Clinical Reviews in Allergy & Immunology

, Volume 54, Issue 3, pp 446–453 | Cite as

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.


Hereditary periodic fever syndromes Autoinflammation Inflammation Interleukin-1 


  1. 1.
    Cooper EL (2010) Evolution of immune systems from self/not self to danger to artificial immune systems (AIS). Phys Life Rev 7(1):55–78. doi: 10.1016/j.plrev.2009.12.001 CrossRefPubMedGoogle Scholar
  2. 2.
    Dzik JM (2010) The ancestry and cumulative evolution of immune reactions. Acta Biochim Pol 57(4):443–466PubMedGoogle Scholar
  3. 3.
    Buchmann K (2014) Evolution of innate immunity: clues from invertebrates via fish to mammals. Front Immunol 23(5):459. doi: 10.3389/fimmu.2014.00459 CrossRefGoogle Scholar
  4. 4.
    Rigante D, Lopalco G, Vitale A et al (2014) Untangling the web of systemic autoinflammatory diseases. Mediat Inflamm 2014:948154. doi: 10.1155/2014/948154 CrossRefGoogle Scholar
  5. 5.
    Aksentijevich I, Kastner DL (2011) Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol 7(8):469–478. doi: 10.1038/nrrheum.2011.94 CrossRefPubMedGoogle Scholar
  6. 6.
    Lamkanfi M, Dixit VM (2012) Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 28:137–161. doi: 10.1146/annurev-cellbio-101011-155745 CrossRefPubMedGoogle Scholar
  7. 7.
    Cantarini L, Lopalco G, Cattalini M, Vitale A, Galeazzi M, Rigante D (2015) Interleukin-1: ariadne’s thread in autoinflammatory and autoimmune disorders. Israel Med Assoc J 17(2):93–97Google Scholar
  8. 8.
    Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA (1984) Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A 81(24):7907–7911CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7(1):31–40CrossRefPubMedGoogle Scholar
  10. 10.
    Vitale A, Rigante D, Lucherini OM et al (2013) Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediat Inflamm 2013:939847. doi: 10.1155/2013/939847 CrossRefGoogle Scholar
  11. 11.
    Ben-Chetrit E, Levy M (1998) Familial Mediterranean fever. Lancet 351(9103):659–664CrossRefPubMedGoogle Scholar
  12. 12.
    Centola M, Wood G, Frucht DM et al (2000) The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95(10):3223–3231PubMedGoogle Scholar
  13. 13.
    Touitou I, Lesage S, McDermott M et al (2004) Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat 24(3):194–198. doi: 10.1002/humu.20080 CrossRefPubMedGoogle Scholar
  14. 14.
    Rigante D, Vitale A, Lucherini OM, Cantarini L (2014) The hereditary autoinflammatory disorders uncovered. Autoimmun Rev 13(9):892–900. doi: 10.1016/j.autrev.2014.08.001 CrossRefPubMedGoogle Scholar
  15. 15.
    Balci B, Tinaztepe K, Yilmaz E et al (2002) MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study. Nephrol Dial Transplant 17(11):1921–1923CrossRefPubMedGoogle Scholar
  16. 16.
    Bilginer Y, Akpolat T, Ozen S (2011) Renal amyloidosis in children. Pediatr Nephrol 26(8):1215–1227. doi: 10.1007/s00467-011-1797-x CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Livneh A, Langevitz P, Zemer D et al (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40(10):1879–1885CrossRefPubMedGoogle Scholar
  18. 18.
    Jéru I, Hentgen V, Cochet E et al (2013) The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach. PLoS One 8(7):e68431. doi: 10.1371/journal.pone.0068431 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Marek-Yagel D, Berkun Y, Padeh S et al (2009) Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum 60(6):1862–1866. doi: 10.1002/art.24570 CrossRefPubMedGoogle Scholar
  20. 20.
    Rigante D, La Torraca I, Avallone L, Pugliese AL, Gaspari S, Stabile A (2006) The pharmacological basis of treatment with colchicine in children with familial Mediterranean fever. Eur Rev Med Pharmacol Sci 10(4):173–178PubMedGoogle Scholar
  21. 21.
    Rigante D, Frediani B, Galeazzi M, Cantarini L (2013) From the Mediterranean to the sea of Japan: the transcontinental odyssey of autoinflammatory diseases. Biomed Res Int 2013:485103. doi: 10.1155/2013/485103 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Aksentijevich I, Galon J, Soares M et al (2001) The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet 69(2):301–314CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Caso F, Cantarini L, Lucherini OM et al (2014) Working the endless puzzle of hereditary autoinflammatory disorders. Mod Rheumatol 24(3):381–389. doi: 10.3109/14397595.2013.843755 CrossRefPubMedGoogle Scholar
