Jervell and Lange Nielsen Syndrome


Article Author:
Krishna Pabba


Article Editor:
Rebanta Chakraborty


Editors In Chief:
Allison Castro


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
3/14/2019 5:24:27 PM

Introduction

Jervell and Lange Nielsen syndrome (JLNS) is a rare autosomal recessive disorder characterized by bilateral sensorineural hearing loss and a prolonged QTc interval (more than 500 msec), which can lead to Torsades de pointes and sudden cardiac death. It is a form of an inherited long QT syndrome (LQTS). The disease was first described in 1957 by Anton Jervell and Fred Lange-Nielsen in a study of 4 children born with congenital deafness that all suffered from syncope. On electrocardiographic studies, there was a marked prolongation of the QT interval with no other identifiable cause for the patient’s fainting spells.[1]

Etiology

JLNS is a congenital disorder that is inherited in an autosomal recessive manner. Most cases are due to deletion mutations in the KCNQ1 (90%) and KCNE1 genes, which encode proteins essential in the functions of the potassium channels in the heart and cochlea.[2]

Epidemiology

The prevalence of the disorder highly depends on the population studied but overall it affects from 1 to 6 people per 1,000,000. Due to established genetic traits, Norway and Sweden both have an unusually high prevalence at 1 in 200,000.[2] There have been also been reports of increased incidence in Turkey.[2][3]

Pathophysiology

The cardiac action potential comprises a depolarization, a plateau/refractory and rapid repolarization phases. The repolarization phase is seen on the ECG as the QTc interval and is associated with an increase in potassium permeability, which moves potassium out of the cardiac cell. This repolarizing potassium current, the delayed outward rectifier current, has a rapidly activating component and a slowly activating component.[4] Mutations in the KCNQ1 and KCNE1 genes encode the alpha and beta subunits of the slowly activating components resulting in a slower movement of potassium outside the cell which prolongs the QTc interval.[2]

History and Physical

Classically, JLNS is suspected in a deaf child who experiences syncopal episodes that are often precipitated by emotion or exercise. Fifty percent of patients have a cardiac event by age three. Other pertinent clues are a history of iron deficiency anemia and elevated gastrin levels.[2] A physical exam is mostly unremarkable other than the deafness.

Evaluation

Once JLNS is suspected in a child who has congenital deafness and syncopal episodes, the next step is to evaluate the QTc interval to check if it is longer than 500 msec. Identifying the pathogenic variants in either the KCNQ1 or KCNE1 confirms the diagnosis. Testing for the genes can either be done as a single-gene test, a multigene panel, or comprehensive genomic testing.[2]

Once the diagnosis is established, the extent of the disease should be assessed. This includes a formal audiology evaluation, geneticist consultation, complete blood count to look for anemia, thorough family history, and exact calculation of the QTc interval.[2]

Treatment / Management

The first-line therapy in preventing syncope, cardiac arrest, and sudden death is a beta blockade. Propranolol and nadolol have been shown to be superior to metoprolol in preventing cardiac events, but the current consensus is that nadolol as the most preferred.[5] In patients with a history of cardiac arrest, an implantable cardioverter defibrillator (ICD) should be placed. Other indications for ICD placement is in patients who are deemed high risk. These include QTc interval greater than 550 msec, syncope before age 5, and a male older than 20 years with the KCNQ1 pathogenic variant.[6]

In symptomatic pediatric patients despite beta-blocker therapy, Fruh et al. from Norway endorse combined modality of atrial pacemaker and beta blocker for therapy.[7]

Hearing loss is usually treated successfully with cochlear implantation.[8]

Anesthesia for any surgical procedure has implications in a patient with JLNS. Any trigger to arrhythmia including sympathetic overdrive, hypo- or hyperthermia, hypovolemia, and hypercarbia should be carefully avoided. High airway pressure should be avoided. Beta blockers should be readily available along with equipment for immediate transcutaneous or transvenous pacing and defibrillation.

Differential Diagnosis

The other most common etiologies of long QT syndromes are Romano-Ward syndrome, Timothy syndrome, Andersen-Tawil syndrome, and acquired.

