When inflammation becomes a TRAP

Introduction: Genetic alterations in components of inflammatory pathways can lead to autoinflammatory syndromes. The tumor necrosis factor receptor associated protein 1 (TRAP1) is a mitochondrial-specific Hsp90 chaperone involved in suppression of mitochondrial reactive oxygen species production, regulation of mitochondrial bioenergetics and inhibition of succinate dehydrogenase activity. It is critical for inducing pro-inflammatory gene expression in activated macrophages. Recently, bi-allelic loss-of-function variants in TRAP1 were identified in four patients with autoinflammation. Functional studies confirmed their contribution to autoinflammation, cellular stress and elevated serum IL-18. We describe two unrelated Argentinean patients with clinical features of autoinflammation and rare bi-allelic variants in TRAP1.

Case Reports: Pt 1: Male 13 years (ys) old. CMV congenital infection with calcifications in CNS. Onset at 2ys: recurrent fever, rash, arthralgias, pericardial effusion, convulsions, leukocytosis, anemia, thrombocytopenia; high sferritin level, sCD25, acute phase reactants and low fibrinogen. Bone marrow: hemophagocytosis. Diagnosis: macrophage activation syndrome (MAS) that resolved with IVIG. 2nd Flare: 2ys 10 months new episode of prolonged fever with hiperinflammation status occurred and transient response to steroids. At 3ys of age, diagnosis of probable systemic-onset juvenile idiopathic arthritis with MAS was done. Treatment: steroids, cyclosporine and anti IL-6R (this one, stopped by adverse reaction). Subsequently, he developed multifocal sterile osteomyelitis with neutrophil infiltration. Next-generation sequencing (NGS) panel: bi-allelic VUS variants in TRAP1: S107A and A571T.
Pt 2: Female 16ys. Onset at 12ys: hyperinflammatory syndrome: fever, rash, aseptic meningitis, lymphoproliferation, myalgia, and elevated acute-phase reactants and sferritin level. Immunological laboratory was unremarkable. Partial response to steroids plus cyclosporine. Off-label anti-IL1 was administered reaching clinical remission. NGS panel: bi-allelic VUS variants in TRAP1: H72Y and Ter705Cysext*?

Discussion: We describe two patients with autoinflammatory features and variants in TRAP1. Autoinflammatory diseases faces diagnostic and therapeutic challenges. Further research is needed to establish the pathological role of TRAP1 in autoinflammatory diseases.

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