Autoinflammatory syndromes behind the scenes of recurrent fevers in children

Abstract

Many children experience recurrent fevers with no easily identifiable source and only a careful follow-up helps in the early identification of other presenting symptoms of other defined conditions which require medical intervention. Autoinflammatory syndromes are rare childhood-onset disorders of the innate immunity in which recurrent flares of fever and inflammation affecting skin, joints, the gastrointestinal tube, or serous membranes are the most striking signs, without any evidence of autoantibody production or underlying infections. Among the pediatric conditions belonging to this group we can consider hereditary recurrent fevers (familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes), pyogenic disorders (PAPA syndrome, CRMO syndrome, Majeed syndrome), immune-mediated granulomatous diseases (Blau syndrome, Crohn's disease), and idiopathic febrile syndromes (systemic-onset juvenile idiopathic arthritis, PFAPA syndrome, Behçet syndrome). Their genetic background has only been partially elucidated and advances in their molecular pathogenesis are shedding new light on the innate immune system, whilst more and more diseases are being reconsidered at a pathogenetic level and included in this new chapter of postgenomic medicine. The diagnosis of most autoinflammatory syndromes relies on clinical history, demonstration of an increased acute-phase response during inflammatory attacks, and, possibly, genetic confirmation, which is still elusive especially for idiopathic febrile syndromes. This astonishing progress in the awareness and knowledge of autoinflammatory syndromes has anticipated the actual possibilities of medical intervention and rationalized treatment with targeted biologic agents.