Author + information
- Received August 13, 2019
- Revision received November 29, 2019
- Accepted January 6, 2020
- Published online June 17, 2020.
- Rob W. Roudijk, MDa,
- Reinder Evertz, MDb,
- Arco J. Teske, MD, PhDa,
- Carlo Marcelis, MDc,
- Dennis Bosboom, MDd,
- Birgitta K. Velthuis, MD, PhDe,
- Floris E.A. Udink ten Cate, MD, PhDf,g and
- Anneline S.J.M. te Riele, MD, PhDa,∗ ()
- aDepartment of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands
- bDepartment of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands
- cDepartment of Clinical Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
- dDepartment of Radiology, Radboud University Medical Center, Nijmegen, the Netherlands
- eDepartment of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands
- fDepartment of Pediatric Cardiology, Academic Center for Congenital Heart Disease, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
- gDivision of Pediatric Cardiology, Department of Pediatrics, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, the Netherlands
- ↵∗Address for correspondence:
Dr. Anneline S.J.M. te Riele, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA, Utrecht, the Netherlands.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is rarely diagnosed in childhood. We describe the case of a 9-year-old girl with genetically confirmed ARVC who presented with syncope, ventricular arrhythmia, and biventricular myocardial dysfunction. This case highlights the need for development of pediatric ARVC diagnosis criteria specific for pediatric patients and discusses potential diagnostic improvement using echocardiographic deformation imaging. (Level of Difficulty: Beginner.)
- arrhythmogenic cardiomyopathy
- arrhythmogenic right ventricular cardiomyopathy
- deformation imaging
- desmosomal mutations
- genetic screening
- ventricular tachycardia
A 9-year-old girl was admitted to the authors’ hospital for evaluation of recurrent syncope. She was not taking any medication. Physical examination was unremarkable.
• Since the diagnostic Task Force Criteria were derived in a predominantly adult cohort, their use in children should be considered experimental, and physicians should be aware of their limitations in the pediatric population.
• Echocardiographic deformation imaging is useful for diagnostic evaluation of arrhythmogenic right ventricular cardiomyopathy.
• Given the incomplete penetrance of disease, genetic testing should be integrated in the evaluation of young patients with unexplained cardiomyopathy, even without a family history of heart disease.
Prior to presentation, she experienced daily episodes of palpitations with nearly syncope and 2 episodes of syncope during exercise (i.e., gymnastics class at school). She did not have chest pain or dyspnea. Her family history was negative for sudden cardiac death or cardiomyopathy. She did not participate in competitive sports. Her medical history included only urticaria.
Syncope in children has a broad differential (Table 1). Exercise-induced syncope associated with palpitations is highly suspicious of a cardiac cause, especially ventricular arrhythmia.
The 12-lead electrocardiography (ECG) showed sinus rhythm, right heart axis, normal conduction intervals, high R-wave amplitude, T-wave inversions in leads V1 to V4 and flattened T waves in the inferior leads (Figure 1). Twenty-four-hour Holter monitor revealed 1,689 premature ventricular complexes and 4 episodes of nonsustained ventricular tachycardia with unknown morphology at 250 to 270 beats/min.
Two-dimensional transthoracic echocardiography showed a morphologically normal heart and left ventricular (LV) wall thickness (Video 1). Mild biventricular dilation and systolic dysfunction were present (LV ejection fraction [EF] of 50% and tricuspid annular plane systolic excursion of 17 mm). Task Force Criteria (TFC) for ARVC were not fulfilled as no right ventricular (RV) wall motion abnormalities were present. However, deformation imaging using speckle tracking indicated biventricular dysfunction (Figures 2 and 3). RV subtricuspid strain showed systolic pre-stretch, as may be observed in adult ARVC (1). Global longitudinal strain was significantly reduced in both the LV (−13.5%; normal: >−18.5%) and RV (−20.0%; normal: >−26.5%).
Cardiac magnetic resonance imaging
Cardiac magnetic resonance (CMR) confirmed biventricular dilation and dysfunction (LV indexed end-diastolic volume [EDV]: 104 ml/m2 and LVEF of 49%; RV EDV: 117 ml/m2; and RVEF: 36%) (Figure 1, Video 2). Akinesia was observed in the inferior RV and RV outflow tract which resulted in a major criterion for ARVC. T2-weighted images showed no myocardial edema suggestive of myocarditis. Epicardial patchy late gadolinium enhancement was present in the LV, midwall septum, extending to the inferior RV.