Romano-Ward syndrome (RWS) is an autosomal dominant syndrome that is characterized by a prolonged QTc interval in the absence of the congenital deafness. The mechanism of action is similar to JLNS in that it also affects the sodium and potassium channels. The diagnosis of RWS is made based on a prolonged QT interval on ECG, clinical presentation, and family history. The most common genes associated with the syndrome are KCNQ1, KCNH2, and SCN5A. Only the KCNQ1 and KCNE1 genes have been linked to both JLNS and RWS.[9]

Timothy syndrome is a rare autosomal disease characterized by multisystem involvement including QTc prolongation, functional 2:1 AV block with bradycardia, tachyarrhythmias, syndactyly, developmental delays, autism spectrum disorders, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy). The diagnosis is made by clinical features and a defective CACNA1C gene, which encodes a calcium channel. The average age of death in patients with this disease is 2.5 years.[10]

Andersen Tawil syndrome is also a rare autosomal dominant disorder characterized by a triad of episodic flaccid paralysis, prolonged QT interval/ventricular arrhythmias, and physical abnormalities including low-set ears, hypertelorism (widely spaced eyes), small jaw, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. The diagnosis is made by clinical characteristics and a pathogenic variant in the KCNJ2 gene.[11]

Acquired causes of QTc interval prolongation are most often caused by specific drugs, hypokalemia, and hypomagnesemia. Drug classes that are commonly implicated are antiarrhythmics, pro-motility, antimicrobial, and antipsychotics. Other causes include myocardial problems such as myopathies and ischemia and central nervous system injuries.[12]

Prognosis

Greater than half of untreated children with JLNS die before age 15.[2] Prognosis is highly dependent on which gene is mutated, gender, and baseline QTc. Mutations in the KCNE1 genes are associated with a more benign disease state. Lower risk individuals include females with a QTc less than 550 msec. Goldenberg et al. in their review of high-risk Long QT syndrome patients showed that Implanted cardioverter defibrillator protects against JNLS related mortality.[13] Starting beta-blocker therapy early in the disease state is associated with less cardiac events and improved mortality.[6]

Complications

Complications of untreated disease can lead to syncope, cardiac arrest, and sudden death.[2]

Deterrence and Patient Education

Jervell and Lange Nielsen Syndrome (JLNS) is a very rare inherited disorder affecting the heart’s electrical system and ears. Symptoms are often seen at an early age and include episodes of fainting spells associated with intense emotion and exercise and also hearing loss. The treatment of JLNS is aimed at fixing the hearing loss and preventing further episodes of unconsciousness called syncope or possibly cardiac arrest. The hearing loss is corrected by a medical device called a cochlear implant, which stimulates the nerve of the brain that recognizes sounds. A medication class called beta-blockers treat the cardiac abnormalities. These medications decrease the electrical stimulation to the heart and help to prevent further abnormal rhythms that can lead to unconsciousness. If the medications fail or if an individual falls into a high-risk category, a device called an implantable automatic cardioverter-defibrillator is usually placed. This device detects an abnormal rhythm and sends an electrical shock to the heart, preventing syncope. Regular follow-up with the patient’s pediatrician/primary care doctor and cardiologist are important in preventing complications. Genetic evaluation of the patient and the family members is recommended.

Pearls and Other Issues

Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive disorder that classically presents in a deaf child with recurrent syncopal episodes. It is a form of a long QT syndrome that is characterized by a QTc greater than  500 msec and bilateral sensorineural hearing loss. Cardiovascular complications are managed with beta blockade (preferably with nadolol) and ICD evaluation. Hearing loss is treated with cochlear implantation. Differential diagnoses of JLNS include Romano-Ward syndrome, Timothy syndrome, Andersen Tawil syndrome, and acquired causes such as electrolyte abnormalities and drugs.

Enhancing Healthcare Team Outcomes

JLNS is a disorder that is usually caught early in life and requires a multi-disciplinary approach in treating the patient. (Level V) This is usually started with the pediatrician who initially diagnoses the disease and coordinates the care between the multidisciplinary team, which includes:

  • Consult with electrophysiology in determining appropriate medical therapy, ICD appropriateness, and activity restrictions
  • Consult with audiology to assess the extent of hearing loss
  • Consult with the ear, nose, and throat physician for cochlear implantation
  • Consult with a geneticist to determine appropriate molecular genetic testing and evaluating family at risk

As morbidity and mortality are high in patients with this disease, regular assessment of patients cardiovascular needs will be important. This comprises beta-blocker dose adjustments and ICD placement evaluation. Once an ICD is placed, periodic evaluation of inappropriate shocks and lead complications are indicated.[2]


  • Image 7319 Not availableImage 7319 Not available
    Image courtesy S Bhimji MD
Attributed To: Image courtesy S Bhimji MD

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Jervell and Lange Nielsen Syndrome - Questions

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A 10-year-old boy presents with a 2-month history of fainting spells. The patient has had severe bilateral hearing loss since he was a small child but has functioned well with amplification. Which of the following studies would be the most critical for this patient?



