Case Report: Overlap of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia in two Chinese children with CALM2-related calmodulinopathy

Introduction Calmodulinopathy is a rare CALM -related hereditary channelopathy presenting with long QT syndrome (LQTS), less commonly with catecholaminergic polymorphic ventricular tachycardia (CPVT) or LQTS/CPVT overlap. It carries high mortality and limited data from Chinese population. Methods We reviewed two Chinese children with CALM2 mutation-related LQTS/CPVT overlap. Clinical data, genetic findings, and treatments were collected; outcomes were obtained via telephone follow-up. A systematic literature review was also performed. Results Case 1 was a 13-year-old girl with seven exercise-induced syncopal episodes. Sinus rhythm QTc 0.55 s, with bidirectional/polymorphic premature ventricular contractions, and ventricular tachycardia during exercise. A de novo CALM2 p.E140Q mutation was found. She remained event-free on propranolol and propafenone for two years. Case 2 was a 15-year-old boy with onset at 4 years. He experienced > 10 syncopal episodes triggered by recurrent exercise or emotional stress. Initial Holter monitoring revealed sinus bradycardia with a mean heart rate of 70 bpm and a maximum QTc of 0.51 s. A de novo CALM2 p.N98S mutation was found. Despite treatment with propranolol plus mexiletine, syncopal episodes continued, with the QTc interval further prolonged to 0.62 s. The p.E140Q variant is novel, whereas p.N98S has been previously reported. Literature suggests that β-blockers combined with Class Ic drugs may be more effective, and implantable cardioverter defibrillator (ICD) implantation should be considered in cases who respond poorly to medical therapy or survivors of aborted cardiac arrest. Patients who experience recurrent syncope coexisting with significant sinus bradycardia may have more severe phenotypes with higher risk of malignant arrhythmias, warranting earlier or more aggressive evaluation for device therapy. Conclusion Genetic testing is recommended for suspected pediatric channelopathies with phenotype-guided individualized treatment.