SUMMARY

 

1.  Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant periodic fever syndrome.  TRAPS was formerly known as familial Hibernian fever.    

 

2.  The onset of clinical symptoms is highly variable, ranging from 2 weeks of age to 50 years (median 3 years).  TRAPS is characterized by intermittent periods of fever lasting 1-3 weeks.  Associated clinical features include the following: 

Elevated CRP/ESR (during and between episodes)
Arthritis and arthralgias
Abdominal pain from peritonitis
Myalgia
Skin rash (erythematous patches)
Conjunctivitis and periorbital edema

 

3.  Amyloidosis occurs in a minority of patients (15%) and usually involves the kidneys.  The risk of developing amyloidosis is significantly higher for patients who have mutations in certain cysteine residues compared to patients with other mutations (24% vs 2%).  

 

4.  TRAPS is caused by mutations in the TNFRSF1A gene.   Many of the mutations result in impaired shedding of the TNF receptor which may result in enhanced binding and inflammatory effects of TNF alpha.  A newer theory suggests that misfolding of the mutant TNF receptor results in retention of the protein in the ER and triggers an intracellular inflammatory response.   

 

5.  The diagnosis should be suspected in patients suffering from episodic febrile attacks, arthritis/myalgias, and a family history suggestive of an autosomal dominant inheritance pattern.  TNFRSF1A gene sequencing provides a definitive diagnosis.  

 

6.  The following therapies have been utilized in the treatment of TRAPS:
 

-Oral Steroids - a dose of 1mg/kg for 7-10 days can help to abort an acute attack.
-Etanercept - this anti-TNF agent has been used prophylactically to reduce symptoms (25mg subcutaneously 2x/week for adults and 0.4mg/kg subcutaneously 2x/week for children).  Etanercept has been effective in the treatment of amyloidosis in some patients.  Interestingly infliximab use in TRAPS has been associated with severe adverse reactions.  
-Anakinra - successful use of this recombinant IL-1 receptor antagonist has been reported in a small number of patients. 

 

 

 

 

OVERVIEW


     The periodic fever syndromes encompass a group of autoinflammatory disorders characterized by recurrent fevers and inflammation in the absence of infectious triggers.  Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant periodic fever syndrome.  TRAPS was formerly known as familial Hibernian fever.    

 

     The onset of clinical symptoms is highly variable, ranging from 2 weeks of age to 50 years (median 3 years).  TRAPS  is characterized by intermittent periods of fever lasting 1-3 weeks.  Associated clinical features include the following: 

 

-Elevated CRP/ESR (during and between episodes)
-Arthritis and arthralgias
-Abdominal pain from peritonitis
-Myalgia
-Skin rash (erythematous patches)
-Conjunctivitis and periorbital edema

 

     Amyloidosis occurs in a minority of patients (15%) and usually involves the kidneys.  The risk of developing amyloidosis is significantly higher for patients who have mutations in certain cysteine residues compared to other mutations (24% vs 2%).  

         

 

 

PATHOGENESIS

 

     TRAPS is caused by mutations in the TNFRSF1A gene.   Many of the mutations result in impaired shedding of the TNF receptor which may result in enhanced binding and inflammatory effects of TNF alpha.  Mice engineered to have non-sheddable TNF receptor exhibit markedly increased inflammatory responses.  A newer theory suggests that misfolding of the mutant TNF receptor results in retention of the protein in the ER and triggers an intracellular inflammatory response.   

         

 

 

 

DIFFERENTIAL DIAGNOSIS

 

1.Hyper IgD Syndrome
2.Mevalonic Aciduria
3.Familial Mediterranean Fever
4.Crypopyrin associated periodic fevers (muckle wells, FCAS, NOMID) 
5.PFAPA

 

 

 

EVALUATION

 

The diagnosis should be suspected in patients suffering from long febrile attacks, arthritis/myalgias, and a family history suggestive of an autosomal dominant inheritance pattern.  TNFRSF1A gene sequencing provides a definitive diagnosis.  

 

Step 1:  Screening Studies

 

-C reactive protein / Erythrocyte sedimentation rate
-BUN/Creatinine and Urine Protein

 

-CRP and ESR are often elevated during and between attacks.  
-Renal function and urine protein should be checked to screen for potential renal disease from amyloid deposition.  

 

 

Step 2:  Genetic confirmation

 

-TNFRSF1A gene sequencing

 

-This is the definitive test for establishing a diagnosis of TRAPS and is commercially available (Gene Dx).  

 

 

 

 

MANAGEMENT

 

The following therapies have been employed in the treatment of TRAPS:


1.  Oral Steroids - a dose of 1mg/kg for 7-10 days can help to abort an acute attack.

 

2.  Etanercept - this anti-TNF agent has been used prophylactically to reduce symptoms (25mg subcutaneously 2x/week for adults and 0.4mg/kg subcutaneously 2x/week for children).  Etanercept has been effective in the treatment of amyloidosis in some patients.  Interestingly infliximab use in TRAPS has been associated with severe adverse reactions.  

 

3.  Anakinra - successful use of this recombinant IL-1 receptor antagonist has been reported in a small number of patients. 

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources

 

1. Gene Dx:  Offers sequencing for TNFRSF1A.   
A sample submission and informed consent form is required.  
Testing typically takes 6-8 weeks.   
www.genedx.com/services/dis_cg.php
Phone 301-519-2100     FAX 301-519-2892

 

 

Literature Resources

 

 

1.  Gattorno 2008 
     Diagnosis and management of autoinflammatory diseases in childhood (review)

 

2.  Nedjai 2008 
     Abnormal TNF receptor expression on the cell surface leads to exagerrated inflammation in TRAPS
     

3.  Aksentijevich 2001 
     TRAPS mutations with altered cysteine reidues have greater risk of amyloidosis
     

4.  Drewe 2004 
    Treatment of renal amyloidosis with Etanercept in a TRAPS patient
     

5.  Gattorno 2008 
     The efficacy of anakinra (anti-IL1) in patients with TRAPS
     

6.  Church 2006 
     The use of biologics in autoinflammatory syndromes