  24. 24.
    Cantarini L, Rigante D, Merlini G et al (2014) The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum 43(6):818–823. doi: 10.1016/j.semarthrit.2013.12.002 CrossRefPubMedGoogle Scholar
  25. 25.
    Savic S, Dickie LJ, Wittmann M, McDermott MF (2012) Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives. Best Pract Res Clin Rheumatol 26(4):505–533. doi: 10.1016/j.berh.2012.07.009 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Rigante D, Lopalco G, Vitale A et al (2014) Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome. Clin Rheumatol 33(9):1197–1207. doi: 10.1007/s10067-014-2722-z CrossRefPubMedGoogle Scholar
  27. 27.
    Stojanov S, McDermott MF (2005) The tumour necrosis factor receptor-associated periodic syndrome: current concepts. Expert Rev Mol Med 7(22):1–18CrossRefPubMedGoogle Scholar
  28. 28.
    Rigante D, Cantarini L, Imazio M et al (2011) Autoinflammatory diseases and cardiovascular manifestations. Ann Med 43(5):341–346. doi: 10.3109/07853890.2010.547212 CrossRefPubMedGoogle Scholar
  29. 29.
    Ravet N, Rouaghe S, Dodé C et al (2006) Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene. Ann Rheum Dis 65(9):1158–1162CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Aksentijevich I, D Putnam C, Remmers EF et al (2007) The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum 56(4):1273–1285CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Cantarini L, Lucherini OM, Frediani B et al (2011) Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes. Int J Immunopathol Pharmacol 24(4):827–836CrossRefPubMedGoogle Scholar
  32. 32.
    Tanaka N, Izawa K, Saito MK et al (2011) High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum 63(11):3625–3632. doi: 10.1002/art.30512 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hoffman HM, Wanderer AA, Broide DH (2001) Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 108(4):615–620CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Aganna E, Martinon F, Hawkins PN et al (2002) Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 46(9):2445–2452CrossRefPubMedGoogle Scholar
  35. 35.
    Prieur AM, Griscelli C, Lampert F et al (1987) A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatol 66:57–68CrossRefGoogle Scholar
  36. 36.
    Rigante D (2010) The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration. Eur Rev Med Pharmacol Sci 14(1):1–18PubMedGoogle Scholar
  37. 37.
    Esposito S, Ascolese B, Senatore L et al (2014) Current advances in the understanding and treatment of mevalonate kinase deficiency. Int J Immunopathol Pharmacol 27(4):491–498CrossRefPubMedGoogle Scholar
  38. 38.
    Mendey SH, Kuijk LM, Frenkel J, Waterham HR (2006) A role for geranylgeranylation in interleukin-1β secretion. Arthritis Rheum 54(11):3690–3695CrossRefGoogle Scholar
  39. 39.
    Mendey SH, Schneiders MS, Koster J, Waterham HR (2006) Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat 27(8):796–802CrossRefGoogle Scholar
  40. 40.
    van der Burgh R, ter Haar NM, Boes ML, Frenkel J (2013) Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol 147(3):197–206. doi: 10.1016/j.clim.2012.09.011 CrossRefPubMedGoogle Scholar
  41. 41.
    Berody S, Galeotti C, Koné-Paut I, Piram M (2015) A restrospective survey of patients journey before the diagnosis of mevalonate kinase deficiency. Joint Bone Spine 82(4):240–244. doi: 10.1016/j.jbspin.2014.12.011 CrossRefPubMedGoogle Scholar
  42. 42.
    Bader-Meunier B, Florkin B, Sibilia J et al (2011) Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics 128(1):e152–159. doi: 10.1542/peds.2010-3639 CrossRefPubMedGoogle Scholar
  43. 43.
    Ammouri W, Cuisset L, Rouaghe S et al (2007) Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatology (Oxford) 46(10):1597–1600CrossRefGoogle Scholar
  44. 44.
    Rigante D, Emmi G, Fastiggi M, Silvestri E, Cantarini L (2015) Macrophage activation syndrome in the course of monogenic autoinflammatory disorders. Clin Rheumatol 34(8):1333–1339. doi: 10.1007/s10067-015-2923-0 CrossRefPubMedGoogle Scholar
  45. 45.
    Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A (2003) The contribution of genotypes at the MEFV and SSA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum 48(4):1149–1155CrossRefPubMedGoogle Scholar
  46. 46.
