Journal of Clinical Immunology

, Volume 34, Issue 5, pp 584–593 | Cite as

Clinical and Genetic Characterization of Japanese Sporadic Cases of Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis Syndrome from a Single Medical Center in Japan

  • Kazuo Kubota
  • Hidenori Ohnishi
  • Takahide Teramoto
  • Norio Kawamoto
  • Kimiko Kasahara
  • Osamu Ohara
  • Naomi Kondo
Original Research



To investigate clinical presentation, genetic background and cytokine profile of Japanese sporadic cases of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.


Nine PFAPA syndrome patients were recruited. DNA sequence analysis of auto inflammatory disorder susceptibility genes, MEFV, MVK, NLRP3, and TNFRSF1A, were performed. Serum cytokine levels and monocyte IL-1β levels were measured by ELISA.


The study population consisted of six males and three females (mean age of onset 26.8 months). Febrile episodes lasted 3–6 days with symptom-free intervals ranging from 2 to 12 weeks. Fever was accompanied by pharyngitis (n = 8), aphthous stomatitis (n = 4), and cervical adenitis (n = 5). White blood cells and C-reactive protein were increased during the attack phase. Mean IgD serum levels were 7.32 ± 9.51 mg/dl during the attack phase, and were mildly elevated in two patients. Heterozygous MEFV, NLRP3 and TNFRSF1A variants were detected in four, one and three cases, respectively. Serum TNF-α and IL-18 levels were elevated during the attack-free and attack periods compared with controls. Other cytokines, IL-1β, IL-1ra, IL-6, and sTNFR1, were only increased during the attack phase. Oral prednisolone was administered to eight patients and immediately reduced fever. Tonsillectomy performed in five patients induced cessation of fever in four patients. One case with repeated fever attacks after tonsillectomy showed increased monocyte IL-1β production, similar to the other active case with genetic variants of auto inflammatory disorder-associated genes.


Japanese PFAPA syndrome patients may have cytokine regulation dysfunction as a result of genetic variants of auto inflammatory disorder-associated genes.


PFAPA IgD MEFV IL-1β tonsillectomy 



We thank the members of the families who agreed to participate in the study. We thank Dr. Y. Uchida, Dr. A. Imamura, Dr. K. Goto and Dr. A. Sakai for patient recruitment. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Health and Labour Science Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour and Welfare.

Conflict of Interest

The authors declare no conflicts of interest.


