Yao syndrome (YAOS) is a NOD2-associated autoinflammatory disease marked by periodic fevers, dermatitis, polyarthritis, distal extremity swelling, and nearly universal gastrointestinal symptoms. A recent study was the first to comprehensively assess the gastrointestinal symptoms and manifestations of YAOS, finding that most testing is normal, without gastrointestinal mucosal inflammation, and many patients have constipation and rectal evacuation disorders. Building on this foundation, this paper highlights future directions and research priorities in furthering the understanding of YAOS. These draw heavily from the literature on Crohn disease, which is also associated with NOD2 variants. These future research priorities include detailed genotype-phenotype correlation focusing on specific NOD2 variants, prospective, comprehensive gastrointestinal phenotyping, and multi-omics approaches to investigate genetic, microbiome, epigenetic, and environmental interactions underlying YAOS pathogenesis. Insights gained from such investigation may guide improved diagnostic criteria and targeted, personalized therapeutic development for patients with YAOS.

Yao syndrome, Autoinflammatory disease, NOD2, Microbiome, Crohn disease, Inflammatory bowel disease