Discussion

Ankyrin-B syndrome, associated with variants in ANK2, is recognised as a rare and heterogeneous form of inherited arrhythmia, historically classified as long QT syndrome type 4.^{Reference Ackerman and Mohler1,Reference Mohler, Splawski and Napolitano3} Unlike the more prevalent channelopathies involving ion channel pore-forming subunits, ankyrin-B dysfunction disrupts intracellular trafficking and membrane localisation of multiple ion transporters, resulting in diverse electrical phenotypes.^{Reference Mohler, Le Scouarnec and Denjoy2,Reference Cunha, Hund and Hashemi5} Clinical manifestations may include sinus node dysfunction, atrial arrhythmias, ventricular arrhythmias, and conduction disturbances in addition to QT prolongation.^{Reference Mohler, Le Scouarnec and Denjoy2,Reference Musa, Murphy and Curran4}

In the present case, the proband demonstrated marked QT prolongation during epinephrine provocation testing, together with persistent high-degree atrioventricular block. Although bradyarrhythmias and conduction abnormalities have been described in ankyrin-B–related disease, reports of high-degree atrioventricular block requiring permanent pacing in children harbouring an ANK2 variant are limited.^{Reference Mohler, Le Scouarnec and Denjoy2,Reference Mohler, Splawski and Napolitano3} The observed conduction disturbance persisted despite withdrawal of beta-blocker therapy, suggesting intrinsic conduction system involvement rather than medication-related suppression.

The underlying mechanism of conduction disease in ankyrin-B syndrome is not fully elucidated but is thought to reflect impaired membrane targeting of key ion transporters within specialised conduction tissue.^{Reference Mohler, Le Scouarnec and Denjoy2} Experimental models have demonstrated altered calcium handling and sodium channel regulation associated with ankyrin-B deficiency, which may predispose to both bradyarrhythmic and tachyarrhythmic events.^{Reference Mohler, Le Scouarnec and Denjoy2,Reference Koenig and Mohler9} The coexistence of QT prolongation and atrioventricular block in this patient may suggest pleiotropic electrical effects potentially attributable to ANK2 dysfunction, though causality cannot be established given the VUS classification of the identified variant.^{Reference Ackerman and Mohler1,Reference Robaei, Ford and Ooi10}

Genetic testing identified a heterozygous ANK2 variant classified as a VUS. Family testing showed maternal transmission, with the same variant detected in the mother and brother and absent in the father. However, the phenotype among variant carriers was variable, and the deceased sister was not genotyped. Moreover, available autopsy findings in the sister documented structural cardiac abnormalities. Therefore, although the family data provide important phenotypic context, they do not establish pathogenicity of the ANK2 variant. This case underscores the complexity of variant interpretation in inherited arrhythmia syndromes and the importance of integrating genotype with detailed family phenotyping.^{Reference Walsh, Thomson and Ware11,Reference Lubitz and Ellinor12}

Because the identified ANK2 variant remains a VUS, alternative causes of atrioventricular block were also considered. Structural heart disease was not identified on echocardiography. Coronary CT angiography was not performed. Although maternal rheumatoid factor testing was negative, SSA antibody testing was unavailable; therefore, autoimmune-mediated atrioventricular conduction disease could not be completely excluded. However, in the absence of a reversible metabolic or drug-related cause and with persistence of high-degree atrioventricular block after nadolol withdrawal, intrinsic conduction system disease was considered the most likely explanation in this case.

Management of high-degree atrioventricular block in children with inherited arrhythmic disorders presents unique challenges. Permanent pacing strategies must balance immediate symptom control with long-term considerations, including somatic growth, preservation of venous access, device longevity, and the potential future need for implantable cardioverter-defibrillator therapy.^{Reference Shah, Silka and Silva6} In this patient, a leadless pacemaker system was selected to minimise transvenous lead-related complications and vascular burden. The device was successfully implanted, and electrical performance parameters remained stable during follow-up. Because the device currently serves primarily as backup pacing, the ventricular pacing burden remains extremely low (<0.1%), suggesting a low current risk of pacemaker-induced cardiomyopathy. Nadolol was resumed because of the marked QT prolongation observed during epinephrine provocation testing. Although the pacemaker provides backup protection against bradycardia, the patient was advised to avoid competitive sports and strenuous exercise, with continued follow-up for reassessment of repolarisation-related arrhythmic risk. Long-term follow-up should include serial device interrogation, echocardiographic surveillance for pacing-related ventricular dysfunction, continued surveillance for evolving sinus node dysfunction, and individualised planning regarding future device retrieval or additional implantation at battery depletion.

Although leadless pacing in paediatric populations remains relatively limited, emerging data suggest favourable short- and mid-term outcomes.^{Reference Shah, Borquez and Cortez7} However, long-term experience, extraction feasibility, and implications for future device therapy require continued surveillance.

This case illustrates clinically significant conduction disease in a child with the identification of an ANK2 variant and demonstrates the feasibility of leadless pacing in this context. Careful rhythm monitoring and individualised management strategies are essential in families with inherited arrhythmia syndromes exhibiting variable phenotypic expression.