Fever is a common symptom in childhood, although it cannot always be caused by a common infection. If infections, autoimmune and malignancies have been ruled out, a congenital/hereditary periodic fever syndrome (HPF) may be present. HPF syndromes are characterized by recurrent episodes of fever accompanied by a systemic inflammatory response (elevated CRP, serum amyloid protein A) that particularly affects the skin, mucous membranes, serous interfaces, and joints and may lead to secondary amyloidosis in some conditions. Between episodes, most patients are asymptomatic.
HPF syndromes are classified as autoinflammatory diseases characterized by dysregulation of the innate immune response. In contrast to classical autoimmune diseases, autoantibodies or antigen-specific T cells are absent. In particular, the cytokine interleukin 1 (IL-1) plays a key role in the induction of inflammation by mediating the development of fever, activation of leukocytes, and production of other inflammatory mediators. Several observations support the hypothesis that dysregulation of IL-1 signaling is a direct or indirect cause of the majority of HPF syndromes.
Differential diagnosis is often difficult because of the similarity and variability of symptoms so a diagnosis is often not achieved until adulthood. In addition to the clinical picture, duration and frequency of febrile episodes, age at first manifestation, family history, and ethnicity provide directional information. In recent years, genes have been identified in which certain mutations are causative for the development of HPF syndrome so nowadays molecular genetic testing has become an important part of diagnostics. Knowledge of the genes involved and functional effects of mutations have led to the development of specific therapies (IL-1 and TNF-alpha blockers) that not only improve the quality of life of patients but also significantly reduce the risk of sequelae (sec. amyloidosis).
Gattorno et al. 2019, Ann Rheum Dis 78:1025 / Martorana et al. 2017, Front Immunol 8:344 / ter Haar et al. 2015, Ann Rheum Dis 74:1636 / Federici and Gattorno 2014, Best Pract Res Clin Rheumatol 28:263 / Grumbt (Bangol) et al. 2011, Kinderärztliche Praxis 82:232 / Shinar et al. 2012, Ann Rheum Dis 71:1599