The puzzling clinical spectrum and course of juvenile sarcoidosis

Review Article



Juvenile sarcoidosis is a rare, chronic, multisystem, granulomatous disease of obscure etiology which is seen in childhood and adulthood. The disease in childhood has a course different from that in adulthood.

Data sources

PubMed database was searched using terms sarcoidosis, children or childhood sarcoidosis or juvenile sarcoidosis in combination with one of the following terms: epidemiology, clinical manifestations, genetics, diagnosis, treatment, and prognosis. We also retrieved the terms such as early onset sarcoidosis and Blau syndrome. Furthermore, e-medicine and European Respiratory Society monographs for sarcoidosis were reviewed.


Sarcoidosis in childhood presents with two age dependent, distinct forms. In younger children it is clinically evident before the age of four years and characterized by the triad of rash, arthritis and uveitis. In their older counterparts, the juvenile late onset sarcoidosis involves several organs and its clinical appearance resembles the adult type of the disease, with the respiratory system being most frequently affected (hilar lymphadenopathy, pulmonary infiltrations). Steroid is the main agent of treatment whereas methotrexate is also used for beneficial steroid sparing effects. New, novel therapies may change the outcome of the disease especially in difficult morbid cases.


Sarcoidosis in childhood is recognized as a systemic disease affecting various organs and having diverse clinical course depending on the age of onset.

Key words

corticosteroids early onset sarcoidosis juvenile sarcoidosis late onset sarcoidosis methotrexate 


