Exploring the role of NOD2 variants in pediatric undifferentiated recurrent fever: a clinical and functional perspective.
| Title: | Exploring the role of NOD2 variants in pediatric undifferentiated recurrent fever: a clinical and functional perspective. |
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| Authors: | Taşkın RB; Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Türkiye.; Kamiloğlu AH; Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Türkiye.; Bara B; Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Türkiye.; Akyol G; Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Türkiye.; Aydın İ; Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Türkiye.; Aytac G; Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Türkiye.; Karaca NE; Department of Pediatric Immunology, Ege University Faculty of Medicine, Izmir, Türkiye.; Aksu G; Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Türkiye.; Department of Pediatric Immunology, Ege University Faculty of Medicine, Izmir, Türkiye.; Berdeli A; Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Türkiye.; Molecular Genetics Laboratory, Department of Pediatrics, Ege University Faculty of Medicine, Izmir, Türkiye.; Bozok V; Department of Medical Biology, Ege University Faculty of Medicine, Izmir, Türkiye.; Kütükçüler N; Department of Pediatric Rheumatology, Ege University Faculty of Medicine, Izmir, Türkiye.; Department of Pediatric Immunology, Ege University Faculty of Medicine, Izmir, Türkiye. |
| Source: | Frontiers in immunology [Front Immunol] 2025 Nov 21; Vol. 16, pp. 1657782. Date of Electronic Publication: 2025 Nov 21 (Print Publication: 2025). |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| MeSH Terms: | Hereditary Autoinflammatory Diseases*/blood ; Hereditary Autoinflammatory Diseases*/drug therapy ; Hereditary Autoinflammatory Diseases*/genetics ; Nod2 Signaling Adaptor Protein*/genetics; Cytokines/blood ; NF-kappa B/metabolism ; Colchicine/therapeutic use ; Gout Suppressants/therapeutic use ; Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Young Adult ; Follow-Up Studies ; Longitudinal Studies ; MAP Kinase Signaling System |
| Abstract: | Introduction: Syndrome of Undifferentiated Recurrent Fever (SURF) is an autoinflammatory disorder with onset in childhood, marked by recurrent episodes of fever without an established molecular diagnosis. Although NOD2 gene variants that are generally considered non-pathogenic are often identified in these patients, their contribution to disease development is still not well understood.; Methods: This study aimed to assess the clinical characteristics, long-term progression, and functional implications of NOD2 variants in a group of twelve children diagnosed with SURF, along with two Blau syndrome cases and two healthy controls. Clinical information was gathered at presentation and during follow-up. Peripheral blood mononuclear cells were examined for cytokine secretion and NF-kB pathway activation, both at baseline and following muramyl dipeptide stimulation, using multiplex cytokine analysis, Western blot, and ELISA.; Results: The median follow-up period was 3.75 years, with most children developing symptoms before 10 years of age. Abdominal pain and limb pain were the most frequent complaints. All patients were treated with colchicine, and selected cases required corticosteroids or disease-modifying antirheumatic drugs. Elevated levels of proinflammatory cytokines, including IL-2, TNF-a, IL- 6, and IL-8, were observed in SURF patients. Our functional studies suggested that variants like R702W, G908R, P268S/V955I, and R702W/P268S might have triggered stronger inflammatory responses, whereas L682F, L1007fs, and R587C might have been linked to diminished cytokine production and lower NF-kB activity. Certain variants, such as A1000T and P268S, appeared to show baseline NF-kB activation with moderate inflammatory activity.; Discussion: Our findings emphasize the clinical and functional diversity of NOD2 variants in SURF and may point to a possible genotype-phenotype relationship that could aid in understanding disease pathways and refining diagnostic approaches.; (Copyright © 2025 Taşkın, Kamiloğlu, Bara, Akyol, Aydın, Aytac, Karaca, Aksu, Berdeli, Bozok and Kütükçüler.) |
| Competing Interests: | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. |
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| Contributed Indexing: | Keywords: NOD2; autoinflammation; autoinflammatory disease; cytokines; mutation; pediatric; recurrent fever; undifferentiated fever |
| Substance Nomenclature: | 0 (Cytokines); 0 (NF-kappa B); 0 (NOD2 protein, human); 0 (Nod2 Signaling Adaptor Protein); SML2Y3J35T (Colchicine); 0 (Gout Suppressants) |
| Entry Date(s): | Date Created: 20251208 Date Completed: 20251215 Latest Revision: 20251215 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12678341 |
| DOI: | 10.3389/fimmu.2025.1657782 |
| PMID: | 41357180 |
| Database: | MEDLINE |
Journal Article