TNF receptor associated periodic syndrome

Autosomal dominant autoinflammatory disorder

TNF Receptor-Associated Periodic Syndrome (TRAPS)
Synonyms	Familial Hibernian Fever, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome
Pronounce
Field	Rheumatology, Immunology
Symptoms	Recurrent fever, rash, abdominal pain, myalgia, periorbital edema
Complications	Pericarditis, amyloidosis, uveitis, splenomegaly
Onset	Childhood or early adulthood
Duration	Chronic, episodic flares
Types
Causes	Mutations in the TNFRSF1A gene
Risks	Genetic predisposition (autosomal dominant inheritance)
Diagnosis	Blood test, genetic testing, clinical evaluation
Differential diagnosis	Familial Mediterranean fever, CAPS, Still's disease
Prevention	None known
Treatment	Corticosteroids, NSAIDs, Biologic therapy (e.g., etanercept, infliximab)
Medication	TNF inhibitors, IL-1 blockers
Prognosis	Chronic, may lead to complications like amyloidosis if untreated
Frequency	Rare
Deaths	Rare (if amyloidosis develops)

TNF Receptor-Associated Periodic Syndrome (TRAPS) is a rare autoinflammatory disorder characterized by recurrent episodes of fever, inflammation, and pain. It is caused by mutations in the TNFRSF1A gene, which encodes the tumor necrosis factor receptor-1 (TNFR1). TRAPS follows an autosomal dominant inheritance pattern, meaning a single copy of the defective gene can lead to the disorder.

Symptoms and Signs

TRAPS presents with episodic inflammatory attacks lasting days to weeks, with variable severity. The most common symptoms include:

• Recurrent fevers – Lasting longer (usually >7 days) than fevers seen in other periodic fever syndromes.
• Inflammatory symptoms:
• Painful erythematous skin rashes (often migratory and resembling cellulitis)
• Myalgia (muscle pain) – Deep, aching pain in the limbs and trunk
• Periorbital edema (puffy eyes)
• Severe abdominal pain, nausea, vomiting, or diarrhea during attacks
• Long-term complications:
• Pericarditis – Inflammation of the heart lining
• Splenomegaly – Enlarged spleen
• Amyloidosis – A serious long-term complication leading to kidney failure
• Uveitis and vertigo (less common)

Causes

TRAPS is caused by mutations in the TNFRSF1A gene on chromosome 12 (12p13.31). These mutations impair the body's normal inflammatory response by disrupting tumor necrosis factor (TNF) signaling, leading to excessive inflammation.

TRAPS follows an autosomal dominant inheritance pattern, meaning an affected person has a 50% chance of passing the condition to their children.

Pathophysiology

Macrophages produce TNF, a key inflammatory cytokine.

TRAPS is caused by a dysfunctional TNF receptor-1 (TNFR1), leading to: 1. Impaired TNF signaling – Resulting in prolonged and exaggerated inflammatory responses. 2. Dysregulation of immune cells – Macrophages and neutrophils remain overactive, leading to tissue damage. 3. Increased pro-inflammatory cytokines – Elevated IL-1β, IL-6, and TNF-alpha contribute to fever and systemic inflammation.

Diagnosis

The diagnosis of TRAPS is based on clinical presentation, laboratory tests, and genetic testing.

Diagnostic Criteria 1. Clinical evaluation – Recurrent fever episodes (>7 days), migratory rash, muscle pain. 2. Blood tests:

• Elevated inflammatory markers (CRP, ESR, serum amyloid A)
• Elevated IgD (in some cases)

3. Genetic testing – Identifies mutations in the TNFRSF1A gene.

Differential Diagnosis

TRAPS must be differentiated from other autoinflammatory syndromes, including:

• Familial Mediterranean Fever (FMF) – Shorter episodes, autosomal recessive inheritance.
• Cryopyrin-Associated Periodic Syndromes (CAPS) – Includes Muckle-Wells syndrome and FCAS.
• Still’s Disease – Persistent fever, arthritis, and rash.

Treatment

There is no cure for TRAPS, but treatment aims to control inflammation and prevent complications.

First-Line Treatments

• Corticosteroids (e.g., prednisone) – Reduce symptom severity but have long-term side effects.
• NSAIDs – Provide symptom relief for fever and pain.

Biologic Therapies For moderate-to-severe cases, TNF inhibitors and IL-1 blockers are used:

• Etanercept – A TNF-receptor blocker, effective in reducing flare frequency.
• Infliximab and Adalimumab – Have mixed results; some cases worsen symptoms.
• Anakinra (IL-1 blocker) – May be more effective than TNF inhibitors in some patients.

Complication Management Patients with amyloidosis require renal function monitoring and may need IL-1 inhibitors or colchicine.

Prognosis

TRAPS is a lifelong condition, with variable severity. If untreated, complications such as amyloidosis and kidney failure can develop. With appropriate treatment and monitoring, most patients can manage symptoms and prevent major complications.

See Also

• Periodic Fever Syndromes
• Familial Mediterranean Fever
• Autoinflammatory diseases
• TNFRSF1A

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