TNF receptor-associated periodic syndrome (TRAPS): Description of a novel TNFRSF1A mutation and response to etanercept

Abstract

TRAPS is the most common of the autosomal dominant periodic fever syndromes. It is caused by mutations in the TNFRSF1A gene, which encodes for the type 1 TNF-receptor (TNFR1). We describe here a Brazilian patient with TRAPS associated to a novel TNFRSF1A de novo mutation and the response to anti-TNF therapy. The patient is a 9-year-old girl with recurrent fevers since the age of 3 years, usually lasting 3 to 7 days, and recurring every other week. These episodes are associated with mild abdominal pain, nausea, vomiting and generalized myalgia. Recurrent conjunctivitis and erysipela-like skin lesions in the lower limbs also occur. Laboratory studies show persistent normocytic normochromic anemia, thrombocytosis, elevated erythrocyte sedimentation rate and C-reactive protein. IgD levels are normal. Mutational screening of TNFRSF1A revealed the association of a novel C30F mutation with the common R92Q low-penetrance mutation. The R92Q mutation is seen in 5% of the general population and is associated with an atypical inflammatory phenotype. The patient had a very good response to etanercept, with cessation of fever and normalization of inflammatory markers. Our report expands the spectrum of TNFRSF1A mutations associated with TRAPS, adding further evidence for possible additive effects of a low-penetration R92Q and cysteine residue mutations, and confirms etanercept as an efficacious treatment alternative.

Síndromes autoinflamatórias hereditárias na faixa etária pediátrica

“…Receptor shedding is believed to be necessary for blocking TNF-alpha activity and preventing exacerbated inflammatory response. 42,43 Additional studies have suggested that the mutated receptor has defective intracellular trafficking; it is retained in the endoplasmic reticulum. This intracellular buildup of the receptor could lead to spontaneous activation, triggering an inflammatory response.…”

“…48 Roughly half of all patients have erythematous macules or, more rarely, edematous, urticaria-like plaques over myalgic areas. 21,43 Less commonly, the rash is disseminated and Hereditary autoinflammatory syndromes -Jesus AA et al…”

“…43 Etanercept significantly reduces the number and severity of episodes, although its efficacy may decrease with prolonged use. 55 Successful use of IL-1 receptor antagonist (anakinra) in etanerceptrefractory cases has been reported.…”

“…6,7 Unlike in FMF, colchicine is of limited efficacy in TRAPS; less than 22% of patients are responsive. 2,43 Non-steroidal anti-inflammatory drugs (NSAIDs) usually offer no relief beyond suppression of fever. 6,7 Cryopyrin-associated periodic syndrome (CAPS) or cryopyrinopathies…”

“…8 Depending on disease severity, inflammatory markers may remain elevated even in the afebrile intercritical period. 43 Normocytic/normochromic anemia is also often present. 8,43 Definitive diagnosis is established by DNA sequencing of the TNFRSF1A gene.…”