Early Severe Moyamoya Disease Due to a Monoallelic RNF213 Variant in Monozygotic Twins

Abstract

Moyamoya disease (MMD) is an arteriopathy causing pediatric ischemic stroke and is characterized by progressive stenosis of the intracranial internal carotid arteries. Although genetic risk factors have been identified, the pathogenesis of MMD remains incompletely understood, and significant gaps persist in linking genetic variation to disease mechanisms and outcomes. We describe ex-30 week monozygotic twins presenting with recurrent ischemic events beginning in infancy found to have bilateral terminal internal carotid artery stenosis consistent with MMD. Two rounds of clinical genetic testing were performed, revealing a novel de novo missense variant in RNF213. Both children were managed with maximal medical therapy, including antiplatelet treatment, but experienced ongoing infarcts, ultimately requiring surgical revascularization. Intraoperative identification of robust superficial temporal arteries allowed bilateral pial synangiosis in both patients. These findings underscore the importance of selecting appropriately broad genetic testing strategies in pediatric stroke and MMD because rapid 2000-gene panel failed to initially capture causal variants. The identified RNF213 variant is predicted to disrupt a salt bridge critical for protein folding and function, providing possible mechanistic insight into pediatric onset vasculopathy, and uncovering a localized hotspot for pathogenic variants. These observations expand the spectrum of RNF213-associated MMD and inform approaches to early-onset disease.