Laboratory Studies

When a patient presents with cutaneous manifestations of chronic mucocutaneous candidiasis (CMC), the studies described below should be performed.

Scrapings from the infected site are suspended in 10-20% KOH and microscopically examined. The presence of yeast cells and pseudohyphae confirms the diagnosis. Fungal stains, such as chlorazol black E stain or Parker blue-black ink, may be added to highlight the organism.

Candidal organisms grow well on several culture media. They grow as yeasts on Sabouraud agar with chloramphenicol and cycloheximide. C albicans also grows on dermatophyte test medium but does not demonstrate the red color change characteristic of dermatophytes.

Screening laboratory tests for a CMC-associated endocrine dysfunction include blood glucose or glycosylated hemoglobin testing, thyroid function tests, liver functions tests, serum electrolyte evaluation, corticotropin testing, and serum cortisol values. Consider a complete blood cell count, to screen for leukopenia, and an HIV test. Other endocrine screening tests that may be considered include follicle-stimulating hormone, luteinizing hormone, prolactin, testosterone, parathyroid-stimulating hormone, calcium, phosphate, magnesium, and short synacthen test. Perform baseline and yearly follow-up tests to screen for associated endocrinopathy.

Other Tests

Results from cellular immunity tests, such as the prick-test with Candida antigens, may be negative. In vitro lymphocyte proliferation is usually reduced for C albicans extracts.

Immunoglobulin G subclass deficiencies have been reported in some patients with CMC, who have a predisposition toward respiratory tract infections. Isolated immunoglobulin A and immunoglobulin M deficiencies have also been reported, in addition to a single case of complete agammaglobulinemia.^[32]

In patients with other recurrent infections, immune studies should be considered; immunoglobulin levels should include B- and T-cell levels, as well as IgE to test for underlying autoimmune causes such as hyper-IgE syndrome.

If the clinical suspicion for APECED is high, genetic analysis of the AIRE gene can be confirmatory.^{[10, 15]}

Anti–interferon-1 and anti-interleukin antibodies have been found to be highly specific for APECED and to precede the appearance of chronic mucocutaneous candidiasis (CMC), suggesting a possible diagnostic test.^[33]

Procedures

A skin biopsy is rarely needed to make a diagnosis of Candida infection, but it may be performed to rule out the possibility of superinfection of a primary dermatosis. A periodic acid-Schiff stain can confirm the presence of pseudohyphae. Nutritional deficiencies with cutaneous manifestations should also be considered, such as iron, vitamin B-6, vitamin B-12, vitamin C, and zinc.

Histologic Findings

Routine hematoxylin and eosin–stained sections of superficial candidiasis lesions reveal subcorneal pustules. Granulomatous lesions of chronic mucocutaneous candidiasis (CMC) show hyperkeratosis and parakeratosis, with a dense mixed dermal infiltrate containing lymphocytes and plasma cells. Periodic acid-Schiff or silver stains of skin biopsy specimens can help identify organisms in the stratum corneum and dermis.

