Hypertrophic Cardiomyopathy in Children: Pathophysiology, Diagnosis, and Treatment of Non-sarcomeric Causes

Abstract

Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterized by left ventricular hypertrophy not solely explained by abnormal loading conditions. Despite its rare prevalence in pediatric age, HCM carries a relevant risk of mortality and morbidity in both infants and children. Pediatric HCM is a large heterogeneous group of disorders. Other than mutations in sarcomeric genes, which represent the most important cause of HCM in adults, childhood HCM includes a high prevalence of non-sarcomeric causes, including inherited errors of metabolism (i.e., glycogen storage diseases, lysosomal storage diseases, and fatty acid oxidation disorders), malformation syndromes, neuromuscular diseases, and mitochondrial disease, which globally represent up to 35% of children with HCM. The age of presentation and the underlying etiology significantly impact the prognosis of children with HCM. Moreover, in recent years, different targeted approaches for non-sarcomeric etiologies of HCM have emerged. Therefore, the etiological diagnosis is a fundamental step in designing specific management and therapy in these subjects. The present review aims to provide an overview of the non-sarcomeric causes of HCM in children, focusing on the pathophysiology, clinical features, diagnosis, and treatment of these rare disorders.

Keywords: children; diagnosis; etiology; hypertrophic cardiomyopathy; treatment.

Figure 1

Possible scenarios in clinical practice. LVH, left ventricular hypertrophy; NSML, Noonan syndrome with multiple lentigines.

Figure 2

Diagnostic approach for the infant and young child with hypertrophic cardiomyopathy. AD, autosomal dominant; AR, autosomal recessive; AV, atrioventricular; LVH, left ventricular hypertrophy.

Figure 3

Etiology of hypertrophic cardiomyopathy in infants (age < 1 year) and in a young child (age 1–18 years). Modified from Limongelli et al. Int J Cardiol 2020 (3).

Figure 4

Diagnostic flowchart in patients with unexplained left ventricular hypertrophy and electrocardiographic evidence of ventricular preexcitation. FFA, free fatty acids; MELAS, mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers.

Figure 5

Proposed algorithm for the diagnosis of mitochondrial cardiomyopathies. CACT, carnitine-acylcarnitine translocase; CTPII, carnitine palmitoyltransferase II; FFA, free fatty acids; LCHAD/MTP, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; LHON, Leber's hereditary optic neuropathy; MADD, multiple-acyl-CoA dehydrogenase deficiencies; MELAS, mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes; MERRF, myoclonic epilepsy with ragged red fibers; MGA, methylglutaconic aciduria; NARP, neurogenic muscle weakness with sensory neuropathy; VLCADD, very-long-chain acyl-CoA dehydrogenase deficiency.