Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Chronic mucocutaneous candidiasis

Chaim M Roifman, MD, FRCPC, FCACB
Section Editor
Jordan S Orange, MD, PhD
Deputy Editor
Elizabeth TePas, MD, MS


Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of syndromes with common features including chronic noninvasive Candida infections of the skin, nails, and mucous membranes and associated autoimmune manifestations (most commonly endocrinopathies). It is caused by genetic faults in the immune system.

An overview of CMCC is given and the pathogenesis and clinical manifestations of identified genetic defects leading to CMCC are reviewed here. The differential diagnosis and treatment of CMCC are also discussed. A general discussion of Candida infections and their clinical manifestations are presented separately. (See "Overview of Candida infections" and "Candida infections in children" and "Clinical manifestations of oropharyngeal and esophageal candidiasis".)


CMCC was first described in 1929 by Thorpe and Handley [1,2], followed by a more extensive description in the 1950s and 1960s [3-5]. CMCC traditionally referred to a heterogeneous group of patients who suffered persistent, noninvasive Candida infections of the skin, mucous membranes, and nails, as well as autoimmune manifestations, most commonly involving the endocrine system. Since the discovery of autoimmune regulator (AIRE) mutations as a cause of CMCC, a number of other genes have been fully or partially implicated in CMCC and related clinical phenotypes including the interleukin-17 (IL-17) sensing system.

Mutations in the AIRE gene lead to CMCC in distinct populations, such as the Finns and Sardinians [6,7]. However, the majority of patients with CMCC outside of these ethnic groups do not carry mutations in this gene. Most papers related to CMCC were published prior to the discovery of AIRE, making it impossible to correlate phenotypes with the AIRE genotype in most publications.

Progress in techniques that will allow for genomic sequencing as well as development of novel bioinformatic models should improve our understanding of the genetic causes of CMCC. These methodologies should also unravel phenotype diversity in classical Mendelian inherited disorders, such as AIRE deficiency. Fundamental questions, such as why these patients are susceptible to infections with Candida, are just beginning to be answered.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Sep 27, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Thorpe ES, Handley HE. Chronic tetany and chronic mycelia stomatitis in a child aged four and one half years. Am J Dis Child 1929; 38:228.
  2. CRAIG JM, SCHIFF LH, BOONE JE. Chronic moniliasis associated with Addison's disease. AMA Am J Dis Child 1955; 89:669.
  3. ESSELBORN VM, LANDING BH, WHITAKER J, WILLIAMS RR. The syndrome of familial juvenile hypoadrenocorticism, hypoparathyroidism and superficial moniliasis. J Clin Endocrinol Metab 1956; 16:1374.
  5. Blizzard RM, Gibbs JH. Candidiasis: studies pertaining to its association with endocrinopathies and pernicious anemia. Pediatrics 1968; 42:231.
  6. Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990; 322:1829.
  7. Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet 1997; 17:399.
  8. Herrod HG. Chronic mucocutaneous candidiasis in childhood and complications of non-Candida infection: a report of the Pediatric Immunodeficiency Collaborative Study Group. J Pediatr 1990; 116:377.
  9. Oyefara BI, Kim HC, Danziger RN, et al. Autoimmune hemolytic anemia in chronic mucocutaneous candidiasis. Clin Diagn Lab Immunol 1994; 1:38.
  10. Twomey JJ, Waddell CC, Krantz S, et al. Chronic mucocutaneous candidiasis with macrophage dysfunction, a plasma inhibitor, and co-existent aplastic anemia. J Lab Clin Med 1975; 85:968.
  11. Deeg HJ, Lum LG, Sanders J, et al. Severe aplastic anemia associated with chronic mucocutaneous candidiasis. Immunologic and hematologic reconstitution after allogeneic bone marrow transplantation. Transplantation 1986; 41:583.
  12. Kirkpatrick CH, Windhorst DB. Mucocutaneous candidiasis and thymoma. Am J Med 1979; 66:939.
  13. Kirkpatrick CH, Chandler JW, Schimke RN. Chronic mucocutaneous moniliasis with impaired delayed hypersensitivity. Clin Exp Immunol 1970; 6:375.
  14. Nahum A, Roifman CM, et al, 2010, personal communication.
  15. Kirkpatrick CH, Sohnle PG. Chronic mucocutaneous candidiasis. In: Immunodermatology, Safai B, Good RA (Eds), Plenum Press, New York 1981. p.495.
