Jervell and Lange-Nielsen Syndrome

Definition and epidemiology

Jervell and Lange-Nielsen syndrome (JLNS) was described in 1957 in a family with congenital hearing loss, a prolonged QT interval and sudden death (Jervell and Lange-Nielsen, 1957). It is inherited in an autosomal recessive manner and is the form of long QT syndrome (LQTS) that occurs with hearing loss. About 90% of cases are caused by biallelic variants in KCNQ1 and fewer than 10% in KCNE1; a variant in one of these genes has been found in 94% of people with a clinical diagnosis (Tranebjærg et al., 2017).

The syndrome is rare. A prevalence of at least 1 in 200,000 has been reported in Norway and Sweden (Tranebjærg et al., 2017); a national Swedish study identified 19 cases in 13 families and linked the high prevalence to founder effects (Winbo et al., 2012). In Türkiye, a study of 350 children with congenital hearing loss found JLNS in 1 in 175 (Öcal et al., 1997; Tranebjærg et al., 2017). Because inheritance is recessive, consanguinity increases the risk. Consanguineous marriage is declining in Türkiye but remains common: according to the 2018 Turkey Demographic and Health Survey, the rate was about 40% among women who married in 1993 or earlier and 16% among those who married in 2014-2018 (Koç, 2022).

Symptoms and signs

All people with molecularly confirmed JLNS have congenital bilateral profound sensorineural hearing loss (Tranebjærg et al., 2017). The loss is present at birth, does not progress and is detected by newborn hearing screening. Vestibular function is also affected: all 14 children examined in Norway, with or without cochlear implants, had vestibular dysfunction (Siem et al., 2008), so delayed head control and walking can be expected.

The cardiac finding is a markedly prolonged QT interval on the ECG. The corrected QT (QTc) is normally below 440 ms in males and below 460 ms in post-pubertal females; in JLNS the QTc is usually above 500 ms, averaging about 550 ms (Tranebjærg et al., 2017). In an international series of 135 families the QTc was 557±65 ms (Schwartz et al., 2006). Long QT can lead to a ventricular arrhythmia called torsades de pointes and to syncope (fainting) and, untreated, to sudden death. Half of patients have their first cardiac event before age 3, and the main triggers are excitement, fright and exercise. More than half of untreated children die before age 15 (Tranebjærg et al., 2017).

Fainting episodes are easily mistaken for epilepsy, so an ECG should always be reviewed before a ‘seizure’ diagnosis is made in a child with hearing loss. Iron deficiency anaemia and hypergastrinaemia are also more common in KCNQ1-related JLNS (Tranebjærg et al., 2017).

Causes and risk factors

KCNQ1 and KCNE1 together form a channel carrying the slowly activating potassium current (IKs). This channel is critical in two tissues. In the inner ear, it allows cells of the stria vascularis to secrete potassium into the endolymph; when it does not work, endolymph does not form and the cochleosaccular structures degenerate. In the heart, it contributes to repolarisation of the ventricular muscle; loss of function prolongs the action potential, which appears as long QT on the ECG (Tranebjærg et al., 2017).

When both copies carry a variant, both hearing and the heart are affected. Carriers (heterozygotes) usually hear normally, but some have autosomal dominant long QT syndrome (Romano-Ward syndrome); about 67% of JLNS-associated variants have also been linked to dominant LQTS (Tranebjærg et al., 2017). Parents and siblings of a child with the diagnosis should therefore have an ECG even if their hearing is normal. In consanguineous families two carrier parents are more likely to meet, and each pregnancy carries a 25% chance of an affected child.

Audiological and clinical assessment

Tranebjærg et al. (2017) advise suspecting JLNS in any infant with bilateral profound sensorineural hearing loss, no GJB2 variants and a normal physical examination. Reporting the Norwegian experience, Siem et al. (2008) also recommended ECG screening of children with congenital profound hearing loss. An ECG is cheap, quick and painless and should be among the first steps in the aetiological work-up of hearing loss.

