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Tumor Necrosis Factor Receptor-Associated Periodic Syndrome

NORD is very grateful to Ivona Aksentijevich, MD, National Human Genome Research Institute, National Institutes of Health, for assistance in the preparation of this report.

Synonyms of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome

  • autosomal dominant periodic fever with amyloidosis
  • benign autosomal dominant familial periodic fever
  • familial hibernian fever
  • TNF receptor-associated periodic syndrome
  • TRAPS

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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.

Symptoms

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.

Causes

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 regardless of the gender of the resulting child.

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 TRNFSF1A gene result in defective TNFR1 that cannot properly perform its normal functions. Defective TRNF1 allows for unchecked signaling of TNF, which causes an excessive inflammatory response by the body. The exact process by which defective TRNF1 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.

Affected Populations

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 hundred 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.

Related Disorders

Symptoms of the following disorders can be similar to those of TRAPS. Comparisons may be useful for a differential diagnosis.

Autoinflammatory syndromes are a group of disorder characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. Patients with autoinflammatory disorders present with chronic and recurrent bouts of systemic inflammation that are mediated by the cells of innate immunity. The onset of inflammation is often in childhood, sometimes as early as the neonatal period. Symptoms often include recurrent fevers, various types of skin rash, abdominal pain, joint pain, bone pain, central nervous system (CNS) inflammation and other characteristic findings associated with systemic chronic inflammation.

The autoinflammatory diseases are inherited in an autosomal-recessive (two mutations are received, one from the father and second from the mother) or autosomal-dominant fashion (mutation that is received either from the father or the mother), but there are a considerable number of sporadic cases. Recessively inherited diseases include hyperimmunoglobulin D syndrome (HIDS), familial Mediterranean fever (FMF), deficiency of IL-1-receptor antagonist (DIRA), early-onset enterocolitis (IBD), deficiency of interleukin-36 receptor antagonist (DITRA), and immunoproteasome related diseases (CANDLE, JMP, Japanese autoinflammatory syndrome).

Dominantly inherited autoinflammatory diseases include the cryoprin-associated periodic syndromes (familial cold autoinflammatory syndrome, NOMID/CINCA, and Muckle-Wells syndrome), the pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA), familial cold autoinflammatory syndrome 2 (Guadeloupe fever), and Blau syndrome. (The Rare Disease Database currently has additional information available for some of the above mentioned conditions.)

Hyper IgD syndrome (HIDS) is a rare inflammatory genetic disorder characterized by periodic episodes of fever associated with additional symptoms including joint pain (arthralgia), skin rash and abdominal pain. Most episodes last several days and occur periodically throughout life. The frequency of episodes and their severity vary greatly from case to case. HIDS is associated from decreased activity of the enzyme mevalonate kinase (MVK). Although many factors can set off a characteristic HIDS episode (e.g., minor infections), most episodes occur without a distinct precipitating event. HIDS is inherited as an autosomal recessive trait and is usually found in patients of North European descent. (For more information on this disorder, choose "hyper IgD" as your search term in the Rare Disease Database.)

Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by recurrent attacks of fever and acute inflammation of the membranes that line the abdominal cavity (peritonitis) and/or the lungs (pleuritis); pain and swelling of the joints (arthritis); and/or the heart (pericarditis) and, in some cases, skin rashes affecting lower parts of extremities. In addition, many affected individuals may develop a serious complication known as amyloidosis, which is characterized by abnormal accumulation of serum amyloid A (SAA) in various parts of the body. If amyloid accumulates in the kidneys (renal amyloidosis), it may impair kidney function, which can potentially result in life-threatening complications. FMF is a very common disease in many Mediterranean populations such as Sephardic Jews, Arabs, Armenians, Turks and Italians. FMF is inherited as an autosomal recessive trait. The causative gene on the short arm of chromosome 16 has been identified (cloned) in 1997. (For more information on this disorder, choose "familial Mediterranean fever" as your search term in the Rare Disease Database.)

Muckle-Wells syndrome (MWS), is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the NLRP3/CIAS1 gene. These syndromes are characterized by fever, rash and joint pain. Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition familial cold autoinflammatory syndrome, but can also be triggered by other stimuli. In most cases, Muckle-Wells syndrome patients develop progressive hearing loss. In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient's tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated. (For more information on this disorder, choose "Muckle-Wells syndrome" as your search term in the Rare Disease Database.)

Familial cold autoinflammatory syndrome (FCAS), another one of the CAPS, is also known as familial cold urticaria. It is a rare, inherited inflammatory disorder characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS occurs during infancy and early childhood and persists throughout the patient's life. As in other CAPS, amyloidosis can rarely develop later in life in FCAS patients. (For more information on this disorder, choose "familial cold autoinflammatory syndrome" as your search term in the Rare Disease Database.)

Neonatal-onset multisystem inflammatory disease (NOMID), the most severe form of the CAPS, is also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome. It is a rare, congenital, systemic, inflammatory condition distinguished by fever, rash, joint disease, and central nervous system disease. The hallmark of NOMID is onset during infancy or early childhood. (For more information on this disorder, choose "neonatal-onset multisystem inflammatory disease" as your search term in the Rare Disease Database.)

Familial cold autoinflammatory syndrome 2 (Guadeloupe fever), is a rare disease similar to MWS and FCAS. It is caused by dominantly inherited mutations in the NLRP12 gene. Patients present with weeklong episodic fevers triggered by cold exposure and associated with arthralgia, myalgia,and other constitutional symptoms. Two affected members of one family had sensorineural hearing loss. Clinical manifestations are generally prevented by avoiding exposure to the cold.

PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome is a rare autosomal dominant auto-inflammatory disease arising from mutations in the PSTPIP1/CD2BP1 gene on chromosome 15q. Symptoms typically start in early puberty and include painful flares of recurrent sterile arthritis with variable skin involvement that may present as ulcerations, pyoderma gangrenosum, or severe cystic acne.

DIRA and DITRA are recently described recessively inherited autoinflammatory diseases linked to activation of the IL-1 pathway. DIRA, an acronym for deficiency of the interleukin 1 (IL-1) receptor antagonist, patients presents in the neonatal period with a severe "pustular" skin eruption, skin pathergy, and osteolytic bone lessions. DITRA, an acronym for deficiency of the IL-36R antagonist (IL-36Ra), patients present with generalized pustular psoriasis.

Mutations in PSMB8, encoding the ß5i subunit of the immunoproteasome (a complex that degrades proteins in immune cells), have recently been shown to cause recessively inherited syndromes variously presenting with fever, panniculitis, lipodystrophy, and early death. One such disorder has been denoted chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). The treatment options for CANDLE patients are very limited.

Standard Therapies

Diagnosis
A diagnosis of a 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 mutations in the TNFRSF1A gene. Genetic counseling is strongly recommended in families with TRAPS.

Treatment
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.

Investigational Therapies

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.

Additional medications have also shown early promise as therapies for individuals with TRAPS including biologics such as anakinra and tacrolimus. As with etanercept, these drugs need to undergo larger clinical trials to determine their long-term safety and effectiveness in treating individuals with TRAPS.

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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Tumor Necrosis Factor Receptor-Associated Periodic Syndrome

References

JOURNAL ARTICLES
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.

INTERNET
Shinawi M, Scaglia F. Hereditary Periodic Fever Syndromes. Emedicine. http://emedicine.medscape.com/article/952254-overview. Updated November 8, 2010. Accessed March 21, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Periodic Fever, Familial, Autosomal Dominant. Entry No: 142680. Last Edited May 18, 2010. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 21, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/05/08 00:00:00 GMT+0

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