    Ben-Zvi I, Livneh A (2011) Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol 7(2):105–112. doi: 10.1038/nrrheum.2010.181 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Hentgen V, Grateau G, Kone-Paut I et al (2013) Evidence-based recommendations for the practical management of familial Mediterranean fever. Semin Arthritis Rheum 43(3):387–391. doi: 10.1016/j.semarthrit.2013.04.011 CrossRefPubMedGoogle Scholar
  48. 48.
    Roldan R, Ruiz AM, Miranda MD, Collantes E (2008) Anakinra: new therapeutic approach in children with familial Mediterranean fever resistant to colchicine. Joint Bone Spine 75(4):504–505. doi: 10.1016/j.jbspin.2008.04.001 CrossRefPubMedGoogle Scholar
  49. 49.
    Meinzer U, Quartier P, Alexandra JF, Hentgen V, Retornaz F, Koné-Paut I (2011) Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum 41(2):265–271. doi: 10.1016/j.semarthrit.2010.11.003 CrossRefPubMedGoogle Scholar
  50. 50.
    Bulua AC, Mogul DB, Aksentijevich I et al (2012) Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study. Arthritis Rheum 64(3):908–913. doi: 10.1002/art.33416 CrossRefPubMedGoogle Scholar
  51. 51.
    Nedjai B, Hitman GA, Quillinan N et al (2009) Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 60(2):619–625. doi: 10.1002/art.24294 CrossRefPubMedGoogle Scholar
  52. 52.
    Grimwood C, Despert V, Jeru I, Hentgen V (2015) On-demand treatment with anakinra: a treatment option for selected TRAPS patients. Rheumatology (Oxford) 54(9):1749–1751. doi: 10.1093/rheumatology/kev111 CrossRefGoogle Scholar
  53. 53.
    Federico G, Rigante D, Pugliese A, Ranno O, Catania S, Stabile A (2003) Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome. Scand J Rheumatol 32(5):312–314CrossRefPubMedGoogle Scholar
  54. 54.
    Koné-Paut I, Galeotti C (2014) Anakinra for cryopyrin-associated periodic syndrome. Expert Rev Clin Immunol 10(1):7–18. doi: 10.1586/1744666X.2014.861325 CrossRefPubMedGoogle Scholar
  55. 55.
    Rigante D, Ansuini V, Caldarelli M, Bertoni B, La Torraca I, Stabile A (2006) Hydrocephalus in CINCA syndrome treated with anakinra. Childs Nerv Syst 22(4):334–337CrossRefPubMedGoogle Scholar
  56. 56.
    Kuemmerle-Deschner JB, Hachulla E, Cartwright R et al (2011) Two-years results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis 70(12):2095–2102. doi: 10.1136/ard.2011.152728 CrossRefPubMedGoogle Scholar
  57. 57.
    Blech M, Peter D, Fischer P et al (2013) One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. J Mol Biol 425(1):94–111. doi: 10.1016/j.jmb.2012.09.021 CrossRefPubMedGoogle Scholar
  58. 58.
    Lachmann HJ, Koné-Paut I, Kuemmerle-Deschner JB et al (2009) Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360(23):2416–2425. doi: 10.1056/NEJMoa0810787 CrossRefPubMedGoogle Scholar
  59. 59.
    Koné-Paut I, Lachmann HJ, Kuemmerle-Deschner JB et al (2011) Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study. Arthritis Res Ther 13:R202. doi: 10.1186/ar3535 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Anton J, Calvo I, Fernández-Martin J et al (2015) Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort. Clin Exp Rheumatol 33(6 Suppl 94):S67–71PubMedGoogle Scholar
  61. 61.
    Steichen O, van der Hilst J, Simon A, Cuisset L, Grateau G (2009) A clinical criterion to exclude the hyperimmunoglobulin D syndrome (mild mevalonate kinase deficiency) in patients with recurrent fever. J Rheumatol 36(8):1677–1681. doi: 10.3899/jrheum.081313 CrossRefPubMedGoogle Scholar
  62. 62.
    Bodar EJ, Kuijk LM, Drenth JP, van der Meer JW, Simon A, Frenkel J (2011) On-demand anakinra treatment is effective in mevalonate kinase deficiency. Ann Rheum Dis 70(12):2155–2158. doi: 10.1136/ard.2011.149922 CrossRefPubMedGoogle Scholar
  63. 63.
    Galeotti C, Meinzer U, Quartier P et al (2012) Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford) 51(10):1855–1859CrossRefGoogle Scholar
  64. 64.
    Neven B, Valayannopoulos V, Quartier P et al (2007) Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med 356(26):2700–2703CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Donato Rigante
    • 1
  • Bruno Frediani
    • 2
  • Luca Cantarini
    • 2
  1. 1.Institute of Pediatrics, Periodic Fever Research Center, Fondazione Policlinico Universitario A. GemelliUniversità Cattolica Sacro CuoreRomeItaly
  2. 2.Research Center of Systemic Autoinflammatory Diseases and Behçet’s Disease Clinic, Department of Medical Sciences, Surgery and NeurosciencesUniversity of SienaSienaItaly

Personalised recommendations