Jervell And Lange-Nielsen Syndrome

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2021-01-18

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Genes

KCNQ1, KCNE1, KCNE1B, RWS, GAST, KCNH2, HFE, NT5E, SCN5A, KCNQ4, KCNE2

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Summary

Clinical characteristics.

Jervell and Lange-Nielsen syndrome (JLNS) is characterized by congenital profound bilateral sensorineural hearing loss and long QTc, usually >500 msec. Prolongation of the QTc interval is associated with tachyarrhythmias, including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation, which may culminate in syncope or sudden death. Iron-deficient anemia and elevated levels of gastrin are also frequent features of JLNS. The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. Fifty percent of individuals with JLNS had cardiac events before age three years. More than half of untreated children with JLNS die before age 15 years.

Diagnosis/testing.

The diagnosis of JLNS is established in a child with congenital sensorineural deafness, long QT interval, and presence of biallelic pathogenic variants in either KCNQ1 or KCNE1.

Management.

Treatment of manifestations: Cochlear implantation to treat hearing loss; beta-adrenergic blockers for long QT interval (Note: Beta-blocker treatment is only partially effective.); implantable cardioverter defibrillators (ICDs) for those with a history of cardiac arrest and/or failure to respond to other treatments; ensure availability of automated external defibrillators where appropriate; standard treatment for those with iron-deficiency anemia.

Prevention of secondary complications: Special precautions during anesthesia are necessary because of the increased risk for cardiac arrhythmia.

Surveillance: Beta-blocker dose should be regularly assessed for efficacy and adverse effects, with evaluation every three to six months during rapid growth phases; periodic evaluations of ICDs for inappropriate shocks and pocket or lead complications.

Agents/circumstances to avoid: Drugs that cause further prolongation of the QT interval; activities known to precipitate syncopal events in persons with long QT syndrome.

Evaluation of relatives at risk: Hearing evaluation by standard newborn hearing screening programs and electrocardiograms for at-risk sibs; molecular genetic testing to confirm the diagnosis if the pathogenic variants in an affected family member are known.

Pregnancy management: Consideration should be given as to whether a mother who has a fetus affected with JLNS herself has long QT syndrome.

Other: Training for family members in cardiopulmonary resuscitation; use of an ID bracelet explaining the diagnosis; notifying local emergency medical services of high-risk persons with JLNS.

Genetic counseling.

JLNS is inherited in an autosomal recessive manner. Parents of a child with JLNS are usually heterozygotes; rarely, only one parent is heterozygous (i.e., the proband has one inherited and one de novo pathogenic variant). Parents may or may not have the long QT syndrome (LQTS) phenotype. At conception, each sib of an affected individual usually has a 25% chance of being affected with JLNS, a 50% chance of being a carrier of a JLNS-causing pathogenic variant and potentially at risk for LQTS, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family are known.

Diagnosis

Suggestive Findings

Jervell and Lange-Nielsen syndrome (JLNS) should be suspected in a proband with the following features:

Profound congenital sensorineural deafness
Long QTc interval (>500 msec), often manifest as syncope, most often elicited by emotion or exercise. Note: Normal QTc interval in males is <440 msec and in post-pubertal females is <460 msec.

Establishing the Diagnosis

The diagnosis of JLNS is established in a proband with the above suggestive findings. Identification of biallelic pathogenic variants in either KCNQ1 or KCNE1 confirms the diagnosis, particularly if clinical features are inconclusive.

Note: (1) It is not currently known how many children with molecularly confirmed JLNS have a borderline QTc interval (440-500 msec) or a normal QTc interval. (2) Hearing loss commonly occurs in individuals with long QT syndrome (LQTS). The hearing loss may be entirely unrelated to the etiology of the LQTS, particularly if the hearing loss is moderate.

