International Cohort of Neonatal Timothy Syndrome

Abstract

<b><i>Introduction:</i></b> Timothy syndrome (TS) is an extremely rare, multisystem disorder classically associated with long QT, syndactyly, ventricular arrhythmias, and hypoglycaemia. A neonatal diagnosis allows maximal medical and device therapy to be implemented to avoid malignant arrhythmias and sudden cardiac death. <b><i>Methods:</i></b> This was a retrospective case series study of type I TS (TS1) patients using data from the Timothy Syndrome Foundation’s international registry, encompassing patients with a genetic diagnosis (<i>CACNA1C</i> variant G406R in exon 8A) recruited over a 28-year period. <b><i>Results:</i></b> Forty-four cases of TS1 were included (26 male; 60%). Mean gestational age (GA) was 35.6 weeks (range 28 weeks – term), with 43% of patients born less than 37 weeks GA. In TS1 patients presenting with foetal bradycardia, mean GA was significantly lower (34.2 weeks, <i>p</i> &lt; 0.05). Foetal bradycardia secondary to atrioventricular block was present in 20 patients (45%), resulting in premature delivery in 14 patients (32%). Fifteen patients (34%) were diagnosed with TS1 as neonates. Long QT at birth helped secure a diagnosis in 25 patients (57%). Syndactyly was seen in most patients (<i>n</i> = 40, 91%). Twenty patients died, with an average age of death of 2.3 years (range 1 month–6 years). Of the 7 patients who died before the first year of life (16%), the average age of death was 2.5 months. <b><i>Conclusion:</i></b> TS is associated with high early mortality. TS should be considered in paediatric patients presenting with long QT and syndactyly. Recognition of TS in the neonatal period allows for early intervention to prevent life-threatening arrhythmias.