  16. Bentur L, Nisbet-Brown E, Levison H, Roifman CM. Lung disease associated with IgG subclass deficiency in chronic mucocutaneous candidiasis. J Pediatr 1991; 118:82.
  17. Kalfa VC, Roberts RL, Stiehm ER. The syndrome of chronic mucocutaneous candidiasis with selective antibody deficiency. Ann Allergy Asthma Immunol 2003; 90:259.
  18. Levy RL, Bach ML, Huang S, et al. Thymic transplantation in a case of chronic mucocutaneous candidiasis. Lancet 1971; 2:898.
  19. Kirkpatrick CH, Ottenson EA, Smith TK, et al. Reconstitution of defective cellular immunity with foetal thymus and dialysable transfer factor. Long-term studies in a patient with chronic mucocutaneous candidiasis. Clin Exp Immunol 1976; 23:414.
  20. Ballow M, Hyman LR. Combination immunotherapy in chronic mucocutaneous candidiasis. Synergism between transfer factor and fetal thymus tissue. Clin Immunol Immunopathol 1977; 8:504.
  21. Valdimarsson H, Moss PD, Holt PJ, H OBBS JR. Treatment of chronic mucocutaneous candidiasis with leucocytes from HL-A compatible sibling. Lancet 1972; 1:469.
  22. Kirkpatrick CH, Rich RR, Graw RG Jr, et al. Treatment of chronic mucocutaneous moniliasis by immunologic reconstitution. Clin Exp Immunol 1971; 9:733.
  23. Siggs OM, Makaroff LE, Liston A. The why and how of thymocyte negative selection. Curr Opin Immunol 2006; 18:175.
  24. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol 2006; 24:571.
  25. Anderson MS, Venanzi ES, Klein L, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 2002; 298:1395.
  26. Anderson MS, Venanzi ES, Chen Z, et al. The cellular mechanism of Aire control of T cell tolerance. Immunity 2005; 23:227.
  27. Liston A, Lesage S, Wilson J, et al. Aire regulates negative selection of organ-specific T cells. Nat Immunol 2003; 4:350.
  28. Ramsey C, Winqvist O, Puhakka L, et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 2002; 11:397.
  29. Betterle C, Greggio NA, Volpato M. Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab 1998; 83:1049.
  30. Karvonen M, Viik-Kajander M, Moltchanova E, et al. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23:1516.
  31. Halonen M, Eskelin P, Myhre AG, et al. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab 2002; 87:2568.
  32. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev 2002; 23:327.
  33. Yu L, Brewer KW, Gates S, et al. DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison's disease. J Clin Endocrinol Metab 1999; 84:328.
  34. Gavanescu I, Benoist C, Mathis D. B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients. Proc Natl Acad Sci U S A 2008; 105:13009.
  35. Puel A, Döffinger R, Natividad A, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 2010; 207:291.
  36. Kisand K, Bøe Wolff AS, Podkrajsek KT, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 2010; 207:299.
  37. Browne SK, Holland SM. Anticytokine autoantibodies in infectious diseases: pathogenesis and mechanisms. Lancet Infect Dis 2010; 10:875.
  38. Sarkadi AK, Taskó S, Csorba G, et al. Autoantibodies to IL-17A may be correlated with the severity of mucocutaneous candidiasis in APECED patients. J Clin Immunol 2014; 34:181.
  39. Ng WF, von Delwig A, Carmichael AJ, et al. Impaired T(H)17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Allergy Clin Immunol 2010; 126:1006.
  40. Pedroza LA, Kumar V, Sanborn KB, et al. Autoimmune regulator (AIRE) contributes to Dectin-1-induced TNF-α production and complexes with caspase recruitment domain-containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1. J Allergy Clin Immunol 2012; 129:464.
  41. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 2006; 91:2843.
  42. Capalbo D, Improda N, Esposito A, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy from the pediatric perspective. J Endocrinol Invest 2013; 36:903.
  43. Mazza C, Buzi F, Ortolani F, et al. Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Clin Immunol 2011; 139:6.
  44. Richman RA, Rosenthal IM, Solomon LM, Karachorlu KV. Candidiasis and multiple endocrinopathy. With oral squamous cell carcinoma complications. Arch Dermatol 1975; 111:625.
