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Familial DCM is typically transmitted in an autosomal dominant fashion, although X-linked and autosomal recessive transmission do occur, especially in the setting of neuromuscular disease It is worth noting that the family history alone is insufficiently sensitive to assess the possibility of familial DCM.279 Furthermore, DCM shows incomplete penetrance, age-related penetrance, and variable expressivity, underscoring the importance of long-term screening and monitoring, given the current yield of genetic testing This is reflected in the consensus statements regarding the need for long-term screening A number of mutations in cystoskeletal, nuclear, sarcomeric, ion channel and desmosomal proteins may cause dilated cardiomyopathy (see Table 61.1) The majority of patients with a positive genetic test will have a mutation in titin (~20% of patients) with less than 5% of patients having mutations in other genes (most commonly MYH7, LMNA, TNNT2, and TPM1).284,285 The relative proportion of cases with positive gene testing and the frequency of mutation within specific genes appears to be different in pediatric and adult disease Titin appears to again harbor the most mutations, whereas there appears to be a concentration of cases due to RNA binding motif protein 20 RBM20 in children.285 However, it is again worth noting that the reclassification of pathogenicity is common in the current era, and thus the yield and frequency of individual mutations is likely to change over time A small proportion of patients with familial DCM will have X-linked transmission The most common causes are associated with muscular dystrophy (Duchenne, Becker, and Emery-Dreifuss muscular dystrophies).286 Rare cases of dystrophinopathy in females have been reported; however, the majority of carriers do not have cardiac disease until well into adulthood.287,288 Barth syndrome is another cause of X-linked DCM due to mutations in the TAZ gene It is typically characterized by skeletal myopathy, growth restriction, neutropenia, and DCM, although there is significant heterogeneity in the specific phenotype.289 Pathology Grossly, DCM is characterized by a globular heart with ventricular cavity enlargement as well as dilation of the atria (Fig 61.8) The heart typically has increased overall mass but decreased wall thickness.290 Microscopically, DCM shows nonspecific pathologic findings characterized by fiber hypertrophy, myocyte degeneration, and interstitial fibrosis There may be occasional foci of inflammatory cells as well, although the characteristics of infiltrate help to distinguish DCM from active myocarditis.291,292 FIG 61.8 Gross pathologic specimen showing concentric left ventricular hypertrophy in an 8-week-old infant with mitochondrial disease Pathophysiology More than 50 genes in multiple signaling pathways have been reported to cause DCM (see Table 61.1).282 Mutations in sarcomeric proteins as well as cytoskeletal and nuclear proteins are associated with DCM.282 Although the molecular signatures may be unique (ranging from abnormal force generation to abnormalities in maintaining structural integrity of the sarcomere), the final phenotypic expression of disease is common and nonspecific, featuring myocyte death and fibrosis Clinical Features The symptoms of DCM are typically age dependent and often nonspecific Historically, approximately 90% of children present with symptoms of congestive heart failure, with only 5% presenting with sudden death, 3% identified by screening, and 2% due to exercise intolerance or arrhythmia.35,232,273,293,294 Symptoms Respiratory symptoms and feeding intolerance and/or failure to thrive are the predominant symptoms and presentation among infants As patients become progressively older, they will increasingly report subjective activity intolerance or shortness of breath on exertion; nonspecific gastrointestinal complaints also persist as patients get older Physical Examination Given that the majority of pediatric patients are symptomatic at the time of diagnosis, the physical exam is typically abnormal Patients, especially infants, typically present with persistent sinus tachycardia, whereas patients with more advanced disease may present with weak pulses, pulsus alternans, and hypotension Isolated atrial and ventricular ectopy is common, and conduction abnormalities or atrial/ventricular tachycardia raise the possibility of myocarditis or specific genetic defects The apical impulse is typically prominent and laterally displaced, and the left chest may be disproportionately prominent as compared with the right Auscultation may reveal a gallop as well as a murmur consistent with mitral regurgitation Respiratory findings, including tachypnea and increased work of breathing, may be found upon presentation in children of all ages Wheezing and basilar crackles may be present, especially among infants; this may delay the initial diagnosis due to a presumptive diagnosis of reactive airway disease or bronchiolitis Jugular venous distention is often difficult to assess or evaluate in the infant but is commonly present in all children Hepatomegaly and elevation of liver enzymes may also be present and reflect elevated venous pressures Edema of the extremities and face and ascites may also be present Assessing myotonia, muscular tone, and bulk is important given the heterogeneous causes of DCM in children, including mitochondrial disease and neuromuscular disease It may be difficult to distinguish inherent muscle weakness from chronic failure to thrive on initial presentation and without longitudinal exams Abnormal ophthalmologic or sensorineural deafness may be present in mitochondrial disease Woolly hair and keratoderma may occur in the setting of cardiocutaneous syndromes  ... or shortness of breath on exertion; nonspecific gastrointestinal complaints also persist as patients get older Physical Examination Given that the majority of pediatric patients are symptomatic at the time of diagnosis, the physical exam is typically abnormal