Definition and genetics
TNF receptor-associated periodic syndrome (TRAPS) is a monogenic autoinflammatory disease caused by heterozygous mutations in TNFRSF1A (chromosome 12p13), which encodes the 55-kDa TNF receptor (TNFR1/p55). Inheritance is autosomal dominant with variable penetrance and expressivity. Mutations — predominantly affecting cysteine residues in the extracellular domain — cause misfolding and intracellular retention of the receptor, with defective shedding and an intracellular stress response that drives exaggerated, IL-1-dependent inflammation. Low-penetrance variants (notably R92Q and P46L) are common in the general population and produce a milder, more variable phenotype. TRAPS occurs across all ethnicities and was historically described in northern European (“familial Hibernian fever”) kindreds.
Episode pattern
TRAPS is distinguished from FMF by long attacks. Episodes typically last more than 5 days and often 1–3 weeks (sometimes longer), recurring at irregular intervals. Onset is usually in childhood but can be delayed to adulthood. Attacks may be triggered by stress, minor trauma, infection, or hormonal changes, and inter-attack intervals are less regular than the term “periodic” implies. The prolonged attack duration is one of the most useful bedside discriminators: where FMF resolves within days, TRAPS smoulders for one to several weeks, and the slow build-up and resolution can blur the boundary between attack and recovery.
Clinical features
Fever accompanies a characteristic constellation: migratory myalgia due to monocytic fasciitis, with an overlying centrifugal, migratory erythematous rash that tracks distally over the affected muscle group; periorbital oedema with conjunctivitis (a near-signature finding); abdominal pain (often with peritoneal signs); pleuritic chest pain; arthralgia; and large-joint arthritis. Acute-phase reactants are markedly elevated during attacks and frequently remain elevated between them, reflecting persistent subclinical inflammation.
Diagnosis
Diagnosis rests on the clinical phenotype plus TNFRSF1A sequencing. Cysteine-residue and other structural mutations are highly informative; low-penetrance variants (R92Q, P46L) require cautious clinical correlation. The 2019 Eurofever/PRINTO classification criteria combine genetic and clinical variables to separate TRAPS from FMF, MKD/HIDS, and CAPS.
See the full criteria: TNF Receptor-Associated Periodic Syndrome (TRAPS)
Red flags
- AA (secondary) amyloidosis — the major long-term complication, with the highest reported rate among the classic hereditary recurrent fevers (notably in cysteine-mutation genotypes). Monitor inter-attack SAA/CRP and screen for proteinuria; nephrotic-range proteinuria signals renal amyloid.
- Persistently elevated acute-phase reactants between attacks.
- Periorbital oedema with prolonged (>1 week) febrile attacks — supports TRAPS over FMF.
Management overview
Attacks are glucocorticoid-responsive but colchicine-unresponsive — a useful pharmacological discriminator from FMF — though escalating steroid requirements are undesirable for chronic control. IL-1 blockade (e.g. canakinumab, anakinra) is the mainstay for controlling attacks and suppressing inflammation to protect against amyloidosis. TNF inhibition with the soluble-receptor fusion protein has been used historically but is less reliable, and anti-TNF monoclonal antibodies may paradoxically worsen disease and are avoided. (Therapeutic classes only — confirm agent, dose, and monitoring against current formularies.)
References
- Gattorno M, et al. Ann Rheum Dis. 2019;78:1025–1032 (Eurofever/PRINTO).
- Hull KM, et al. Medicine (Baltimore). 2002;81:349–368.
- Lachmann HJ, et al. Ann Rheum Dis. 2014;73:2160–2167.
- Nelson Textbook of Pediatrics, 21st ed.
Decision support for qualified clinicians only — verify against current primary guidelines and your clinical judgement.