Pyogenic Arthritis Pyoderma Gangrenosum And Acne Syndrome
Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome is a rare autosomal-dominant autoinflammatory syndrome characterized by early-onset episodes of destructive inflammation of joints and skin.
Genetics and pathogenesis
PAPA is caused by mutations in the proline serine threonine phosphatase-interacting protein on chromosome 15, and the encoded cytoplasmic protein modulates T-cell activation, cytoskeletal organization, and IL-1 beta release. PSTPIP1 interacts with pyrin, and PAPA-associated PSTPIP1 mutations increase the strength of this interaction. Increased PSTPIP1-pyrin interaction causes increased IL-1 beta activation. Alternatively, increased avidity of PSTPIP1 for pyrin may lead to the formation of macromolecular complexes, denoted pyroptosomes, leading to cell death and inflammatory cytokine release.
PAPA syndrome typically manifests with recurrent episodes of sterile erosive arthritis in early childhood. Occasionally, patients with PAPA syndrome develop significant joint destruction.
While the synovial fluid and skin lesions may have the appearance of an infectious process, culture of skin and joints are sterile.
Radiographic findings include periosteal proliferation of involved bones and, in some cases, ankyloses.
Consistent with this proposed pathogenesis, there are reports of successful treatment with anakinra, etanercept, and infliximab in some patients.
Treating Tnf Receptor Associated Periodic Fever Syndrome In End
1Hospital Amato Lusitano, Castelo Branco, Portugal
2Centro Hospitalar Cova da Beira, Covilhã, Portugal
Tumor necrosis factor receptor associated periodic syndrome is a rare monogenic autoinflammatory disease. Its most severe manifestation is secondary amyloidosis. A 44-year-old male presented with nephrotic syndrome. Kidney biopsy was conclusive for secondary amyloidosis. The patient and his children had a history of recurrent febrile periods since infancy. All subjects were positive for a heterozygous variant of the TNFRSF1A gene, confirming TRAPS diagnosis. The patient progressed to end-stage renal failure and developed recurrent pericarditis episodes. He was started on anakinra while on hemodialysis with marked reduction of his serum amyloid A protein levels. Meanwhile he received a cadaveric renal transplant and maintains anakinra treatment. Despite renal failure being the most feared complication of AA amyloidosis caused by TRAPS, little data is available about safety of anti-IL-1 treatment in patients with severe kidney failure. The authors report this case of a patient on dialysis treated with anakinra in which no complications were registered. Though amyloidosis is established, the authors believe containing its progression and reducing inflammatory activity can improve patient prognosis and reduce recurrence of amyloidosis in kidney transplant, as has been demonstrated in transplanted patients due to familial Mediterranean fever amyloidosis.
What Is Tumor Necrosis Factor Receptor
Fever, chills, muscle aches. These are common features of many conditions, from seasonal flu to a rare disease called tumor necrosis factor receptor-associated periodic syndrome . But youâd never mistake TRAPS for a common illness.
With TRAPS, fever lasts more than a week: sometimes 3 weeks, sometimes months. Itâs recurrent, which means it comes back again and again throughout your life. And those muscle aches? For a lot of people, theyâre more like severe muscle pain.
TRAPS is an autoinflammatory disease that causes certain white blood cells, which normally fight infection, to attack and sometimes destroy healthy cells. It happens because a faulty gene makes your body think you have an infection when you donât. The result: Inflammatory chemicals surge inside your body and you feel lousy.
TRAPS, which used to be called familial Hibernian fever, is quite rare. The odds of having it are literally around 1 in a million. Experts say only a thousand people around the world have ever been diagnosed with TRAPS.
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The Genetic Basis Of Traps
TRAPS was initially called familial Hibernian fever, due to its first characterization in a single family of Irish/Scottish ancestry . Since 1998, genome-wide searches and linkage analysis in the affected families have been used to map the susceptibility locus to chromosome 12p13 . This chromosome region includes several candidate genes: CD4, LAG-3, CD27, C1R, C1S and TNFRSF1A . The identification of several mutations in the TNFRSF1A gene and low levels of soluble TNFR observed in the
What Are The Symptoms Of Traps
TRAPS flares include the following symptoms:
- Persistent fever
- Nausea, vomiting, diarrhoea or constipation
- Painful, often migrating red rash on the upper body and/or arms/legs
- Swollen eyes and/or conjunctivitis
- Joint and muscle pain, often in areas where the rash occurs
TRAPS flares can last a few days to a few months, but typically last about 3 weeks.They usually occur spontaneously, but can also be triggered by:
- Minor injury
Possible symptoms of TRAPS
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How Is Traps Diagnosed
A diagnosis of TRAPS should be considered clinically when acute recurrent febrile attacks occur together with the characteristic muscle pain and overlying skin changes, in the absence of infection or autoimmune disease.