  45. van de Veerdonk FL, Plantinga TS, Hoischen A, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 2011; 365:54.
  46. Roifman CM. Monoallelic STAT1 mutations and disease patterns. LymphoSign Journal 2014; 1:57.
  47. Nahum A, Dalal I. Clinical manifestations associated with novel mutations in the coiled-coil domain of STAT1. LymphoSign Journal 2014; 1:97.
  48. Liu L, Okada S, Kong XF, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 2011; 208:1635.
  49. Maródi L, Cypowyj S, Tóth B, et al. Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species. J Allergy Clin Immunol 2012; 130:1019.
  50. Takezaki S, Yamada M, Kato M, et al. Chronic mucocutaneous candidiasis caused by a gain-of-function mutation in the STAT1 DNA-binding domain. J Immunol 2012; 189:1521.
  51. Sampaio EP, Hsu AP, Pechacek J, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol 2013; 131:1624.
  52. Uzel G, Sampaio EP, Lawrence MG, et al. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol 2013; 131:1611.
  53. Kumar N, Hanks ME, Chandrasekaran P, et al. Gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation-related primary immunodeficiency is associated with disseminated mucormycosis. J Allergy Clin Immunol 2014; 134:236.
  54. Faitelson Y, Bates A, Shroff M, et al. A mutation in the STAT1 DNA-binding domain associated with hemophagocytic lymphohistocytosis. LymphoSign Journal 2014; 1:87.
  55. Sharfe N, Nahum A, Newell A, et al. Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. J Allergy Clin Immunol 2014; 133:807.
  56. Nahum A, Bates A, Sharfe N, Roifman CM. Association of the lymphoid protein tyrosine phosphatase, R620W variant, with chronic mucocutaneous candidiasis. J Allergy Clin Immunol 2008; 122:1220.
  57. Ferwerda B, Ferwerda G, Plantinga TS, et al. Human dectin-1 deficiency and mucocutaneous fungal infections. N Engl J Med 2009; 361:1760.
  58. Puel A, Cypowyj S, Bustamante J, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011; 332:65.
  59. Cohen S, Dadi H, Shaoul E, et al. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 1999; 93:2013.
  60. Wu J, Katrekar A, Honigberg LA, et al. Identification of substrates of human protein-tyrosine phosphatase PTPN22. J Biol Chem 2006; 281:11002.
  61. Gjörloff-Wingren A, Saxena M, Williams S, et al. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur J Immunol 1999; 29:3845.
  62. Vang T, Congia M, Macis MD, et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet 2005; 37:1317.
  63. Gregorieff A, Cloutier JF, Veillette A. Sequence requirements for association of protein-tyrosine phosphatase PEP with the Src homology 3 domain of inhibitory tyrosine protein kinase p50(csk). J Biol Chem 1998; 273:13217.
  64. Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004; 36:337.
  65. Bottini N, Vang T, Cucca F, Mustelin T. Role of PTPN22 in type 1 diabetes and other autoimmune diseases. Semin Immunol 2006; 18:207.
  66. Criswell LA, Pfeiffer KA, Lum RF, et al. Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: the PTPN22 620W allele associates with multiple autoimmune phenotypes. Am J Hum Genet 2005; 76:561.
  67. Hinks A, Eyre S, Barton A, et al. Investigation of genetic variation across the protein tyrosine phosphatase gene in patients with rheumatoid arthritis in the UK. Ann Rheum Dis 2007; 66:683.
  68. Kaufman KM, Kelly JA, Herring BJ, et al. Evaluation of the genetic association of the PTPN22 R620W polymorphism in familial and sporadic systemic lupus erythematosus. Arthritis Rheum 2006; 54:2533.
  69. Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004; 75:504.
  70. Lee AT, Li W, Liew A, et al. The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status. Genes Immun 2005; 6:129.
  71. Qu H, Tessier MC, Hudson TJ, Polychronakos C. Confirmation of the association of the R620W polymorphism in the protein tyrosine phosphatase PTPN22 with type 1 diabetes in a family based study. J Med Genet 2005; 42:266.
  72. Netea MG, Brown GD, Kullberg BJ, Gow NA. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 2008; 6:67.
  73. Netea MG, Gow NA, Munro CA, et al. Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. J Clin Invest 2006; 116:1642.
