Clinical Diagnosis

The diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) is definitively established in individuals with all of the following:

• Congenital sensorineural deafness

• Long QT interval, often manifest as syncope, most often elicited by emotion or exercise

• Presence of two disease-causing mutations in either KCNQ1 or KCNE1 [Priori et al 1999]

Hearing loss. All individuals with molecularly confirmed JLNS have profound congenital sensorineural deafness (see Deafness and Hereditary Hearing Loss Overview.)

Long QTc. Based on existing diagnostic criteria, all individuals with JLNS have a QTc interval greater than 500 msec (average 550 msec), indicating increased time for ventricular depolarization and repolarization [Tyson et al 2000]. Generally, the upper limit of normal for the QTc is 440 msec for males and 460 msec for post-pubertal females [Allan et al 2001, Priori et al 1999].

Note: (1) In the "pre-molecular" era, diagnosis of JLNS relied upon clinical criteria alone, and thus it is not currently known how many children with molecularly confirmed JLNS have a borderline QTc interval prolongation of 440 msec to 500 msec or how many children with molecularly confirmed JLNS have a QTc that falls within the "normal" range. This issue will be resolved as data on more affected individuals are gathered. A recent review [Schwartz et al 2006] gives a comprehensive summary of the natural history, molecular basis, and clinical characteristics of 186 affected individuals from 135 families, in whom mutations were identified in 63 (47%). (2) Hearing loss commonly occurs in the setting of familial long QT syndrome (LQTS) (see Romano-Ward Syndrome). In this situation, the hearing loss may be entirely unrelated to the etiology of the LQTS, particularly if the hearing loss is moderate.

Molecular Genetic Testing

Genes. JLNS is caused by mutations in one of two genes: KCNQ1 and KCNE1 [Chen et al 1999, Duggal et al 1998, Neyroud et al 1997, Splawski et al 1997].

• KCNQ1 (sometimes called JLN1) mutations account for more than 90% of individuals with JLNS. In a study of ten families, nine had mutations in KCNQ1 [Tyson et al 2000]. In a second study of 63 families, 57 (90.5%) had mutations in KCNQ1 [Schwartz et al 2006]. In a Norwegian study 12 out of 13 unrelated JLNS patients had four different Norwegian founder mutations [Berge et al 2008].

• KCNE1 (sometimes called JLN2) mutations account for fewer than 10% of individuals with JLNS. Of 63 families, six (9.5%) had mutations in KCNE1 [Schwartz et al 2006]. None of the Norwegian patients with JLNS have been shown to have KCNE1 mutations [Berge et al 2008, Siem et al 2008, Tranebjaerg et al 1999].

Clinical testing

• Sequence analysis/mutation scanning. Mutations have been found in either KCNQ1 or KCNE1 in 94% of individuals with clinical JLNS undergoing molecular testing [Schwartz et al 2006]. The mutations may be located in all coding exons. Current experience indicates that 33% are compound heterozygotes [Schwartz et al 2006].

• Deletion/duplication analysis. Both deletion and duplication of exon(s) of KCNQ1 are known to cause long QT syndrome [Eddy et al 2008].

Table 1. Summary of Molecular Genetic Testing Used in Jervell and Lange-Nielsen Syndrome

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Gene Symbol / Locus	Proportion of JLNS Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and by Test Method 1	Test Availability
KCNQ1	90%	Deletion / duplication analysis 2	Partial- or complete-gene deletion	Unknown	Clinical
		Sequence analysis / mutation scanning	Sequence variants 3	94% 4
KCNE1	10%	Sequence analysis / mutation scanning	Sequence variants 3		Clinical
		Deletion / duplication analysis 2	Partial- or complete-gene deletion	Unknown

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Schwartz et al [2006]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Test KCNQ1, as mutations in this gene account for the majority of JLNS. In countries with founder mutations, like Norway, particular mutations should be tested first [Tranebjaerg et al 1999, Tranebjaerg 2004, Berge et al 2008, Siem et al 2008].

2.

If no KCNQ1 mutation is identified, test KCNE1.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

Heterozygosity for mutations in KCNQ1 and KCNE1 has been observed in children without hearing loss who have long QT syndrome (LQTS) inherited in an autosomal dominant manner [Towbin et al 2001] (also called Romano-Ward syndrome) (see Differential Diagnosis).

Natural History

Homozygotes. Deafness is congenital, bilateral, profound, and sensorineural in all individuals with molecularly confirmed Jervell and Lange-Nielsen syndrome (JLNS) (see Deafness and Hereditary Hearing Loss Overview).