During an acute episode, blood tests show:
- Increased neutrophil count
- Significant increase in acute phase reactants may also be detected between attacks
- Hypochromic anaemia
- Increase in polyclonal immunoglobulin, especially IgA
Skin biopsy shows a nonspecific superficial and deep perivascular mononuclear cell infiltrate.
Investigation of the muscle pain reveals normal levels of muscle enzymes. Muscle biopsy shows inflammation of the deep fascia rather than in the muscle itself.
Genetic testing confirms the diagnosis of TRAPS.
Tumor Necrosis Factor Receptor
NORD gratefully acknowledges 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
Tumor necrosis factor receptor-associated periodic syndrome is a rare multisystem genetic disorder characterized by unexplained periodic episodes or attacks of fever associated with additional symptoms including muscle pain , 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 gene that encodes the 55-kDa receptor for TNF.
Signs & 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.
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Treatment Of Skin Lesions And Other Symptoms In Traps
Topical treatment of TRAPS skin lesions, that may include options to alter the immune response such as topical application of antiinflammatory agents or cooling dressings, has not been reported to be of high clinical effeccacy. However, topical treatment with antiinflammatory agents may be of benefit in some patients.
What Is Tumournecrosis Factor Receptor
Tumour necrosis factor receptor-associated periodic fever syndrome or TRAPS is a rare geneticautoinflammatory syndrome. It presents as recurrent, prolonged episodes of fever typically associated with serosal, synovial and cutaneousinflammation. It can be complicated by amyloidosis, resulting in kidney or liver failure.
TRAPS is the most common autosomal dominant form of periodic fever syndrome and was originally known as familial Hibernian fever .
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Hyperimmunoglobulinemia D With Periodic Fever Syndrome
Hyperimmunoglobulinemia D with periodic fever syndrome is an autosomal-recessive disease that was initially described in several patients of Dutch heritage. HIDS is caused by mutations in the MVK gene, on chromosome 12, which encodes mevalonate kinase. The carrier frequency of MVK mutations in the Dutch population was recently calculated to be 1:65. The predicted disease incidence is far more than actually observed, suggesting reduced penetrance of the most common mutation.
HIDS manifests in early childhood, often by age 6 months. Patients may have no symptoms between attacks. However, in some patients, the attacks may be so frequent that the symptoms persist. The male-to-female ratio was equal in one study but about 3:2 in another large series. This last finding raises the possibility of reduced penetrance in women.
Genetics and pathogenesis
HIDS is caused by mutations in the MVK gene that result in depressed enzymatic activity, which has been confirmed in fibroblasts from patients with hyperimmunoglobulinemia D with periodic fever syndrome. Mevalonate kinase is the first enzyme to follow 3-hydroxy-3-methyl-glutaryl-CoA reductase in the mevalonate pathway and converts mevalonic acid to 5-phosphomevalonic acid. The mevalonate pathway produces cholesterol, a structural component of cellular membranes and precursor for bile acids and steroid hormones. In addition, the mevalonate pathway produces nonsterol isoprene compounds.
Deficiency Of The Interleukin
Deficiency of the IL-1 receptor antagonist is a rare autosomal-recessive auto-inflammatory disease caused by mutations affecting the gene IL1RN encoding the endogenous IL-1 receptor antagonist.
Genetics and pathogenesis
Mutations in the IL1RN gene result in a prematurely truncated protein that is not secreted, resulting in patient cells being hyperresponsive to IL-1 stimulation and, consequently, an increased production of proinflammatory cytokines.
Mutations are commonly found in Puerto Rico, Newfoundland, the Netherlands, and the Lebanon-Israel border. A patient from Newfoundland was homozygous for a deletion of 2 bp that caused a frameshift mutation, N52KfsX25, followed by the incorporation of 24 aberrant amino acids and a termination codon. Of the 5 patients of Dutch ancestry, 3 were homozygous for a nonsense mutation affecting the amino acid at position 77 . Patients from a consanguineous Lebanese family were homozygous for a nonsense mutation . A patient from Puerto Rico was homozygous for a deletion of approximately 175 kb on chromosome 2q that includes 6 genes from a cluster of IL-1related genes: IL1RN and the genes encoding IL-1 family, members 9 , 6 , 8 , 5 , and 10 . It has since been found that this is a relatively common mutation in the Puerto Rican population, with an allele frequency of the founder mutation in the Puerto Rican population around the area of Arecibo to be approximately 1.3%.
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When Do Most People Have Their First Traps Episode
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. 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.
