Rhythm disorders, independent of structural congenital heart disease, have been described with myriad pediatric syndromes.Reviewing all pediatric syndromes associated with rhythm disorders is beyond the scope of this text.However, arrhythmia as a common or defining clinical feature of a pediatric syndrome is relatively rare. A representative sample of pediatric syndromes that prominently feature arrhythmias is presented here.
Bradyarrhythmia in Pediatric Syndromes
Kearns-Sayre Syndrome
Progressive conduction defects are a feature of Kearns-Sayre syndrome, a neuromuscular disorder. It is characterized by the triad of progressive external ophthalmoplegia, pigmentary degeneration of the retina, and cardiac conduction delay.1-2 It is associated with other neuropathies (sensorineural hearing loss, intention tremor, ataxia) and endocrinopathies.3 Symptoms manifest in childhood, usually late in the first decade of life.3 Neurologic deterioration precedes cardiac conduction deficits.1-6 Kearns-Sayre syndrome is caused by a large deletion of 45-75% of the mitochondria DNA.5,7 This compromises the function of the mitochondrial respiratory chain. In cardiac myocytes, there is a maladaptive increase in the number of dysfunctional mitochondria displacing and replacing myofibils.5,7 Parallel to other mitochondrial myopathies, these changes can also be seen as 'ragged red fibers' found on skeletal muscle biopsy.2-5
Serial standard 12 lead electrocardiograms (ECGs) show the progression from first degree heart block to complete heart block. ECG findings included all degrees of heart block, fascicular blocks and ST-T-wave changes. Progression from fascicular block or first and second degree atrioventricular (AV) block to complete heart block is inevitable.2-4,6-8 The rate of progression is unpredictable but accelerated. Notably, PR interval prolongation is often seen before development of complete heart block though it is not a prerequisite.6 Intracardiac electrophysiology studies show that most conduction block occurs infranodally (a disease of the His-Purkinje system).4,6,8
Consequently, patients with fascicular blocks carry the highest risk of early complete heart block.9 Although development of heart block can be asymptomatic, in two-thirds of patients it manifests as syncope, congestive heart failure or cardiac arrest.6 Up to 20% of these patients are at risk of sudden cardiac death.2,6,9 Prognosis in Kearns-Sayre syndrome is directly related to the cardiac manifestations. Permanent pacemaker placement is recommended and improves long-term outcomes including survival.6,10 With more patients with Kearns-Sayre syndrome having timely pacemaker treatment, other late cardiac manifestation of the syndrome are becoming more apparent. These patients need ongoing monitoring for the development of cardiomyopathy and ventricular arrhythmias.4,6,9 Treatment with coenzyme Q10 can ameliorate the neurologic and cardiac symptoms of Kearns-Sayre syndrome.11 The cardiac findings of Kearns-Sayre syndrome are similar to those seen in other neuromuscular disorders such as myotonic dystrophy type-1 (Steinert disease) and Emery-Dreifuss muscular dystrophy.12-13
Tachyarrhythmia in Pediatric Syndromes
Costello Syndrome
Costello syndrome is usually diagnosed in infancy because of the characteristic coarse facies, cutis laxa, and abnormal hand posturing.14 Infants with Costello syndrome have post-natal growth restriction with severe feeding difficulties despite a normal or increased birth weight.15-17 Children manifest developmental delay.18 A hallmark of the syndrome is the development of papillomas, which are most notable around the nose and mouth but can extend to the torso and extremities.15-18 Over 60% of patients with Costello syndrome have cardiac involvement.15,17
Costello syndrome is caused by de novo mutations in the proto-oncogene HRAS gene (chromosome 11p13).19-20 There are five common mutations of HRAS that have been documented in >85% of patients with Costello syndrome.19-20 Consistent with this finding, Costello syndrome patients have an increased risk (10-17%) of malignancy, such as rhabdomyosarcomas and neuroblastomas.19-20
