JERVELL AND LANGE-NIELSEN SYNDROME

JERVELL AND LANGE-NIELSEN SYNDROME
Issa Hejazi MD*, Awni Madani MD*, Fakhri Hakim MD*
ABSTRACT
This study reports two consanguineous sisters with congenital sensorineural hearing loss and prolonged QT
interval on electrocardiogram, and syncope in one of them. An older sibling, apparently also deaf, had previously
died suddenly. These are the hallmarks of Jervell and Lange-Nielsen Syndrome as described in 1957. The study
also contains a select summary of literature about this syndrome, and outlines various treatment options.
Introduction
The congenital long QT syndrome (LQTS) is a
disease characterized by prolongation of ventricular
repolarization, abnormal QT interval prolongation,
rate corrected QT interval (QTc) > 64msec (the range
of values in a normal population is about 350 to 460);
and it may present with syncope, ventricular
arrhythmias, or sudden death in most of the
symptomatic and untreated patients. (1-3) The QTc,
corrected for heart rate, is calculated by dividing the
measured QT by the square root of the RR interval,
both of which are measured in seconds (Bazzet
formula). Jervell and Lange-Nielsen first described it
in 1957 in four children within one family with
deafness, syncope and prolonged corrected QT
interval (QTc). Three of these children died
suddenly. (3)
It is known to be associated with mutation of the
gene KvLQT1 (a gene which encodes a voltage-gated
potassium channel) and the underlying molecular
abnormality leads to cardiac and cochlear dysfunction
through a potassium channel defect (Table I). (4,5) We
report here two sisters with the syndrome; one
presented with syncope attacks and the other is
asymptomatic.
JRMS February 2010; 17(Supp 1): 26-29
Case Report
A three year old, the girl result of consanguineous
healthy parents, known to have congenital deafness
was referred to cardiac clinic at Queen Alia Heart
Institute, after having two syncope attacks. Family
history disclosed a sudden death of one brother at the
age of two years. Audiogram had confirmed a
profound bilateral sensorineural hearing loss.
Cardiac evaluation was performed and a 12-leads
electrocardiogram (ECG) disclosed a significant
prolongation of corrected QT interval (QTc) of
556msec and a structurally normal heart by twodimensional
echocardiography. Family screening of
parents and other sibling have resulted in the
diagnosis of long QTc of 550msec in her 10 years old
deaf sister, and audiogram confirmed a profound
bilateral sensorineural deafness. In view of theses
findings the two sisters have been labeled to have
Jervell and Lange-Nielsen syndrome (JLNS) and
syncope was brought under control by daily
propranolol, while her sister was given propranolol for
prophylaxis.
Discussion
In 1957, Jervell and Lange-Nielsen reported a
*From the Department Pediatric Cardiology, Queen Alia Heart Institute, King Hussein Medical Center, KHMC, Amman-Jordan
Correspondence should be addressed to Dr. I. Hejazii, Queen Alia Heart Institute, KHMC, Amman-Jordan
Manuscript received June 6, 2004. Accepted April 26, 2007
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Table I. Shows the genetic background of inherited forms of LQTS
LQTS type Chromosomal locus Mutated gene Ion current affected
JLN1 11p15.5 KVLQT1 (KCNQ1) (homozygote) Potassium current (IKs)
JLN2 21q22.1-22.2 KCNE1 (homozygote) Potassium current (IKs)
syndrome of congenital sensory deafness associated
with a prolonged QT interval in four children of a
Norwegian family. (1) The affected children had
multiple syncopal episodes, and three died suddenly at
the age of four, five and nine years. Since 1957, other
examples of the long-QT syndrome associated with
deafness (the Jervell and Lange-Nielsen syndrome)
have been described. (6-8) In all cases, the apparent
mode of inheritance was autosomal recessive.
This syndrome is rare (estimated incidence, 106-66
cases per million. (6) Affected persons are susceptible
to recurrent syncope, and they have a high incidence
of sudden death and short life expectancy. Syncope
results from torsade de pointes ventricular tachycardia
and ventricular fibrillation. (9,10)
Based on genetic backgrounds, two types of JLN
syndrome are identified, as shown in Table I.
Homozygous KVLQT1 and KCNE1 mutations are
associated with congenital deafness (JLN syndrome)
and account for less than 1% of cases of LQTA. The
occurrence of syncopal episodes in one deaf sister as
well as the history of unexplained sudden death in one
sibling (in view of apparently healthy parents) brought
the suspicion of JLNS in this unfortunate family.
