Tumor necrosis factor receptor 1 associated periodic syndrome (ORPHA:32960)
Tumor necrosis factor receptor 1 associated periodic syndrome (TRAPS) is a periodic fever syndrome, characterized by recurrent fever, arthralgia, myalgia and tender skin lesions lasting for 1 to 3 weeks, associated with skin, joint, ocular and serosal inflammation and complicated by secondary amyloidosis (see this term).
Epidemiology
Annual incidence in Germany was estimated at 1/1,785,000 children under 16.
Clinical description
The onset of TRAPS is usually in infancy or childhood but rarely in adolescence or adulthood. TRAPS is characterized by recurrent episodes that begin with muscle cramps or migrating myalgia, followed by fever that typically lasts for 1 to 3 weeks along with skin, joint, abdominal and ocular manifestations. These episodes occur either spontaneously or after minor triggers (stress, infection, exercise etc). Skin manifestations include centrifugal, migratory, erysepela-like erythema, edematous plaques and urticarial lesions. Eye involvement can manifest in the form of conjunctivitis, periorbital edema (highly specific feature for TRAPS) or uveitis (see this term). Serosal inflammation (pleuritis, peritonitis) is common. Abdominal pain and arthralgias are frequent symptoms. Secondary amyloidosis with renal and hepatic manifestations may eventually develop. An increased risk of atherosclerosis and acute myocardial infarction has been noted.
Etiology
Mutations in the TNFRSF1A  (12p13.2) gene encoding TNFR1, that plays a key role in systemic inflammation, have been shown to underlie this condition. More than 70 mutations in the TNFRSF1A gene have been associated with TRAPS; about 50% of the mutations described (known as structural mutations) involve cysteine residues and are associated with a higher disease penetrance.
Diagnostic methods
During inflammatory episodes, laboratory tests reveal increased indicators of inflammation: raised erythrocyte sedimentation rate, C reactive protein, fibrinogen and haptoglobulin. There may also be an associated leucocytosis along with thrombocytosis, hypo or normochromic anemia and polyclonal hypergammaglobulinemia. The levels of serum amyloid A (SAA) protein and S100A12 correlate closely with disease activity and treatment efficacy. Serum level of soluble p55 TNF receptor (sTNFRSF1A) may be low. Urinary protein analysis helps to monitor evolution of renal amyloidosis. Mutational analyses can help confirm the diagnosis.
Differential diagnosis
Differential diagnosis includes other diseases characterized by periodic fever such as familial cold urticaria, juvenile idiopathic arthritis, Behçet disease, PFAPA syndrome, and Muckle-Wells syndrome (see these terms).
Genetic counseling
The disease is transmitted in autosomal dominant manner with genetic heterogeneity and variable penetrance.
Management and treatment
Non steroidal anti-inflammatory agents are used for symptomatic relief. Inflammatory episodes can be controlled by corticosteroids but often increasing doses are required. Etenarcept, a TNF inhibitor has been shown to be effective. However its efficacy tends to wane during the time. IL-1 receptor agonist (anakinra) and monoclonal antibody to IL-1 (canakinumab) have also been used in treating TRAPS, providing an optimal control of the inflammatory manifestations in the long term.
Prognosis
With age, fever attacks may decrease in intensity and a more chronic and fluctuating course can be observed. Secondary amyloidosis complicates the course of the disease.

                            Last update: 
                            September 2014


                            - Expert reviewer(s): 
                            Dr Marco GATTORNO