Pos0372 Tnfrsf11a as a Causative Gene in Systemic Autoinflammatory Diseases: A Case Series of 12 Patients

Background: Limited evidence suggests that TNFRSF11A as a causative gene in systemic autoinflammatory diseases (SAIDs) [1,2]. Objectives: To estimate the prevalence of TNFRSF11A variants in a cohort of patients with SAIDs and describe their disease phenotypic expression. Methods: Consecutive patients (n=167) with confirmed SAIDs who underwent screening by next generation sequencing targeting 26 SAID-associated genes, including TNFRSF11A, were included in this study. The demographic, clinical and laboratory parameters of those carrying at least one TNFRSF11A gene variant were recorded. Results: A total of 12 out of 167 patients, 7 males, aged (median) 38 years at disease onset, yielded at least one TNFRSF11A rare variant. All patients carried a coexisting variant in at least one of 10 other SAID-related genes, most frequently MEFV (6 patients), but also TNFRSF1A, NOD2, NLRP3, NLRP7, MVK, IL36RN, RBCK1, PLCG2 and PSMB8. Disease episodes lasting (median) 9 days manifested most frequently with high grade fever (91%), myalgias (75%), malaise (67%), serositis (58%), arthralgias/arthritis (58%), gastrointestinal involvement (33%), and rash (25%), and responded well to corticosteroids. The most common initial clinical diagnosis was TNF-associated periodic fever syndrome (TRAPS), nevertheless, genetic testing was consistent with this diagnosis in only one patient. The emergence of MEFV variations supported the diagnosis of Familial Mediterranean Fever in two cases, albeit with atypical clinical features, whereas the diagnosis of Yao syndrome was considered in two patients with NOD2 variants. The presence of atypical disease in these patients as well as the inability to define diagnosis in the remaining 7 cases, raised thoughts about the possible involvement of TNFRSF11A variants in the phenotypic expression of SAIDs. Conclusion: Herein, we provide first evidence in a case series that TNFRSF11A gene variants, occurring in 7% of SAID patients, contribute to the development of an autoinflammatory syndrome resembling to TRAPS. Additional studies to confirm new pathogenic SAID pathways are clearly warranted. REFERENCES: [1] Jéru I, et al. Brief Report: Involvement of TNFRSF11A molecular defects in autoinflammatory disorders. Arthritis Rheumatol (Hoboken, NJ). 2014;66(9):2621–7. [2] De Jesus AA, Goldbach-Mansky R. Newly recognized Mendelian disorders with rheumatic manifestations. Curr Opin Rheumatol. 2015 Sep 1;27(5):511–9. Acknowledgements: NIL. Disclosure of Interests: None declared.