Pregnant woman with Jervell and Lange-Nielsen syndrome: a case report

Introduction

Jervell and Lange-Nielsen syndrome (JLNS) is a rare autosomal recessive disorder characterised by congenital bilateral sensorineural hearing loss and a prolonged QT interval, which may lead to ventricular tachyarrhythmia and sudden cardiac death. The condition was first described in 1957 by Anton Jervell and Fred Lange-Nielsen in a study of four children born with congenital deafness who experienced recurrent syncope. Electrocardiographic studies in these patients revealed marked prolongation of the QT interval without any other identifiable cause for their fainting spells. ¹ The prevalence of JLNS varies among populations, with an overall estimated prevalence of 1 to 6 per 1,000,000. Owing to genetic factors, the condition is more common in Norway and Sweden, where the prevalence is approximately 1 in 200,000. This increased prevalence has been attributed to a founder effect in historically isolated populations, where pathogenic variants in the KCNQ1 gene have been transmitted through generations within relatively limited genetic pools. ² Reports from other regions, including Asia, are exceedingly rare, and cases during pregnancy are even more uncommon. Here, we present a rare case of pregnancy complicated by JLNS in a 32-year-old woman of Indian ethnicity with a homozygous KCNQ1 variant, highlighting the clinical challenges in diagnosis and management in this unique context.

Case report

A 32-year-old in her first ongoing pregnancy (one previous miscarriage) was admitted at 37 weeks of gestation in view of fetal growth restriction. She had a longstanding history of congenital deafness and recurrent syncopal episodes since 1.5 years of age. In early childhood, she experienced abnormal movements that were initially diagnosed as seizures and was treated with antiepileptic medications until the age of three years. Audiometric evaluation performed during childhood confirmed congenital bilateral profound sensorineural hearing loss, and she had been using a hearing aid since then.

At 22 years of age, she was evaluated for recurrent syncopal episodes and was found to have a prolonged QT interval on electrocardiography, leading to a clinical diagnosis of long QT syndrome (LQTS), with Jervell and Lange-Nielsen syndrome (JLNS) suspected in view of the associated congenital hearing impairment and family history. Genetic testing was not performed at that time because of financial constraints. Due to recurrent arrhythmic events, she underwent implantation of a single-chamber automated implantable cardioverter-defibrillator (AICD) and was started on propranolol therapy. Approximately one year after implantation, she experienced one appropriate ICD shock for a documented arrhythmic event. At that time, electrocardiography showed a QTc interval of 530 ms, following which the propranolol dose was increased from 10 mg three times daily to 20–10–10 mg per day.

Her parents were non-consanguineous, and her sister had died suddenly at the age of 16 years after experiencing similar cardiac symptoms. The patient had been married for one year, had studied up to Class 10, and was able to read and write.

patient at 37 weeks of gestation, her pulse rate was 80 beats per minute with a regular rhythm, and blood pressure was 120/70 mmHg. On examination, the uterine size corresponded to approximately 32 weeks of gestation. Ultrasonography revealed an estimated fetal weight below the first centile with normal amniotic fluid and Doppler parameters.

During pregnancy, electrocardiography demonstrated persistent QT prolongation, and echocardiography showed normal cardiac structure and function. The AICD device was periodically interrogated throughout pregnancy, and the woman continued propranolol 60 mg per day in three divided doses. During every device interrogation battery life was checked. A month prior to the delivery the battery voltage was 3.1 V.

During the current pregnancy, whole-exome sequencing was performed, which identified a homozygous likely pathogenic variant in the KCNQ1 gene (exon 14, c.1716–1719del), confirming the diagnosis of JLNS. Genetic testing of her husband did not reveal the variant.

In view of fetal growth restriction, labour was induced with prostaglandin E1, and she delivered vaginally a live female infant weighing 2 kg. Epidural analgesia was administered during labour. Continuous cardiac monitoring with electrocardiography was maintained throughout labour and for 48 h postpartum in the intensive care unit.

A postpartum electrocardiogram demonstrated a QTc interval of 481 ms (Figure 1). Electrocardiographic evaluation of the neonate was normal, and neonatal echocardiography showed no structural cardiac abnormalities.

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Figure 1.

Postpartum ECG with QTc of 481 ms. 140 x 258 mm (144 x 144 DPI).

Discussion

LQTS is an inherited cardiac channelopathy characterised by delayed ventricular repolarization and prolongation of the QT interval on electrocardiography, predisposing affected individuals to malignant ventricular arrhythmias and sudden cardiac death. JLNS represents a rare autosomal recessive form of LQTS associated with congenital sensorineural hearing loss. JLNS type I caused by homozygous or compound heterozygous variants in KCNQ1 accounts for the majority of cases (approximately 90%), whereas JLNS type II due to homozygous variants in KCNE1 is exceedingly rare. The cardiac action potential consists of depolarisation, plateau (refractory), and repolarisation phases. The repolarisation phase corresponds to the QTc interval on the ECG. During this phase, there is an increased permeability to potassium ions, which move out of the cardiac cells. This repolarising potassium current has both a rapidly activating and a slowly activating component. Mutations in KCNQ1 and KCNE1 affect the slowly activating component, resulting in delayed outward movement of potassium ions and consequently a prolonged QTc interval. ²

