{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T15:23:55Z","timestamp":1783351435876,"version":"3.54.6"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T00:00:00Z","timestamp":1706486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To assess the impact conferred by <jats:italic>NOD2<\/jats:italic> variants on the clinical spectrum of patients with systemic autoinflammatory diseases (SAIDs) in Greece.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Consecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing (NGS) targeting 26 SAID-associated genes, and carried at least one <jats:italic>NOD2<\/jats:italic> gene variant, were retrospectively studied. The demographic, clinical and laboratory parameters were recorded.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In total, 24 rare <jats:italic>NOD2<\/jats:italic> variants in 23\/167 patients (14%) were detected. Notably, 18 patients had at least one co-existing variant in 13 genes other than <jats:italic>NOD2<\/jats:italic>. Nine patients had juvenile- and 14 adult-onset disease. All patients presented with symptoms potentially induced by the <jats:italic>NOD2<\/jats:italic> variants. In particular, the candidate clinical diagnosis was Yao syndrome (YAOS) in 12 patients (7% of the whole SAID cohort). The clinical spectrum of patients with YAOS (mean episode duration 8 days) was fever (n=12\/12), articular symptoms (n=8), gastrointestinal symptoms (n=7; abdominal pain\/bloating in 7; diarrhea in 4; oral ulcers in 3), serositis (n=7), and rash (n=5), while the inflammatory markers were elevated in all but one patient. Most of these patients showed a poor response to nonsteroidal anti-inflammatory drugs (n=7\/9), colchicine (n=6\/8) and\/or anti-TNF treatment (n=3\/4), while a complete response was observed in 6\/10 patients receiving steroids and 3\/5 on anti-IL1 treatment. Another 8 patients were diagnosed with either FMF (n=6) or PFAPA syndrome (n=2) presenting with prominent diarrhea (n=7), oral ulcers (n=2), periorbital swelling and sicca-like symptoms (n=1), or maculopapular rash (n=1). One patient had a clinically undefined SAID, albeit characterized by oral ulcers and diarrhea. Finally, one patient presented with chronic relapsing urticaria with periorbital edema and inflammatory markers, and another one had a Crohn-like syndrome with good response to anti-IL-1 but refractory to anti-TNF treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>NOD2<\/jats:italic> variants were detected in 1 out of 7 SAID patients and seem to have an impact on disease phenotype and treatment response. Further studies should validate combined molecular and clinical data to better understand these distinct nosological entities.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1342668","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T04:35:21Z","timestamp":1706502921000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature 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