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

Serial single-gene testing. Sequence analysis of KCNQ1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found. If only one or no KCNQ1 pathogenic variant is identified, sequence analysis of KCNE1 should be performed next.
In countries with KCNQ1 founder variants (e.g., Norway) KCNQ1 sequencing should be carried out with knowledge of these variants to ensure they will be detected (see Molecular Genetics) [Tranebjærg et al 1999, Tranebjærg 2004, Berge et al 2008, Siem et al 2008].
A multigene panel that includes KCNE1, KCNQ1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Jervell and Lange-Nielsen Syndrome

Gene ^1, 2	Proportion of JLNS Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ³ Detectable by Method
Gene ^1, 2		Sequence analysis ⁴	Gene-targeted deletion/duplication analysis ⁵
KCNE1	<10% ⁶	~100% ⁷	See footnote 8
KCNQ1	~90% ⁶	>95%	1 family ^9, 10

1.: Genes are listed alphabetically.
2.: See Table A. Genes and Databases for chromosome locus and protein.
3.: See Molecular Genetics for information on allelic variants detected in this gene.
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: In a study of ten families, nine had pathogenic variants in KCNQ1 [Tyson et al 2000]. Of 63 families, six (9.5%) had pathogenic variants in KCNE1 [Schwartz et al 2006]. None of the individuals of Norwegian ancestry with JLNS have been shown to have KCNE1 pathogenic variants [Tranebjærg et al 1999, Berge et al 2008, Siem et al 2008]. Pathogenic variants have been found in either KCNQ1 or KCNE1 in 94% of individuals with clinical JLNS undergoing molecular testing [Schwartz et al 2006].
7.: Three variants in KCNE1, all detectable by Sanger sequencing, have been associated with JLNS [Schulze-Bahr et al 1997, Tyson et al 1997].
8.: No deletions or duplications of KCNE1 have been reported to cause JLNS.
9.: Sung et al [2014]
10.: Both deletion and duplication of one or more exons of KCNQ1 are known to cause long QT syndrome [Zehelein et al 2006, Eddy et al 2008, Sung et al 2014]; their frequency is unknown.

Clinical Characteristics

Clinical Description

The classic presentation of JLNS is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright.

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

Long QTc. Individuals with JLNS have a QTc interval greater than 500 msec (average 550 msec), indicating increased time for ventricular depolarization and repolarization [Winbo et al 2012, Winbo et al 2014]. Abnormal cardiac depolarization and repolarization may result in tachyarrhythmias (including ventricular tachycardia, episodes of torsade de pointes ventricular tachycardia, and ventricular fibrillation), which may culminate in syncope or sudden death.

QTc prolongation in JLNS, particularly when severe, appears to be associated with increased risk for death in infancy (SIDS). 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 emotion and exercise being the primary triggers. Although more than half of untreated children with JLNS die before age 15 years, some individuals are reported to have survived several syncopal episodes during adulthood. Note, however, that selection bias for severely affected individuals cannot be excluded: individuals with putative JLNS but no clinical manifestations other than deafness until adulthood (and to age 50 years in one individual) have been described.

Anemia. Individuals with KCNQ1-related JLNS have an increased incidence of iron deficiency anemia and hypergastrinemia [Winbo et al 2013]. This may be due to loss of the KCNQ1 potassium channels and reduced gastric acid secretion.

Other. The sex ratio among individuals with JLNS is even, but females are at lower risk for cardiac arrest/sudden death [Schwartz et al 2006]. Vestibular dysfunction was found in 14/14 deaf individuals with JLNS, irrespective of previous cochlear implantation. The proposed mechanism was disruption of the endolymph homeostasis [Winbo & Rydberg 2015]

Physical examination is unremarkable except for deafness.

Heterozygotes. Individuals who are heterozygous for pathogenic variants associated with JLNS usually have normal hearing. In some heterozygotes, QTc prolongation, fainting, and sudden death never occur. In contrast, some individuals heterozygous for pathogenic variants associated with JLNS may have QTc prolongation associated with fainting and death heritable in an autosomal dominant manner. This form of LQTS is called Romano-Ward syndrome (RWS).

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 one Norwegian individual with JLNS resulting from homozygosity for the c.572_576del pathogenic variant in KCNQ1, histopathologic examination of the temporal bones showed severe atrophy of the stria vascularis and the organ of Corti with absence of cochlear nerve fibers [Tranebjærg L & Merchant SM, unpublished data (2012)].

Phenotype Correlations by Gene

Among six asymptomatic individuals reported by Schwartz et al [2006], two had biallelic KCNQ1 pathogenic variants and four had biallelic KCNE1 pathogenic variants, further confirming the milder presentation of JLNS associated with KCNE1 pathogenic variants compared to JLNS associated with KCNQ1 pathogenic variants.

KCNQ1. Individuals with KCNQ1-related JLNS have an increased incidence of iron deficiency anemia and hypergastrinemia [Winbo et al 2013].

Genotype-Phenotype Correlations

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 inactivating variant (e.g., insertion/deletion, splice variant, truncation) and those with missense variants.