Several K + currents are responsible for the
repolarization that terminates the plateau phase of the
cardiac action potential. Among them, the very
slowly activating delayed rectifier K + current, IKs, is
important in tuning the adaptation of the action
potential duration to the heart rate. (11) The same IKs
current is also essential in maintaining the endolymph
K+ homeostasis in the inner ear. (11,12)
The Romano-Ward syndrome is an autosomal
dominant form of the long-QT syndrome and is not
associated with deafness or other phenotypic
abnormalities. (13,14) The incidence of the Romano-
Ward syndrome is higher than that of the JLNS, but
affected persons generally have milder
symptoms. (15,16)
The classic presentation of JLNS is a deaf child who
experiences syncopal episodes during periods of
stress, exercise, or fright (syncope in LQTS is
believed to be secondary to polymorphic ventricular
tachycardia-torsades de pointes). Some of these
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patients may be misdiagnosed with epilepsy and
incorrectly treated with antiepileptic drugs before the
correct diagnosis of JLNS is established. (3) Al-Rakaf
et al. reported a family with two of its members
having JLNS from Saudi Arabia, with one of them
succumbing after a history of syncopal attack. (17) In
our cases, if a wrong diagnosis of epilepsy had been
made the chance of avoiding sudden death may have
been missed.
In 10 studies that screened 6,557 deaf children, the
average prevalence of JLNS was 0.21% with a range
of 0-0.43%. (18) To survey the prevalence of the long
QT syndrome (LQTS), especially JJLNS in Turkey,
Kusmuoglu et al. have studied 154 deaf mute school
children, where only the EKG of two patients had
showed a QT interval of 0.52 and were diagnosed of
JLNS while , Tuncer et al. could identify 5 out of 132
deaf mute children to have JLNS. (19,20)
In spite of, the rare prevalence of JLNS among
congenital deaf children it remains important because
if it’s potential association with sudden death in theses
children. In our reported family the undiagnosed
sudden death of the brother at the age of two years
may have been preventable, should he had been
investigated for this syndrome. In this regard, Atilla
et al. suggested that assessment of ventricular
repolarization parameters in deaf children because
children with congenital hearing loss cannot
accurately describe the symptoms of syncope. (21) The
QT interval on the ECG, measured from the beginning
of the QRS complex to the end of the T wave,
represents the duration of activation and recovery of
the ventricular myocardium (repolarization).
Prolonged repolarization in people with LQTS
predisposes to torsade de pointes (i.e. polymorphic
ventricular tachycardia), which may lead to
ventricular fibrillation and sudden cardiac death.
Heterogeneity of repolarization throughout the
myocardium is an underlying substrate for this
arrhythmia, which frequently is triggered by a
premature ventricular beat, causing irregularity of the
heart rate in a short-long-short sequence (i.e. short
coupling interval of premature beat, subsequent long
compensatory pause, and another short coupling
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interval of premature beat initiating episode of torsade
de pointes). Torsade de pointes in patients with LQTS
are very likely to self-terminate, which explains the
relatively low overall lethality (risk of dying) of
cardiac event. Arrhythmic response in patients with
LQTS can be precipitated by a variety of adrenergic
stimuli, including exercise, emotion, loud noise, and
swimming, but it also may occur without such
preceding conditions. (22)
Medical treatment includes the administration of βblockers
(propranolol). The protective effect of βblock
is related to their adrenergic blockade
diminishing the risk of cardiac arrhythmias in 70% of
cases. Implantation of cardioverter-defibrillators
appears to be the most effective therapy for high-risk
patients, defined as those with aborted cardiac arrest
or recurrent cardiac events despite conventional
therapy (i.e. β-blockers). Moreover implantation of
cardiac pacemakers (with ventricular or dual chamber
pacing) has been considered a helpful therapeutic
strategy based on the premise that pacing eliminates
arrhythmogenic bradycardia, decreases hear rate
irregularities (eliminating short-long-short series), and
decreases repolarization heterogeneity, therefore
diminishing the risk of torsade de points ventricular
tachycardia. However, recent data indicate that
cardiac events continue to occur in high-risk patients
with cardiac pacing. Because newer models of
implantable cardioverter-defibrillators have a cardiacpacing
function included, cardiac pacing (without
defibrillators) is likely to be used less often in patients
with LQTS. (3,22-24)
Conclusion
The purpose of this report is to draw the attention of
our colleagues to the principal elements of JLNS, as
this will allow identifying this silent killer. There is a
strong case for including a 12 lead ECG as part of the
investigative work up of all children with syncope
which is not clearly a seizure especially if he/she is
deaf.
