A Comprehensive Overview of the Hereditary Periodic Fever Syndromes

Donato Rigante, Bruno Frediani, Luca Cantarini

Innate immunity is a critical partner in the regulation of inflammation and some mutations in genes implied in innate immunity pathways can cause genetic disorders characterized by seemingly unprovoked self-limited inflammatory attacks. These rare conditions are collectively named "hereditary periodic fever syndromes" (HPFS), and protean pathogenetic mechanisms combined with several clinical phenotypes characterize at least four distinct conditions: (1) familial Mediterranean fever, which is the prototype and the most widely recognized among HPFS, inherited as an autosomal recessive disorder showing recurrent dysregulated inflammatory processes, caused by an abnormal interaction between cytoskeleton and inflammasome, a key-signaling platform that releases interleukin-1β (IL-1β); (2) the group of cryopyrin-associated periodic syndrome, which upsets directly the production of IL-1β, with a dominant pattern of inheritance; (3) tumor necrosis factor receptor-associated periodic syndrome, which is an autosomal dominant disorder subverting the functions and traffic of a cell membrane protein; and (4) mevalonate kinase deficiency, which is an autosomal recessive metabolic disorder halting the biosynthesis of cholesterol. MEFV, NLRP3, TNFRSF1A, and MVK are respectively the four causing genes of these conditions, all resulting in excessive IL-1β signaling, though the encoded proteins act at different levels in cytoskeletal filament organization, apoptosis, and activation of the IL-1β-structured inflammasome. The differential diagnosis of HPFS can be challenging, as there are no universally accepted diagnostic algorithms, and near half of patients may have a specific disease without any genetic pathogenetic variant identified. Herein, we outline the most relevant aspects of HPFS at the crossroads between clinical medicine and immunology and all the most recent advances in their treatment, as the increasing use of IL-1 antagonists has achieved unexpected clinical results in a large number of patients.