• Newborn screening and ABR: in babies who do not pass OAE and automated ABR screening, diagnostic ABR shows no response at maximum stimulus levels.
• OAEs: OAEs are absent because outer hair cells do not function; the absence of a cochlear microphonic (CM) helps distinguish the picture from ANSD.
• Tympanometry and acoustic reflexes: the middle ear is normal with a type A tympanogram; acoustic reflexes are absent because of the profound loss.
• Behavioural audiometry: most children respond only at low frequencies and very high levels, often through vibrotactile sensation.
• Vestibular tests: since all children in the Norwegian series had vestibular dysfunction (Siem et al., 2008), documenting vestibular function before implantation helps set expectations for motor development.
• ECG and cardiology: the QTc is measured on a 12-lead ECG; with borderline values, repeat ECGs, Holter monitoring and exercise testing are arranged at the cardiologist’s discretion. Up to 15-20% of paediatric diagnoses based on a QTc above 440 ms may be false positives (Tranebjærg et al., 2017).
• Genetic testing: KCNQ1 and KCNE1 sequencing and deletion/duplication analysis, with carrier testing and ECGs for the parents.

The differential diagnosis includes GJB2 and other non-syndromic hearing loss, Usher syndrome (vestibular involvement and later visual loss) and other inner ear malformations. Normal temporal bone imaging does not exclude JLNS, and cardiac assessment should not wait for imaging results.

Treatment and audiological rehabilitation

Planning and monitoring of cardiac treatment rest with the cardiologist. Beta-blockers are the mainstay; studies have found propranolol and nadolol more effective than metoprolol. In JLNS, however, beta-blockers alone are not fully protective: cardiac events have been reported in 51% of treated patients and cardiac arrest or sudden death in 27% (Tranebjærg et al., 2017). For high-risk patients (QTc above 550 ms, syncope before age 5), options such as an implantable cardioverter-defibrillator (ICD) and left cardiac sympathetic denervation are therefore considered (Schwartz et al., 2006). The Swedish series also found that beta-blockers reduced but did not abolish events and that adherence was decisive (Winbo et al., 2012). Drugs that prolong the QT interval should be avoided (Tranebjærg et al., 2017).

A cochlear implant is the main option for hearing; about 20 implanted people with JLNS have been reported and implantation appears safe (Tranebjærg et al., 2017). Experience with eight children in Oslo showed that implantation can be carried out with appropriate precautions (Siem et al., 2008). Anaesthesia increases the risk of arrhythmia, so special precautions are needed (Tranebjærg et al., 2017): cardiology and anaesthesia teams plan together before surgery, QT-prolonging drugs are avoided, rhythm monitoring is maintained and the team is ready for emergency rhythm management. In one child, sound-triggered syncope increased after implantation (Tranebjærg et al., 2017). It is therefore sensible to carry out the first activation and early programming sessions in coordination with cardiology, avoiding sudden loud stimulation.

Auditory-verbal rehabilitation after implantation follows the same principles as for other children with congenital profound loss. Motor development in children with vestibular dysfunction is supported by a physiotherapist. Families should receive genetic counselling, and siblings and parents should be screened by ECG.

Impact on quality of life and advice

Families of a child with JLNS live with two separate concerns: the effect of hearing loss on communication and education, and the worry of a cardiac event that may happen at any time. The cardiac risk shapes school, sport and social life, so teachers, carers and coaches need to know about the condition and be able to give first aid. Although auditory-verbal development is possible with an implant, operations and the medication routine add to the family’s burden.

Practical advice: give the medicine your cardiologist prescribes every day and do not miss doses; adherence is the basis of protection. Before starting any new medicine, including over-the-counter products, ask your doctor or pharmacist whether it can prolong the QT interval. Avoid triggers such as competitive sports, amusement park rides, frightening films and jumping into cold water (Tranebjærg et al., 2017). Encourage people around your child at home and at school to learn cardiopulmonary resuscitation and how to use an automated external defibrillator (AED). Share your cardiologist’s advice with your audiologist before the sound processor is first switched on or programmed.