Chronic mucocutaneous candidiasis B37.2

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 14.05.2021

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Synonym(s)

APECED Syndrome; Candidiasis chronic mucocutaneous; Candidosis chronic mucocutaneous; Candidosis chronic-mucocutaneous; Chronic mucocutaneous candidiasis; (e) APECED syndromes; (e) Chronic mucocutaneous candidiasis disease; (e) CMC; mucocutaneous candidiasis

History
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Thorpe and Handley, 1929

Definition
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Term for a group of rare, chronic, mucocutaneous candidoses (CMC) with an altered selective immune response to Candida species.

Primary forms become clinically conspicuous as autosomal dominant or autosomal recessive inherited immune deficiency syndromes, already in early childhood. They are rare.

Secondary forms accompany serious systemic diseases (HIV/AIDS, malignant tumours, long-term immunosuppressive therapy), especially if the cell-mediated immune defence is reduced.

Classification
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  • Chronic oral candidiasis:
  • CMC with endocrinological disorders: This combination is also called"Polyglandular Autoimmune Syndrome Type I"):
  • CMC with ectodermal dysplasias: Combinations of CMC with malformations of the skin appendages are called APECED - acronym for"Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy".
    • Localized CMC with hyperkeratosis palmaris
    • Diffuse CMC familial type (e.g. detection of heterozygous "gain-of-function" mutations of STAT1; a total of about 30 different mutations have been described that lead to the phenotype CMC)
    • CMC with interstitial keratitis type Okamoto
    • CMC with triad of keratitis, ichthyosis, numbness.
  • Further:
    • Diffuse CMC with familial spherocytosis
    • CMC with thymoma

Etiopathogenesis
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Primary forms: Etiopathogenetically, different autosomal recessive as well as autosomal dominant defects are underlying, whose molecular genetic characteristics are partly known. Dendritic cell defects and Th1 cell defects are important, whereas defects in innate immunity (phagocytosis, migration of neutrophil granulocytes) and humoral immunity play a minor role. Detectable mutations are as follows:

  • APECED (autosomal recessive forms).
    • Mutation in the autoimmune regulator gene(AIRE) associated with endocrine gland dysfunction.
    • Mutation in PTPN22 gene associated with autoimmune endocrinopathies and antibody deficiency.
    • Mutation in caspase-associated-recruitment
  • Autosomal dominant forms with mutations in STAT (acronym for "Signal Transducer and Activator of Transcription". Group of 7 transcription factors known to date that can be induced by interleukins. STAT proteins can interact with a large number of signalling proteins and thus influence various signalling pathways).

Secondary forms: Mostly a consequence of acquired systemic diseases (chronic infections, metabolic diseases, malignant tumours, immunosuppressive or cytostatic therapies).

Manifestation
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Mostly in childhood, occasionally also in adulthood.

Localization
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Oral, oropharyngeal, vulvovaginal, perianal. Often with nail involvement.

Clinical features
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  • Candidiasis of the oral mucosa, often involving the larynx and esophagus, perlèche, vulvovaginal candidiasis, and intertriginous candidiasis. Sometimes sharply demarcated, hyperkeratotic or granulomatous lesions on the face, here especially on the lips and eyelids, but also favus-like changes in the capillitium as well as on the acra. Thickened, dystrophic nail plate, reddened, edematous swollen nail bed(Paronychia candidamycetica).
  • Persistent, flat raised, reddish plaques with predominantly periorificial arrangement around nose, mouth, eyes, urethra, vagina and anus.
  • Frequent non-scarring alopecia universalis.
  • Vitiligo
  • Endocrinological disorders:
  • Often increased susceptibility to bacterial infections with chronic rhinitis and recurrent pneumonia.
  • With gastrointestinal involvement: diarrhoea, melaena.
  • With urogenital involvement: enuresis and hematuria; in boys often urethral strictures.
  • CMC with interstitial keratitis Okamoto type: Around 5 years of age, bilateral keratoconjunctivitis, vascularization of the cornea with pannus formation, subsequently corneal scarring and development of posterior subcapsular cataracts; most patients go blind between 7 and 9 years of age; later in life (2nd to 3rd decade of life), interstitial pulmonary fibrosis, frequent episodes of spontaneous pneumothorax.
  • CMC with Addison's disease, type I diabetes mellitus, and immunothyroidism (Hashimoto's thyroiditis) see below. Polyendocrinologic syndrome, autoimmunologic.

Laboratory
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Depending on the underlying disease.

Histology
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Chronic dermatitis and mucositis. Keratinization disorder. Electron microscopy: reduced number of desmosomes andgap junctions.

Diagnosis
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Clinic, mycology, laboratory

Differential diagnosis
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Varies according to the predominant type of underlying disease.

External therapy
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Exteriorscontaining Nystatin(e.g. Candio-hermal soft paste/cream, Nystatin dequalinium chloride cream).

Internal therapy
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In difficult protracted cases fluconazole (e.g. Diflucan) p.o. or i.v. 50-100 mg/day. Treatment or support of the immunological defect. Note: Fluconazole is the best tolerated systemic antifungal.

Alternative: Itraconazole p.o. (e.g. Sempera) 100 mg/day for 2-4 weeks (interval therapy possible!).

In case of resistance: voriconazole or posaconazole.

In children: ketoconazole 1 time/day 2.5-5 mg/kg bw.

Adjuvant measures: in case of high bacterial counts in the stool or recurrent courses: 0.5-1.0 million IU nystatin p.o. 3 times/day or 100 mg amphotericin B as a suspension or tablet 4 times/day.

Progression/forecast
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Almost always recurrent course.

Remark: Complete eradication is usually not achievable. Thus, a long-term (possibly also lifelong) antimycotic treatment(Fluconazole 100-200mg; supplementary or alternatively polyenantimycotics such as: Nystatin or Amphotericin B) will be necessary.

Literature
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  1. Coleman R, Hay RJ (1997) Chronic mucocutaneous candidosis associated with hypothyroidism: a distinct syndrome? Br J Dermatol. 136: 24-29
  2. Kirkpatrick CH et al (1989) Chronic mucocutaneous candidiasis. Eur. J. Clin Microbiol Infect Dis 8: 448-456
  3. Lingelbach A et al (2003) Chronic mucocutaneous candidosis with severe esophageal stricture. Mycoses 46:S15-18
  4. Okada S et al(2017) CMCD: Chronic Mucocutaneous Candidiasis Disease.
    Nihon Rinsho Meneki Gakkai Kaishi 40:109-117.
  5. Okamoto GA, Hall JG, Ochs H et al (1977) New syndrome of chronic mucocutaneous candidiasis. Birth Def Orig Art Ser XIII(3B): 117-125
  6. Seebacher C et al (2006) Candidosis of the skin. J Dtsch Dermatol Ges 4: 591-596
  7. Urban MD, Schosser R, Spohn W et al (1991) New clinical aspects of hereditary mucoepithelial dysplasia. At J Med Genet 39: 338-341
  8. Witkop CJ Jr, White JG, King RA et al (1979) Hereditary mucoepithelial dysplasia: a disease apparently of desmosome and gap junction formation. At J Hum Genet 31: 414-427
  9. Yamazaki Y et al(2014) Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody. J Immunol 193:4880-4887
  10. Zuccarello D et al (2002) Familial chronic nail candidiasis with ICAM-1 deficiency: a new form of chronic mucocutaneous candidiasis. J Med Genet 39: 671-675

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Please ask your physician for a reliable diagnosis. This website is only meant as a reference.

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Last updated on: 14.05.2021