TNF receptor associated periodic syndrome
Synonyms and keywords: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS); Familial Hibernian fever; FHF; Familial Caledonian fever

# Overview
TNF receptor-associated periodic syndrome (also known as TRAPS or familial Hibernian fever) is a periodic fever syndrome associated with mutation in a receptor for the molecule tumor necrosis factor (TNF). Since this disease first described in Ireland, it was called  Hibernian fever in reference to the ancient Latin name for Ireland, Hibernia.

# Historical Perspective
- TNF receptor-associated periodic syndrome was first described by Dr. Williamson in 1982 in an Irish-Scottish family affected by an autosomal dominant pattern disorder.
- The association between the TNFRSF1A gene locus and TNF receptor-associated periodic syndrome was made in 1998.
- In 2003, Dr. Weyhreter was the first to use etanercept (a fusion protein of the extracellular domain of TNFRSF1A and the Fc portion of IgG1) for the treatment of TRAPS, which results successful treatment of the patient.

# Classification
- There is no established system for the classification of TNF receptor associated periodic syndrome.

# Pathophysiology
- TNF receptor associated periodic syndrome is an autosomal dominant inherited disorder due to mutation in the  TNF Receptor Super Family 1A (TNFRSF1A) gene.
- Mutation in the gene is associated with abnormally structured TNF receptor which leads to impaired TNF-a binding and subsequent abnormal function of this factor in apoptosis and NF-B pathway. However, the exact mechanisms causing febrile episodes remain to be cleared.
- Another hypotheses is that mutation in the gene results in intracellular accumulation of the receptor. This abnormal accumulation of the receptor leads to an exaggerated inflammatory response to low levels of innate stimuli such as  lipopolysaccharide (LPS).

# Differentiating TNF receptor associated periodic syndrome from Other Diseases
- TNF receptor associated periodic syndrome must be differentiated from other diseases that cause fever, abdominal pain, and arthritis, such as infections, other autoinflammatory diseases, and autoimmune disorders.
- For more information on the differential diagnosis of TNF receptor associated periodic syndrome please click here

# Epidemiology and Demographics
- This disorder is the second most common inflammatory disorder after familial mediterranean fever (FMF).
- The incidence/prevalence of TNF receptor associated periodic syndrome is approximately 0.06 per 100,000 individuals of 16 years of age or younger worldwide.
- Approximately, 1000 cases have been reported worldwide.
- TNF receptor associated periodic syndrome commonly affects individuals of 3 years of age. However, due to overlap of the symptoms with other disorders and possible misdiagnosis, it may be diagnosed in adolescence or adulthood. In addition, the variants with low penetrance tend to manifest later in the adult life.
- Although more common in children, reports of patients developing TRAPS in old age are available.
- Although, first described in Ireland, this disorder has also been reported in other countries. However, it is especially common in Western countries rather than Asian countries.

# Risk Factors
- There are no established risk factors for TNF receptor associated periodic syndrome.

# Screening
- There is insufficient evidence to recommend routine screening for TNF receptor-associated periodic syndrome.

# Natural History, Complications, and Prognosis
- The clinically important complication of TNF receptor associated periodic syndrome is amyloidosis which results from the continuous elevation of serum amyloid A (SAA).
- It is estimated that 10-20% of the individuals with TRAPS may develop amyloidosis.
- Mutations involving cysteine substitution are more commonly associated with amyloidosis.

# Diagnosis

## Diagnostic Study of Choice
- Diagnosis is based on the clinical features. In 2017, Eurofever registry developed a set of criteria for the diagnosis of the four major periodic fever syndromes. Table below is the diagnostic criteria for TRAPS.
- The cut-off value for the diagnosis of TRAPS is score equal or higher than 43 scores.
- The overall sensitivity and specificity of this set of criteria for the diagnosis of this disorder is 59% and 84%, respectively.
- The gold standard diagnostic study for TNF receptor associated periodic syndrome is the genetic analysis.

## History and Symptoms
- The hallmark of TNF-a receptor-associated periodic syndrome is recurrent fever episodes lasting 1 to 4 weeks or more. Fever is accompanied by other symptoms including but not limited to skin rash, abdominal pain, diarrhea, puffy eyes (due to periorbital edema), migrating muscle and joint pain, and erythema of the eye.

## Physical Examination
- Common physical examination findings of TNF receptor-associated periodic syndrome include fever, skin rash, lymphadenopathy, and splenomegaly.
Cutaneous manifestations of TRAPS include an erythematous rash that overlies an area with myalgia, erysipelas-like erythema, and urticaria.
Eye involvement is characteristics for this disease among other autoinflammatory diseases and may manifest with conjunctivitis, periorbital edema, and uveitis.
Signs consistent with acute abdomen may also be present.
- Cutaneous manifestations of TRAPS include an erythematous rash that overlies an area with myalgia, erysipelas-like erythema, and urticaria.
- Eye involvement is characteristics for this disease among other autoinflammatory diseases and may manifest with conjunctivitis, periorbital edema, and uveitis.
- Signs consistent with acute abdomen may also be present.

## Laboratory Findings
- An elevated concentration of blood acute phase reactants are observed both during and in between inflammatory attacks.
- An elevated level of serum TNF-, C3, and C4 have also been reported.

## Electrocardiogram
- There are no ECG findings associated with TNF receptor-associated periodic syndrome.

## X-ray
- There are no x-ray findings associated with TNF receptor-associated periodic syndrome.

## Echocardiography or Ultrasound
- There are no echocardiography/ultrasound findings associated with TNF receptor-associated periodic syndrome.

## CT scan
- There are no CT scan findings associated with TNF receptor-associated periodic syndrome.
- However, para-aortic and mesenteric lymphadenopathies have been reported in one case.

## MRI
- There are no MRI findings associated with TNF receptor-associated periodic syndrome.

## Other Imaging Findings
- There are no other imaging findings associated with TNF receptor-associated periodic syndrome.

## Other Diagnostic Studies
- There are no other diagnostic studies associated with TNF receptor-associated periodic syndrome.

# Treatment

## Medical Therapy
- Several medications have been studied for the treatment of TRAPS including high dose corticosteroids, etanercept, and infliximab.
- Response to the aforementioned treatment options reported to be different in different cases.
- Etanercept has been reported to effectively reduce the severity of attacks as well as the risk of amyloidosis development.

## Surgery
- Surgical intervention is not recommended for the management of TNF receptor-associated periodic syndrome.

## Primary Prevention
- There are no established measures for the primary prevention of TNF receptor-associated periodic syndrome.

## Secondary Prevention
- There are no established measures for the secondary prevention of TNF receptor-associated periodic syndrome.