A Novel TNFRSF1A Gene Variant in a Patient with Recurrent Fevers and Amyloidosis: A Case Report

Background TNF Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder. It is caused by pathogenic variants in the TNFRSF1A gene which encodes the TNF receptor 1. These mutations impair receptor shedding and disrupt TNFα signaling, leading to uncontrolled inflammation with recurrent fever, serositis, and myalgia.[1] Left untreated, chronic inflammation may result in AA amyloidosis and end-stage renal disease (ESRD). Early recognition and treatment with IL-1 inhibitors can mitigate deterioration and prevent irreversible complications such as amyloidosis. Here we present a case of TRAPS complicated by amyloidosis and associated with a novel variant in TNFRSF1A.

Case Report A 48-year-old male was referred for early childhood onset, recurrent 3-5-day febrile episodes accompanied by severe abdominal pain, large joint arthralgias and myalgias. He was treated intermittently with corticosteroids and NSAIDs, with incomplete response. At 43 years old he developed chronic kidney disease with renal biopsy compatible with amyloidosis. This eventually progressed to ESRD requiring hemodialysis. Genetic testing was performed when he was 48 years old and revealed a heterozygous missense variant in TNFRSF1A (c.214_215delinsCT, p.Cys72Leu). The mutation resides in exon 3 within the extracellular cysteine-rich domain, and was predicted to disrupt disulfide bond formation, resulting in misfolded receptor protein and defective TNFα signaling. Substitutions at the same residue (Cys72Arg, Cys72Ser) had been previously demonstrated to be causative for TRAPS.[2] His asymptomatic parents did not carry the mutation. As such, this de novo Cys72Leu variant was classified as Likely Pathogenic, and the patient was diagnosed with TRAPS. Anakinra 100 mg SC daily was started which prevented further attacks. However, he remains on hemodialysis and is on the waitlist for renal transplant.

Conclusion In summary, our case highlights the importance of early recognition of autoinflammatory diseases like TRAPS, in order to initiate targeted treatment and prevent life altering complications such as amyloidosis and ESRD. We report a novel variant in the TNFRSF1A gene, adding to the literature of mutations causing TRAPS. Further studies are needed to functionally characterize the biological impact of Cys72Leu, as well as to elucidate the complex mechanisms between TNF receptor dysfunction and IL-1 signaling.

References [1.] Gaggiano C. Mediators Inflamm 2020;7:8562485. [2.] Lachmann HJ. Ann Rheum Dis 2014;73:2160-7.