Tumor Necrosis Factor Receptor 1 Associated Periodic Syndrome
Tumor necrosis factor receptor 1 associated periodic syndrome is a periodic fever syndrome, characterized by recurrent fever, arthralgia, myalgia and tender skin lesions lasting for 1 to 3 weeks, associated with skin, joint, ocular and serosal inflammation and complicated by secondary amyloidosis .
What Causes Traps In Children
With TRAPS, the innate immune system is activated due to changes in a gene coding for a protein called the tumor necrosis factor receptor, which is involved in the inflammatory response.
The genetic change which leads to TRAPS developing in a child can be inherited from either parent. There are cases of patients with non-inherited mutations for TRAPS, who can in turn pass the mutation on to their children.
Hereditary Periodic Fever Syndrome
Fever is one of the most common signs of illness in children. Most febrile episodes are acute, are of short duration, and are usually caused by upper respiratory infections. The differential diagnoses of febrile attacks are extensive and include infectious, malignant, and autoimmune disorders, as well as factitious and iatrogenic fever. If these attacks persist for longer than one year, especially if they are associated with a family history of periodic fever, the possibility of hereditary periodic fever syndrome should be raised.
The term periodic fever syndrome is defined as three or more episodes of unexplained fever in a six-month period, occurring at least seven days apart. These conditions may demonstrate strict periodicity or recur with varying intervals between attacks.
Hereditary periodic fevers were once grouped based on clinical findings and Mendelian patterns of inheritance into nine distinct groups.
Syndromes with an autosomal-dominant pattern are as follows:
- Tumor necrosis factor receptorassociated periodic syndrome
- Familial cold autoinflammatory syndrome
- Muckle-Wells syndrome
- Neonatal-onset multisystem inflammatory disease , also called chronic infantile neurological cutaneous and articular syndrome
- Cyclic hematopoiesis , also called cyclical neutropenia
- Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome
Syndromes with an autosomal-recessive pattern are as follows:
Table 1. Types of Hereditary Periodic Fever Syndromes.
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Citation Doi And Article Data
- Tumour necrosis factor receptor-associated periodic fever syndrome
- TNF receptor associated periodic syndrome
Tumor necrosis factor receptor-associated periodic syndrome is a condition characterized by recurrent episodes of fever as well as a spectrum of dermatologic findings that includes migratory patches, edematous plaques, periorbital edema, and/or conjunctivitis.
It is characterized by a perivascular dermal infiltrate of lymphocytes and monocytes. Its thought to be dominantly inherited mutations in TNFRSF1A, the gene encoding the 55-kDa tumor necrosis factor receptor.
Clinical Significance Of Serum Soluble Tnf Receptor I/ii Ratio For The Differential Diagnosis Of Tumor Necrosis Factor Receptor
- 1Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
- 2Department of Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- 3Department of Pediatrics, Okayama University Hospital, Okayama, Japan
Objectives: Genetic analysis of TNFRSF1A can confirm the diagnosis of tumor necrosis factor receptor-associated periodic syndrome , but interpretation of the pathogenesis of variants of unknown significance is sometimes required. The aim of this study was to evaluate the clinical significance of serum soluble tumor necrosis factor receptor type I /II ratio to differentiate TRAPS from other autoinflammatory diseases.
Methods: Serum sTNFR-I and sTNFR-II levels were measured using an enzyme-linked immunosorbent assay in patients with TRAPS , familial Mediterranean fever , systemic juvenile idiopathic arthritis , and Kawasaki disease in the active and inactive phase, along with healthy controls .
Results: In the active phase, the serum sTNFR-I/II ratio in patients with s-JIA, KD, and FMF was significantly elevated compared with that in HCs, whereas it was not elevated in patients with TRAPS. In the inactive phase, the serum sTNFR-I/II ratio in patients with s-JIA and FMF was significantly higher compared with that in HCs, and the ratio was lower in TRAPS patients than in patients with s-JIA and FMF.
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Distribution Map Of Serum Stnfr
As shown in Figure 2A, in the active phase, serum sTNFR-I levels and sTNFR-I/II ratio in patients with s-JIA and KD were high. In contrast, both values in TRAPS patients were similar to those in HCs. In patients with FMF, they were mildly elevated and higher than those in patients with TRAPS.
Figure 2. Distribution map of serum sTNFR-I and sTNFR-I/II ratio. Correlation between serum sTNFR-I levels and sTNFR-I/II ratio in each group in the active and inactive phase . TRAPS, tumor necrosis factor receptor-associated periodic syndrome FMF, familial Mediterranean fever s-JIA, systemic juvenile idiopathic arthritis KD, Kawasaki disease HCs, healthy controls.
As shown in Figure 2B, in the inactive phase, serum sTNFR-I levels and sTNFR-I/II ratio in patients with TRAPS were lower than those in HCs.