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.

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.

Normal Function

The TNFRSF1A gene provides instructions for making a protein called tumor necrosis factor receptor 1 (TNFR1). This protein is found spanning the membrane of cells, with part of the TNFR1 protein outside the cell and part of the protein inside the cell. Outside the cell, the TNFR1 protein attaches (binds) to another protein called tumor necrosis factor (TNF). The interaction of the TNF protein with the TNFR1 protein causes the TNFR1 protein to bind to two other TNFR1 proteins, forming a three-protein complex called a trimer. This trimer formation is necessary for the TNFR1 protein to be functional.

The binding of the TNF and TNFR1 proteins causes the TNFR1 protein to send signals inside the cell. Signaling from the TNFR1 protein can trigger either inflammation or self-destruction of the cell (apoptosis). Signaling within the cell initiates a pathway that turns on a protein called nuclear factor kappa B, which triggers inflammation and leads to the production of immune system proteins called cytokines. Apoptosis is initiated when the TNFR1 protein, bound to the TNF protein, is brought into the cell and starts a process known as the caspase cascade.

Health Conditions Related to Genetic Changes

Tumor necrosis factor receptor-associated periodic syndrome

More than 60 mutations in the TNFRSF1A gene have been found to cause tumor necrosis factor receptor-associated periodic syndrome (commonly known as TRAPS). Most of these mutations lead to changes in single protein building blocks (amino acids), typically involving the amino acid cysteine. Cysteines contain sulfur atoms that form connections, called disulfide bonds, with other cysteines. Disulfide bonds help a protein fold by connecting cysteines in different regions of the protein. These bonds stabilize the protein and give it the appropriate shape to carry out its particular function.

When cysteines within the TNFR1 protein are replaced with other amino acids, the disulfide bonds are not formed, and the protein is misfolded. These misfolded proteins are trapped within the cell, unable 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.

Some people with mutations in the TNFRSF1A gene do not develop TRAPS, or they develop very mild features of the disorder. The reason for this variability is unclear, but researchers believe that other factors, such as additional genetic changes or environmental factors, may play a role in causing TRAPS.

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Other Names for This Gene

• p55
• p55-R
• TNF-R
• TNF-R1
• TNF-R55
• TNFR-I
• TNFR1
• TNFR55
• TNR1A_HUMAN
• tumor necrosis factor binding protein 1
• tumor necrosis factor receptor superfamily member 1A
• tumor necrosis factor receptor superfamily, member 1A
• tumor necrosis factor receptor type 1
• tumor necrosis factor-alpha receptor

Genomic Location

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.

While there is no proven treatment for TRAPS, non steroidal anti-inflammatory drugs (NSAIDS) may be used to relieve symptoms of fever, and corticosteroids may be used to reduce severity of symptoms in most people. However, these medications typically don't decrease the frequency of attacks. Etanercept, a TNF inhibitor, has been shown to be effective but its efficacy tends to wane over time. Standard doses of etanercept twice a week have been shown to decrease the frequency, duration, and severity of attacks in some people and it may also reverse or slow the progression of amyloidosis. More studies are needed to evaluate this medication for TRAPS.

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.