Among patients with cardiac manifestations, approximately one-third each will have atrial tachyarrhythmias, structural heart disease and hypertrophic cardiomyopathy.17 Often, there is overlap: patients with rhythm disorders frequently have hypertrophic cardiomyopathy or a structural lesion (pulmonary stenosis and ventricular septal defect (VSD) are common).15-17 The rhythm disturbances are an early manifestation of the disease, usually presenting in the neonatal period. Incessant chaotic (multifocal) atrial tachycardia predominates. Other documented atrial arrhythmias include frequent premature beats, atrial ectopic tachycardia, atrial flutter or fibrillation.15-17 The reported cases suggest that the atrial rhythm disturbances, for the most part, precede the development of hypertrophic cardiomyopathy, suggesting that the rhythm disorder is an independent manifestation of the syndrome. Evaluation of a patient with suspected Costello syndrome warrants an ECG, 24-hr ECG recording, and an echocardiogram. The atrial arrhythmias are often refractory to therapy and may require multiple antiarrhythmic agents for suppression or rate control.19 There is a high rate of mortality (10%) in children less than two years of age.15,17 Most deaths have been due to a proven or suspected cardiac cause.17 Costello syndrome should be considered in the differential diagnosis of infants suspected of having Noonan syndrome, cardio-facial-cutaneous syndrome, or Simpson-Golabi-Behmel syndrome.
Brady- and Tachyarrhythmia in Pediatric Syndromes
Timothy Syndrome (LQTS 8)
Timothy syndrome affects multiple organ systems; however, it presents in the neonate as simple syndactyly and a severely prolonged rate-corrected QT (QTc) interval.22-23 Other features of Timothy syndrome include typical facies, congenital heart disease (most commonly a patent ductus arteriosus),immune deficiency, intermittent hypoglycemia, developmental delay and autism.22-23 Timothy syndrome is caused by a mutation in the cardiac L-type calcium channel gene, Cav1.2 (CACNA1C). A single mutation occurring de novo has been identified in all patients tested with Timothy syndrome.23 Very recently, two additional patients with features of Timothy syndrome without syndactyly were found to have slightly different mutations of the Cav1.2 gene.24
This gene is expressed in heart, brain, gut (including pancreatic islet cells), immune system, and smooth muscle tissues.23-24 The mutation prevents the Ca channel from inactivating.23 In cardiac tissue, this results in profound prolongation of repolarization.
Patients with Timothy syndrome usually present with bradycardia due to severe prolongation of cardiac repolarization causing 2:1 AV block.22-23 Increasingly, patients present antenatally with fetal bradycardia.23 If not diagnosed in utero, fetal 'heart rate decelerationÔÇÖ often precipitate an emergent delivery.23 QT intervals on ECG shortly after delivery are very prolonged. The QTc intervals commonly exceeded 600ms.22 Some infants will manifest T-wave alternans, an ominous sign in long QT syndrome (LQTS).25 These infants develop malignant ventricular arrhythmias, which can begin within hours of delivery, including ventricular tachycardia, torsade de pointes, and ventricular fibrillation.22-25 Splawski et al., who first characterized the genetic underpinning of Timothy syndrome, showed a very high mortality associated with this syndrome.23 Ten of 17 patients had died by an average age of 2.5 years.The cause of death was cardiac arrest (ventricular fibrillation), some spontaneous, others likely triggered by sepsis or hypoglycemic episodes associated with Timothy syndrome. Management of the cardiac manifestations of Timothy syndrome parallels the management of other LQTS in neonates. To minimize triggering tachyarrythmias, the patients undergo permanent pacemaker placement and β-blocker therapy. Once these infants have reached a suitable size and weight, an implantable cardiac defibrillator is placed.12,27
Conclusion
Although uncommon in patients presenting with a constellation of findings suggesting a pediatric syndrome, cardiac dysrhythmia should be considered and anticipated, especially if the heart rate is inappropriately depressed, elevated, or irregular. Outcomes of patients with these syndromes largely depend on the underlying arrhythmia. The timely recognition and management of a rhythm disorder in this patient population can be paramount with respect to their long-term outcome.