JLNS should be suspected in any child presenting with congenital sensorineural deafness and exertional syncopal episodes. The index case had congenital deafness and recurrent syncopal attacks since 1.5 years of age. Approximately 50% of affected individuals experience a cardiac event before the age of three years. Iron deficiency anaemia and elevated gastrin levels have also been reported in association with JLNS. Failure of KCNQ1-encoded voltage-gated potassium ion channels, which support the maintenance of salt and water balance in various epithelial tissues, including the heart, inner ear, and gastrointestinal tract, accounts for these symptoms. When JLNS is suspected, an ECG should be performed to assess the QTc interval. A QTc interval greater than 500 ms strongly suggests LQTS but is not specific for JLNS, as similar QTc prolongation can occur in other LQTS subtypes. JLNS is the most severe type of LQTS, as described by Schwartz et al.: 15% of children have a cardiac event before one year and 90% by age 18 years. ³ In individuals meeting clinical diagnostic criteria for LQTS genetic testing is typically performed using a multigene panel that includes genes with established associations with LQTS, most commonly KCNQ1, KCNH2, and SCN5A. ⁴

The most common triggers of a cardiac event in JLNS include physical activity, swimming, emotion in adults, and prolonged sobbing in children. Besides diarrhoea, sepsis, and hypokalaemia, fever is the most common cause of cardiac events in children. ⁵ QT-prolonging antiarrhythmics such as amiodarone, sotalol, antibiotics such as erythromycin, clarithromycin, and levofloxacin, antifungal agents like fluconazole, antiemetics including ondansetron, and certain antipsychotics such as haloperidol and quetiapine to be avoided in patients with JLNS. ⁶ Electrolyte levels, particularly potassium and magnesium, should be monitored periodically and corrected if abnormalities are detected, as electrolyte disturbances can further prolong the QT interval and increase arrhythmic risk. This is particularly important in pregnant women with persistent vomiting or hyperemesis, where electrolyte imbalance may occur.

Once diagnosed, the extent of the disease should be evaluated thoroughly. Further assessments include audiological testing, genetic consultation, complete blood count, and obtaining a detailed family history.

The primary goal in the management of JLNS is to prevent adverse cardiac events such as syncope and arrhythmia. Beta-blockers are the first-line therapy, with propranolol and nadolol considered superior to metoprolol. In paediatric patients, nadolol is preferred because of its longer half-life, stable plasma levels, and superior ability to prevent ventricular arrhythmias. This is particularly important in children, where maintaining consistent drug levels is crucial, as adherence to multiple daily doses of propranolol may be challenging. ⁷

The efficacy of beta-blockers in LQTS is genotype-dependent, underscoring the importance of identifying the genetic subtype. LQTS type 1 is the most common form, in which beta-blockers provide significant protection against exertion-induced arrhythmias. In contrast, LQTS type 3 events often occur at rest or during sleep, and beta-blockers offer limited benefit. LQTS type 2 falls between these extremes, with partial protection from beta-blocker therapy. JLNS is associated with homozygous variants in genes corresponding to the LQT1 and LQT5 subtypes of long QT syndrome. ⁸ In patients with LQTS type 3, mexiletine has been shown to shorten the QT interval and reduce arrhythmic risk and is currently recommended as a Class I therapy in appropriate patients.

Implantable cardioverter-defibrillators (ICDs) are recommended for JLNS patients who have survived cardiac arrest or continue to experience syncope despite optimal pharmacological therapy. ⁹ According to the 2022 ESC Guidelines on Ventricular Arrhythmias, ICD implantation is indicated in LQTS patients who remain symptomatic despite appropriate medical management, and may also be considered for asymptomatic patients with a high-risk profile as assessed by the LQTS Risk Calculator. ¹⁰ The 2021 PACES Expert Consensus Statement similarly emphasises the high-risk nature of JLNS and supports ICD implantation in patients with recurrent arrhythmic events despite beta-blocker therapy. Left cardiac sympathetic denervation may be considered in patients in whom medical therapy is contraindicated or not tolerated, or in those who continue to experience recurrent arrhythmic events or ICD shocks despite optimal pharmacological treatment. ¹¹ Regular device interrogation should be performed during pregnancy to ensure appropriate functioning and adequate battery life before delivery. The index case had undergone ICD implantation due to recurrent arrhythmic events despite propranolol therapy.

The risk of life-threatening cardiac events increases in the peripartum period, owing to interactions between the inherited channelopathy, hormonal fluctuations, and physiological changes that persist into the postpartum phase. Cardiac events typically occur at elevated heart rates during emotional or physical stress and are strongly associated with pregnancy, labour, and delivery, often extending into the postpartum period. In a study involving 68 live births among 31 women with LQTS, five arrhythmic events occurred in four mothers, all during the postpartum period. ¹²

During pregnancy, fetal growth restriction should be monitored if the woman is on beta-blockers. A fetal echocardiogram after 27 weeks is recommended to detect any fetal rhythm abnormalities. The mode of delivery – vaginal or caesarean – should be determined based on obstetric indications. A multi-disciplinary cardio-obstetric team should be involved in the management of labour and delivery. Early neuraxial anaesthesia can be considered. During labour, parenteral beta-blockers and antiarrhythmic drugs should be readily available, along with an external cardioverter-defibrillator. Close cardiac monitoring is essential in the postpartum period, and beta-blocker therapy should be continued. Genetic counselling and newborn genetic testing should be offered to the family. ¹³

Conclusion

JLNS represents one of the most severe forms of congenital LQTS, with a high risk of ventricular arrhythmias and sudden cardiac death. Pregnancy in women with JLNS requires careful risk stratification and coordination between obstetricians, cardiologists, anaesthetists, and neonatologists. Early genetic diagnosis facilitates targeted management and family counselling. Continuous cardiac monitoring during labour, vigilant observation in the postpartum period, and adherence to beta-blocker therapy are critical to reducing maternal morbidity and mortality. This case highlights that, with a multidisciplinary approach and appropriate peripartum care, favourable maternal and neonatal outcomes can be achieved even in this rare and high-risk condition.