Pediatric Long QT Syndrome

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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.)

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

The frequency of long QT syndrome is unknown (possibly about 1 per 5000 population). 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.

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)

Type of Long QT Syndrome

Chromosomal Locus

Mutated Gene

Ion Current Affected

LQT1

11p15.5

KVLQT1or KCNQ1 (heterozygotes)

Potassium (IKs)

LQT2

7q35-36

HERG, KCNH2

Potassium (IKr)

LQT3

3p21-24

SCN5A

Sodium (INa)

LQT4

4q25-27

ANK2, ANKB

Sodium, potassium and calcium

LQT5

21q22.1-22.2

KCNE1 (heterozygotes)

Potassium (IKs)

LQT6

21q22.1-22.2

MiRP1, KNCE2

Potassium (IKr)

LQT7 (Andersen syndrome)

17q23

KCNJ2

Potassium (IK1)

LQT8 (Timothy syndrome)

12q13.3

CACNA1C

Calcium (ICa-Lalpha)

JLN1

11p15.5

KVLQT1or KCNQ1 (homozygotes)

Potassium (IKs)

JLN2

21q22.1-22.2

KCNE1 (homozygotes)

Potassium (IKs)

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 (Ikr). 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 [3] :

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. [4]

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

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. [5] They compared these patients with 2174 patients who had the phenotypically determined dominant form of long QT syndrome, RWS.

The importance of educating the patient and his or her caregivers cannot be overstated. At least 2 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 Arizona Center for Education and Research on Therapeutics Web site under Drugs that Prolong the QT Interval and/or Induce Torsades de Pointes Ventricular Arrhythmia.

The Sudden Arrhythmia Death Syndromes Foundation (SADS) and Cardiac Arrhythmias Research and Education Foundation (CARE) have support groups for families with long QT syndrome.

Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007 May 22. 115(20):2613-20. [Medline].

Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation. 1993 Aug. 88(2):782-4. [Medline].

Gupta A, Lawrence AT, Krishnan K, Kavinsky CJ, Trohman RG. Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes. Am Heart J. 2007 Jun. 153(6):891-9. [Medline].

Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006 Sep 13. 296(10):1249-54. [Medline].

Goldenberg I, Moss AJ, Zareba W, et al. Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome. J Cardiovasc Electrophysiol. 2006 Nov. 17(11):1161-8. [Medline].

Albertella L, Crawford J, Skinner JR. Presentation and outcome of water-related events in children with long QT syndrome. Arch Dis Child. 2011 Aug. 96(8):704-7. [Medline].

Hintsa T, Keltikangas-Jarvinen L, Puttonen S, et al. Depressive symptoms in the congenital long QT syndrome. Ann Med. 2009 Jun 23. 1-6. [Medline].

Vyas H, Ackerman MJ. Epinephrine QT stress testing in congenital long QT syndrome. J Electrocardiol. 2006 Oct. 39(4 Suppl):S107-13. [Medline].

Monnig G, Eckardt L, Wedekind H, et al. Electrocardiographic risk stratification in families with congenital long QT syndrome. Eur Heart J. 2006 Sep. 27(17):2074-80. [Medline].

Cuneo BF, Strasburger JF, Yu S, Horigome H, Hosono T, Kandori A. In utero diagnosis of long QT syndrome by magnetocardiography. Circulation. 2013 Nov 12. 128(20):2183-91. [Medline].

Mitchell JL, Cuneo BF, Etheridge SP, Horigome H, Weng HY, Benson DW. Fetal heart rate predictors of long QT syndrome. Circulation. 2012 Dec 4. 126(23):2688-95. [Medline].

Moss AJ, Shimizu W, Wilde AA, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007 May 15. 115(19):2481-9. [Medline].

Arnestad M, Crotti L, Rognum TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation. 2007 Jan 23. 115(3):361-7. [Medline].

Tester DJ, Ackerman MJ. Postmortem long QT syndrome genetic testing for sudden unexplained death in the young. J Am Coll Cardiol. 2007 Jan 16. 49(2):240-6. [Medline].

[Guideline] Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices) developed in collaboration with the American Association for Thoracic Surgery and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008 May 27. 51(21):e1-62. [Medline]. [Full Text].