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, in which the cardiac and cochlear pathologies are 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 [Tranebjærg et al 1999]. This prevalence stems from four Norwegian founder variants [Berge et al 2008, Siem et al 2008, Winbo et al 2012].
Sweden also has a prevalence of one in 200,000 based on a study of preadolescent children, identifying 19 affected individuals from 13 families. Eight KCNQ1 pathogenic variants were identified, of which p.Arg518Ter constituted 12/24 alleles [Winbo et al 2012]. Founder variants accounted for 83% of pathogenic variants [Winbo et al 2014].
In a study of 350 children with congenital deafness in Turkey, one in 175 had JLNS [Ocal et al 1997].
A particular missense KCNQ1 variant 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, prevalence of JLNS was not increased in Finland [Piippo et al 2001].
An overview of worldwide occurrence was published by Tranebjærg [2004]

These data are the best available; however, diagnostic criteria using a QTc >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 review by Schwartz et al [2006] did not allow refinement of prevalence estimates.

Differential Diagnosis

Deafness and prolonged QTc with or without long QT syndrome (LQTS) both have multiple etiologies, including genetic and environmental causes. In many individuals with both deafness and prolonged QTc (or LQTS), the deafness and prolonged QTc (or LQTS) have separate etiologies. All of these possibilities must be considered in each affected individual, particularly in the absence of parental consanguinity or an affected sib. The following considerations are relevant in an individual who has both deafness and prolonged QTc:

Prior to the availability of molecular genetic testing, the diagnosis of Jervell and Lange-Nielsen syndrome (JLNS) was based on clinical criteria alone. (Romano-Ward syndrome was commonly diagnosed in persons with LQTS and normal hearing.)
Some children with JLNS may be misdiagnosed with epilepsy and incorrectly treated with antiepileptic drugs before the correct diagnosis of JLNS is established [Tranebjærg et al 1999].

Long QT syndrome. Long QT multigene panels may include testing for a number of the genes related to disorders discussed in this section. Note: The genes involved and methods used vary by laboratory.

Romano-Ward syndrome. The term "Romano-Ward syndrome" (RWS) refers to forms of long QT syndrome with a purely cardiac electrophysiologic disorder, inherited in an autosomal dominant manner (LQTS types 1-3, type 5, type 6, and types 9-15). RWS is characterized by QT prolongation and T-wave abnormalities on ECG and the ventricular tachycardia torsade de pointes (TdP). The diagnosis of RWS is made on the basis of a prolonged QT interval on ECG, clinical presentation, and family history; or identification of a pathogenic variant in one or more of the 15 genes known to be associated with LQTS (of which KCNQ1, KCNH2, and SCN5A are the most common) in the absence of profound congenital sensorineural deafness (the presence of which is highly suggestive of Jervell and Lange-Nielsen syndrome). Individuals with pathogenic variants in KCNE1 may also have atrial fibrillation [Olesen et al 2012]. Diagnostic criteria have been established for the resting ECG QTc value in the absence of specific conditions known to lengthen the QTc interval. For a summary of the genes known to be associated with RWS, see Long QT Syndrome. Only KCNQ1 and KCNE1 have been implicated in both RWS and JLNS.

Timothy syndrome is a multisystem disorder characterized by cardiac, hand/foot, facial, and neurodevelopmental features. Typical cardiac findings include a rate-corrected QT interval >480 msec, functional 2:1 AV block with bradycardia, tachyarrhythmias, and congenital heart defects (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy).

Andersen-Tawil syndrome is characterized by a triad of episodic flaccid muscle weakness (i.e., periodic paralysis), ventricular arrhythmias and prolonged QT interval, and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis.

Acquired causes of QTc interval prolongation include the following:

Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia
Malnutrition or liquid protein diet
Drugs: vasodilators, tricyclic antidepressants, organophosphates, antihistamines, phenothiazines, procainamide, disopyramide, quinidine, and many others. For a complete, updated list see www.crediblemeds.org (registration required).
Primary myocardial problems: cardiomyopathy, myocarditis, ischemia
Central nervous or autonomic system injury; subarachnoid hemorrhage; stellate ganglion blockade

Hearing loss. The differential diagnosis for hearing loss includes consideration of other forms of syndromic and nonsyndromic disorders, as well as acquired disorders. For more information on hereditary hearing loss, see Deafness and Hereditary Hearing Loss Overview.

