Introduction: Hypomethylation at the imprinting control region 2 (IC2) on chromosome 11p15.5 is the commonest identifiable cause of Beckwith-Wiedemann Syndrome (BWS). IC2 is located in KCNQ1 intron 10 and is associated with Long QT syndrome (LQTS). A recent consensus statement on BWS1 recommends annual cardiac evaluation with electrocardiogram (ECG) in these patients. The natural history of LQTS secondary to hypomethylation at IC2 in BWS is unknown, despite it being the commonest aetiology. It is also unknown whether adequate attention is paid to the risk of arrhythmias in patients with IC2 lesions by multidisciplinary teams managing patients with this condition. Sudden death due to ion channel disease is made on the strength of negative autopsy with ECG, personal or family history or molecular diagnosis of ion channel pathology2. We report a case of infant death attributed to arrhythmia associated with BWS.
Case Report: A female neonate from in-vitro fertilisation, born to a primigravida mother with benign intracranial hypertension, presented with hypoglycaemia on day four of life. Congenital hyperinsulinism was confirmed and responded to diazoxide (10mg/kg/day) and chlorothiazide (6.5mg/kg/day). She had gastroesophageal reflux disease, which responded to ranitidine. A swallow assessment showed safe swallow. Cardiac assessment was normal. She tolerated a six hour fast prior to discharge and following this, blood glucose control was excellent. Genetic tests confirmed BWS with hypomethylation at KCNQ1OT1: TSS-DMR located within 11p15.5.
At four months of life, the mother was playing with the child in her arms when she suddenly became floppy and blue. Resuscitation failed and she was pronounced dead. Hypoglycemia was excluded and an autopsy, including toxicology, found no cause of death. There was no milk in the tracheo-bronchial tree and no histological abnormalities in the lungs or oesophagus. The pancreas showed the histology of diffuse hyperinsulinism. Cause of death was considered to be due to arrhythmia.
Conclusion: This is to our knowledge, the first report of an infant death attributed to arrhythmia associated with BWS. Prospective studies are required to examine the natural history of cardiac arrhythmia in BWS patients with IC2 abnormalities. Given the location of IC2 in the KCNQ1 gene it is possible that mutations, both genetic and epigenetic, may give rise to both BWS and LQTS.
Reference: 1. Nature Reviews Endocrinology volume 14, pages 229249 (2018)
2. Basso C. Postmortem diagnosis in sudden cardiac death victims: macroscopic, microscopic and molecular findings. Cardiovascular Research 50: 290300, 2001.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology