T.R.A.P.S. stands for Tumor Necrosis Factor Receptor-Associated Periodic Syndrome. It is a rare autosomal dominant disorder characterized by prolonged episodes of periodic fever and erythematous macules, patches, and edematous dermal plaques. The skin eruption usually lasts for 4-21 days (mean 13 days). There are numerous other systemic signs and symptoms associated with the syndrome including:
Pleuritic chest pain
For many years, this disorder was known by many other names (see outline below). Only with the discovery of the gene encoding the tumor necrosis factor (TNF) and associated mutations was a unifying etiology established. This disease is closely related to two other inherited conditions that have periodic fever:
Familial Mediterranean fever
Hyperimmunoglobulinemia D syndrome
In these two latter diseases, the cause is secondary to mutations in different genes.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
Familial Hibernian Fever
Benign autosomal dominant familial periodic fever
Autosomal dominant periodic fever with amyloidosis
GEOGRAPHY Overrepresentation of patients with Irish and Scottish heritage AGE
- Tumor necrosis factor receptor-associated periodic syndrome in a young adult who had features of periodic fever, aphthous stomatitis, pharyngitis, and adenitis as a child.
Saulsbury FT, Wispelwey B.
Department of Pediatrics, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
J Pediatr. 2005 Feb;146(2):283-5. Abstract quote
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) was diagnosed in a 22-year-old man after a 1-year history of periodic fever, myalgia, conjunctivitis, cervical lymphadenopathy, and oral ulcers. As a child he had signs and symptoms suggestive of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.
This report indicates the importance of considering TRAPS as a cause of periodic fever in older children and adults and that TRAPS may present with signs and symptoms suggestive of periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome in young children.
DISEASE ASSOCIATIONS CHARACTERIZATION Familial Hibernian Fever Described in large Irish kindred
PATHOGENESIS CHARACTERIZATION MUTATIONS
The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder.
Hull KM, Drewe E, Aksentijevich I, Singh HK, Wong K, McDermott EM, Dean J, Powell RJ, Kastner DL.
Office of the Clinical Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Medicine (Baltimore) 2002 Sep;81(5):349-68 Abstract quote
The present report describes and expands the clinical and genetic spectrum of the autoinflammatory disorder, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). A total of 20 mutations have been identified since our initial discovery of 6 missense mutations in TNF receptor super family 1A (TNFRSF1A) in 1999. Eighteen of the mutations result in amino acid substitutions within the first 2 cysteine-rich domains (CRDs) of the extracellular portion of the receptor. A single splicing mutation also affects the first CRD by causing the insertion of 4 amino acids.
Haplotype analysis of the most commonly occurring and ethnically heterogeneous mutation, R92Q, demonstrates an ancient founder; however, analysis of the T50M mutation, another commonly occurring mutation in Irish and Scottish families, does not, suggesting that T50M is a recurring mutation. Mutations that result in cysteine substitutions demonstrate a higher penetrance of the clinical phenotype (93% versus 82% for noncysteine residue substitutions), and also increase the probability of developing life-threatening amyloidosis (24% versus 2% for noncysteine residue substitutions).
Retrospective and prospective evaluation of more than 50 patients, representing 10 of the 20 known mutations, allows us to expand and better define the clinical spectrum of TRAPS. Recurrent episodes of fever, myalgia, rash, abdominal pain, and conjunctivitis that often last longer than 5 days are the most characteristic clinical features of TRAPS. Defective shedding of TNFRSF1A can only partially explain the pathophysiologic mechanism of TRAPS, since some mutations have normal shedding. Consequently, other mechanisms may be mediating the observed phenotype.
We are currently investigating other possible mechanisms using stable and transiently transfected cell systems in vitro, as well as developing a knockin mouse model. Preliminary data suggest that etanercept may be effective in decreasing the severity, duration, and frequency of symptoms in TRAPS patients. Additionally, it provides a viable therapeutic alternative to glucocorticoid therapy, which has numerous serious, long-term adverse effects.
Two clinical trials are being conducted to evaluate the efficacy of etanercept in decreasing the frequency and severity of symptoms in TRAPS. Lastly, we have summarized data that R92Q and P46L, and probably as yet undiscovered substitutions, represent very low penetrance mutations that may play a much larger role in more broadly defined inflammatory diseases such as rheumatoid arthritis.
Our laboratories are currently undertaking both clinical and basic research studies to define the role of these mutations in more common inflammatory diseases.
The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome.
Dode C, Andre M, Bienvenu T, Hausfater P, Pecheux C, Bienvenu J, Lecron JC, Reinert P, Cattan D, Piette JC, Szajnert MF, Delpech M, Grateau G; French Heraditary Recurrent Inflammatory Disorder Study Group.
Hopital Cochin, Institut Cochin, and Institut federitif de recherche, de l'INSERM, Universite Paris V, Paris, France.
Arthritis Rheum 2002 Aug;46(8):2181-8 Abstract quote
OBJECTIVE: To characterize the frequency, clinical signs, and genotypic features of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a series of 394 patients of various ethnic origins who have recurrent inflammatory syndromes.
METHODS: Sequencing of the coding region of the TNFRSF1A gene was performed in 128 patients in whom there was a high suspicion of TRAPS, and denatured high-performance liquid chromatography was used to systematically screen for TNFRSF1A in 266 patients with recurrent inflammatory syndrome and no or only 1 Mediterranean fever gene (MEFV) mutation.
RESULTS: TNFRSF1A mutations were found in 28 (7.1%) of 394 unrelated patients. Nine (32%) of the 28 patients had a family history of recurrent inflammatory syndromes. In 13 patients, the length of the attack of inflammation was fewer than 5 days. Three of the mutations (Y20H, L67P, and C96Y) were novel. Two mutations, R92Q and (mainly) P46L, found in 12 and 10 patients, respectively, had lower penetrance compared with other mutations. TNFRSF1A mutations were found in patients of various ethnic origins, including those at risk for familial Mediterranean fever (FMF): Armenians, Sephardic Jews, and especially Arabs from Maghreb. Only 3 (10.7%) of the 28 patients had amyloidosis.
CONCLUSION: TRAPS is an underdiagnosed cause of recurrent inflammatory syndrome. Its presence in the population of persons of Mediterranean ancestry and the short duration of the attacks of inflammation can lead to a fallacious diagnosis of FMF. Because an accurate diagnosis in patients with recurrent inflammatory syndromes is crucial for proper clinical management and treatment, genetic screening for TNFRSF1A is warranted.
An Israeli Arab patient with a de novo TNFRSF1A mutation causing tumor necrosis factor receptor-associated periodic syndrome.
Aganna E, Zeharia A, Hitman GA, Basel-Vanagaite L, Allotey RA, Booth DR, Hawkins PN, Thacker C, Syndercombe-Court D, McDermott MF.
MRCPI: Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, UK.
Arthritis Rheum 2002 Jan;46(1):245-9 Abstract quote
OBJECTIVE: To investigate genetic susceptibility to recurrent fevers, generalized severe myalgia, and migratory erythema in an Israeli Arab child with no family history of similar disease.
METHODS: DNA sequencing of exons 1-6 of the TNFRSF1A gene (formerly TNFR1) was performed in the patient and his parents to determine the presence of the autosomal-dominant tumor necrosis factor receptor-associated periodic syndrome (TRAPS); informative markers spanning the TNFRSF1A locus were used to genotype all available members of the patient's family. The TNFRSF1A gene was subsequently screened in 69 healthy Arab controls and 96 Caucasian controls. Formal forensic paternity testing was performed on the child.
RESULTS: We found a de novo missense mutation in exon 3 of the TNFRSF1A gene, involving a novel C-->T transition encoding a Cys70Arg (C70R) variant, in the Israeli Arab patient. Eight of the common familial Mediterranean fever (FMF) gene MEFV mutations were excluded. This mutation was not present in the parents or siblings, or among the 69 healthy Arab controls. However, another TNFRSF1A variant, Pro46Lys (P46L), was present in 1 of the Arab controls.
CONCLUSION: We have identified a TNFRSF1A mutation associated with periodic fever in an Arab patient, and a TNFRSF1A variant, which is variably pathogenic in Caucasians, in an Arab control. This is the first report of a de novo mutation in periodic fevers in general, and also of TRAPS in the Arab population. These findings demonstrate the need to include TRAPS in the differential diagnosis of recurrent fevers in this population.
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 fevers.
Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH, Goldbach-Mansky R, Dean J, Athreya B, Reginato AJ, Henrickson M, Pons-Estel B, O'Shea JJ, Kastner DL.
Section of Genetics, Arthritis and Rheumatism Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Am J Hum Genet 2001 Aug;69(2):301-14 Abstract quote
Mutations in the extracellular domain of the 55-kD tumor-necrosis factor (TNF) receptor (TNFRSF1A), a key regulator of inflammation, define a periodic-fever syndrome, TRAPS (TNF receptor-associated periodic syndrome [MIM 142680]), which is characterized by attacks of fever, sterile peritonitis, arthralgia, myalgia, skin rash, and/or conjunctivitis; some patients also develop systemic amyloidosis.
Elsewhere we have described six disease-associated TNFRSF1A mutations, five of which disrupt extracellular cysteines involved in disulfide bonds; four other mutations have subsequently been reported. Among 150 additional patients with unexplained periodic fevers, we have identified four novel TNFRSF1A mutations (H22Y, C33G, S86P, and c.193-14 G-->A), one mutation (C30S) described by another group, and two substitutions (P46L and R92Q) present in approximately 1% of control chromosomes.
The increased frequency of P46L and R92Q among patients with periodic fever, as well as functional studies of TNFRSF1A, argue that these are low-penetrance mutations rather than benign polymorphisms. The c.193-14 G-->A mutation creates a splice-acceptor site upstream of exon 3, resulting in a transcript encoding four additional extracellular amino acids. T50M and c.193-14 G-->A occur at CpG hotspots, and haplotype analysis is consistent with recurrent mutations at these sites. In contrast, although R92Q also arises at a CpG motif, we identified a common founder chromosome in unrelated individuals with this substitution. Genotype-phenotype studies identified, as carriers of cysteine mutations, 13 of 14 patients with TRAPS and amyloidosis and indicated a lower penetrance of TRAPS symptoms in individuals with noncysteine mutations.
In two families with dominantly inherited disease and in 90 sporadic cases that presented with a compatible clinical history, we have not identified any TNFRSF1A mutation, despite comprehensive genomic sequencing of all of the exons, therefore suggesting further genetic heterogeneity of the periodic-fever syndromes.
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) in a Dutch family: evidence for a TNFRSF1A mutation with reduced penetrance.
Aganna E, Aksentijevich I, Hitman GA, Kastner DL, Hoepelman AI, Posma FD, Zweers EJ, McDermott MF.
Unit of Molecular Medicine, Department of Diabetes and Metabolic Medicine, St Bartholomew's and the Royal London School of Medicine and Dentistry, Queen Mary and Westfield College, London, UK.
Eur J Hum Genet 2001 Jan;9(1):63-6 Abstract quote
Mutations of the tumor necrosis factor receptor 1 (TNFRSF1A) gene underly susceptibility to a subset of autosomal dominant recurrent fevers (ADRFs).
We report on a two-generation six-member Dutch family in which a novel R92P mutation and reduced plasma TNFRSF1A levels were found in all the children, including two who are unaffected. However, only the daughter proband and father exhibited a typical TNF-receptor associated periodic syndrome (TRAPS) phenotype. PCR-RFLP analysis revealed that the mutation was not present in 120 control chromosomes from unaffected Dutch individuals.
As this R92P mutation is present in two unaffected carriers it appears to be less penetrant than previously reported TNFRSF1A mutations involving cysteine residues in the extracellular domains.
Mutations in the gene encoding for the 55 kDa tumor necrosis factor receptor (TNFRSF1A) Cell 1999;97:133-144
7 affected families with 6 different missense mutations
CLINICAL VARIANTS CHARACTERIZATION BONE AND JOINTS
- Tumor necrosis factor receptor-associated periodic syndrome (TRAPS): definition, semiology, prognosis, pathogenesis, treatment, and place relative to other periodic joint diseases.
Masson C, Simon V, Hoppe E, Insalaco P, Cisse I, Audran M.
Rheumatology Department, Angers Teaching Hospital, 49033 Angers cedex 1, France.
Joint Bone Spine. 2004 Jul;71(4):284-90. Abstract quote
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant inherited condition of periodic fever and pain. Most patients are of northern European descent. The attacks manifest as fever and pain in the joints, abdomen, muscles, skin, or eyes, with variations across patients. An acute-phase response occurs during the attacks. Patients with TRAPS are at risk for AA amyloidosis, the most common targets being the kidneys and liver.
Soluble TNFRSF1A is usually low between the attacks and may be normal during the attacks, when TNF levels are high. TNFRSF1A is found in abnormally high numbers on leukocyte cell membranes. TRAPS is the first condition for which naturally occurring mutations in a TNF receptor were found; the mutations affect the soluble TNFRSF1A gene in the 12p13 region. In some patients, the pathogenesis involves defective TNFRSF1A shedding from cell membranes in response to a given stimulus. Thus, TRAPS is a model for a novel pathogenic concept characterized by failure to shed a cytokine receptor. This review compares TRAPS to other inherited periodic febrile conditions, namely, familial Mediterranean fever, Muckle-Wells syndrome, cold urticaria, and hyper-IgD syndrome.
The place of TRAPS relative to other intermittent systemic joint diseases is discussed. Colchicine neither relieves nor prevents the attacks, whereas oral glucocorticoid therapy is effective when used in dosages greater than 20 mg/day. The pathogenic hypothesis involving defective TNFRSF1A shedding suggests that medications targeting TNF may be effective in TRAPS.
- Myocarditis and sacroiliitis: 2 previously unrecognized manifestations of tumor necrosis factor receptor associated periodic syndrome.
Trost S, Rose CD.
Department of Rheumatology, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19899, USA.
J Rheumatol. 2005 Jan;32(1):175-7. Abstract quote
Tumor necrosis factor receptor associated periodic syndrome (TRAPS) is an autosomic-dominant periodic syndrome associated with mutations in the extracellular domain of the 55 kDa TNF receptor.
Clinically, episodes of severe myalgia, arthralgia/arthritis, sterile peritonitis, scrotal inflammation, serositis, migratory rash, conjunctivitis, and recurrent fever are characteristic.
We describe a 9-year-old African American boy with the P46L mutation of the TNF receptor who presented with 2 previously unrecognized manifestations: sacroiliitis and myocardiopathy, both showing a reversible course.
- Small vessel vasculitis and relapsing panniculitis in tumour necrosis factor receptor associated periodic syndrome (TRAPS).
Lamprecht P, Moosig F, Adam-Klages S, Mrowietz U, Csernok E, Kirrstetter M, Ahmadi-Simab K, Schroder JO, Gross WL.
Department of Rheumatology, University Hospital of Schleswig-Holstein, 23538 Luebeck, Germany.
Ann Rheum Dis. 2004 Nov;63(11):1518-20. Abstract quote
CASE REPORTS: A 66 year old female patient had relapsing fever and non-suppurative panniculitis suggestive of enigmatic "Weber-Christian disease" (WCD). Antineutrophil cytoplasmic antibodies with specificity for human leucocyte elastase (HLE-ANCA) were detected. A biopsy showed small vessel vasculitis and panniculitis. A 53 year old man had recurrent episodes of abdominal pain, erythematous rash, and myalgia. Fever attacks had stopped a few years ago. A biopsy showed panniculitis and fasciitis. In both patients mutations (R92Q, T50M) of the tumour necrosis factor receptor super family (TNFRSF) 1A gene were disclosed. Mutations of the TNFRSF 1A gene are the cause of tumour necrosis factor receptor associated periodic syndrome (TRAPS). Both patients responded favourably to treatment with the human soluble p75 TNF alpha receptor fusion protein etanercept (2 x 25 mg subcutaneously/week).
DISCUSSION: Small vessel vasculitis and panniculitis have not been reported in TRAPS so far. The cases underline the importance of TNF alpha regulation in inflammatory processes including vasculitis. Genetically determined causes of fever may account for some cases of WCD.
Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations.
Toro JR, Aksentijevich I, Hull K, Dean J, Kastner DL.
National Cancer Institute, National Institutes of Health, Bldg 10, Room 12N-238, 10 Center Dr, MSC 1908, Bethesda, MD 20892-1908, USA.
Arch Dermatol 2000 Dec;136(12):1487-94 Abstract quote
BACKGROUND: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an inflammatory disorder characterized by prolonged episodes of periodic fever and localized inflammation and dominantly inherited mutations in TNFRSF1A, the gene encoding the 55-kDa tumor necrosis factor receptor. To our knowledge, the cutaneous pathologic characteristics of TRAPS have not been described previously.
OBJECTIVES: To characterize the dermatologic manifestations of TRAPS by clinical, microscopic, and molecular methods, and to investigate its immunophenotype.
DESIGN, SETTING, AND PATIENTS: At the National Institutes of Health Clinical Center, Bethesda, Md, a tertiary care referral center, 25 patients with a clinical and molecular diagnosis of TRAPS were evaluated clinically and 10 biopsy specimens of lesional skin were examined by light microscopy and immunohistochemistry. Patients were screened for mutations in TNFRSF1A, the gene coding for the p55 tumor necrosis factor receptor.
MAIN OUTCOME MEASURES: Clinical, light microscopic, and immunohistochemical features.
RESULTS: The skin eruption usually lasted 4 to 21 days (mean, 13 days). Of 25 patients, 21 (84%) presented with migratory erythematous macules and patches and 10 (40%) had edematous dermal plaques. Conjunctivitis, characterized by pain and redness and/or periorbital edema, was present in 11 patients (44%). Most patients had their first skin eruption during the first 2 years of life. All patients had fever associated with the skin eruption. Most patients had associated abdominal pain (22 [88%]) and myalgia (20 [80%]). Other symptoms included arthralgia (13 [52%]), pleuritic chest pain (10 [40%]), and headache (17 [68%]). Microscopic examination of 10 biopsy specimens of lesional skin showed a superficial and deep perivascular and interstitial infiltrate of lymphocytes and monocytes. None of the biopsy specimens showed multinucleated macrophages or granulomatous or leukocytoclastic vasculitis. The results of immunohistochemistry showed a perivascular infiltrate of CD3+, CD4+, CD8+, CD68+, CD79a-, and CD20- cells. All the mutations were missense mutations in exons 2 through 4 of TNFRSF1A, directly affecting the extracellular domain of the protein.
CONCLUSIONS: TRAPS is characterized by a spectrum of dermatologic findings, including migratory patches, edematous plaques, periorbital edema, and/or conjunctivitis. TRAPS is characterized by a perivascular dermal infiltrate of lymphocytes and monocytes.
HISTOLOGICAL TYPES CHARACTERIZATION General Superficial and deep perivascular and interstitial infiltrate of lymphocytes and monocytes
CHARACTERIZATION Special stains Immunoperoxidase
Lymphocytes positive for:
CD3, CD4, CD8
CD79 and CD20 negative
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Infantile multisystem inflammatory disease (IOMID) Presence of neutrophilic eccrine hidradenitis Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) Shorter attacks
The three main symptoms rarely occur in TRAPS
Familial Mediterranean Fever Autosomal recessive
Present in infancy or early childhood
Hyperimmunoglobulinemia D syndrome Autosomal recessive
Present in infancy or early childhood
PROGNOSIS AND TREATMENT CHARACTERIZATION Treatment Corticosteroid treatment
NSAIDS effective in mild attacks
ETANERCEPT Arthritis Rheum 1999;42:S117
Bioengineered fusion protein of p75 soluble TNF receptor that neutralizes TNF-alpha
- Etanercept plus colchicine treatment in a child with tumour necrosis factor receptor-associated periodic syndrome abolishes auto-inflammatory episodes without normalising the subclinical acute phase response.
Arostegui JI, Solis P, Aldea A, Cantero T, Rius J, Bahillo P, Plaza S, Vives J, Gomez S, Yague J.
Servicio de Immunologia, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain.
Eur J Pediatr. 2005 Jan;164(1):13-6. Epub 2004 Nov 10. Abstract quote
We investigated the cause of hereditary periodic fever syndrome in a Spanish child with recurrent long episodes of fever, migratory skin rash, myalgia, arthralgia, conjunctivitis and abdominal pain. Infectious and autoimmune causes were ruled out. No familial history was reported.
Analysis of the tumour necrosis factor receptor superfamily 1A (TNFRSF1A) gene identified a missense mutation (G36E) on exon 3. The absence of this variant in the patient's parents and in controls identified it as a de novo disease-associated mutation. Clinical symptoms disappeared with administration of etanercept; however, levels of acute-phase reactants remained increased and could not be stabilised by the addition of colchicine.
We believe that this patient gained some symptomatic relief with etanercept therapy, although not enough to completely avoid the risk of amyloidosis. Thus it is debatable whether etanercept alone or combined with other drugs, is the treatment of choice for patients with tumour necrosis factor receptor-associated periodic syndrome.
CONCLUSION: Since there is variability in treatment responses among different patients with tumour necrosis factor receptor-associated periodic syndrome, we suggest that a systematic evaluation of acute-phase reactants, especially SAA-1, could be useful in maintaining or modifying a given therapeutic approach in these patients.
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