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Tumor necrosis factor receptor-associated periodic syndrome

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Description

Tumor necrosis factor receptor-associated periodic syndrome (commonly known as TRAPS) is a condition characterized by recurrent episodes of fever. These fevers typically last about 3 weeks but can last from a few days to a few months. The frequency of the episodes varies greatly among affected individuals; fevers can occur anywhere between every 6 weeks to every few years. Some individuals can go many years without having a fever episode. Fever episodes usually occur spontaneously, but sometimes they can be brought on by a variety of triggers, such as minor injury, infection, stress, exercise, or hormonal changes.

During episodes of fever, people with TRAPS can have additional signs and symptoms. These include abdominal and muscle pain and a spreading skin rash, typically found on the limbs. Affected individuals may also experience puffiness or swelling in the skin around the eyes (periorbital edema); joint pain; and inflammation in various areas of the body including the eyes, heart muscle, certain joints, throat, or mucous membranes such as the moist lining of the mouth and digestive tract. Occasionally, people with TRAPS develop amyloidosis, an abnormal buildup of a protein called amyloid in the kidneys that can lead to kidney failure. It is estimated that 15 to 20 percent of people with TRAPS develop amyloidosis, typically in mid-adulthood.

The fever episodes characteristic of TRAPS can begin at any age, from infancy to late adulthood, but most people have their first episode in childhood.

Frequency

TRAPS has an estimated prevalence of one per million individuals; it is the second most common inherited recurrent fever syndrome, following a similar condition called familial Mediterranean fever. More than 1,000 people worldwide have been diagnosed with TRAPS.

Causes

TRAPS is caused by mutations in the TNFRSF1A gene. This gene provides instructions for making a protein called tumor necrosis factor receptor 1 (TNFR1). This protein is found within the membrane of cells, where it attaches (binds) to another protein called tumor necrosis factor (TNF). This binding sends signals that can trigger the cell either to initiate inflammation or to self-destruct. Signaling within the cell initiates a pathway that turns on a protein called nuclear factor kappa B that triggers inflammation and leads to the production of immune system proteins called cytokines. The self-destruction of the cell (apoptosis) is initiated when the TNFR1 protein, bound to the TNF protein, is brought into the cell and triggers a process known as the caspase cascade.

Most TNFRSF1A gene mutations that cause TRAPS result in a TNFR1 protein that is folded into an incorrect 3-dimensional shape. These misfolded proteins are trapped within the cell and are not able to get to the cell surface to interact with TNF. Inside the cell, these proteins clump together and are thought to trigger alternative pathways that initiate inflammation. The clumps of protein constantly activate these alternative inflammation pathways, leading to excess inflammation in people with TRAPS. Additionally, because only one copy of the TNFRSF1A gene has a mutation, some normal TNFR1 proteins are produced and can bind to the TNF protein, leading to additional inflammation. It is unclear if disruption of the apoptosis pathway plays a role in the signs and symptoms of TRAPS.

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. However, some people who inherit the altered gene never develop features of TRAPS. (This situation is known as reduced penetrance.) It is unclear why some people with a mutated gene develop the disease and other people with the mutated gene do not.

In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Other Names for This Condition

  • autosomal dominant familial periodic fever
  • familial Hibernian fever
  • FPF
  • TNF receptor-associated periodic fever syndrome
  • TRAPS

Additional Information & Resources

Genetic and Rare Diseases Information Center

Research Studies from ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • Aganna E, Hammond L, Hawkins PN, Aldea A, McKee SA, van Amstel HK, Mischung C, Kusuhara K, Saulsbury FT, Lachmann HJ, Bybee A, McDermott EM, La Regina M, Arostegui JI, Campistol JM, Worthington S, High KP, Molloy MG, Baker N, Bidwell JL, Castañer JL, Whiteford ML, Janssens-Korpola PL, Manna R, Powell RJ, Woo P, Solis P, Minden K, Frenkel J, Yagüe J, Mirakian RM, Hitman GA, McDermott MF. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum. 2003 Sep;48(9):2632-44. Citation on PubMed
  • Greco E, Aita A, Galozzi P, Gava A, Sfriso P, Negm OH, Tighe P, Caso F, Navaglia F, Dazzo E, De Bortoli M, Rampazzo A, Obici L, Donadei S, Merlini G, Plebani M, Todd I, Basso D, Punzi L. The novel S59P mutation in the TNFRSF1A gene identified in an adult onset TNF receptor associated periodic syndrome (TRAPS) constitutively activates NF-κB pathway. Arthritis Res Ther. 2015 Apr 3;17:93. doi: 10.1186/s13075-015-0604-7. Citation on PubMed or Free article on PubMed Central
  • Kimberley FC, Lobito AA, Siegel RM, Screaton GR. Falling into TRAPS--receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. Arthritis Res Ther. 2007;9(4):217. Review. Citation on PubMed or Free article on PubMed Central
  • Masson C, Simon V, Hoppé E, Insalaco P, Cissé I, Audran M. Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases. Joint Bone Spine. 2004 Jul;71(4):284-90. Review. Citation on PubMed
  • Pettersson T, Kantonen J, Matikainen S, Repo H. Setting up TRAPS. Ann Med. 2012 Mar;44(2):109-18. doi: 10.3109/07853890.2010.548399. Epub 2011 Feb 1. Review. Citation on PubMed
  • Rebelo SL, Bainbridge SE, Amel-Kashipaz MR, Radford PM, Powell RJ, Todd I, Tighe PJ. Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function. Arthritis Rheum. 2006 Aug;54(8):2674-87. Citation on PubMed
  • Rezaei N. TNF-receptor-associated periodic syndrome (TRAPS): an autosomal dominant multisystem disorder. Clin Rheumatol. 2006 Nov;25(6):773-7. Epub 2006 Jan 26. Review. Citation on PubMed
  • Wong KK, Jackson J, Whidborne R, Mallon D, Bennetts B, D'Orsogna LJ. Autosomal recessive transmission of TRAPS in a family with a novel TNFRSF1A mutation. Scand J Rheumatol. 2015 May;44(3):255-6. doi: 10.3109/03009742.2015.1005663. Epub 2015 Mar 6. Citation on PubMed
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