Treatment & Management

Lilic D. New perspectives on the immunology of chronic mucocutaneous candidiasis. Curr Opin Infect Dis. 2002 Apr. 15(2):143-7. [QxMD MEDLINE Link].
Lilic D, Gravenor I, Robson N, Lammas DA, Drysdale P, Calvert JE, et al. Deregulated production of protective cytokines in response to Candida albicans infection in patients with chronic mucocutaneous candidiasis. Infect Immun. 2003 Oct. 71(10):5690-9. [QxMD MEDLINE Link].
van de Veerdonk FL, Plantinga TS, Hoischen A, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011 Jul 7. 365(1):54-61. [QxMD MEDLINE Link].
Al Rushood M, McCusker C, Mazer B, Alizadehfar R, Grimbacher B, Depner M, et al. Autosomal Dominant Cases of Chronic Mucocutaneous Candidiasis Segregates with Mutations of Signal Transducer and Activator of Transcription 1, But Not of Toll-Like Receptor 3. J Pediatr. 2013 Mar 26. [QxMD MEDLINE Link].
Hori T, Ohnishi H, Teramoto T, Tsubouchi K, Naiki T, Hirose Y, et al. Autosomal-dominant chronic mucocutaneous candidiasis with STAT1-mutation can be complicated with chronic active hepatitis and hypothyroidism. J Clin Immunol. 2012 Dec. 32(6):1213-20. [QxMD MEDLINE Link].
Marazzi MG, Bondi E, Giannattasio A, Strozzi M, Savioli C. Intracranial aneurysm associated with chronic mucocutaneous candidiasis. Eur J Pediatr. 2007 Apr 19. [QxMD MEDLINE Link].
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 Mar. 116(3):377-82. [QxMD MEDLINE Link].
Puel A, Cypowyj S, Maródi L, Abel L, Picard C, Casanova JL. Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Curr Opin Allergy Clin Immunol. 2012 Dec. 12 (6):616-22. [QxMD MEDLINE Link].
Vazquez JA, Sobel JD. Mucosal candidiasis. Infect Dis Clin North Am. 2002 Dec. 16 (4):793-820. [QxMD MEDLINE Link].
Brännström J, Hässler S, Peltonen L, Herrmann B, Winqvist O. Defect internalization and tyrosine kinase activation in Aire deficient antigen presenting cells exposed to Candida albicans antigens. Clin Immunol. 2006 Dec. 121(3):265-73. [QxMD MEDLINE Link].
Lindh E, Brännström J, Jones P, Wermeling F, Hässler S, Betterle C, et al. Autoimmunity and cystatin SA1 deficiency behind chronic mucocutaneous candidiasis in autoimmune polyendocrine syndrome type 1. J Autoimmun. 2012 Oct 31. [QxMD MEDLINE Link].
Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006 Aug. 91(8):2843-50. [QxMD MEDLINE Link].
Valenzise M, Fierabracci A, Cappa M, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: report of seven additional sicilian patients and overview of the overall series from sicily. Horm Res Paediatr. 2014. 82(2):127-32. [QxMD MEDLINE Link].
Mora M, Hanzu FA, Pradas-Juni M, et al. New splice site acceptor mutation in AIRE gene in autoimmune polyendocrine syndrome type 1. PLoS One. 2014. 9(7):e101616. [QxMD MEDLINE Link]. [Full Text].
Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006 Jun. 154(6):1088-93. [QxMD MEDLINE Link].
Kisand K, Bøe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010 Feb 15. 207 (2):299-308. [QxMD MEDLINE Link].
Puel A, Döffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, 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 Feb 15. 207 (2):291-7. [QxMD MEDLINE Link].
Atkinson TP, Schäffer AA, Grimbacher B, Schroeder HW Jr, Woellner C, Zerbe CS, et al. An immune defect causing dominant chronic mucocutaneous candidiasis and thyroid disease maps to chromosome 2p in a single family. Am J Hum Genet. 2001 Oct. 69(4):791-803. [QxMD MEDLINE Link].
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 Feb. 127 (2):528-31. [QxMD MEDLINE Link].
Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol. 2011 Jun. 41 (6):1517-27. [QxMD MEDLINE Link].
Okada S, Puel A, Casanova JL, Kobayashi M. Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17 immunity. Clin Transl Immunology. 2016 Dec. 5 (12):e114. [QxMD MEDLINE Link].
Minegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, et al. Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. J Exp Med. 2009 Jun 8. 206 (6):1291-301. [QxMD MEDLINE Link].
de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med. 2008 Jul 7. 205 (7):1543-50. [QxMD MEDLINE Link].
Renner ED, Rylaarsdam S, Anover-Sombke S, Rack AL, Reichenbach J, Carey JC, et al. Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome. J Allergy Clin Immunol. 2008 Jul. 122 (1):181-7. [QxMD MEDLINE Link].
Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013 Mar 28. 121 (13):2385-92. [QxMD MEDLINE Link].
Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S, Prando C, et al. Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med. 2013 Oct 31. 369 (18):1704-14. [QxMD MEDLINE Link].
Prando C, Samarina A, Bustamante J, Boisson-Dupuis S, Cobat A, Picard C, et al. Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine (Baltimore). 2013 Mar. 92 (2):109-22. [QxMD MEDLINE Link].
Marujo F, Pelham SJ, Freixo J, Cordeiro AI, Martins C, Casanova JL, et al. A Novel TRAF3IP2 Mutation Causing Chronic Mucocutaneous Candidiasis. J Clin Immunol. 2021 Apr 7. [QxMD MEDLINE Link].
Li J, Ritelli M, Ma CS, et al. Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β. Sci Immunol. 2019 Nov 29. 4 (41):[QxMD MEDLINE Link].
Dotta L, Scomodon O, Padoan R, Timpano S, Plebani A, Soresina A, et al. Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease. Clin Immunol. 2016 Mar. 164:1-9. [QxMD MEDLINE Link].
Toubiana J, Okada S, Hiller J, Oleastro M, Lagos Gomez M, Aldave Becerra JC, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Front Immunol. 2016 Jun 23. 127 (25):3154-64. [QxMD MEDLINE Link].
Patiroglu T, Tahan F. Chronic mucocutaneous candidiasis with agammaglobulinaemia. J Eur Acad Dermatol Venereol. 2007 Jul. 21(6):833-4. [QxMD MEDLINE Link].
Meager A, Visvalingam K, Peterson P, Möll K, Murumägi A, Krohn K, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 2006 Jul. 3(7):e289. [QxMD MEDLINE Link].
Masi M, De Vinci C, Baricordi OR. Transfer factor in chronic mucocutaneous candidiasis. Biotherapy. 1996. 9(1-3):97-103. [QxMD MEDLINE Link].
Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, et al. Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1. J Clin Immunol. 2016 Oct. 36 (7):641-8. [QxMD MEDLINE Link].
Higgins E, Al Shehri T, McAleer MA, Conlon N, Feighery C, Lilic D, 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 Feb. 135 (2):551-3. [QxMD MEDLINE Link].
Mössner R, Diering N, Bader O, Forkel S, Overbeck T, Gross U, et al. Ruxolitinib Induces Interleukin 17 and Ameliorates Chronic Mucocutaneous Candidiasis Caused by STAT1 Gain-of-Function Mutation. Clin Infect Dis. 2016 Apr 1. 62 (7):951-3. [QxMD MEDLINE Link].
Hsia CC, Sun TT, Wang YY, Anderson LM, Armstrong D, Good RA. Enhancement of formation of the esophageal carcinogen benzylmethylnitrosamine from its precursors by Candida albicans. Proc Natl Acad Sci U S A. 1981 Mar. 78 (3):1878-81. [QxMD MEDLINE Link].
[Guideline] Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Executive Summary: Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Feb 15. 62 (4):409-17. [QxMD MEDLINE Link].