  1. 1.
    Hoffman HM, Simon A. Recurrent Febrile Syndromes: What a Rheumatologist Needs to Know. Nat Rev Rheumatol. 2009;5:249–56.PubMedCrossRefGoogle Scholar
  2. 2.
    Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of Periodic Fever, Pharyngitis, and Aphthous Stomatitis. J Pediatr. 1987;110:43–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Thomas KT, Feder Jr HM, Lawton AR, Edwards KM. Periodic Fever Syndrome in Children. J Pediatr. 1999;135:15–21.PubMedCrossRefGoogle Scholar
  4. 4.
    Padeh S, Brezniak N, Zemer D, Pras E, Livneh A, Langevitz P, et al. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenopathy Syndrome: Clinical Characteristics and Outcome. J Pediatr. 1999;135:98–101.PubMedCrossRefGoogle Scholar
  5. 5.
    Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror Autoinflammaticus: the Molecular Pathophysiology of Autoinflammatory Disease (*). Annu Rev Immunol. 2009;27:621–68.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Long SS. Syndrome of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA)–What it isn’t. What is it? J Pediatr. 1999;135:1–5.PubMedCrossRefGoogle Scholar
  7. 7.
    Stojanov S, Hoffmann F, Kery A, Renner ED, Hartl D, Lohse P, et al. Cytokine Profile in PFAPA Syndrome Suggests Continuous Inflammation and Reduced Anti-Inflammatory Response. Eur Cytokine Netw. 2006;17:90–7.PubMedGoogle Scholar
  8. 8.
    Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S, Zulian F, et al. Differentiating PFAPA Syndrome from Monogenic Periodic Fevers. Pediatrics. 2009;124:e721–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Atas B, Caksen H, Arslan S, Tuncer O, Kirimi E, Odabas D. PFAPA Syndrome Mimicking Familial Mediterranean Fever: Report of a Turkish Child. J Emerg Med. 2003;25:383–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Saulsbury FT, Wispelwey B. Tumor Necrosis Factor Receptor-Associated Periodic Syndrome in a Young Adult who had Features of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis as a Child. J Pediatr. 2005;146:283–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Adachi M, Watanabe A, Nishiyama A, Oyazato Y, Kamioka I, Murase M, et al. Familial Cases of Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome. J Pediatr. 2011;158:155–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Gattorno M, Sormani MP, D’Osualdo A, Pelagatti MA, Caroli F, Federici S, et al. A Diagnostic Score for Molecular Analysis of Hereditary Autoinflammatory Syndromes With Periodic Fever in Children. Arthritis Rheum. 2008;58:1823–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Ohnishi H, Teramoto T, Iwata H, Kato Z, Kimura T, Kubota K, et al. Characterization of NLRP3 Variants in Japanese Cryopyrin-Associated Periodic Syndrome Patients. J Clin Immunol. 2012;32:221–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the Diagnosis of Familial Mediterranean Fever. Arthritis Rheum. 1997;40:1879–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Kubota K, Ohnishi H, Teramoto T, Matsui E, Murase K, Kanoh H, et al. In Vitro Analysis of the Functional Effects of an NLRP3 G809S Variant with the co-Existence of MEFV Haplotype Variants in Atypical Autoinflammatory Syndrome. J Clin Immunol. 2013;33:325–34.PubMedCrossRefGoogle Scholar
  16. 16.
    Lierl M. Periodic Fever Syndromes: a Diagnostic Challenge for the Allergist. Allergy. 2007;62:1349–58.PubMedCrossRefGoogle Scholar
  17. 17.
    Kovacs L, Hlavata A, Baldovic M, Paulovicova E, Dallos T, Fehervizyova Z, et al. Elevated Immunoglobulin D Levels in Children With PFAPA Syndrome. Neuroendocrinol Lett. 2010;31:743–6.PubMedGoogle Scholar
  18. 18.
    Sampaio IC, Rodrigo MJ, Monteiro Marques JG. Two Siblings With Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. Pediatr Infect Dis J. 2009;28:254–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Valenzuela PM, Majerson D, Tapia JL, Talesnik E. Syndrome of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) in Siblings. Clin Rheumatol. 2009;28:1235–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Cochard M, Clet J, Le L, Pillet P, Onrubia X, Gueron T, et al. PFAPA Syndrome is not a Sporadic Disease. Rheumatology (Oxford). 2010;49:1984–7.CrossRefGoogle Scholar
  21. 21.
    Cazeneuve C, Genevieve D, Amselem S, Hentgen V, Hau I, Reinert P. MEFV Gene Analysis in PFAPA. J Pediatr. 2003;143:140–1.PubMedCrossRefGoogle Scholar
  22. 22.