One disorder that should be noted specifically is DFNB1, the most common autosomal recessive form of nonsyndromic hearing loss. DFNB1 is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment. No other associated medical findings are present. Diagnosis of DFNB1 depends on molecular genetic testing to identify biallelic pathogenic variants in GJB2 (sequence variants as well as variants in upstream cis-regulatory elements [GJB6 deletions] that alter expression of the gap junction beta-2 protein [connexin 26]). JLNS should be suspected in any infant who has profound bilateral sensorineural hearing loss, no identifiable GJB2 pathogenic variants, and a normal physical examination.

Brugada syndrome is characterized by cardiac conduction abnormalities (ST-segment abnormalities in leads V1-V3 on ECG and a high risk for ventricular arrhythmias) that can result in sudden death.

Sudden infant death syndrome (SIDS) (OMIM 272120). Data from multicenter studies indicate that 9.5% of infants with SIDS may be heterozygous for functionally significant variants in one of the known LQTS-related genes. Sudden arrhythmic death may thus be an important contributor to SIDS; it is unknown what proportion of infants with SIDS have or would develop profound hearing impairment. Implementation of universal neonatal hearing screening, supplemented with early electrocardiography, may have the potential to identify high-risk children. However, a recent large population study did not find a higher incidence of JLNS in newborns identified with hearing loss by universal screening [Chang et al 2014].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Jervell and Lange-Nielsen syndrome (JLNS), the following evaluations are recommended if they have not already been completed:

Formal audiology evaluation for extent of hearing loss
Cardiac examination including calculation of QTc
A three-generation family history that focuses on cardiac disease, syncope, and hearing ability
Complete blood count to screen for anemia. If anemia is present, screening for iron deficiency is recommended.
Consultation with a clinical geneticist

Treatment of Manifestations

Hearing loss in JLNS may be treated successfully with cochlear implantation, 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 includes approximately 20 individuals with JLNS who have received cochlear implantation. Of note, the diagnosis of JLNS was only verified with molecular genetic testing in four Norwegian individuals, all of whom had pathogenic variants in KCNQ1. An increase in sound-related syncopal episodes was noted after cochlear implantation in one child [Al-Aama et al 2015].

Note: Although cochlear implantation appears to be safe, special precautions are necessary during anesthesia because of the increased risk for cardiac arrhythmia [Daneshi et al 2008, Siem et al 2008, Yanmei et al 2008]. One affected individual died during a perioperative cardiac arrest [Broomfield et al 2010].

Cardiac issues. 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 (56%) of 32 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. 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 to individuals with Romano-Ward syndrome. 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. Propranolol and nadolol have been shown to be more effective than metoprolol in suppressing cardiac events [Chockalingam et al 2012, Winbo et al 2014]. A recent consensus statement advocates use of nadolol as the preferred beta blocker for drug therapy of individuals with long QT syndrome [Ackerman et al 2017].
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, age >20 years with KCNQ1 pathogenic variant
The risk for sudden cardiac death appears to be low in individuals younger than age five years, but medical therapy should be administered early in these high-risk individuals and ICD placement 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 effective for some individuals.

Iron deficiency anemia. The treatment of iron deficiency anemia should follow standard guidelines.

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 for cardiac arrhythmia [Daneshi et al 2008, Siem et al 2008, Yanmei et al 2008].

Surveillance

Beta-blocker dose should be regularly assessed for efficacy and adverse effects, and doses altered as needed. Because dose adjustment is especially important in growing children, evaluation is appropriate every three to six months during rapid growth phases.

Regular, periodic evaluation of implantable cardioverter defibrillators (ICDs) for inappropriate shocks and pocket or lead complications is indicated.

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.crediblemeds.org for a complete and updated list (registration required).
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
- Frightening 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

It is appropriate to evaluate sibs and parents of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk family members.
If the pathogenic variants in the family are not known, ECG testing should be undertaken to evaluate for QT prolongation.
Standard newborn screening programs are sufficient to identify hearing loss in children with JLNS.

Because of the relationship between JLNS and long QT syndrome, ECG should be considered for relatives at risk for JLNS even if they have normal hearing.

If the JLNS-causing pathogenic variants 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.

Pregnancy Management

Consideration should be given as to whether a mother who has a fetus affected with JLNS herself has long QT syndrome [Seth et al 2007].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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) as 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, including those with JLNS [Hazinski et al 2004].