  74. Jouault T, Ibata-Ombetta S, Takeuchi O, et al. Candida albicans phospholipomannan is sensed through toll-like receptors. J Infect Dis 2003; 188:165.
  75. Brown GD, Herre J, Williams DL, et al. Dectin-1 mediates the biological effects of beta-glucans. J Exp Med 2003; 197:1119.
  76. Taylor PR, Tsoni SV, Willment JA, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nat Immunol 2007; 8:31.
  77. Gantner BN, Simmons RM, Canavera SJ, et al. Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 2003; 197:1107.
  78. Nahum A, Dadi H, Bates A, Roifman CM. The L412F variant of Toll-like receptor 3 (TLR3) is associated with cutaneous candidiasis, increased susceptibility to cytomegalovirus, and autoimmunity. J Allergy Clin Immunol 2011; 127:528.
  79. Grouhi M, Dalal I, Nisbet-Brown E, Roifman CM. Cerebral vasculitis associated with chronic mucocutaneous candidiasis. J Pediatr 1998; 133:571.
  80. Roifman C, University of Toronto, 2012, personal communication.
  81. Glocker EO, Hennigs A, Nabavi M, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 2009; 361:1727.
  82. Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 2008; 452:773.
  83. Chu EY, Freeman AF, Jing H, et al. Cutaneous manifestations of DOCK8 deficiency syndrome. Arch Dermatol 2012; 148:79.
  84. Ersoy F, Berkel AI, Sanal O, Oktay H. Twenty-year follow-up of 160 patients with ataxia-telangiectasia. Turk J Pediatr 1991; 33:205.
  85. Ouederni M, Sanal O, Ikinciogullari A, et al. Clinical features of Candidiasis in patients with inherited interleukin 12 receptor β1 deficiency. Clin Infect Dis 2014; 58:204.
  86. Prando C, Samarina A, Bustamante J, et al. Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine (Baltimore) 2013; 92:109.
  87. Fukushima C, Matsuse H, Tomari S, et al. Oral candidiasis associated with inhaled corticosteroid use: comparison of fluticasone and beclomethasone. Ann Allergy Asthma Immunol 2003; 90:646.
  88. Hachiya KA, Kobayashi RH, Antonson DL. Candida esophagitis following antibiotic usage. Pediatr Infect Dis 1982; 1:168.
  89. Husebye ES, Perheentupa J, Rautemaa R, Kämpe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med 2009; 265:514.
  90. Burke WA. Use of itraconazole in a patient with chronic mucocutaneous candidiasis. J Am Acad Dermatol 1989; 21:1309.
  91. Kirkpatrick CH. Chronic mucocutaneous candidiasis. Pediatr Infect Dis J 2001; 20:197.
  92. Kamai Y, Maebashi K, Kudoh M, et al. Characterization of mechanisms of fluconazole resistance in a Candida albicans isolate from a Japanese patient with chronic mucocutaneous candidiasis. Microbiol Immunol 2004; 48:937.
  93. Rautemaa R, Richardson M, Pfaller MA, et al. Activity of amphotericin B, anidulafungin, caspofungin, micafungin, posaconazole, and voriconazole against Candida albicans with decreased susceptibility to fluconazole from APECED patients on long-term azole treatment of chronic mucocutaneous candidiasis. Diagn Microbiol Infect Dis 2008; 62:182.
  94. Füchtenbusch M, Vogel A, Achenbach P, et al. Lupus-like panniculitis in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Exp Clin Endocrinol Diabetes 2003; 111:288.
  95. Ulinski T, Perrin L, Morris M, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome with renal failure: impact of posttransplant immunosuppression on disease activity. J Clin Endocrinol Metab 2006; 91:192.
  96. Padeh S, Theodor R, Jonas A, Passwell JH. Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression. Arch Dis Child 1997; 76:532.
  97. Hoh MC, Lin HP, Chan LL, Lam SK. Successful allogeneic bone marrow transplantation in severe chronic mucocutaneous candidiasis syndrome. Bone Marrow Transplant 1996; 18:797.
  98. Wildbaum G, Shahar E, Katz R, et al. Continuous G-CSF therapy for isolated chronic mucocutaneous candidiasis: complete clinical remission with restoration of IL-17 secretion. J Allergy Clin Immunol 2013; 132:761.
  99. Higgins E, Al Shehri T, McAleer MA, et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation. J Allergy Clin Immunol 2015; 135:551.