Discussion

Restrictive cardiomyopathy in the paediatric population is characterised not only by progressive diastolic dysfunction but also by a high burden of complications, notably thromboembolic events. The overall prognosis remains poor, with a 5-year cumulative incidence of heart transplantation reaching 58% in those with a pure restrictive phenotype, reflecting the aggressive natural course of the disease. ^{Reference Zampieri, Di Filippo and Zocchi3} Thromboembolism, in particular, significantly contributes to morbidity and mortality and may be the initial or sole presenting feature in some cases. ^{Reference Al-Shammari, Muslim and Almuslim7}

Multiple reports underscore the elevated thromboembolic risk in children, irrespective of underlying rhythm abnormalities. A wide range of thrombus incidence has been reported, from 0% to 42%, with embolism rates between 12% and 33%, highlighting the need for early and routine surveillance strategies. ^{Reference Ditaranto, Caponetti and Ferrara2} The mechanisms predisposing to thrombus formation are multifactorial, including marked biatrial enlargement, low intracavitary flow velocities, and structural distortion of atrial anatomy. While atrial fibrillation has long been recognised as a prothrombotic substrate, paediatric cases demonstrate that even in sinus rhythm, significant thrombotic complications may arise. ^{Reference Al-Shammari, Muslim and Almuslim7–Reference Yamamoto, Itamoto and Hayashi9}

Case reports further illuminate the severity of this phenomenon. Turhan et al. described a child who developed a free-floating left atrial ball thrombus during sinus rhythm, leading to the recognition that atrial contractile dysfunction alone may suffice to generate life-threatening emboli. ^{Reference Turhan, Ocal, Erbay, Yasar, Cicekcioglu and Yetkin8} Similarly, Yamamoto et al. reported recurrent pulmonary thromboembolism originating from the right atrial appendage in a patient without atrial fibrillation, underscoring that even in the absence of conventional arrhythmic risk factors, restrictive physiology itself predisposes to thrombus formation. ^{Reference Yamamoto, Itamoto and Hayashi9} Al-Shammari et al. presented a dramatic case of acute bilateral lower limb ischaemia due to complete aortic and iliac artery occlusion by emboli from atrial thrombi in a child with idiopathic RCM, further illustrating the catastrophic potential of this complication. ^{Reference Al-Shammari, Muslim and Almuslim7}

Although most literature on atrial thrombosis in RCM stems from adult cohorts, emerging paediatric data support the proactive use of antithrombotic therapy. Given the absence of reliable predictors for thromboembolic events and the unpredictability of their timing, current expert opinion favours the early initiation of anticoagulation upon diagnosis, even in asymptomatic children or those without arrhythmia. ^{Reference Ditaranto, Caponetti and Ferrara2,Reference Chen, Williams, Chan and Mondal5} This approach is bolstered by genetic studies reporting fatal thrombotic events in family members carrying pathogenic sarcomeric gene mutations, suggesting that certain genetic backgrounds may confer an intrinsic thrombotic predisposition. ^{Reference Denfield and Webber10}

Our case highlights the coexistence of significant thromboembolic complications and malignant arrhythmias in paediatric restrictive cardiomyopathy. The patient developed recurrent, multisystem embolic events, including ischaemic stroke, bilateral lower limb ischaemia, renal infarctions, despite being in sinus rhythm for most of the clinical course. Serial imaging revealed intracardiac thrombi, emphasising the contribution of atrial dilation and impaired flow dynamics to thrombus formation in the absence of atrial fibrillation. Also genetic testing identified heterozygous variants in β-fibrinogen 455 G/A and MTHFR A1298C, suggesting a prothrombotic predisposition. The β-fibrinogen 455 G/A polymorphism has been shown to be associated with left atrial thrombus formation and severe spontaneous echo contrast in patients with atrial fibrillation, suggesting a role as a genetic risk modifier for thromboembolism. ^{Reference Bozdemir, Kirimli and Akdeniz11} In addition, meta-analytic data indicate that the β-fibrinogen 455 G/A polymorphism is associated with an increased risk of ischaemic stroke, supporting its contribution to thromboembolic susceptibility in genetically predisposed individuals. ^{Reference Luo, Li and Jiang12} Parallel to these findings, studies in non-valvular atrial fibrillation-related cardioembolic stroke cohorts have demonstrated that MTHFR polymorphisms, especially the A1298C variant, are associated with greater stroke severity and recurrence. ^{Reference Chita, Tudor and Christodorescu13} Moreover, MTHFR variants, including A1298C, have been linked to an increased risk of venous thromboembolism independent of plasma homocysteine levels, pointing toward a genotype-driven thrombotic risk rather than a purely metabolic mechanism. ^{Reference Liu, Silva, Malone and Seetharaman14} In our patient, the coexistence of MTHFR A1298C and β-fibrinogen 455 G/A variants may have acted as synergistic genetic risk modifiers, contributing to the pronounced thromboembolic phenotype observed despite the absence of atrial arrhythmias.

Arrhythmias, although not always the primary trigger, remain closely linked to thromboembolism. Approximately 15% of paediatric patients develop clinically significant rhythm disturbances, ^{Reference Denfield and Webber10} while some studies report arrhythmia rates as high as 60%, including atrial fibrillation, Atrioventricular blocks, supraventricular tachycardias, and ventricular tachyarrhythmias. ^{Reference Wittekind, Ryan and Gao15} Continuous rhythm monitoring is thus essential for risk stratification and management. Although Wittekind et al. found no direct association between arrhythmias and outcomes, likely due to preemptive ICD or pacemaker implantation, rhythm disturbances may exacerbate intracardiac turbulence and increase the risk of thrombus embolisation. ^{Reference Wittekind, Ryan and Gao15} Moreover, Walsh et al. emphasised the association between conduction abnormalities and sudden cardiac events, reinforcing the need for prophylactic pacing in selected cases.Reference Walsh, Grenier, Jefferies, Towbin, Lorts and Czosek ¹⁶

In our patient, pulseless ventricular tachycardia occurred and required ICD placement, a life-threatening arrhythmic complication that has also been described in previous paediatric cases. This observation highlights the malignant arrhythmic potential of restrictive cardiomyopathy in children and supports the need for early rhythm surveillance and timely consideration of device therapy, even in the absence of preceding atrial arrhythmias.

Our case differs from previously reported paediatric restrictive cardiomyopathy cases in several important aspects. Unlike many reports in which thromboembolic events were isolated, preceded by atrial arrhythmias, or limited to a single vascular territory, our patient experienced recurrent, multisystemic thromboembolism involving the cerebral, peripheral, renal, and intracardiac circulations despite sustained sinus rhythm for most of the disease course. Furthermore, the thromboembolic burden progressed over time and persisted despite initial anticoagulation, ultimately coinciding with malignant ventricular arrhythmia requiring ICD implantation. In addition to advanced atrial remodelling and restrictive physiology, the identification of concomitant heterozygous prothrombotic genetic variants (β-fibrinogen 455 G/A and MTHFR A1298C) distinguishes this case and suggests a cumulative genetic contribution to thromboembolic susceptibility.