Pediatric Long QT Syndrome

Many causes of sudden death in the pediatric population are due to genetic heart disorders, which can lead to structural abnormalities (eg, hypertrophic cardiomyopathy) and arrhythmogenic abnormalities (eg, familial long QT syndrome). Indeed, sudden cardiac death in the pediatric population can be the first presentation of an underlying heart problem. (See Etiology and Pathophysiology and Presentation.)

Long QT syndrome is a genetically transmitted cardiac arrhythmia caused by ion channel protein abnormalities. It is characterized by electrocardiographic abnormalities and a high incidence of syncope and sudden cardiac death. (See Etiology and Pathophysiology, Prognosis, and Workup.)

Long QT syndrome can be mistaken for palpitations, neurocardiogenic syncope, and epilepsy. ^[1] The diagnosis is suggested when ventricular repolarization abnormalities result in prolongation of the corrected QT interval. (See DDx and Workup.)

Diagnostic criteria

Schwartz et al suggested incorporating clinical and electrocardiogram (ECG) findings in a probability-based diagnostic criteria for long QT syndrome. ^[2] The maximum score is 9, and a score of more 3 indicates a high probability of long QT syndrome. The criteria are as follows (see Presentation and Workup):

ECG findings (without medications or disorders known to affect ECG features) include the following:

• QT corrected for heart rate (QTc), calculated using Bazett's formula, of more than 480 milliseconds (ms) - 3 points

• QTc of 460-470 ms - 2 points

• QTc of 450 ms in male patients - 1 point

• Torsade de pointes (mutually exclusive) - 2 points

• T-wave alternans - 1 point

• Notched T wave in 3 leads - 1 point

• Low heart rate for age (ie, resting heart rate below the second percentile for age) - 0.5 point

Clinical history includes the following:

• Syncope with stress (mutually exclusive) - 2 points

• Syncope without stress - 1 point

• Congenital deafness - 0.5 point

Family history includes the following (the same family member cannot be counted in both categories):

• Family member with definite long QT syndrome - 1 point

• Unexplained sudden cardiac death (age < 30 y) in an immediate family member - 0.5 point

Epidemiology

The frequency of long QT syndrome is unknown (possibly about 1 per 2000 population ^[3] ). The condition is present in all races and ethnic groups, although frequency may differ among these populations. However, population-based prevalence studies are not available on this disease at the current time.

Long QT syndrome is responsible for approximately 1000 deaths each year in the United States, most of which occur in children and young adults.

This syndrome, once diagnosed by clinical profile, has been more clearly defined by specific genetic defects that cause ion channel abnormalities, resulting in a syndrome that predisposes to lethal cardiac arrhythmias.

Initial studies using monophasic action potentials have shown evidence of early after depolarizations (EADs) in congenital and acquired long QT syndrome. Excessive prolongation of action potential results in reactivation of certain L-type calcium channels, leading to after depolarizations.

Sympathetic activity is thought to enhance the EADs, which, in turn, can initiate a lethal form of ventricular arrhythmia termed torsade de pointes. Abnormal cardiac repolarization renders the heart susceptible to these lethal ventricular tachyarrhythmias, increasing the risk of sudden cardiac death in patients of all ages.

Molecular basis of long QT syndrome

Six genetic loci for long QT syndrome have been identified. Sporadic cases occur as a result of spontaneous mutations. Jervell and Lang-Nielsen (JLN) syndrome is an autosomal recessive form of congenital long QT syndrome. Romano-Ward syndrome (RWS) is the dominant form.

The establishment of a long QT syndrome registry and the discovery of genetic mutations that cause long QT syndrome have greatly contributed to the understanding of this condition. Since the first report in 1991 of a deoxyribonucleic acid (DNA) marker in the short arm of chromosome 11, numerous studies have reported genetic mutations and molecular descriptions of ion channel abnormalities in long QT syndrome.

However, the genetic heterogeneity of this condition has made using genetic mutations to screen for it difficult. Nevertheless, the genetic markers have been effectively translated for the clinical management of this disease. They include KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2, and CAV3.