  1. 1.
    Lazarus A. Sarcoidosis: epidemiology, etiology, pathogenesis, and genetics. Dis Mon 2009;55:649–660.PubMedCrossRefGoogle Scholar
  2. 2.
    Shetty AK, Gedalia A. Sarcoidosis: a pediatric perspective. Clin Pediatr (Phila) 1998;37:707–717.CrossRefGoogle Scholar
  3. 3.
    Cimaz R, Ansell BM. Sarcoidosis in the pediatric age. Clin Exp Rheumatol 2002;20:231–237.PubMedGoogle Scholar
  4. 4.
    Pattishall EN, Kendig EL Jr. Sarcoidosis in children. Pediatr Pulmonol 1996;22:195–203.PubMedCrossRefGoogle Scholar
  5. 5.
    Milman N, Hoffmann AL, Byg KE. Sarcoidosis in children. Epidemiology in Danes, clinical features, diagnosis, treatment and prognosis. Acta Paediatr 1998;87:871–878.PubMedCrossRefGoogle Scholar
  6. 6.
    Hoffmann AL, Milman N, Byg KE. Childhood sarcoidosis in Denmark 1979–1994: incidence, clinical features and laboratory results at presentation in 48 children. Acta Paediatr 2004;93:30–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Shetty AK, Gedalia A. Childhood sarcoidosis: a rare but fascinating disorder. Pediatr Rheumatol Online 2008;6:6.CrossRefGoogle Scholar
  8. 8.
    Rybicki BA, Iannuzzi MC, Frederick MM, Thompson BW, Rossman MD, Bresnitz EA, et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med 2001;164:2085–2091.PubMedGoogle Scholar
  9. 9.
    Grutters JC, Sato H, Welsh KI, du Bois RM. The importance of sarcoidosis genotype to lung phenotype. Am J Respir Cell Mol Biol 2003;29(3 Suppl):S59–62.PubMedGoogle Scholar
  10. 10.
    Brewerton DA. Discovery: HLA and disease. Curr Opin Rheumatol 2003;15:369–373.PubMedCrossRefGoogle Scholar
  11. 11.
    Rossman MD, Thompson B, Frederick M, Iannuzzi MC, Rybicki BA, Pander JP, et al. HLA and environmental interactions in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2008;25:125–132.PubMedGoogle Scholar
  12. 12.
    Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153–2165.PubMedCrossRefGoogle Scholar
  13. 13.
    Grunewald J, Brynedal B, Darlington P, Nisell M, Cederlund K, Hillert J, et al. Different HLA-DRB1 allele distributions in distinct clinical subgroups of sarcoidosis patients. Respir Res 2010;11:25.PubMedCrossRefGoogle Scholar
  14. 14.
    Hwang E, McBride R, Neugut AI, Green PH. Sarcoidosis in patients with celiac disease. Dig Dis Sci 2008;53:977–981.PubMedCrossRefGoogle Scholar
  15. 15.
    Statement on sarcoidosis. 15 Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care Med 1999;160:736–755.Google Scholar
  16. 16.
    Song Z, Marzilli L, Greenlee BM, Chen ES, Silver RF, Askin FB, et al. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005;201:755–767.PubMedCrossRefGoogle Scholar
  17. 17.
    Ishihara M, Ohno S, Ono H, Isogai E, Kimura K, Isogai H, et al. Seroprevalence of anti-Borrelia antibodies among patients with confirmed sarcoidosis in a region of Japan where Lyme borreliosis is endemic. Graefes Arch Clin Exp Ophthalmol 1998;236:280–284.PubMedCrossRefGoogle Scholar
  18. 18.
    Hiramatsu J, Kataoka M, Nakata Y, Okazaki K, Tada S, Tanimoto M, et al. Propionibacterium acnes DNA detected in bronchoalveolar lavage cells from patients with sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2003;20:197–203.PubMedGoogle Scholar
  19. 19.
    Tsagris VA, Liapi-Adamidou G. Sarcoidosis in infancy: a case with pulmonary involvement as a cardinal manifestation. Eur J Pediatr 1999;158:258–260.PubMedCrossRefGoogle Scholar
  20. 20.
    Pattishall EN, Strope GL, Spinola SM, Denny FW. Childhood sarcoidosis. J Pediatr 1986;108:169–177.PubMedCrossRefGoogle Scholar
  21. 21.
    Hetherington S. Sarcoidosis in young children. Am J Dis Child 1982;136:13–15.PubMedGoogle Scholar
  22. 22.
    Fink CW, Cimaz R. Early onset sarcoidosis: not a benign disease. J Rheumatol 1997;24:174–177.PubMedGoogle Scholar
  23. 23.
