Chronic mucocutaneous candidiasis B37.2

Thorpe and Handley, 1929

Name for a group of rare, chronic, mucocutaneous infections caused by Candida species (CMC), with impaired selective immune response to these pathogens. These are autosomal dominant or autosomal recessive inherited immunodeficiency syndromes that are clinically prominent in early childhood. They are rare.

Systemic Candida infections that can accompany serious systemic diseases (HIV/AIDS, malignant tumors, immunosuppressive or antibiotic long-term therapy) are to be separated.

CMC with endocrinologic disorders (also referred to as"type I polyglandular autoimmune syndrome"):

• Hypoparathyroidism (approx. 60-80%)
• Hypothyroidism (about 3%)
• Adrenal insufficiency or failure (approx. 60-75%)
• Chronic lymphocytic thyroiditis
• Ovarian insufficiency (ca. 25%)
• Diabetes mellitus (approx. 12%)
• Growth hormone synthesis disorders.

CMC with ectodermal dysplasias: Combinations of CMC with malformations of the skin appendages are referred to as APECED (acronym for"Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy ) -.

• Localized CMC with hyperkeratosis palmaris
• CMC of familial type (see overview and classification)
• CMC with interstitial keratitis Okamoto type
• CMC with triad of keratitis, ichthyosis, deafness.

Other:

• Diffuse CMC with familial spherocytosis.
• CMC with thymoma

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Systemic or localized candididiasis (reactive forms in artificial immunodeficiency or also in intensive care)

• Candiasis in dental inflammation
• Systemic candiasis in HIV infection
• Systemic (or localized) candiasis during treatment with inhaled glucocorticoids
• Systemic (or localized) candiasis in long-term treatment with broad-spectrum antibiotics.

Primary forms:

Etiopathogenetically, different autosomal recessive as well as autosomal dominant defects underlie, whose molecular genetic characteristics are partially known. Dendritic cell defects and Th1 cell defects are significant, whereas defects in innate immunity (phagocytosis, migration of neutrophil granulocytes) and humoral immunity play a minor role. Other mutations affect the IL17 signaling pathway.

Detectable mutations include the following:

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 signaling proteins and thus influence various signaling pathways).

• Mutations in the STAT1 gene
• Mutations in the STAT3 gene(hyper IgE syndrome)
• Mutations in the STAT3 gene ("DiGeorge syndrome" - see below 22q11.2 deletion syndrome)

Mutations in genes affecting the IL-17 pathway at different reaction points:

• IL17RA

• IL17RC

• IL-17F

• ACT1

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

• Candidiasis of the oral mucosa, often with involvement of the larynx and esophagus, perlèche, vulvovaginal candidiasis, and intertriginous candididiasis. Partially 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
• Endocrinologic disorders:
  • Thyroid dysfunction(autoimmune thyreopathy).
  • Hypothyroidism(hypoparathyroidism) with calcium deficiencies.
  • Hypogonadism
  • Hypofunction of the adrenal cortex(Addison's disease) with fatigue, lack of appetite, nausea and vomiting, etc.
• Often increased susceptibility to bacterial infections with chronic rhinitis and recurrent pneumonia.
• With gastrointestinal involvement: diarrhea, 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.

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

Varies according to the predominant type of underlying disease.

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

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.

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.

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