Diagnostic confirmation by genetic testing
ARVC with LV involvement was thought to be more likely than dilated cardiomyopathy (DCM) due to the evident RV involvement and occurrence of episodes of ventricular arrhythmia in the early stages of the disease (Table 1). However, ARVC could not be definitively diagnosed during clinical evaluation because the 2010 TFC for ARVC were not fulfilled (Table 3) (2).
Genetic testing confirmed the diagnosis of ARVC. The patient was heterozygous for 2 plakophillin (PKP2) variants, c.397C>T, p.(Gln133∗), classified as pathogenic, and c.2615C>T, p.(Thr872Ile), classified as variants of unknown significance; and 1 pathogenic desmoglein (DSG2) variant (c.1003A>G, p.(Thr335Ala)). Cascade screening confirmed ARVC diagnosis in her asymptomatic mother (age 44 years) who carried both PKP2 variants and had T-wave inversions in V1 to V3, and a major CMR criterion. The mother of the patient was treated with sotalol and received a primary prophylactic implantable cardioverter-defibrillator (ICD). The girl’s asymptomatic father (age 50 years) carried the DSG2 variant and had normal cardiac evaluation (including an ECG, an echocardiogram, and CMR).
The patient was started on sotalol therapy to suppress her symptomatic ventricular arrhythmia episodes and spironolactone to prevent further adverse ventricular remodeling. She was advised to avoid competitive sports. A subcutaneous ICD was implanted before she was discharged (3).
ARVC is rarely diagnosed before adolescence, and the diagnostic TFC are not validated for use in pediatric cohorts (4,5). The case presented here emphasizes the limitations of the TFC in children and highlights opportunities for improvement.
Low sensitivity of the TFC in pediatric patients
The diagnostic TFC were developed in a predominantly adult cohort (2). To deal with this limitation, repolarization abnormalities were excluded from the TFC in children <14 years of age. Of note, CMR cutoff values were based on a comparison between adult ARVC probands and controls, the implications of which for pediatric ARVC evaluation remains unknown (2,6). The present case illustrates the fact that the TFC are relatively insensitive for pediatric diagnosis, and future studies should focus on validation in pediatric cohorts and development of imaging criteria specific for children (3).
Low sensitivity of imaging criteria in early ARVC
In this patient, both echocardiography and CMR were suggestive of ARVC, but only CMR provided a major criterion for ARVC diagnosis. This is not unexpected, as echocardiography is less sensitive for ARVC evaluation than CMR (7). However, this case illustrates the fact that echocardiographic deformation imaging may unmask the abnormal structural substrate, suggesting a possible role in screening for ARVC.
Biventricular involvement in ARVC
Left ventricular involvement is well recognized in ARVC and leads to diagnostic overlap with DCM. Indeed, this patient clearly had biventricular involvement and, hence, should be regarded as spanning the spectrum between ARVC and DCM. Given the overlapping phenotypes, it seems important to be vigilant for arrhythmic risk and genetic causes in apparent DCM cases.
Early development of ARVC in this pediatric case might have been influenced by variants in both the PKP2 and the DSG2 genes. Indeed, multiple pathogenic variants are associated with worse prognosis (8). In contrast, although exercise is a known environmental modifier of the ARVC phenotype, this patient did not participate in vigorous physical exercise.
During 2.5 years of follow-up, the patient did not experience syncope or ICD interventions, and the LVEF and RVEF were stable. Device interrogation revealed frequent episodes of nonsustained ventricular tachycardia (maximum: 160 beats/min) without requiring device therapy and a stable premature ventricular complex burden of 5% of QRS complexes.
This report provides detailed phenotypic information for a young girl carrying 2 pathogenic desmosomal variants. Albeit a diagnosis of ARVC is highly likely to explain her symptoms, the data highlight the fact that the diagnostic TFC have low sensitivity for disease among children. Echocardiographic deformation imaging may have added value for ARVC screening.
Supported by Dutch Heart Foundation grants 2015T058 to Dr. te Riele; and CVON2015-12 eDETECT, 2012-10 PREDICT, and CVON PREDICT Young Talent Program to Dr. te Riele; and the University Medical Center Utrecht Fellowship Clinical Research Talent grant to Dr. te Riele. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reports author instructions page.
- Abbreviations and Acronyms
- arrhythmogenic right ventricular cardiomyopathy
- cardiac magnetic resonance
- dilated cardiomyopathy
- Received August 13, 2019.
- Revision received November 29, 2019.
- Accepted January 6, 2020.
- 2020 The Authors
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