Bar-Cohen Y, Silka MJ. Congenital Long QT Syndrome: Diagnosis and Management in Pediatric Patients. Curr Treat Options Cardiovasc Med. 2006 Sep. 8(5):387-395. [Medline].

Vohra J. The Long QT Syndrome. Heart Lung Circ. 2007. 16 Suppl 3:S5-12. [Medline].

Hamang A, Solberg B, Bjorvatn C, Greve G, Oyen N. [Genetic counseling in congenital long QT syndrome]. Tidsskr Nor Laegeforen. 2009 Jun 11. 129(12):1226-9. [Medline].

Johnson JN, Ackerman MJ. Return to play? Athletes with congenital long QT syndrome. Br J Sports Med. 2013 Jan. 47(1):28-33. [Medline].

Maron BJ, Chaitman BR, Ackerman MJ, et al. Recommendations for physical activity and recreational sports participation for young patients with genetic cardiovascular diseases. Circulation. 2004 Jun 8. 109(22):2807-16. [Medline].

Chockalingam P, Crotti L, Girardengo G, Johnson JN, Harris KM, van der Heijden JF. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol. 2012 Nov 13. 60(20):2092-9. [Medline].

Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol. 2007 Mar 13. 49(10):1092-8. [Medline]. [Full Text].

Barsheshet A, Moss AJ, McNitt S, Polonsky S, Lopes CM, Zareba W. Risk of syncope in family members who are genotype-negative for a family-associated long-QT syndrome mutation. Circ Cardiovasc Genet. 2011 Oct. 4(5):491-9. [Medline].

Hofman N, Wilde AA, Tan HL. Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system?. Eur Heart J. 2007 Jun. 28(11):1399. [Medline].

Type of Long QT Syndrome

Chromosomal Locus

Mutated Gene

Ion Current Affected

LQT1

11p15.5

KVLQT1or KCNQ1 (heterozygotes)

Potassium (IKs)

LQT2

7q35-36

HERG, KCNH2

Potassium (IKr)

LQT3

3p21-24

SCN5A

Sodium (INa)

LQT4

4q25-27

ANK2, ANKB

Sodium, potassium and calcium

LQT5

21q22.1-22.2

KCNE1 (heterozygotes)

Potassium (IKs)

LQT6

21q22.1-22.2

MiRP1, KNCE2

Potassium (IKr)

LQT7 (Andersen syndrome)

17q23

KCNJ2

Potassium (IK1)

LQT8 (Timothy syndrome)

12q13.3

CACNA1C

Calcium (ICa-Lalpha)

JLN1

11p15.5

KVLQT1or KCNQ1 (homozygotes)

Potassium (IKs)

JLN2

21q22.1-22.2

KCNE1 (homozygotes)

Potassium (IKs)

Group

Prolonged QTc (s)

Borderline QTc (s)

Reference Range (s)

Children and adolescents (< 15 y)

>0.46

0.44-0.46

< 0.44

Men

>0.45

0.43-0.45

< 0.43

Women

>0.46

0.45-0.46

< 0.45

Sreekanth S Raghavan, MBBS, , FACC Consulting Pediatric Cardiologist, Head and Director of Pediatric Cardiac Services, Manipal Heart Institute, India

Sreekanth S Raghavan, MBBS, , FACC is a member of the following medical societies: American College of Cardiology, American Society of Echocardiography, Pediatric Cardiac Society of India

Disclosure: Nothing to disclose.

Stuart Berger, MD Executive Director of The Heart Center, Interim Division Chief of Pediatric Cardiology, Lurie Childrens Hospital; Professor, Department of Pediatrics, Northwestern University, The Feinberg School of Medicine

Stuart Berger, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American College of Chest Physicians, American Heart Association, Society for Cardiovascular Angiography and Interventions

Disclosure: Nothing to disclose.

John W Moore, MD, MPH Professor of Clinical Pediatrics, Section of Pediatric Cardiology, Department of Pediatrics, University of California San Diego School of Medicine; Director of Cardiology, Rady Children’s Hospital

John W Moore, MD, MPH is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, and Society for Cardiac Angiography and Interventions

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Pediatric Long QT Syndrome

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