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Pediatric Radiology

, Volume 49, Issue 1, pp 23–36 | Cite as

Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature

  • Claudia Martinez-RiosEmail author
  • Mehul P. Jariwala
  • Kerri Highmore
  • Karen Watanabe Duffy
  • Lynn Spiegel
  • Ronald M. Laxer
  • Jennifer Stimec
Review

Abstract

Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare autosomal-dominant autoinflammatory disease of incomplete penetrance and variable expression. PAPA syndrome is the result of a mutation in the proline serine threonine phosphatase-interacting protein 1 (PSTPIP1/CD2BP1) gene located on chromosome 15, which results in an abnormal overproduction of the pro-inflammatory cytokine interleukin-1β (IL-1). This syndrome clinically manifests as early onset of recurrent episodes of acute aseptic inflammation of the joints, generally occurring in the first two decades of life, followed by manifestation of characteristic skin lesions in the third decade, after an obvious decline in the joint symptoms. Although uncommon, the potential clinical implications of PAPA syndrome warrant an appropriate diagnosis in a timely fashion.

Keywords

Acne Arthritis Children Genetic mutation Magnetic resonance imaging Musculoskeletal Pyogenic arthritis, pyogrenosum and acne syndrome Pyoderma gangrenosum 

Notes

Compliance with ethical standards

Conflicts of interest

Dr. R. M. Laxer has acted as a consultant for Sobi (manufacturer of anakinra) and Novartis (manufacturer of canakinumab). These relationships are not related to the development of this manuscript.