Abnormal cardiac depolarization and repolarization may result in prolongation of the QT interval and tachyarrhythmias (including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation), which may culminate in syncope or sudden death. The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright.

In the Schwartz et al [2006] study of 135 families with JLNS, the QTc was markedly prolonged (557±65 msec); 50% of individuals had cardiac events before age three years, with emotions and exercise being the primary triggers. Note, however, that selection bias for severely affected individuals cannot be excluded: individuals have been described with putative JLNS without any clinical manifestations other than deafness until adulthood, and to age 50 years in one case.

QTc prolongation in JLNS, particularly when severe, appears to be associated with increased risk of death in infancy (SIDS). Although more than half of untreated children with JLNS die prior to age 15 years, some individuals are reported to have survived several syncopal episodes during adulthood.

The sex ratio among individuals with JLNS is even, but females are at lower risk for cardiac arrest/sudden death [Schwartz et al 2006].

Physical examination is unremarkable except for deafness.

Heterozygotes. Heterozygotes usually have normal hearing. In some individuals who are heterozygous for mutations associated with JLNS, QTc prolongation, fainting, and sudden death never occur. In contrast, some individuals heterozygous for mutations associated with JLNS may have QTc prolongation associated with fainting and death heritable in a dominant manner. This form of LQTS is called Romano-Ward syndrome (RWS). RWS can also be caused by mutations in several genes that do not cause deafness/JLNS in a homozygous form (see Differential Diagnosis.) These mutations may be associated with highly variable QTc intervals, from normal to markedly abnormal.

Histopathology of temporal bone. Histologic examination of a few temporal bones was performed prior to the availability of molecular genetic testing, but not since. In a mouse model with knock-out for the Kcnq1 gene (which can be considered an animal model for JLNS in humans), atrophy of the stria vascularis and collapse of the endolymphatic compartments and surrounding membranes are marked. Complete degeneration of the organ of Corti and associated degeneration of the spiral ganglion were found [Rivas & Francis 2005].

Genotype-Phenotype Correlations

Data to establish better predictors for a correlation between genotype and phenotype were provided from a large number of individuals with molecularly confirmed JLNS. Among 63 individuals who were genotyped, 33% were compound heterozygotes [Schwartz et al 2006]. No clinical difference was evident between persons with at least one complex mutation (insertion/deletion, splice mutation, truncation) and those with missense mutations.

Among six asymptomatic individuals in the study of Schwartz et al [2006], two had KCNQ1 mutations and four had KCNE1 mutations, further confirming the milder presentation of JLNS associated with KCNE1 mutations compared to JLNS associated with KCNQ1 mutations.

Nomenclature

Lange-Nielsen syndrome has also been called cardioauditory syndrome of Jervell and Lange-Nielsen and surdo cardiac syndrome.

JLNS is now appreciated to be a true syndrome with both the cardiac and the cochlear pathologies attributable to a common molecular etiology. Although there are several case reports in the older literature of individuals with long QT syndrome and non-profound hearing loss, in many of these reports it is likely that the hearing loss and prolonged QT interval have different etiologies (see Differential Diagnosis).

Prevalence

Prevalence varies depending on the population studied:

• Norway has an unusually high prevalence of at least one in 200,000 [Tranebjaerg et al 1999]. This prevalence stems from four Norwegian founder mutations [Berge et al 2008, Siem et al 2008]

• The syndrome is more common in cultures in which consanguineous marriage is common.

• In a study of 350 children with congenital deafness in Turkey, one in 175 had JLNS [Ocal et al 1997].

• A particular missense KCNQ1 mutation has been identified in the heterozygous state in autosomal dominant LQTS and in the homozygous state in JLNS in a few individuals from Finland; however, no clustering of JLNS was observed in Finland, in contrast to that observed in several other rare autosomal recessive disorders [Piippo et al 2001].

• An overview of worldwide occurrence was published by Tranebjaerg [2004].

These data are the best available; however, diagnostic criteria using a QTc greater than 440 msec in children are likely to include some false positives, perhaps as many as 15%-20% [Allan et al 2001]. The design of the recent review by Schwartz et al [2006] did not allow refinement of prevalence estimates.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Jervell and Lange-Nielsen syndrome (JLNS), the following evaluations are recommended:

• Formal audiologic evaluation for extent of hearing loss

• Cardiac examination including calculation of QTc

• A three-generation thorough family history on cardiac disease, syncope, and hearing

Treatment of Manifestations

Hearing loss in JLNS may be treated successfully with cochlear implantation (CI), an intervention that does not interfere with bipolar pacemakers [Green et al 2000, Chorbachi et al 2002] (see Deafness and Hereditary Hearing Loss Overview). To date, the cumulative published experience is about 15 individuals with JLNS.