    Miller JJ 3rd. Early-onset “sarcoidosis” and “familial granulomatous arthritis (arteritis)”: the same disease. J Pediatr 1986;109:387–388.PubMedCrossRefGoogle Scholar
  24. 24.
    Rose CD, Eichenfield AH, Goldsmith DP, Athreya BH. Early onset sarcoidosis with aortitis-“juvenile systemic granulomatosis?”. J Rheumatol 1990;17:102–106.PubMedGoogle Scholar
  25. 25.
    Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr 1985;107:689–693.PubMedCrossRefGoogle Scholar
  26. 26.
    Blau EB. Autosomal dominant granulomatous disease of childhood: the naming of things. J Pediatr 1998;133:322–323.PubMedCrossRefGoogle Scholar
  27. 27.
    Ting SS, Ziegler J, Fischer E. Familial granulomatous arthritis (Blau syndrome) with granulomatous renal lesions. J Pediatr 1998;133:450–452.PubMedCrossRefGoogle Scholar
  28. 28.
    Saini SK, Rose CD. Liver involvement in familial granulomatous arthritis (Blau syndrome). J Rheumatol 1996;23:396–399.PubMedGoogle Scholar
  29. 29.
    Tromp G, Kuivaniemi H, Raphael S, Ala-Kokko L, Christiano A, Considine E, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet 1996;59:1097–1107.PubMedGoogle Scholar
  30. 30.
    Rybicki BA, Maliarik MJ, Bock CH, Elston RC, Baughman RP, Kimani AP, et al. The Blau syndrome gene is not a major risk factor for sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:203–208.PubMedGoogle Scholar
  31. 31.
    Rosé CD, Wouters CH, Meiorin S, Doyle TM, Davey MP, Rosenbaum JT, et al. Pediatric granulomatous arthritis: an international registry. Arthritis Rheum 2006;54:3337–3344.PubMedCrossRefGoogle Scholar
  32. 32.
    Milman N, Nielsen OH, Hviid TV, Fenger K. CARD15 single nucleotide polymorphisms 8, 12 and 13 are not increased in ethnic Danes with sarcoidosis. Respiration 2007;74:76–79.PubMedCrossRefGoogle Scholar
  33. 33.
    Kanazawa N, Okafuji I, Kambe N, Nishikomori R, Nakata-Hizume M, Nagai S, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood 2005;105:1195–1197.PubMedCrossRefGoogle Scholar
  34. 34.
    Kambe N, Nishikomori R, Kanazawa N. The cytosolic patternrecognition receptor Nod2 and inflammatory granulomatous disorders. J Dermatol Sci 2005;39:71–80.PubMedCrossRefGoogle Scholar
  35. 35.
    Okafuji I, Nishikomori R, Kanazawa N, Kambe N, Fujisawa A, Yamazaki S, et al. Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis. Arthritis Rheum 2009;60:242–250.PubMedCrossRefGoogle Scholar
  36. 36.
    Wasfi YS, Rose CS, Murphy JR, Silveira LJ, Grutters JC, Inoue Y, et al. A new tool to assess sarcoidosis severity. Chest 2006;129:1234–1245.PubMedCrossRefGoogle Scholar
  37. 37.
    Kataria S, Trevathan GE, Holland JE, Kataria YP. Ocular presentation of sarcoidosis in children. Clin Pediatr (Phila) 1983;22:793–797.CrossRefGoogle Scholar
  38. 38.
    Clark SK. Sarcoidosis in children. Pediatr Dermatol 1987;4:291–299.PubMedCrossRefGoogle Scholar
  39. 39.
    Mallory SB, Paller AS, Ginsburg BC, McCrossin ID, Abernathy R. Sarcoidosis in children: differentiation from juvenile rheumatoid arthritis. Pediatr Dermatol 1987;4:313–319.PubMedCrossRefGoogle Scholar
  40. 40.
    Sahn EE, Hampton MT, Garen PD, Warrick J, Smith D, Silver RM. Preschool sarcoidosis masquerading as juvenile rheumatoid arthritis: two case reports and a review of the literature. Pediatr Dermatol 1990;7:208–213.PubMedCrossRefGoogle Scholar
  41. 41.
    Coutant R, Leroy B, Niaudet P, Loirat C, Dommergues JP, André JL, et al. Renal granulomatous sarcoidosis in childhood: a report of 11 cases and a review of the literature. Eur J Pediatr 1999;158:154–159.PubMedCrossRefGoogle Scholar
  42. 42.
    Dimitriades C, Shetty AK, Vehaskari M, Craver RD, Gedalia A. Membranous nephropathy associated with childhood sarcoidosis. Pediatr Nephrol 1999;13:444–447.PubMedCrossRefGoogle Scholar
  43. 43.
    Weinberg A, Ginsburg CM. Epididymal sarcoidosis in a prepubertal child. Am J Dis Child 1982;136:71–72.PubMedGoogle Scholar