References

  1. 1.
    Demidowich AP, Freeman AF, Kuhns DB et al (2012) Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne). Arthritis Rheum 64:2022–2027CrossRefGoogle Scholar
  2. 2.
    Wise CA, Gillum JD, Seidman CE et al (2002) Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 11:961–969CrossRefGoogle Scholar
  3. 3.
    Yeon HB, Lindor NM, Seidman JG et al (2000) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet 66:1443–1448CrossRefGoogle Scholar
  4. 4.
    Wang D, Höing S, Patterson HC et al (2013) Inflammation in mice ectopically expressing human pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome-associated PSTPIP1 A230T mutant proteins. J Biol Chem 288:4594–4601CrossRefGoogle Scholar
  5. 5.
    Lindor NM, Arsenault TM, Solomon H et al (1997) A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 72:611–615CrossRefGoogle Scholar
  6. 6.
    Online Mendelian Inheritance in Man (2018) National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/omim. Accessed 1 March 2018
  7. 7.
    Tallon B, Corkill M (2006) Peculiarities of PAPA syndrome. Rheumatology 45:1140–1143CrossRefGoogle Scholar
  8. 8.
    Smith EJ, Allantaz F, Bennet L et al (2010) Clinical, molecular, and genetic characteristics of PAPA syndrome: a review. Curr Genomics 11:519–527CrossRefGoogle Scholar
  9. 9.
    Loffler W, Lohse P, Weihmayr T et al (2017) Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome: differential diagnosis of septic arthritis by regular detection of exceedingly high synovial counts. Infection 45:395–402CrossRefGoogle Scholar
  10. 10.
    Holzinger D, Roth J (2016) Alarming consequences — autoinflammatory disease spectrum due to mutations in proline-serine threonine phosphatase-interacting protein 1. Curr Opin Rheumatol 28:550–559CrossRefGoogle Scholar
  11. 11.
    Fathalla BM, Al-Wahadneh AM, Al-Mutawa M et al (2014) A novel de novo PSTPIP1 mutation in a boy with pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) syndrome. Clin Exp Rheumatol 32:956–958Google Scholar
  12. 12.
    Wise CA, Bennet LB, Pascual V et al (2000) Localization of a gene for familial recurrent arthritis 43:2041–2045Google Scholar
  13. 13.
    Cortis E, Benedetti DF, Insalaco A et al (2004) Abnormal production of the tumor necrosis factor inhibitor etanercept and clinical efficacy of tumor in a patient with PAPA syndrome. J Pediatr 145:851–855CrossRefGoogle Scholar
  14. 14.
    Dierselhuis MP, Frenkel J, Wulffraat NM et al (2005) Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology 44:406–408CrossRefGoogle Scholar
  15. 15.
    Brenner M, Ruzicka G, Plewig G (2009) Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol 161:1199–1201CrossRefGoogle Scholar
  16. 16.
    Tofteland ND, Shaver TS (2010) Clinical efficacy of etanercept for treatment of PAPA syndrome. J Clin Rheumatol 16:244–245CrossRefGoogle Scholar
  17. 17.
    Schellevis MA, Stoffels M, Hoppenreijs EPAH et al (2011) Variable expression and treatment of PAPA syndrome. Ann Rheum Dis 70:1168–1170CrossRefGoogle Scholar
  18. 18.
    Caorsi R, Picco P, Buoncompagni A et al (2014) Osteolytic lesion in PAPA syndrome responding to anti-interleukin 1 treatment. J Rheumatol 41:2333–2334CrossRefGoogle Scholar
  19. 19.
    Omenetti A, Carta S, Caorsi R et al (2016) Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome. Rheumatology 55:1325–1335CrossRefGoogle Scholar
  20. 20.
    Jacobs JC, Goetzi EJ (1975) Streaking leukocyte factor, arthritis, and pyoderma gangrenosum. Pediatrics 56:570–578Google Scholar
  21. 21.
    Shoham NG, Centola M, Mansfield E et al (2003) Pyrin binds PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A 100:13501–13506CrossRefGoogle Scholar
  22. 22.
    McDermott MF (2004) A common pathway in periodic fever syndromes. Trends Immunol 25:457–460CrossRefGoogle Scholar
  23. 23.
    Omenetti A, Caorsi R, Carta S et al (2013) PW02-006-PAPA syndrome clinical spectrum and IL1B release. Pediatr Rheumatol 11:A146CrossRefGoogle Scholar
  24. 24.
    Caorsi R, Marotto D, Insalaco A et al (2015) The phenotypic variability of PAPA syndrome: evidence from the Eurofever registry. Pediatr Rheumatol 13:08CrossRefGoogle Scholar
  25. 25.
    Yang H, Reinherz EL (2006) CD2BP1 modulates CD2-dependent T cell activation via linkage to protein tyrosine phosphatase (PTP)-PEST. J Immunol 176:5898–5907CrossRefGoogle Scholar
  26. 26.
    Starnes TW, Bennin DA, Bing X et al (2014) The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages. Blood 123:2703–2714CrossRefGoogle Scholar
  27. 27.
    Yu JW, Wu J, Zhang Z et al (2006) Cryopyrin and pyrin activate caspase-1, but not NF-kappa B, via ASC oligomerization. Cell Death Differ 13:236–249CrossRefGoogle Scholar
  28. 28.
    Arostegui JI, Yagüe J (2008) Hereditary systemic autoinflammatory diseases. Part II: cryopyrin-associated periodic syndromes, pediatric systemic granulomatosis and PAPA syndrome. Med Clin 130:429–438CrossRefGoogle Scholar
  29. 29.
    Braun-Falco M, Kovnerystyy O, Lohse P et al (2012) Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol 66:409–415CrossRefGoogle Scholar
  30. 30.
    Lambertucci JR (2014) Fever of undetermined origin in a patient with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA syndrome). Rev Soc Bras Med Trop 47:122CrossRefGoogle Scholar
  31. 31.
    Marzano AV, Borghi A, Meroni PL et al (2016) Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation. Br J Dermatol 175:882–891CrossRefGoogle Scholar
  32. 32.
    Varga G, Gattorno M, Foell D et al (2015) Redox distress and genetic defects conspire in systemic autoinflammatory diseases. Nat Rev Rheumatol 11:670–680CrossRefGoogle Scholar
  33. 33.
    Löhrer R, Eming R, Wolfrum N et al (2011) Autoinflammatory diseases as cause of wound healing defects. Hautarzt 62:524–533CrossRefGoogle Scholar
  34. 34.
    Verbsky JW (2012) Monogenic causes of inflammatory disease in rheumatology. Curr Opin Rheumatol 24:506–514CrossRefGoogle Scholar
  35. 35.
