Case presentation

A 30-year-old woman presented with recurrent syncope and congenital profound sensorineural hearing loss. Physical examination was unremarkable. Echocardiography revealed normal cardiac function. Electrocardiogram showed sinus rhythm with prolonged corrected QT interval of 532 milliseconds, which was calculated using the Bazett formula (Figure 1(a)). Holter monitoring demonstrated a short episode of polymorphic ventricular tachycardia (Figure 1(b)). Genetic testing revealed homozygosity for the KCNQ1 c.914G>A (p.W305*) mutation, confirming the diagnosis. ^{Reference Ackerman, Priori and Dubin4} Propranolol therapy was initiated, and an implantable cardioverter defibrillator was placed. Her 19-year-old sister, also with congenital profound sensorineural hearing loss, had similar syncopal episodes, prolonged corrected QT interval (501 milliseconds), and the same homozygous mutation (Supplementary Figure 1). There were no identifiable triggers for syncope. The younger sister declined implantable cardioverter defibrillator implantation and remains under medical therapy and close follow-up. Both were born to consanguineous parents. The elder sister’s child had a normal electrocardiogram and hearing screening.

Figure 1. ( a ) Twelve-lead electrocardiogram of the 30-year-old patient showing sinus rhythm and prolonged corrected QT interval of 532 milliseconds. ( b ) Holter monitoring of the same patient demonstrating a short episode of polymorphic ventricular tachycardia, consistent with high arrhythmic risk. QTc was calculated using the Bazett formula.

As part of family screening, both parents underwent electrocardiographic evaluation (Supplementary Figure 2). The mother had a corrected QT interval of 422 ms and the father 440 ms, and both were asymptomatic, findings consistent with a heterozygous carrier phenotype. According to the family history, no additional relatives were known to have hearing impairment; however, electrocardiographic data from extended family members were not available (Figure 2).

Figure 2. Extended pedigree of the family demonstrating parental consanguinity (double marriage line) and two affected sisters with Jervell and Lange-Nielsen syndrome. The two sisters and their parents underwent clinical and electrocardiographic evaluation (mother QTc 422 ms; father QTc 440 ms; both asymptomatic). The presence or absence of hearing loss among other relatives was based on self-reported family history, and genetic testing was not available for relatives other than the two affected sisters.

Discussion

Jervell and Lange-Nielsen syndrome carries a high risk of ventricular arrhythmias and sudden cardiac death due to loss-of-function mutations in potassium channels leading to prolonged cardiac repolarization. ^{Reference Schwartz, Spazzolini and Crotti2,Reference Winbo, Stattin and Diamant3} The KCNQ1 c.914G>A mutation affects the C-terminal intracellular tail of the Kv7.1 channel, disrupting regulation. ^{Reference Ackerman, Priori and Dubin4} Most patients present in childhood, but these cases highlight that diagnosis can be delayed into adulthood when early syncopal events are misattributed to benign causes. A corrected QT interval above 500 milliseconds is a strong predictor of arrhythmic risk. ^{Reference Winbo, Stattin and Diamant3,Reference Coto, García-Fernández and Calvo5} Implantable cardioverter defibrillator implantation remains lifesaving in high-risk patients, although patient acceptance may be challenging. ^{Reference Ackerman, Priori and Dubin4} Both sisters had prolonged corrected QT intervals without identifiable triggers, suggesting an intrinsic arrhythmogenic substrate. This report underscores the importance of considering Jervell and Lange-Nielsen syndrome in adults presenting with unexplained syncope and congenital profound sensorineural hearing loss.

Both sisters had congenital profound sensorineural hearing loss. Neither parent had hearing impairment. Detailed information regarding early childhood audiological interventions was not available.

Despite congenital profound sensorineural hearing loss, which represents a recognised red flag for Jervell and Lange-Nielsen syndrome, electrocardiographic screening was likely missed due to limited access to specialised healthcare services in a rural setting, highlighting a system-level gap between recommendations and real-life practice.

As part of family screening, both parents underwent electrocardiographic evaluation. The mother had a corrected QT interval of 422 ms and the father 440 ms, and both were asymptomatic, findings consistent with a heterozygous carrier phenotype.

Electrocardiographic data from extended family members were not available, representing a limitation; however, systematic family screening was strongly recommended, highlighting the importance of cascade screening in inherited arrhythmia syndromes.

Current guidelines and expert consensus recommend nadolol as the preferred beta-blocker in patients with long QT syndrome, including Jervell and Lange-Nielsen syndrome, due to its longer half-life and superior protection against arrhythmic events. ^{Reference Ackerman, Priori and Willems6,Reference Wilde and Amin7} However, nadolol is not commercially available in our country, and propranolol was therefore selected as an alternative in real-life clinical practice. This represents a limitation of our report. Nevertheless, given the high-risk clinical profile of the patient, implantable cardioverter defibrillator implantation provided additional protection against malignant ventricular arrhythmias.

Although homozygous nonsense mutations in the KCNQ1 gene are typically associated with an early and severe clinical course, substantial phenotypic variability has been reported in Jervell and Lange-Nielsen syndrome, even among patients carrying identical mutations. ^{Reference Schwartz, Spazzolini and Crotti2,Reference Winbo, Stattin and Diamant3} Survival into adulthood may be influenced by incomplete penetrance, modifier genes affecting repolarization currents, autonomic factors, and the absence of adrenergic triggers. ^{Reference Winbo, Stattin and Diamant3,Reference Crotti, Monti and Insolia8} In the present family, both parents exhibited asymptomatic heterozygous phenotypes with normal corrected QT intervals, suggesting a relatively mild electrophysiological background that may have contributed to survival into adulthood. Importantly, delayed diagnosis should not be interpreted as a benign phenotype, as the affected sister demonstrated marked QT prolongation and malignant ventricular arrhythmia once evaluated.

Conclusion

Late diagnosis of Jervell and Lange-Nielsen syndrome in adulthood is uncommon but possible. Cardiologists should maintain suspicion for congenital long QT syndromes in patients with sensorineural hearing loss and recurrent syncope. Genetic confirmation is essential for diagnosis, risk stratification, and family counselling.

Learning points

• • Jervell and Lange-Nielsen syndrome, though congenital, may remain undiagnosed until adulthood.

• • A prolonged corrected QT interval and sensorineural hearing loss should prompt genetic evaluation.

• • Early recognition and implantable cardioverter defibrillator implantation are critical to prevent sudden cardiac death.