NORD gratefully acknowledges Ivona Aksentijevich, MD, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare multisystem genetic disorder characterized by unexplained periodic episodes or attacks of fever associated with additional symptoms including muscle pain (myalgia), abdominal pain, headaches and skin rashes. The specific symptoms can vary greatly from one person to another. The duration of the characteristic episodes can also vary, lasting anywhere from a couple days to one week to more than one month. Onset is usually during infancy or childhood. TRAPS is caused by mutations of the tumor necrosis factor receptor-1 (TNFRSF1A) gene that encodes the 55-kDa receptor for TNF.
The specific symptoms associated with TRAPS vary from one person to another. Nearly all affected individuals will develop recurrent episodes of high-grade fever, pain and inflammation. However, some individuals may only develop fever or only fever and abdominal pain. The duration of the episodes varies, but they usually last more than one week. Some individuals may experience constant inflammation.
Characteristic febrile episodes may also be accompanied by chills, abdominal pain, headaches, joint pain (arthralgia), chest pain, and muscle pain (myalgia), stiffness and tightness. Abdominal pain may be associated with nausea, vomiting, and diarrhea or constipation. Chest pain is caused by inflammation of the thin covering (pleura) that lines the lungs (pleuritis). In some cases, muscle pain is severe.
Muscle pain may be associated with skin lesions, specifically tender, warm, reddish (erythematous), raised plaques. Skin lesions develop during a febrile episode and they move from the proximal toward distal sites of the body. Skin lesions may last anywhere from a few days to three weeks. Skin lesions associated with TRAPS usually begin as tiny bumps (macules or papules) that spread and come together to form larger lesions (plaques).
When muscle pain (myaligia) underlies skin lesions, it also moves (migrates) following skin lesions. As muscle pain progresses, different joints and muscle groups become involved. Although joint pain occurs, arthritis rarely develops.
Individuals with TRAPS may also develop painful inflammation of the delicate membranes that line the inside of the eyelids (conjunctivitis). This may occur with or without swelling of the eyelids (periorbital edema). Additional symptoms that have been reported in males with TRAPS include testicular pain and a higher rate of inguinal hernia than is found in the general population. Inguinal hernia is a condition in which a portion of the intestines protrudes through a tear in the lower abdominal wall.
A serious complication that occurs in approximately 10-15 percent of TRAPS cases is amyloidosis, a condition in which specialized proteins called amyloids abnormally accumulate in various tissues and organs of the body. For example, amyloid may accumulate in the kidneys, impairing kidney function and potentially causing life-threatening complications such as kidney failure. Although the kidneys are most often affected, numerous other organs can potentially become involved.
TRAPS can occur randomly due to a spontaneous genetic change (i.e., new mutation) or it may be inherited as an autosomal dominant trait (a mutation that is received either from the father or the mother).
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
The TNFRSF1A gene is located on the short arm (p) of chromosome 12 (12p13.2). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 12p13.2” refers to band 13.2 on the short arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The TNFRSF1A gene contains instructions for creating (encoding) a specialized protein known as tumor necrosis factor receptor-1 (TNFR1, p55, CD120a). TNFR1 is found on the surface of most cells of the body and serves as a receptor for tumor necrosis factor (TNF). TNF is a protein that helps defend the body against infection and foreign substances. Specifically, TNF stimulates the body’s inflammatory response to infection. TNFR1 can receive and send signals that set off an inflammatory response within the body. These signals can be turned off when the TNF receptor detaches from the surface of the cell (a normal process called “shedding”). The loose receptors soak up excess TNF before it reaches cells, thereby preventing the signaling for the body’s inflammatory response. Mutations of the TNFRSF1A gene result in defective TNFR1 that cannot properly perform its normal functions. Defective TNFR1 allows for unchecked signaling of TNF, which causes an excessive inflammatory response by the body. The exact process by which defective TNFR1 results in TRAPS is under investigation.
The characteristic episodes of TRAPS may be triggered or worsened due to stress, minor trauma and exercise. However, no specific trigger is necessary for the development of episodes.
TRAPS was first described in the medical literature in 1982 in a large Irish family and initially termed familial Hibernian fever. The name was later changed when numerous individuals from other ethnic groups were identified to have mutations in the same gene, namely TNFRSF1A. TRAPS has been reported in individuals of many different ethnic groups, although initially many reported patients were of Scottish and Irish heritage. The exact incidence of the disorder is unknown, but there are couple of hundreds of cases reported in the literature. TRAPS is a rare disease that often goes undiagnosed or misdiagnosed making it difficult to determine the disorder’s true frequency in the general population.