The clinical heterogeneity is usually attributed to variable penetrance. One of the reasons for this variability in expression could be the coexistence of common single nucleotide polymorphisms (SNPs) on long QT syndrome ̶ causing genes, on unknown genes, or on both. Some synonymous and nonsynonymous exonic SNPs identified in long QT syndrome–causing genes may have an effect on the cardiac repolarization process and may modulate the clinical expression of a latent long QT syndrome pathogenic mutation.

Table 1. Genetic Basis of Long QT Syndrome, Including Jervell and Lang-Nielsen (JLN) Syndrome (Open Table in a new window)

In a retrospective study (1998-2017) of genotypring data from 20 Thai children and young adults (17 families) with congenital long QT syndrome, investigators found genetic variants in KCNQ1, KCNH2, and SCN5A in 6 (35%), 4 (24%), and 2 (12%) families, respectively. ^[4] Another patient had  variance of unknown significance (VUS) in KCNH2 and yet another patient had one in ANK2. Most of the patients with long QT syndrome were symptomatic at presentation, with genetic mutations mainly in LQT1, LQT2, and LQT3 genes. ^[4]

More recently, a novel mutation (KCNQ1p.Thr312del) has been reported in a Chinese family with LQT1 over a three-generation pedigree. ^[5] The investigators indicate that this mutation induces a loss of function in channel electrophysiology, and it is a high-risk mutation responsible for LQT1.

Acquired long QT syndrome

The acquired causes of long QT syndrome include drugs, electrolyte imbalance, marked bradycardia, cocaine, organophosphorus compounds, subarachnoid hemorrhage, myocardial ischemia, protein-sparing fasting, autonomic neuropathy, and human immunodeficiency virus (HIV) disease.

Drug-induced long QT syndrome is characterized by a prolonged QTc and an increased risk of torsade de pointes. Virtually all drugs that prolong QTc block the rapid component of the delayed rectifier current (I_kr). Some drugs prolong QTc in a dose-dependent manner, whereas others do so at any dose.

Most patients who develop drug-induced torsade de pointes have underlying risk factors. Incidence is more common in females. Implicated drugs include the following ^[6] :

• Class IA and III antiarrhythmics

• Macrolide antibiotics

• Pentamidine

• Antimalarials

• Antipsychotics

• Arsenic trioxide

• Methadone

The prognosis for patients with long QT syndrome who have been treated with beta-blockers (and other therapeutic measures, if needed) is satisfactory. Fortunately, episodes of torsade de pointes are usually self terminating in patients with long QT syndrome; only about 4-5% of cardiac events are fatal.

Patients at high risk (ie, those with aborted cardiac arrest or recurrent cardiac events despite beta-blocker therapy) have a markedly increased risk of sudden death. Treat these patients with an implantable cardioverter-defibrillator (ICD), which will lead to a good prognosis.

In a study of adolescent patients with clinically suspected long QT syndrome, Hobbs et al found that the timing and frequency of syncope, QTc prolongation, and sex were predictive of risk for aborted cardiac arrest and sudden cardiac death during adolescence. ^[7]  In another study, Ozawa et al found that KCNH2 mutation carriers present with late-onset but severe symptoms, and female LQT2 children have a greater risk of repeated torsade de pointes shortly after previous events, particularly after puberty. ^[8]

Neurologic deficits after aborted cardiac arrest may complicate the clinical course even after successful resuscitation.

JLN syndrome

A study by Goldberg et al found that patients with JLN syndrome experienced a high rate of cardiac and fatal events from early childhood despite medical therapy. The investigators studied the clinical course and risk stratification of 44 patients with JLN syndrome from the US portion of the International Long QT Syndrome Registry. ^[9] They compared these patients with 2174 patients who had the phenotypically determined dominant form of long QT syndrome, RWS.

Quality of life (QOL)

Children with long QT syndrome and their parents report lower QOL than normal children due to physical and psychosocial factors. ^[10]

The importance of educating the patient and his or her caregivers cannot be overstated. At least two family members (one of which should be the primary care giver) should enroll and master the basics of cardiopulmonary resuscitation (CPR).

Information regarding the drugs that should not be given in patients with long QT syndrome and the drugs that can prolong QT interval are available at the CredibleMeds site, which was created and maintained by the Arizona (AZ) Center for Education and Research on Therapeutics (CERT).

The Sudden Arrhythmia Death Syndromes Foundation (SADS) has support groups for families with long QT syndrome.