Periodic fever syndromes

The term auto-inflammatory disease has been proposed to describe a group of disorders characterized by attacks of seemingly unprovoked inflammation without significant levels of either autoantibodies or autoreactive T cells. The genetic causes of eight hereditary autoinflammatory syndromes have been identified in the last 7 years: Familial Mediterranean fever (FMF) Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) Familial cold autoinflammatory syndrome (FCAS)/familial cold urticaria syndrome (FCUS) Muckle-Wells syndrome (MWS) Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular (CINCA) syndrome Blau syndrome PAPA (Pyogenic sterile Arthritis, Pyoderma gangrenosum and Acne) syndrome This article discusses those syndromes that are associated with recurrent fevers. Members of a recently described family of genes, the pyrin family, account for several hereditary periodic fever syndromes. The study of autoinflammatory disease has progressed from clinical characterization to genetic analysis and to definition of the functional defects, linking pyrin genes or domains to apoptotic proteins and signal transduction pathways. As a result, the periodic fever syndromes have been associated with the field of innate immunology, and the classification of these disorders has been changed to autoimmune hereditary fevers. Most patients with hereditary periodic fevers have mutations in either the pyrin or the tumor-necrosis factor (TNF) receptor superfamily of molecules, both of which are intimately involved in innate immunity. Both pyrin and a related gene, cryopyrin, contain an N-terminal domain that encodes a death domain related structure, now known as the pyrin domain, or PyD. The PyD is a conserved sequence motif identified in more than 20 human proteins with putative functions in apoptotic and inflammatory signaling pathways [1]. Both pyrin and cryopyrin interact through their PyDs with a common adaptor protein, apoptotic speck protein (ASC). ASC itself participates in apoptosis, recruitment, and activation of pro-caspase-1 (with associated processing and secretion of interleukin [IL]-1 beta), and nuclear factor (NF)-kappa B, inflammation, neurologic symptoms, or amyloidosis. Instead, a very regular periodic fever, irregular severe febrile episodes, relatively mild arthralgia, dry cough, inflammatory cardiomyopathy and nephropathy, and euthyroid thyroiditis were observed [105]. Current management of patients with this syndrome consists of education, movement to warmer climates, and warming treatments. Anti-inflammatory agents, anabolic steroids, high-dose corticosteroids, and colchicine have variable effect in these parents. Antihistamines are generally not effective. Three patients responded favorably to treatment with stanozolol [106], and anakinra, has also been reported to be effective [101].