Schwartz P, Skinner J, Stellbrink C, Tfelt-Hansen J and Deneke T (2022) European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases, EP Europace, 10.1093/europace/euac030 Campuzano O, Sarquella-Brugada G, Cesar S, Arbelo E, Brugada J and Brugada R (2020) Update on Genetic Basis of Brugada Syndrome: Monogenic, Polygenic or Oligogenic?, International Journal of Molecular Sciences, 10.3390/ijms21197155, 21:19, (7155) Wilde A, Semsarian C, Márquez M, Sepehri Shamloo A, Ackerman M, Ashley E, Sternick Eduardo B, Barajas‐Martinez H, Behr E, Bezzina C, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob M, Lubitz S, Makita N, Ohno S, Ortiz‐Genga M, Sacilotto L, Schulze‐Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware J, Winlaw D, Kaufman E, Aiba T, Bollmann A, Choi J, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn A, Mac Intyre C, Mackall J, Mont L, Napolitano C, Ochoa Juan P, Peichl P, Pereira A, Schwartz P, Skinner J, Stellbrink C, Tfelt‐Hansen J and Deneke T (2022) European Heart Rhythm Association ( EHRA )/Heart Rhythm Society ( HRS )/Asia Pacific Heart Rhythm Society ( APHRS )/Latin American Heart Rhythm Society ( LAHRS ) Expert Consensus Statement on the state of genetic testing for cardiac diseases , Journal of Arrhythmia, 10.1002/joa3.12717 Related articlesCorrection to: In Children and Adolescents From Brugada Syndrome–Families, Only SCN5A Mutation Carriers Develop a Type-1 ECG Pattern Induced By FeverCirculation. 2020;142:e237-e237 July 7, 2020Vol 142, Issue 1 Advertisement Article InformationMetrics © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.045720PMID: 32628552 Originally publishedJuly 6, 2020 KeywordspediatricsfeverBrugada syndromecardiac arrhythmiasretrospective studiesPDF download Advertisement SubjectsArrhythmiasElectrophysiologyGeneticsSudden Cardiac Death
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