    Dagan E, Gershoni-Baruch R, Khatib I, Mori A, Brik R. MEFV, TNF1rA, CARD15 and NLRP3 Mutation Analysis in PFAPA. Rheumatol Int. 2010;30:633–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Ryan JG, Masters SL, Booty MG, Habal N, Alexander JD, Barham BK, et al. Clinical Features and Functional Significance of the P369S/R408Q Variant in Pyrin, the Familial Mediterranean Fever Protein. Ann Rheum Dis. 2010;69:1383–8.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kolly L, Busso N, von Scheven-Gete A, Bagnoud N, Moix I, Holzinger D, et al. Periodic Fever, Aphthous Stomatitis, Pharyngitis, Cervical Adenitis Syndrome is Linked to Dysregulated Monocyte IL-1beta Production. J Allergy Clin Immunol. 2013;131:1635–43.PubMedCrossRefGoogle Scholar
  25. 25.
    Pelagatti MA, Meini A, Caorsi R, Cattalini M, Federici S, Zulian F, et al. Long-Term Clinical Profile of Children With the low-Penetrance R92Q Mutation of the TNFRSF1A Gene. Arthritis Rheum. 2011;63:1141–50.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Vigo G, Zulian F. Periodic Fevers With Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA). Autoimmun Rev. 2012;12:52–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Ozen S, Hoffman HM, Frenkel J, Kastner D. Familial Mediterranean Fever (FMF) and Beyond: A new Horizon. Fourth International Congress on the Systemic Autoinflammatory Diseases Held in Bethesda, USA, 6–10 November 2005. Ann Rheum Dis. 2006;65:961–4.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Dinarello CA. Blocking IL-1 in Systemic Inflammation. J Exp Med. 2005;201:1355–9.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Galon J, Aksentijevich I, McDermott MF, O’Shea JJ, Kastner DL. TNFRSF1A Mutations and Autoinflammatory Syndromes. Curr Opin Immunol. 2000;12:479–86.PubMedCrossRefGoogle Scholar
  30. 30.
    Stojanov S, Kastner DL. Familial Autoinflammatory Diseases: Genetics, Pathogenesis and Treatment. Curr Opin Rheumatol. 2005;17:586–99.PubMedCrossRefGoogle Scholar
  31. 31.
    Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA, et al. Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) is a Disorder of Innate Immunity and Th1 Activation Responsive to IL-1 Blockade. Proc Natl Acad Sci U S A. 2011;108:7148–53.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Brown KL, Wekell P, Osla V, Sundqvist M, Savman K, Fasth A, et al. Profile of Blood Cells and Inflammatory Mediators in Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis (PFAPA) Syndrome. BMC Pediatr. 2010;10:65.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Simsek I, Pay S, Pekel A, Dinc A, Musabak U, Erdem H, et al. Serum Proinflammatory Cytokines Directing T Helper 1 Polarization in Patients With Familial Mediterranean Fever. Rheumatol Int. 2007;27:807–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Latz E, Xiao TS, Stutz A. Activation and Regulation of the Inflammasomes. Nat Rev Immunol. 2013;13:397–411.PubMedCrossRefGoogle Scholar
  35. 35.
    Peridis S, Pilgrim G, Koudoumnakis E, Athanasopoulos I, Houlakis M, Parpounas K. PFAPA Syndrome in Children: a Meta-Analysis on Surgical Versus Medical Treatment. Int J Pediatr Otorhinolaryngol. 2010;74:1203–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Berlucchi M, Meini A, Plebani A, Bonvini MG, Lombardi D, Nicolai P. Update on Treatment of Marshall’s Syndrome (PFAPA Syndrome): Report of Five Cases With Review of the Literature. Ann Otol Rhinol Laryngol. 2003;112:365–9.PubMedGoogle Scholar
  37. 37.
    Garavello W, Pignataro L, Gaini L, Torretta S, Somigliana E, Gaini R. Tonsillectomy in Children with Periodic Fever with Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome. J Pediatr. 2011;159:138–42.PubMedCrossRefGoogle Scholar
  38. 38.
    Feder HM, Salazar JC. A Clinical Review of 105 Patients With PFAPA (a Periodic Fever Syndrome). Acta Paediatr. 2010;99:178–84.PubMedGoogle Scholar
  39. 39.
    Renko M, Salo E, Putto-Laurila A, Saxen H, Mattila PS, Luotonen J, et al. A Randomized, Controlled Trial of Tonsillectomy in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome. J Pediatr. 2007;151:289–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Colotto M, Maranghi M, Durante C, Rossetti M, Renzi A, Anatra MG. PFAPA Syndrome in a Young Adult With a History of Tonsillectomy. Intern Med. 2011;50:223–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Kazuo Kubota
    • 1
  • Hidenori Ohnishi
    • 1
  • Takahide Teramoto
    • 1
  • Norio Kawamoto
    • 1
  • Kimiko Kasahara
    • 1
  • Osamu Ohara
    • 2
    • 3
  • Naomi Kondo
    • 1
  1. 1.Department of Pediatrics, Graduate School of MedicineGifu UniversityGifuJapan
  2. 2.Laboratory for ImmunogenomicsRIKEN Research Center for Allergy and ImmunologyYokohamaJapan
  3. 3.Department of Human Genome ResearchKazusa DNA Research InstituteKisarazuJapan

Personalised recommendations