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Which congenital heart disorder is associated with Jervell-Lange Nielsen syndrome?



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A 5-year-old female with congenital, bilateral sensorineural hearing loss presents for a routine evaluation by her pediatric provider. The patient’s mother states that whenever her daughter gets upset, she loses consciousness for a period of time. Which phase of the cardiac action potential does this disease affect?



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A 3-year-old boy presents to his pediatric provider for recurrent episodes of syncope while running. The patient is not on any medications, and his electrolytes are within normal limits. He is diagnosed with Jervell and Lange-Nielsen syndrome (JLNS). Which abnormality is seen in patients with JLNS that is not seen in Romano-Ward syndrome?



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What is the fundamental physiological abnormality behind the pathophysiology of Jervell and Lange-Nielsen syndrome?



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A 7-year-old girl is diagnosed with Jervell and Lange Nielsen syndrome based on an EKG after a presyncopal episode during a school event. What is the first choice medication that needs to be considered for treatment?



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Which of the following conditions is not associated with Jervell and Lange Nielsen syndrome?



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A 4-year-old male child was diagnosed with Jervell and Lange-Nielsen syndrome after three episodes of syncope. QTc has been persistently above 550 milliseconds. What is the management of this patient?



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Jervell and Lange Nielsen Syndrome - References

References

JERVELL A,LANGE-NIELSEN F, Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. American heart journal. 1957 Jul     [PubMed]
Tranebjærg L,Samson RA,Green GE, Jervell and Lange-Nielsen Syndrome null. 1993     [PubMed]
Shih HT, Anatomy of the action potential in the heart. Texas Heart Institute journal. 1994     [PubMed]
Ackerman MJ,Priori SG,Dubin AM,Kowey P,Linker NJ,Slotwiner D,Triedman J,Van Hare GF,Gold MR, Beta-blocker therapy for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia: Are all beta-blockers equivalent? Heart rhythm. 2017 Jan     [PubMed]
Schwartz PJ,Spazzolini C,Crotti L,Bathen J,Amlie JP,Timothy K,Shkolnikova M,Berul CI,Bitner-Glindzicz M,Toivonen L,Horie M,Schulze-Bahr E,Denjoy I, The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome. Circulation. 2006 Feb 14     [PubMed]
Green JD,Schuh MJ,Maddern BR,Haymond J,Helffrich RA, Cochlear implantation in Jervell and Lange-Nielsen syndrome. The Annals of otology, rhinology     [PubMed]
Alders M,Bikker H,Christiaans I, Long QT Syndrome null. 1993     [PubMed]
Napolitano C,Splawski I,Timothy KW,Bloise R,Priori SG, Timothy Syndrome null. 1993     [PubMed]
Nguyen HL,Pieper GH,Wilders R, Andersen-Tawil syndrome: clinical and molecular aspects. International journal of cardiology. 2013 Dec 5     [PubMed]
Kallergis EM,Goudis CA,Simantirakis EN,Kochiadakis GE,Vardas PE, Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review. TheScientificWorldJournal. 2012     [PubMed]
Uysal F,Turkgenc B,Toksoy G,Bostan OM,Evke E,Uyguner O,Yakicier C,Kayserili H,Cil E,Temel SG, "Homozygous, and compound heterozygous mutation in 3 Turkish family with Jervell and Lange-Nielsen syndrome: case reports". BMC medical genetics. 2017 Oct 16     [PubMed]
Früh A,Siem G,Holmström H,Døhlen G,Haugaa KH, The Jervell and Lange-Nielsen syndrome; atrial pacing combined with ß-blocker therapy, a favorable approach in young high-risk patients with long QT syndrome? Heart rhythm. 2016 Nov     [PubMed]
Goldenberg I,Moss AJ,Zareba W,McNitt S,Robinson JL,Qi M,Towbin JA,Ackerman MJ,Murphy L, Clinical course and risk stratification of patients affected with the Jervell and Lange-Nielsen syndrome. Journal of cardiovascular electrophysiology. 2006 Nov     [PubMed]

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