Reference
1. Jervell A, Lang-Nielsen F. Congenital deaf
mutism, functional heart disease with prolongation of
Q-T interval and sudden death. Am Heart J 1957; 54:
59-78.
28
2. Roden D, Lazzara R, Rosen M, et al. Multiple
mechanisms in the long-QT syndrome. Circulation
1996; 94: 1996-2012.
3. Vincent G. The long QT sundrom. Indian Pacing
Electrophysiol J 2002; 2(4): 127
4. Lee MP, Ravenel JD, Hu RJ, et al. Targeted
disruption of the Kvlqt1 gene causes deafness and
gastric hyperplasis in mice. J Clin Invest 2000; 12:
1447-1455.
5. Schmitt N, Schwarz M, Peretz A, et al. A recessive
C-terminal Jervell and Lange-Nielsen mutation of the
KCNQ1 channel impairs subunit assembly. EMBO J
2000; 19:332-340.
6. Fraser GR, Froggatt P, James TN. Congenital
deafness associated with electrocardiographic
abnormalities, fainting attacks and sudden death: a
recessive syndrome. Q J Med 1964; 33: 361-385.
7. Jervell A, Thingstad R, Endsjo TO. The surdocardiac
syndrome: three new cases of congenital
deafness with syncopa; attacks and QT prolongation
in the electrocardiogram. Am Heart J 1966; 72: 582-
593.
8. Tesson F, Donger C, Denhoy I, et al. Exclusion of
KCNE1 (IsK) as a candidate genefor JLNS. J Mol
Cell Cardol 1996; 28: 2051-2055.
9. Till JA, Shinebourne EA, Pepper J, et al.
Complete denervation of the heart in a child with
congenital long QT and deafness, Am J Cariol
1988; 62: 1319-1321.
10. Holland JJ. Cardiac arrest under anesthesia in a
child with previously undiagnosed JLNS. Anesthesia
1993; 48: 149-151.
11. Romey G, et al. Molecular mechanism and
functional significance of the mink control of the
KVLQT1 channel activity. J Biol Chem 1997; 272:
16713-16716.
12. Vetter D, et al. Inner ear defects induced by null
mutation of the Isk gene. Neuron 1996; 17: 1251-
1264
13. Romano C, Gemme G, Pongiglione R. Artimie
ecardiache rare delleta pediatric. Accessi sincopali
per fibrillazion ventricolare parossitica. Clin Pediate
1963; 45-656-683.
14. Ward OC. A new familial cardiac syndrome in
children. J Ir Med Assoc 1964; 54: 103-106.
15. Moss AJ, Schwartz PJ, Crampton RS, et al. The
long QT syndrome: a prospective international study.
Circulation 1985; 71: 13-21.
16. Moss AJ, Schwartz PJ, Crampton RS, et al. The
QT syndrome: prospective longitudinal study of 328
families. Circulation 1991; 84: 1136-114.
17. Al-RAkaf M, Zakzoyuk S, Al-Shahwa NS. Jervell
and Lange-Nielsen QT syndrome: a case report from
JOURNAL OF THE ROYAL MEDICAL SERVICES
Vol. 17 Supp No. 1 February 2010

Suadi Arabis. Int J Pediatr Otorhinolaryngol 1997;
6: 39(2): 163-168.
18. Schwartz PJ, Periti M, Malliani A. The long QT
syndrome. Am Heart J 1975; 89: 378-390.
19. Komusuoglo B, Goldeli O, Kulan K, et al. Jervell
and Lange-Nielsen syndrome. Int J Cardiol 1994;
47(2): 189-192.
20. Tuncer C, et al. Assessment of ventriclar
repolarization in deaf mute children. Pediatr Cardiol
2000; 21(2): 135-140.
21. Atilla I, Cemal T, Sezer S, et al. Jervell and Lange-
JOURNAL OF THE ROYAL MEDICAL SERVICES
Vol. 17 Supp No. 1 February 2010
Nielsen syndrome: neurological and cardiolofic
evelaution. Pediatric Neurology 1999; 21(5): 809-
813.
22. Wojciech Z, et al. Long QT syndrome. Electronic
Medicine Journal 2002.
23. Wehrens X, Vos M, Doevendans P, Wellens H.
Novel insight in the congenital LQTS. Annals pf
Internal Medicine 2002; 12: 981-992.
24. Moss A, Zareba W, Hall w, et al. Effectiveness
and limitation of β-blocker therapy in congenital
LQTS. Circulation 2000; 101: 616
29