Of note, the diagnosis of JLNS was only verified with molecular genetic testing in four Norwegian patients, all of whom had mutations in KCNQ1.

Note: Although cochlear implantation seems safe, special precautions are necessary during anesthesia because of the increased risk of cardiac arrhythmia [Daneshi et al 2008, Siem et al 2008, Yanmei et al 2008].

The main goal in management of JLNS is prevention of syncope, cardiac arrest, and sudden death. Note that efficacy of beta-blocker treatment is only partial: 51% of treated individuals had cardiac events and 27% had cardiac arrest or sudden death. Even with additional therapies (e.g., pacemaker, implantable cardioverter/defibrillator, left sympathetic denervation), 18 of 32 (56%) individuals experienced additional symptoms, including sudden death in seven [Schwartz et al 2006].

• Administration of beta-adrenergic blockers has been the traditional first-line medical therapy for cardiac events, but more aggressive immediate treatment may be appropriate. In contrast to Romano-Ward syndrome (RWS), cardiac events in JLNS frequently occur despite beta blockade [Schwartz et al 2006]. Goldenberg et al [2006] demonstrated markedly increased mortality in individuals with JLNS treated exclusively with beta blockers in comparison with individuals with RWS. A mortality rate of 35% over five years was observed for individuals receiving beta blockers exclusively; 86% of individuals treated exclusively with beta blockers experienced a cardiac event. The interactions of beta blockers with other medical conditions (e.g., asthma, diabetes mellitus, depression) should also be considered.

• Implantable cardioverter defibrillators (ICDs) should be considered in individuals with a history of cardiac arrest or failure to respond to other treatments [Goel et al 2004]. More recent recommendations have strongly urged ICD placement for high-risk individuals, defined by the following criteria [Schwartz et al 2006]:

  • QTc interval >550 msec

  • Syncope before age five years

  • Male gender, older than age 20 years with KCNQ1 mutation

Sudden cardiac death appears to be low in individuals younger than age five years, but medical therapy should be administered early on in these high-risk individuals and ICD placement should be considered after age five years [Richter & Brugada 2006].

• In certain cases, the availability of automated external defibrillators in the home, workplace, or school may be applicable, as is appropriate CPR training of family members and those who have regular contact with individuals with JLNS.

• Left cardiac sympathetic denervation has been used with effect for some patients.

Prevention of Primary Manifestations

See Treatment of Manifestations regarding prevention of syncope, cardiac arrest, and sudden death.

Prevention of Secondary Complications

Special precautions during anesthesia are necessary because of the increased risk of cardiac arrhythmia [Daneshi et al 2008, Siem et al 2008, Yanmei et al 2008].

Agents/Circumstances to Avoid

The following should be avoided:

• Drugs that cause further prolongation of the QT interval or provoke torsade de pointes; see www.azcert.org for a complete and updated list.

• Triggers for intense or sudden emotion; activities that are known to precipitate syncopal events in individuals with long QT syndrome, including:

  • Competitive sports

  • Amusement park rides

  • Scary movies

  • Jumping into cold water

A cardiologist should make recommendations for activity restrictions based on the effectiveness of medical intervention.

Evaluation of Relatives at Risk

Standard newborn screening programs are sufficient to identify hearing loss in children with JLNS.

Because of the relationship between JLNS and Romano-Ward syndrome, electrocardiogram should be considered for relatives at risk for JLNS even if they have normal hearing.

If the JLNS disease-causing mutations in an affected family member are known, molecular genetic testing of a relative with congenital profound sensorineural hearing loss is recommended to confirm the diagnosis of JLNS.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Family members of individuals with JLNS should be trained in cardiopulmonary resuscitation (CPR) since up to 95% of individuals with JLNS have a cardiac event before adulthood [Schwartz et al 2006].

Affected individuals should wear an ID bracelet explaining their diagnosis.

It is appropriate to notify local Emergency Medical Services (EMS) of high-risk persons such as those with JLNS [Hazinski et al 2004].

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Jervell and Lange-Nielsen syndrome (JLNS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• Parents of a child with JLNS are usually obligate heterozygotes. In rare cases, only one parent is a carrier and the other mutation is de novo [Schwartz et al 2000].

