Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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TNF Receptor-1 Associated Periodic Syndrome (TRAPS) [R50]

OMIM numbers: 142680191190 (TNFRSF1A)

Dr. rer. nat. Barbara Bangol, Dr. med. Kaimo Hirv

Scientific Background

The TNF receptor-1 associated periodic syndrome (TRAPS) is one of the rare hereditary periodic fever syndromes and shows autosomal dominant inheritance with reduced penetrance. On average, the first signs and symptoms occur within the 3rd year of life; however, the disease may also manifest at an adult age. Patients of any ethnicity may be affected by TRAPS. Clinical signs and symptoms of TRAPS include recurring episodes of fever that last approximately 7 days to several weeks. The attacks are frequently accompanied by severe abdominal pain, myalgia, arthralgia, conjunctivitis and/or periorbital edema as well as a migratory, erysipelas-like erythema. Most patients are free of signs or symptoms during the time between the attacks. However, in approximately 20% of all TRAPS patients that were not treated or diagnosed late a subclinical inflammation leads to amyloidosis which mainly affects the kidneys. Symptomatic therapy of choice is administration of streoids. The soluble TNF-α receptor etanercept can be a therapeutic alternative, especially in the case of defective receptor shedding. Patients with mutations affecting the cysteine residues of the TNF receptor show a good clinical and biochemical response to the treatment with anakinra (IL-1 receptor blocker).

TRAPS is caused by mutations in the TNFRSF1A gene (tumor necrosis factor receptor superfamily, member 1A), which encodes the cell membrane-bound receptor TNFR1 (also know as TNFR p55). The binding of TNF-α to the receptor leads, for instance, to cytokine secretion, activation of leukocytes and fever. As a negative feedback mechanism the extracellular part of the receptor is shedded from the surface after stimulation and in the soluble form it absorbs free TNF-α. Almost all of the over 70 known mutations (predominantly missense mutations) are located in the exons 2–4 and 6, that encode the first two extracellular receptor domains and the cleavage site.