Media Gallery

Thickened, fragmented, hyperkeratotic nails and erythematous periungual skin. Courtesy of Walter Reed Army Medical Center.
Crusted hyperkeratotic plaques on and around the nose. Courtesy of Walter Reed Army Medical Center.
Crusted hyperkeratotic plaques on eyebrow, forehead, and scalp. Courtesy of Walter Reed Army Medical Center.

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Author

Hassan I Galadari, MD Assistant Professor, Division of Dermatology, Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates (UAE) University, UAE

Hassan I Galadari, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Medical Student Association/Foundation, American Society for Dermatologic Surgery, Asian Dermatological Association, Dermatologic and Aesthetic Surgery International League, Emirates Medical Association, International Society for Dermatologic Surgery, International Society of Dermatology, Massachusetts Medical Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Sasha Haddad, BS MD Candidate, Kirksville College of Osteopathic Medicine, AT Still University

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Jeffrey J Miller, MD Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center

Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Society for Investigative Dermatology, Association of Professors of Dermatology, North American Hair Research Society

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Carrie L Kovarik, MD Assistant Professor of Dermatology, Dermatopathology, and Infectious Diseases, University of Pennsylvania School of Medicine

Carrie L Kovarik, MD is a member of the following medical societies: Alpha Omega Alpha

Disclosure: Nothing to disclose.

Neil Sandhu, MD, FAAD Dermatologist (Medical/Cosmetic) and Mohs Surgeon, Gulf Coast Dermatology

Neil Sandhu, MD, FAAD is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery

Disclosure: Nothing to disclose.

Blanca Anais Estupiñan University of Central Florida College of Medicine

Blanca Anais Estupiñan is a member of the following medical societies: American College of Physicians, American Medical Association, American Psychiatric Association

Disclosure: Nothing to disclose.

Acknowledgements

Michael G Bryan, MD Staff Dermatologist, Dermatology, Las Vegas Skin and Care Clinics