  44. 44.
    Evans SS, Fisher RG, Scott MA, Kennedy BG, Brock JW 3rd, Wilson GJ. Sarcoidosis presenting as bilateral testicular masses. Pediatrics 1997;100(3 Pt 1):392–394.PubMedCrossRefGoogle Scholar
  45. 45.
    Schulte W, Kirsten D, Drent M, Costabel U. Cardiac involvement in sarcoidosis. European Respiratory Monograph 2005;10 (Monograph 32):130–149.CrossRefGoogle Scholar
  46. 46.
    Fernandes SR, Singsen BH, Hoffman GS. Sarcoidosis and systemic vasculitis. Semin Arthritis Rheum 2000;30:33–46.PubMedCrossRefGoogle Scholar
  47. 47.
    Kwong T, Valderrama E, Paley C, Ilowite N. Systemic necrotizing vasculitis associated with childhood sarcoidosis. Semin Arthritis Rheum 1994;23:388–395.PubMedCrossRefGoogle Scholar
  48. 48.
    Hoitsma E, Sharma OP. Neirosarcoidosis. Eur Respir Monogr 2005;10 (Monogr 32):164–187.CrossRefGoogle Scholar
  49. 49.
    Koné-Paut I, Portas M, Wechsler B, Girard N, Raybaud C. The pitfall of silent neurosarcoidosis. Pediatr Neurol 1999;20:215–218.PubMedCrossRefGoogle Scholar
  50. 50.
    Basdemir D, Clarke W, Rogol AD. Growth hormone deficiency in a child with sarcoidosis. Clin Pediatr (Phila) 1999;38:315–316.CrossRefGoogle Scholar
  51. 51.
    Baumann RJ, Robertson WC Jr. Neurosarcoid presents differently in children than in adults. Pediatrics 2003;112:e480–e486.PubMedCrossRefGoogle Scholar
  52. 52.
    Mañá J. Nuclear imaging. 67Gallium, 201thallium, 18F-labeled fluoro-2-deoxy-D-glucose positron emission tomography. Clin Chest Med 1997;18:799–811.PubMedCrossRefGoogle Scholar
  53. 53.
    Bean MJ, Horton KM, Fishman EK. Concurrent focal hepatic and splenic lesions: a pictorial guide to differential diagnosis. J Comput Assist Tomogr 2004;28:605–612.PubMedCrossRefGoogle Scholar
  54. 54.
    Zsolway K, Sinai LN, Magnusson M, Tunnessen WW Jr. Two unusual pediatric presentations of sarcoidosis. Arch Pediatr Adolesc Med 1998;152:410–411.PubMedGoogle Scholar
  55. 55.
    Sharma GD. Pediatric Sarcoidosis. (accessed July 20, 2010).
  56. 56.
    Bénéteau-Burnat B, Baudin B, Morgant G, Baumann FC, Giboudeau J. Serum angiotensin-converting enzyme in healthy and sarcoidotic children: comparison with the reference interval for adults. Clin Chem 1990;36:344–346.PubMedGoogle Scholar
  57. 57.
    Brunner J, Scholl-Bürgi S, Prelog M, Zimmerhackl LB. Chitotriosidase as a marker of disease activity in sarcoidosis. Rheumatol Int 2007;27:1185–1186.PubMedCrossRefGoogle Scholar
  58. 58.
    Bargagli E, Maggiorelli C, Rottoli P. Human chitotriosidase: a potential new marker of sarcoidosis severity. Respiration 2008;76:234–238.PubMedCrossRefGoogle Scholar
  59. 59.
    Rust M, Bergmann L, Kühn T, Tuengerthal S, Bartmann K, Mitrou PS, et al. Prognostic value of chest radiograph, serumangiotensin-converting enzyme and T helper cell count in blood and in bronchoalveolar lavage of patients with pulmonary sarcoidosis. Respiration 1985;48:231–236.PubMedCrossRefGoogle Scholar
  60. 60.
    Boot RG, Hollak CE, Verhoek M, Alberts C, Jonkers RE, Aerts JM. Plasma chitotriosidase and CCL18 as surrogate markers for granulomatous macrophages in sarcoidosis. Clin Chim Acta 2010;411:31–36.PubMedCrossRefGoogle Scholar
  61. 61.
    Bargagli E, Mazzi A, Mezzasalma F, Perrone A, Olivieri C, Prasse A, et al. The analysis of tryptase in serum of sarcoidosis patients. Inflammation 2009;32:310–314.PubMedCrossRefGoogle Scholar
  62. 62.
    Park HJ, Jung JI, Chung MH, Song SW, Kim HL, Baik JH, et al. Typical and atypical manifestations of intrathoracic sarcoidosis. Korean J Radiol 2009;10:623–631.PubMedCrossRefGoogle Scholar
  63. 63.
    Mana J, Van Kroonrnburg M. Clinical usefulness of nuclear imaging techniques in sarcoidosis. Euro Respir Monogr 2005;10(Monogr 32):284–300.CrossRefGoogle Scholar
  64. 64.