• Parents may or may not have the LQTS phenotype. Studies have documented autosomal dominant inheritance of moderately prolonged QTc intervals in some, but not all, families in which one or more sibs have JLNS [Splawski et al 1997].

• Recommendations for evaluation of the parents of a child with JLNS include comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS.

Sibs of a proband

• At conception, each sib of an individual with JLNS usually has a 25% chance of being affected with JLNS, a 50% chance of being heterozygous for a JLNS-associated mutation and at risk for LQTS, and a 25% chance of being unaffected and not a carrier. Thus, at conception, each sib of a proband with JLNS has a 3/4 chance of having either JLNS or LQTS.

• Sibs with normal hearing have a 2/3 risk of being carriers of a mutation causing JLNS and being at risk for LQTS.

• Sibs of a proband who has a de novo mutation are not at increased risk for JLNS but are at 50% risk for LQTS.

• Recommendations for evaluation of sibs of a proband with JLNS include: audiologic evaluation, electrophysiologic evaluation for evidence of LQTS, molecular genetic testing if the disease-causing mutations in the proband are known, and comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS.

Offspring of a proband

• The offspring of an individual with JLNS inherit one abnormal allele; thus, 100% of the proband's offspring are at risk for LQTS.

• In the event that the reproductive partner of the proband is also a carrier for a mutation in the same gene in which two mutations have been identified in the proband, the risk to offspring for JLNS is 50%.

• Recommendations for evaluation of the offspring of an individual with JLNS include comprehensive electrocardiographic testing for evidence of QTc prolongation by a physician familiar with LQTS.

Other family members. Sibs of a proband's parents may also be at 50% risk of having a mutation in KCNE1 or KCNQ1 and at risk for LQTS.

Carrier Detection

Carrier testing is possible for family members once the mutations have been identified in the family.

Related Genetic Counseling Issues

Because prolonged QTc interval in families with JLNS may follow an autosomal dominant inheritance pattern, it is important that family members at risk undergo electrocardiographic testing for evidence of LQTS early in life. Individuals with LQTS are at increased risk for sudden death and thus require cardiologic intervention. The actual risk of LQTS is not known.

Carriers for JLNS have a single mutation in a gene for LQTS that may cause QTc prolongation or LQTS in either a clinically significant or clinically insignificant form. Whether the mutation is clinically significant or insignificant, it may be transmitted in a clinically significant fashion to future generations as either LQTS (i.e., Romano-Ward syndrome) or JLNS, a confusing phenomenon during pedigree evaluation.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements

Requests for prenatal testing for conditions such as LQTS that do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Jervell and Lange-Nielsen syndrome (JLNS) is caused by an aberration in a potassium channel found in the stria vascularis of the cochlea (inner ear) and the heart.

• KCNQ1 and KCNE1 encode the alpha and beta subunit proteins (K_VLQT1/minK) for the slow potassium current, I_Ks of the cochlea and the heart.

• When stimulated by sound, potassium from the scala media of the cochlea passes through the apex of the hair cells, depolarizing the hair cells and causing a calcium-channel-induced release of neurotransmitter onto the auditory nerve. Depolarizations of the auditory nerve are sent centrally where they are perceived as sound. The maintenance of high potassium concentration in the endolymphatic fluid of the inner ear is required for normal hearing. The potassium-rich fluid of the scala media is created by the I_Ks potassium channels (exclusively K_VLQT1/minK) in the stria vascularis.

• Malfunction in these channels in the cochlea causes deafness.

• Malfunction in these channels in the heart results in abnormal ventricular electrical activity and LQTS.

Published Guidelines/Consensus Statements

1. American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available online. 2002. Accessed 12-5-11.
2. American College of Medical Genetics. Statement on universal newborn hearing screening. Available online. 2000. Accessed 12-5-11.

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Author History

Shane M Daley, MD; Mayo Clinic-Scottsdale (2002-2010)
Glenn Edward Green, MD (2002-present)
Ricardo A Samson, MD (2002-present)
Lisbeth Tranebjaerg, MD, PhD (2002-present)

Revision History

• 23 February 2010 (me) Comprehensive update posted live

• 19 March 2007 (me) Comprehensive update posted to live Web site

• 29 July 2004 (me) Comprehensive update posted to live Web site

• 13 January 2003 (gg) Revision: Molecular Genetic Testing

• 29 July 2002 (me) Review posted to live Web site

• 8 October 2001 (gg) Original submission