A diagnosis of TRAPS is made based upon a thorough clinical evaluation, identification of characteristic symptoms (e.g., long lasting fever episodes), and blood tests for inflammatory markers. A diagnosis of TRAPS is usually confirmed by molecular genetic testing, which can identify either de novo or dominantly inherited heterozygous mutations in the TNFRSF1A gene. All TRAPS pathogenic variants are clustered in the exons 2-4, which encodes the extracellular domain of the protein. Most are missense nucleotide changes that affect the folding of the extracellular domain. Pathogenic variants in other protein domains maybe associated with another phenotype. There is also evidence for gonadal mosaicism in TRAPS, which can be found in patients with late onset symptoms. Genetic counseling is strongly recommended in families with TRAPS.
Therapy with high doses of corticosteroids (e.g., prednisone) is often successful at treating the characteristic episodes of TRAPS. However, the effectiveness of this drug often decreases over time and prolonged therapy with high-doses of prednisone can cause serious side effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) can be beneficial in treating fever, but are not effective against other symptoms of TRAPS. Neither corticosteroids nor NSAIDs reduces the frequency of attacks. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Based on the mechanism of the diseases a drug called Etanercept was introduced for the treatment of individuals with TRAPS. Etanercept binds to TNF receptor-1 and acts to inhibit the actions of tumor necrosis factor (TNF). Initial results demonstrated significant improvement of symptoms in about 75% of affected individuals. The NIH researchers conducted a small clinical trial to determine the long-term outcome of etanercept treatment during a 10-year follow up period. Etanercept was efficient in reducing symptoms and serum levels of inflammatory markers of TRAPS but did not completely normalize symptoms. Many patients have poor compliance with etanercept, however continuing to receive etanercept provides some relief of symptoms such as the decrease in duration of attack, and the severity and frequency of symptoms.
Targeted therapy with an IL1 cytokine inhibitor, canakinumab, has been shown very effective in reducing the frequency and severity of attacks (PMID: 29768139). Another IL-1 inhibitor, anakinra, has also been used successfully in ameliorating the disease activity. This therapy is overall well tolerated; the most frequent reported adverse events were infections. Mechanisms of IL-1 blockade in TRAPS are unclear, one study suggested that TNF cytokine regulates the activity of the pyrin inflammasome, which can ultimately lead to increased production of IL-1 in patients’ cells.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
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Gattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019 Aug;78(8):1025-1032.
Sharma D, Malik A, Guy C, Vogel P, Kanneganti TD. TNF/TNFR axis promotes pyrin inflammasome activation and distinctly modulates pyrin inflammasomopathy J Clin Invest. 2019 Jan 2;129(1):150-162.
Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017 Jul 19;18(8):832-842.
Rowczenio DM, Trojer H, Omoyinmi E. et al. Brief Report: Association of tumor necrosis factor receptor-associated periodic syndrome with gonosomal mosaicism of a novel 24-nucleotide TNFRSF1A deletion. Arthritis Rheumatol. 2016 Aug;68(8):2044-9.
Bulua AC, Mogul DB, Aksentijevich I, et al. Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: A prospective, open-label, dose-escalation study. Arthritis &Rheum. 2012;908-13.
Aksentijevich I, Kastner DL. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol. 2011;7(8):469-78.
Cantarini L, Rigante D, Lucherini OM, et al. Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature. Int J Immunopathol Pharmacol. 2010; 701-7.
Gattorno M, Pelagatti MA, Meini A, et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2008;58:1516-1520.
Hull KM, Drewe E, Aksentijevich I, et al. The TNF receptor-associated periodic syndrome (TRAPS). Emerging concepts of an autoinflammatory disorder. Medicine (Baltimore). 2002;81:349-368.
Aksentijevich I, Galon J, Soares M, et al. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fever. Am J Hum Genet. 2001;69:301-314.
McDermott MF, Aksentijevich I, Galon JM.F et al. Germline mutations in the extracellular domain of the p55 kDA TNF receptor, TNFR1, define afamily of dominantly inherited autoinflammatory syndromes. Cell, 1999;133-144.
Shinawi M, Scaglia F. Hereditary Periodic Fever Syndromes. Medscape. Last Update Updated: Jul 19, 2019. http://emedicine.medscape.com/article/952254-overview. Accessed Oct 7, 2019.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Periodic Fever, Familial, Autosomal Dominant. Entry No: 142680. Last Update 08/23/2017. Available at: http://omim.org/entry/142680 Accessed Oct 7, 2019.
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