    Bolat S, Berding G, Dengler R, Stangel M, Trebst C. Fluorodeoxyglucose positron emission tomography (FDGPET) is useful in the diagnosis of neurosarcoidosis. J Neurol Sci 2009;287:257–259.PubMedCrossRefGoogle Scholar
  65. 65.
    Costabel U, Bonella F, Ohshimo S, Guzman J. Diagnostic modalities in sarcoidosis: BAL, EBUS, and PET. Semin Respir Crit Care Med 2010;31:404–408.PubMedCrossRefGoogle Scholar
  66. 66.
    Clement A, Epaud R, Fauroux B. Sarcoidosis in children. Euro Respir Monogr 2005;10 (Monogr 32):251–258.CrossRefGoogle Scholar
  67. 67.
    Mallory SB, Paller AS, Ginsburg BC, McCrossin ID, Abernathy R. Sarcoidosis in children: differentiation from juvenile rheumatoid arthritis. Pediatr Dermatol 1987;4:313–319.PubMedCrossRefGoogle Scholar
  68. 68.
    White ES, Lynch JP 3rd. Current and emerging strategies for the management of sarcoidosis. Expert Opin Pharmacother 2007;8:1293–1311.PubMedCrossRefGoogle Scholar
  69. 69.
    Shetty AK, Gedalia A. Sarcoidosis in children. Curr Probl Pediatr 2000;30:149–176.PubMedCrossRefGoogle Scholar
  70. 70.
    Kiper N, Anadol D, Ozçelik U, Göçmen A. Inhaled corticosteroids for maintenance treatment in childhood pulmonary sarcoidosis. Acta Paediatr 2001;90:953–956.PubMedCrossRefGoogle Scholar
  71. 71.
    Chadelat K, Baculard A, Grimfeld A, Tournier G, Boule M, Boccon-Gibod L, et al. Pulmonary sarcoidosis in children: serial evaluation of bronchoalveolar lavage cells during corticosteroid treatment. Pediatr Pulmonol 1993;16:41–47.PubMedCrossRefGoogle Scholar
  72. 72.
    Cron RQ, Sharma S, Sherry DD. Current treatment by United States and Canadian pediatric rheumatologists. J Rheumatol 1999;26:2036–2038.PubMedGoogle Scholar
  73. 73.
    Shetty AK, Zganjar BE, Ellis GS Jr, Ludwig IH, Gedalia A. Low-dose methotrexate in the treatment of severe juvenile rheumatoid arthritis and sarcoid iritis. J Pediatr Ophthalmol Strabismus 1999;36:125–128.PubMedGoogle Scholar
  74. 74.
    Gedalia A, Molina JF, Ellis GS Jr, Galen W, Moore C, Espinoza LR. Low-dose methotrexate therapy for childhood sarcoidosis. J Pediatr 1997;130:25–29.PubMedCrossRefGoogle Scholar
  75. 75.
    Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;155:846–851.PubMedCrossRefGoogle Scholar
  76. 76.
    Yasui K, Yashiro M, Tsuge M, Manki A, Takemoto K, Yamamoto M, et al. Thalidomide dramatically improves the symptoms of early-onset sarcoidosis/Blau syndrome: its possible action and mechanism. Arthritis Rheum 2010;62:250–257.PubMedCrossRefGoogle Scholar
  77. 77.
    Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001;135:27–31.PubMedGoogle Scholar
  78. 78.
    Milman N, Andersen CB, Hansen A, van Overeem Hansen T, Nielsen FC, Fledelius H, et al. Favourable effect of TNF-alpha inhibitor (infliximab) on Blau syndrome in monozygotic twins with a de novo CARD15 mutation. APMIS 2006;114:912–919.PubMedCrossRefGoogle Scholar
  79. 79.
    Milman N, Hoffmann AL. Childhood sarcoidosis: long-term follow-up. Eur Respir J 2008;31:592–598.PubMedCrossRefGoogle Scholar
  80. 80.
    Marcille R, McCarthy M, Barton JW, Merten DF, Spock A. Long-term outcome of pediatric sarcoidosis with emphasis on pulmonary status. Chest 1992;102:1444–1449.PubMedCrossRefGoogle Scholar

Copyright information

© Children's Hospital, Zhejiang University School of Medicine and Springer-Verlag Berlin Heidelberg 2011

Authors and Affiliations

  • Andrew Fretzayas
    • 1
    • 3
  • Maria Moustaki
    • 1
  • Olga Vougiouka
    • 2
  1. 1.Third Department of PediatricsUniversity of Athens, School of Medicine “Attikon” University HospitalAthensGreece
  2. 2.Second Department of PediatricsUniversity of Athens, School of Medicine, “P & A Kyriakou” Children’s HospitalAthensGreece
  3. 3.Third Department of Pediatrics, “Attikon” University HospitalAthens University School of MedicineAthensGreece

Personalised recommendations