Tumor necrosis factor receptor-associated periodic syndrome

Alternate names

FPF; Familial Hibernian fever; FHF; TRAPS; Hibernian fever, familial; TNF receptor-associated periodic syndrome; Periodic fever, familial, autosomal dominant; TNF receptor-associated periodic fever syndrome

Definition

Tumor necrosis factor receptor-associated periodic syndrome (commonly known as TRAPS) is a condition characterized by recurrent episodes of fever.

Summary

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. 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.

Cause

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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

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.

Symptoms

Fevers are often associated with other symptoms, which may include muscle, joint, and/or abdominal pain; a spreading rash; puffiness and/or swelling around the eyes; and/or inflammation in various other areas of the body including the heart muscle, joints, throat, or mucous membranes. About 25% of people with TRAPS develop amyloidosis, which can lead to kidney or liver failure.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abdominal pain(Pain in stomach)
• Diarrhea(Watery stool)
• Elevated C-reactive protein level
• Elevated erythrocyte sedimentation rate(High ESR)
• Erysipelas
• Myalgia(Muscle ache)
• Pericarditis(Swelling or irritation of membrane around heart)
• Recurrent fever(Episodic fever)
• Skin rash

30%-79% of people have these symptoms

• Arthritis(Joint inflammation)
• Constipation
• Erythema
• Intestinal obstruction(Bowel obstruction)
• Leukocytosis(Elevated white blood count)
• Lymphadenopathy(Swollen lymph nodes)
• Orchitis(Inflammation of testicles)
• Pleuritis(Inflammation of tissues lining lungs and chest)
• Splenomegaly(Increased spleen size)
• Vomiting(Throwing up)

5%-29% of people have these symptoms

• Abnormal myocardium morphology
• Abnormality of the sacroiliac joint
• Arthralgia(Joint pain)
• Behavioral abnormality(Behavioral changes)
• Bruising susceptibility(Bruise easily)
• Cellulitis(Bacterial infection of skin)
• Chest pain
• Conjunctivitis(Pink eye)
• Cranial nerve paralysis
• Fasciitis(Inflammation of the fascia)
• Hypermelanotic macule(Hyperpigmented spots)
• Migraine(Intermittent migraine headaches)
• Myositis(Muscle inflammation)
• Paresthesia(Pins and needles feeling)
• Periorbital edema
• Peritonitis
• Recurrent pharyngitis(Recurrent sore throat)
• Uveitis
• Vasculitis(Inflammation of blood vessel)
• Vertigo(Dizzy spell)

Diagnosis

The diagnosis of TRAPS may show an increased IgD level in a possibly affected individual, other methods to ascertain a definite finding is via the following:

• Blood test
• Genetic test
• Clinical evaluation

Treatment

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. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Canakinumab (Brand name: Ilaris)Treatment for Familial Mediterranean Fever (FMF) in adult and pediatric patients; for Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS) in adult and pediatric patients; and for Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD) in adult and pediatric patients.

Prognosis

The long-term outlook (prognosis) for people with TRAPS depends largely on the development of amyloidosis, which happens in a minority of affected people. The risk to develop amyloidosis depends on the specific mutation an affected person has, as well as possible environmental factors.Without amyloidosis, life expectancy is normal. In general, people with TRAPS continue to have episodes of fevers and symptoms throughout life. However, with age, fever attacks may decrease in intensity and a more chronic and fluctuating course may continue.

Epidemiology

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.