Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart?

Abstract

Cardiomyopathy (CMP) is a rare disease in the pediatric population, with a high risk of morbidity and mortality. The genetic etiology of CMPs in children is extremely heterogenous. These two factors play a major role in the difficulties of establishing standard diagnostic and therapeutic protocols. Isolated CMP in children is a frequent finding, mainly caused by sarcomeric gene variants with a detection rate that can reach up to 50% of analyzed cohorts. Complex multisystemic forms of pediatric CMP are even more heterogenous. Few studies in literature take into consideration this topic as the main core since it represents a rarity (systemic CMP) within a rarity (pediatric population CMP). Identifying etiology in this cohort is essential for understanding prognosis, risk stratification, eligibility to heart transplantation and/or mechanical-assisted procedures, preventing multiorgan complications, and relatives' recurrence risk calculation. The previous points represent a cornerstone in patients' empowerment and personalized medical care approach. The aim of this work is to propose a new approach for an algorithm in the setting of the diagnostic framework of systemic pediatric CMP. On the other hand, during the literature review, we noticed a relatively common etiologic pattern in some forms of complex/multisystem CMP. In other words, certain syndromes such as Danon, Vici, Alström, Barth, and Myhre syndrome share a common pathway of directly or indirectly defective "autophagy" process, which appears to be a possible initiating/triggering factor for CMPs. This conjoint aspect could be important for possible prognostic/therapeutic implications in this category of patients. However, multicentric studies detailed functional and experimental models are needed prior to deriving conclusions.

Keywords: cardiomyopathies; children; heterogeneity; multisystemic; personalized approach; syndromes.

Figure 2

CMP + dysmorphic features + intellectual disability. Abbreviations: ACM; arrhythmogenic cardiomyopathy; ASD, atrial septal defects; AVB, atrioventricular block; AVCDs, atrioventricular canal defects; CHDs, congenital heart defects; CMP, cardiomyopathy; CoAo, coarctation of aorta; DCM, dilated cardiomyopathy; EMF, endomyocardial fibrosis; ID, intellectual disability; IUGR, intrauterine growth restriction; HCM; hypertrophic cardiomyopathy; LVNC, left ventricular non-compaction; PDA, patent ductus arteriosus; PVC, premature ventricular contraction; S, syndrome; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

Figure 3

CMP + short stature. Abbreviations; ASD, atrial septal defects; AV, aortic valve; AVCDs, atrioventricular canal defects; BAV, bicuspid aortic valve; CHDs, congenital heart defects; CMP, cardiomyopathy; CoAo, coarctation of aorta; DCM, dilated cardiomyopathy; ID, intellectual disability; GHD, growth hormone deficiency; HCM; hypertrophic cardiomyopathy; HF, heart failure; HLHS, hypoplastic left heart syndrome; LBBB, left bundle branch block; LQT, long QT; LVNC, left ventricular non-compaction; PDA, patent ductus arteriosus; LVOTA, left ventricular outflow tract area; MV, mitral valve; PVS, pulmonary vein stenosis; RAD, right axis deviation; RBBB, right bundle branch block; RCM, restrictive cardiomyopathy; S, syndrome; Rt, right side; TOF, tetralogy of Fallot; VSD, ventricular septal defect; WPW, Wolff Parkinson White.

Figure 4

CMP + limb defects. Abbreviations: AF, atrial fibrillation; ASD, atrial septal defects; AVCD, atrioventricular canal defects; BrS, Brugada Syndrome; CCD, cardiac conduction defects; CHDs, congenital heart defects; CMP, cardiomyopathy; DCM, dilated cardiomyopathy; HCM; hypertrophic cardiomyopathy; HLHS, hypoplastic left heart syndrome; LQTS, long QT syndrome; LVNC, left ventricular non-compaction; NSVT, non-sustained ventricular tachycardia; PDA, patent ductus arteriosus; S, syndrome; TA, troncus arteriosus; TOF, tetralogy of Fallot; TAPVR, total anomalous pulmonary venous return; VF, ventricular fibrillation; VSD, ventricular septal defect; VT, ventricular tachycardia.

Figure 5

CMP + progressive neuromuscular disease + delayed motor milestone. Abbreviations: AF, atrial fibrillation; AR, autosomal recessive; AVB, atrioventricular block; CHDs, congenital heart defects; CMP, cardiomyopathy; CSF, cerebrospinal fluid; DCM, dilated cardiomyopathy; CPK; creatine phosphokinase; EO, external ophthalmoplegia; ESHF, end-stage heart failure; GHD, growth hormone deficiency; HCM; hypertrophic cardiomyopathy; ID, intellectual disability; LQT, long QT; NSVT, non-sustained ventricular tachycardia; PCD, progressive conduction defects; RP, retinitis pigmentosa; S, syndrome; SCD, sudden cardiac death; SVT, sustained ventricular tachycardia; VF, ventricular fibrillation; WPW, Wolff Parkinson White.

Figure 6

CMP + skin + hair. Abbreviations: ACM; arrhythmogenic cardiomyopathy; ASD, atrial septal defects; AVB, atrioventricular block; CHDs, congenital heart defects; CMP, cardiomyopathy; CoAo, coarctation of aorta; DCM, dilated cardiomyopathy; ID, intellectual disability; NSVT, non-sustained ventricular tachycardia; PDA, patent ductus arteriosus; PVC, premature ventricular contraction; PS, pulmonary stenosis; S, syndrome; TGA, transposition of great arteries, VSD, ventricular septal defect; VT, ventricular tachycardia.

Figure 7

CMP + eye. Abbreviations: AR, autosomal recessive; CMP, cardiomyopathy; DCM, dilated cardiomyopathy; HCM; hypertrophic cardiomyopathy; ID, intellectual disability; LAD, left axis deviation; LQT, long QT; LVH, left ventricular hypertrophy; RCM, restrictive cardiomyopathy; S, syndrome; T2, type 2.

Figure 8

CMP + corpus callosum agenesis. Abbreviations: ASD, atrial septal defects; AR, autosomal recessive; CHDs, congenital heart defects; CMP, cardiomyopathy; DCM, dilated cardiomyopathy; FTT, failure to thrive; HCM; hypertrophic cardiomyopathy; ID, intellectual disability; PDA, patent ductus arteriosus; PFO, patent forame ovale.

Figure 9

CMP + recurrent infections. Abbreviations: 3-MGC, methylglutaconic aciduria; CMP, cardiomyopathy; DCM, dilated cardiomyopathy; HCM; hypertrophic cardiomyopathy; LQT, long QT, LVNC, left ventricular non-compaction; S, syndrome.

Figure 10

CMP + tall stature. Abbreviations: BAV, bicuspid aortic valve; CMP, cardiomyopathy; CHDs, congenital heart defects; DCM, dilated cardiomyopathy; MV, mitral valve, RCM, restrictive cardiomyopathy; S, syndrome.

Figure 1

Diagnostic algorithm in pediatric-onset CMP. The algorithm brings light to a step-by-step method for the clinical approach when facing the management of a cohort with CMP in children. Abbreviations: CF, clinical features; CMP, cardiomyopathy; CPK; creatine phosphokinase; ECG electrocardiography; FGF21, fibroblast growth factor 21; GAG, glycosaminoglycan; MRI, magnetic resonance imaging; GDF15, growth differentiation factor 15; NGS, next-generation sequencing; US, ultrasound.

Figure 11

NGS detection rate in isolated CMPs. Abbreviations: CMPs, cardiomyopathies; NGS, next-generation sequencing.