TNFRSF11A variants contribute to systemic autoinflammatory diseases: A case series of 12 patients

• Published in: Seminars in arthritis and rheumatism 2024-10, Vol.68, p.152505, Article 152505
• Main Authors: Papatheodorou, Vasileios, Gerodimos, Charalampos, Dimitrakopoulos, Antonios, Lada, Efrosini, Tektonidou, Maria G, Germenis, Anastasios, Sfikakis, Petros P, Laskari, Katerina
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Autoinflammatory disease; Female; Gene variation; Genetic Predisposition to Disease; Hereditary Autoinflammatory Diseases - diagnosis; Hereditary Autoinflammatory Diseases - genetics; Humans; Male; Middle Aged; Mutation; Nod2 Signaling Adaptor Protein - genetics; Phenotype; Pyrin - genetics; Receptors, Tumor Necrosis Factor, Type I - genetics; TNFRSF11A; Young Adult
• ISSN: 0049-0172; 1532-866X; 1532-866X
• DOI: 10.1016/j.semarthrit.2024.152505

•TNFRSF11A gene variants occur in 7% of SAID patients.•Variations in TNFRSF11A gene contribute to TRAPS11 periodic syndrome.•We recommend TNFRSF11A screening in patients with unclassified disease with long-lasting episodes and features resembling to TRAPS. Limited evidence suggests that variants in TNFRSF11A gene, encoding RANK, may contribute to systemic autoinflammatory disease (SAID). To estimate the prevalence of TNFRSF11A variants in a cohort of patients with SAIDs screened for 26 related genes and describe the disease phenotypic expression. 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 other SAID-related gene, most frequently MEFV (6 patients), but also TNFRSF1A, NOD2, NLRP3, NLRP7, MVK, IL36RN, RBCK1, PLCG2 and PSMB8. SAID episodes lasting (median) 9 days manifested with high grade fever (91%), myalgias (75%), malaise (67%), serositis (58%), arthralgias/arthritis (58%), gastrointestinal involvement (33%), and rash (25%), and responded to corticosteroids. The most common initial clinical diagnosis was TNF-associated periodic fever syndrome (TRAPS), which was, however, confirmed, in only one patient. The emergence of MEFV variations supported the diagnosis of atypical Familial Mediterranean Fever in two cases, whereas the diagnosis of Yao syndrome was speculated in two patients with NOD2 variants. The presence of atypical disease and the inability of defining diagnosis in the remaining 7 patients, supported the possible involvement of TNFRSF11A variants in the phenotypic expression of SAIDs. TNFRSF11A variants, occurring in 7% of SAID patients always in combination with other SAID-related gene variants, contribute to the development of an autoinflammatory syndrome resembling to TRAPS. Additional studies to confirm novel pathogenic SAID pathways are clearly warranted. [Display omitted]