Phenotypic Manifestations of Arrhythmogenic Cardiomyopathy in Children and Adolescents

Abstract

Background: Arrhythmogenic cardiomyopathy (ACM) is a variably penetrant disease increasingly identified in young patients.

Objectives: This study sought to describe the diverse phenotype, genotype, and outcomes in pediatric and adolescent patients.

Methods: Records from 1999 to 2016 were reviewed for individuals age <21 years with a consistent personal or family history. Patients were categorized by right ventricular (RV), left dominant (LD), or biventricular subtypes using 2010 Task Force Criteria or proposed features of LD disease, encompassing electrocardiographic, structural, histological, and arrhythmic characteristics. Genetic variants classified as pathogenic and/or likely pathogenic by 2015 American College of Medical Genetics and Genomics criteria in recognized disease-associated genes were included.

Results: Manifest disease was evident in 32 patients (age 15.1 ± 3.8 years), of whom 22 were probands, including 16 RV, 7 LD, and 9 biventricular ACM. Nondiagnostic features were seen in 5 of 15 family members. RV disease was associated with cardiac arrest and ventricular tachycardia (p = 0.02) and prevalence of PKP2 variants (p < 0.01), whereas biventricular disease was associated with a younger age of onset (p = 0.02). LD ACM was associated with variants in DSP and LMNA, and biventricular ACM with more a diverse etiology in desmosomal genes. Cardiac arrest was observed in 5 probands (age 15.3 ± 1.9 years) and ventricular tachycardia in 10 (age 16.6 ± 2.7 years), 6 probands, and 4 family members. Features suggestive of myocardial inflammation were seen in 6 patients, with ventricular tachycardia and/or cardiac arrest in 3 patients. Cardiac transplantation was performed in 10 patients. There were no deaths. In RV and biventricular disease, electrocardiographic preceded imaging features, whereas the reverse was seen in LD disease.

Conclusions: ACM in the young has highly varied phenotypic expression incorporating life-threatening arrhythmia, heart failure, and myocardial inflammation. Increased awareness of early onset, aggressive disease has important implications for patient management and familial screening.

Keywords: arrhythmogenic right ventricular cardiomyopathy; desmosomes; diagnostic criteria; genetics; pediatrics; phenotype.

CENTRAL ILLUSTRATION. Phenotype and Genotype Data From 32 Patients With Manifest Arrhythmogenic Cardiomyopathy

The 3 cardiac phenotypes are shown, including arrhythmogenic right ventricular cardiomyopathy (ARVC) with thinning of the ventricular myocardium, right ventricular dilatation, and aneurysms; left dominant arrhythmogenic cardiomyopathy (ACM) with thinning of the left ventricular myocardium; and biventricular ACM with involvement of both ventricles including marked left ventricular dilatation. The specific demographic and phenotypic features along with the pertinent genetic findings are shown for each subtype. *Variant of unknown significance. +1 patient represented in both cardiac arrest and ventricular tachycardia groups.

FIGURE 1. Arrhythmic Phenotype Preceding ECG Features in Classical Right-Sided ACM

(A) A 12-lead electrocardiograph (ECG) from a 17-year-old Haitian American male patient (H1) who presented following recurrent syncopal episodes, with normal depolarization and repolarization parameters. Cardiac magnetic resonance showed normal ventricular volumes and systolic function with nonspecific changes in the right ventricular free wall. An electrophysiology study including programmed ventricular stimulation in the presence of isoproterenol was negative, and a loop recorder was implanted. (B) He experienced a further pre-syncopal episode with documented monomorphic ventricular tachycardia at 300 beats/min. On subsequent investigation, his sister fulfilled the International Task Force criteria for classical right-sided disease. ACM = arrhythmogenic cardiomyopathy.

FIGURE 2. ECG and Imaging Manifestations of Myocardial Inflammation Associated With a Desmoplakin Truncating Variant

(A) A 12-lead electrocardiogram (ECG) recorded from a 16-year-old-male patient (Q1) who presented with a cardiac arrest after a week-long history of chest pain, diagnosed as myocarditis. The ECG shows a broad complex tachycardia with right bundle morphology consistent with left ventricular tachycardia. (B) He represented 5years later with further chest pain and elevated troponin levels (troponin T: 2.95 ng/ml) and experienced an in-hospital cardiac arrest. Note ST-segment changes in the top rhythm strip. (C, D) Cardiac magnetic resonance performed shortly after showed mild leftventricular dilatation and with appropriate systolic wall thickening (mid-ventricular short-axis cine image in end-diastole [C]) with a large region of epicardial and/or mid-myocardial late gadolinium enhancement in the inferior and inferolateral segments of the left ventricle. (E) A 12-lead ECG from a 10-year-old male proband (BB1) who presented with chest pain and troponin release (troponin T: 2.75 ng/ml; normal: <0.01 ng/ml) demonstrating severe ST-segment elevation across numerous leads.

FIGURE 3. Biventricular ACM

Cardiac magnetic resonance cine images in end-diastole from a 14-year-old male patient (Z1) who presented with severe cardiac failure: (A) 4-chamber view; (B) 2-chamber left ventricular (LV) view; and (C) 3-chamber right ventricular view. There was severe biventricular enlargement (LV end-diastolic volume: 247 ml/m², right ventricular end-diastolic volume: 340 ml/m²) and severe biventricular systolic dysfunction (LV and right ventricular ejection fractions: <10%). (D) There were multiple segments with late gadolinium enhancement and wall thinning including the LV apex. After support with an LV device, he underwent successful cardiac transplantation. (E, F) Gross pathological assessment showed extensive chamber dilatation (note LV assistive device site) with marked myocardial thinning and fibrofatty replacement. (G) Additional histological analysis (hematoxylin and eosin stain) again showed extensive fibrofatty replacement. (H) Genetic testing identified a previously described splice acceptor variant in desmocollin-2, which exposed a cryptic splice acceptor site with subsequent premature truncation (33). His asymptomatic mother with a normal clinical evaluation carried the same variant (Table 3). ACM = arrhythmogenic cardiomyopathy; EA = extracellular anchor domain; EC1 = extracellular domain 1; IA = intracellular anchor domain; ICS = intracellular cadherin-typical sequence; SSPro = signal peptide/propetide sequence; TM = transmembrane domain.