SCIENTIFIC BACKGROUND

TNFRSF1A

Category:

TNF receptor-1-associated periodic syndrome (TRAPS) is a rare congenital periodic fever syndrome and it is inherited in an autosomal dominant manner with reduced penetrance. On average, the first symptoms appear in the 3rd year of life, but the disease may manifest in adulthood. TRAPS can affect patients of any ethnicity. Clinically, TRAPS is characterized by recurrent febrile episodes lasting from about 7 days to several weeks. The attacks are often accompanied by severe abdominal pain, myalgias, arthralgias, conjunctivitis and/or periorbital edema, and migratory erysipelas-like erythema. Between relapses, most patients are asymptomatic. However, subclinical inflammation leads to amyloidosis in approximately 20% of untreated or late-diagnosed TRAPS patients, primarily affecting the kidneys. Symptomatic therapy is the administration of steroids. The soluble TNF-α receptor etanercept may represent an alternative therapeutic option, especially in the presence of a receptor cleavage defect. Patients with mutations of the cysteine residues of the TNF receptor show a good clinical and laboratory response to therapy with anakinra (IL-1 receptor blocker).

 

The cause of the disease is variants in the TNFRSF1A gene (TNF receptor superfamily-1A), which encodes the cell membrane-bound receptor TNFR1 (also TNFR p55). The binding of TNF-α to the receptor leads to cytokine secretion, leukocyte activation, and fever, among other effects. As a negative feedback loop, the extracellular portion of the receptor is shed from the surface after stimulation and traps free TNF-α in soluble form. Almost all of the more than 70 known mutations (predominantly missense mutations) are located in exons 2-4 and 6, which encode the first two extracellular receptor domains and the cleavage site.

 

References

Gattorno et al. 2019, Ann Rheum Dis 78:1025 / ter Haar et al. 2015, Ann Rheum Dis 74:1636 / Lainka et al. 2009, Rheumatology 48:987 / Aksentijevich et al. 2001, Am J Hum Genet 69:301

GENES
TNFRSF1A
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