    Caso F, Rigante D, Vitale A (2013) Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues. Int J Rheumatol 2013:513782CrossRefGoogle Scholar
  36. 36.
    Thacker PG, Binkovitz LA, Thomas KB (2012) Deficiency of interleukin-1-receptor antagonist syndrome: a rare auto-inflammatory condition that mimics multiple classic radiographic findings. Pediatr Radiol 42:495–498CrossRefGoogle Scholar
  37. 37.
    Aksentijevich I, Masters SL, Ferguson PJ et al (2009) An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 360:2426–2437CrossRefGoogle Scholar
  38. 38.
    Stenerson M, Dufendach K, Aksentijevich I (2011) The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. Arthritis Rheum 63:4018–4022CrossRefGoogle Scholar
  39. 39.
    Daldrup-Link HE, Steinbach L (2009) MR imaging of pediatric arthritis. Magn Reson Imaging Clin N Am 17:451–467CrossRefGoogle Scholar
  40. 40.
    Macaubas C, Nguyen K, Milojevic D et al (2009) Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat Rev Rheumatol 5:616–626CrossRefGoogle Scholar
  41. 41.
    Oberle EJ, Harris JG, Verbsky JW (2014) Polyarticular juvenile idiopathic arthritis-epidemiology and management approaches. J Clin Epidemiol 6:379–393Google Scholar
  42. 42.
    Monsalve J, Kan JH (2015) Septic arthritis in children: frequency of coexisting unsuspected osteomyelitis and implications on imaging work-up and management. AJR Am J Roentgenol 204:1289–1295CrossRefGoogle Scholar
  43. 43.
    Karchevsky M, Schweitzer ME, Morrison WB et al (2004) MRI findings of septic arthritis and associated osteomyelitis in adults. AJR Am J Roentgenol 182:119–122CrossRefGoogle Scholar
  44. 44.
    Funk SS, Copley LAB (2017) Acute hematogenous osteomyelitis in children. Pathogenesis, diagnosis and treatment. Orthop Clin N Am 48:199–208CrossRefGoogle Scholar
  45. 45.
    Guillerman RP (2013) Osteomyelitis and beyond. Pediatr Radiol 43:S193–S203CrossRefGoogle Scholar
  46. 46.
    Ferguson PJ, Sandu M (2012) Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis. Curr Rheumatol Rep 14:130–141CrossRefGoogle Scholar
  47. 47.
    Ferguson PJ, Chen S, Tayeh MK et al (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42:551–557CrossRefGoogle Scholar
  48. 48.
    Chen W, Obermayer-Pietsch B, Hong JB (2011) Acne-associated syndromes: models for better understanding of acne pathogenesis. J Eur Acad Dermatol Venereol 25:637–646CrossRefGoogle Scholar
  49. 49.
    Stichweh DS, Punaro M, Pascual V (2005) Dramatic improvement of pyoderma gangrenosum with infliximab in a patient with PAPA syndrome. Pediatr Dermatol 22:262–265CrossRefGoogle Scholar
  50. 50.
    Khatibi K, Heit JJ, Telischak NA (2015) Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm. BMJ Case Rep.  https://doi.org/10.1136/bcr-2015-011753
  51. 51.
    Horiuchi I, Fukatsu Y, Ushijima J et al (2016) A pregnancy-associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome. Clin Case Rep 4:989–991CrossRefGoogle Scholar
  52. 52.
    Hong J, Su Y, Chiu H (2009) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome): report of a sporadic case without an identifiable mutation in the CD2BP1 gene. J Am Acad Dermatol 61:533–535CrossRefGoogle Scholar
  53. 53.
    Nguyen MT, Borchers A, Selmi C et al (2012) The SAPHO syndrome. Semin Arthritis Rheum 42:254–265CrossRefGoogle Scholar
  54. 54.
    Basmaci R, Bonacorsi S (2017) Kingella kingae: from carriage to infection. Commentary on Canadian Medical Association Journal. CMAJ 189:E1105–E1106CrossRefGoogle Scholar
  55. 55.
    Edrees AF, Kaplan DL, Abdou NI (2002) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) associated with hypogammaglobulinemia and elevated serum tumor necrosis factor-a levels. J Clin Rheumatol 8:273–275CrossRefGoogle Scholar
  56. 56.
    Finetti M, Caorsi R, Marotto D et al (2015) Long-term efficacy of IL-1 blockers in PAPA patients. Pediatr Rheumatol 13:P207CrossRefGoogle Scholar
  57. 57.
    Gattorno M, Tassi S, Carta S et al (2007) Pattern of interleukin-1 beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. Arthritis Rheum 56:3138–3148CrossRefGoogle Scholar
  58. 58.
    Geusau A, Mothes-Luksch N, Nahavandi H et al (2013) Identification of a homozygous PSTPIP1 mutation in a patient with a PAPA-like syndrome responding to canakinumab treatment. JAMA Dermatol 149:209–215CrossRefGoogle Scholar
  59. 59.
    Ter Haar N, Lachmann H, Özen S et al (2013) Treatment of autoinflammatory diseases: results from the Eurofever registry and a literature review. Ann Rheum Dis 72:678–685CrossRefGoogle Scholar
  60. 60.
    Stone D, Ombrello A, Almeida ADJ et al (2015) Use of TNF inhibitors in the treatment of PAPA syndrome. Pediatr Rheumatol 13:P138CrossRefGoogle Scholar
  61. 61.
    Lee H, Park SH, Kim SK (2012) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) with E250K mutation in CD2BP1 gene treated with the tumor necrosis factor inhibitor adalimumab. Clin Exp Rheumatol 30:452Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Claudia Martinez-Rios
    • 1
    • 2
    • 3
    Email author return OK on get
  • Mehul P. Jariwala
    • 4
  • Kerri Highmore
    • 1
  • Karen Watanabe Duffy
    • 5
  • Lynn Spiegel
    • 6
    • 7
    • 8
  • Ronald M. Laxer
    • 6
    • 7
    • 8
  • Jennifer Stimec
    • 2
    • 3
  1. 1.Pediatric Radiology Division, Department of Medical Imaging, University of OttawaChildren’s Hospital of Eastern OntarioOttawaCanada
  2. 2.Department of Diagnostic ImagingThe Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of Medical ImagingUniversity of TorontoTorontoCanada
  4. 4.Division of Pediatric Rheumatology, Department of PediatricsRoyal University Hospital, University of SaskatchewanSaskatoonCanada
  5. 5.Division of Rheumatology, Department of Pediatrics, University of OttawaChildren’s Hospital of Eastern OntarioOttawaCanada
  6. 6.Department of PediatricsUniversity of TorontoTorontoCanada
  7. 7.Division of RheumatologyThe Hospital for Sick ChildrenTorontoCanada
  8. 8.Department of Medicine, University of TorontoThe Hospital for Sick ChildrenTorontoCanada

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