Overview

Chronic mucocutaneous candidiasis (CMC) is the label given to a group of overlapping syndromes that have in common a clinical pattern of persistent, severe, and diffuse cutaneous candidal infections. These infections affect the skin, nails and mucous membranes. As suggested by Kirkpatrick’s papers on this topic [1196, 1197, 1198], the syndromes of CMC can be grouped as follows:

Classification of Chronic Mucocutaneous Candidiasis (CMC)

  1. (A):Chronic oral candidiasis
    • Related to denture stomatitis
    • HIV-associated candidiasis
    • Related to inhaled corticosteroid use
  2. (A):CMC and polyendocrinopathy
  3. Localized CMC
  4. Diffuse CMC
  5. CMC with thymoma
  6. CMC with interstitial keratitis
  7. CMC associated with “KID” (keratitis, ichthyosis, deafness)

While the causative factors in the oral syndromes in group 1 are easily understood, patients affected with the other forms of CMC usually have one or more associated underlying disorders. Endocrine dysfunctions are the most common association, but almost any organ system can be involved. Of note, CMC almost always remains limited to the skin. The rare reported cases of invasive fungal infection in patients with CMC have been candidal and cryptococcal meningitis [828, 1170].

Disorders associated with Chronic Mucocutaneous Candidiasis (CMC) Syndrome

Category Disorder References
(A):Endocrinopathies
  1. Hypoparathyroidism
  2. Adrenal failure
  3. Chronic lymphocytic thyroiditis
  4. Ovarian failure
  5. Diabetes
  6. Growth hormone insufficiency
 [260, 480, 758, 1085, 1375]
Infectious Diseases
  1. Dermatophytosis
  2. Herpes simplex
  3. Herpes zoster
  4. Pyogenic infections
  5. Septicemia
  6. Disseminated Mycobacterium avium infection
  7. Invasive fungal infections
 [437, 828, 1041, 1170, 1203]
Gastrointestinal Tract Dysfunctions
  1. Malabsorption
  2. Iron deficiency
  3. Hepatitis
 [1196]
Hematologic Dysfunctions
  1. Aplastic anemia
  2. Hemolytic anemia
  3. Pernicious anemia
  4. Thrombocytopenia
  5. Neutropenia
 [260, 1041, 1203]
Cancer
  1. Thymomas
  2. Oropharyngeal
 [1204]
Ectodermal
  1. Alopecia
  2. Vitiligo
  3. Dental dysplasia
 [1203]
Others
  1. Pulmonary fibrosis
  2. Keratoconjunctivitis

Immunopathogenesis

Immunologic studies of patients with CMC often reveal defects related to cell-mediated immunity, but the defects themselves vary widely. Thus, just as there are a variety of clinical patterns associated with this condition, there is an equally broad range of underlying defects. Kirkpatrick has described seven types of immunologic response that are summarized in the following table:

Immunologic Disorders of the CMC complex (Adapted from Kirkpatrick [1197])

Group Lymphocyte Count DTH1 LT2 MIF3 Associated Primary Disorder(s)
1 Low Absent to all P4/P P/P Severe Combined Immunodeficiency (SCID), DiGeorge syndrome, HIV Infection, and defects in the T-lymphocyte receptor or signal transduction mechanism
2 Normal Absent to all P/Nl5 P/Nl CMC
3 Normal Absent to all Nl/Nl P/Nl CMC (20%)
4 Normal Candida anergy P/Nl P/Nl CMC
5 Normal Candida anergy Nl/Nl P/Nl CMC
6 Normal Candida anergy P/Nl Nl/? CMC
7 Normal Candida anergy Nl/Nl Nl/Nl CMC

Footnotes: 1Delayed-Type Hypersensitivity (DTH) to tetanus toxoid, streptococcal protein, mumps skin test, and candidal antigens, 2Lymphocyte Transformation (LT) in response to Candida / phytohemagglutinin, 3Secretion of Migration Inhibitory Factor (MIF) in response to Candida / phytohemagglutinin, 4P = Poor to absent, and 5Nl = Normal.


However, the true details of the defect(s) associated with the various CMC syndromes remain poorly understood. For example, cytokine production has only recently been assessed in patients with CMC. In the one study on this topic, patients with CMC showed reduced or absent IL-2 secretion and increased IL-6 secretion [1343]. This pattern suggests that patients with CMC have a Th2-like response rather than a Th1-like response. As a Th1-like response is important to control at least some candidal infections [404, 1958], demonstration of a Th2-like pattern in CMC is intriguing. In addition, some patients demonstrate abnormalities of antibody production and the susceptibility to viral and bacterial infections that is typical of antibody deficiency [1041]. Hypergammaglobulinemia associated with high levels of IgG and IgA antigen-specific anti-Candida antibody have also been described [1342].

Epidemiology

CMC is rare, but data giving a good estimate of its frequency are not available. Ahonen et al. registered all patients diagnosed with CMC in Finland between 1910 and 1988 [28]. During this 78 year period, these authors found only 68 patients with CMC in combination with either hypoparathyroidism or hypoadrenalism. There is also an Iranian Jewish population with at least a moderately high frequency of these syndromes [252]. Sporadic cases have been noted in many other regions of the world [252]. As discussed below, a specific gene has been linked to the variety of CMC noted in the Finnish and Iranian Jewish populations.

Chronic mucocutaneous candidiasis is virtually always caused by Candida albicans [1196].

Clinical Manifestations

Although CMC may become clinically apparent at any time in life, it typically presents before 3 years of age. [1198]. Affected areas can be single or multiple and include the mouth, esophagus, nails, or skin [1198]. The clinical signs, symptoms, and manifestations of CMC are initially similar to those for the familiar forms of mucocutaneous candidal infection (e.g., (A):oropharyngeal candidiasis, (A):esophageal candidiasis, (A):vulvovaginal candidiasis, perianal candidiasis, or (A):candidal onychomycosis).

Although the initial lesions are identical than the ones seen in the general population, over time patients with CMC characteristically develop unique disfiguring lesions [1198]. It is the chronicity of infection and the large, disfiguring nature of the resulting keratotic lesions that are the true key characteristics of CMC. The secondary illnesses seen in these patients produce the (A):subtypes of CMC described above. Following the concepts put forth by Kirkpatrick, the key features of each of these subtypes are as follows:

  1. Chronic Oral Candidiasis
    This category is really quite distinct from all of the other forms of CMC. In the affected patients, persistence of well-known risk factors (either local or systemic) produces recurrent oropharyngeal candidiasis. However, the exuberant hyperkeratotic lesions of other forms of CMC are not seen. In addition, (A):relapsing or recurrent candidal vaginitis is not included in Kirkpatrick’s schema despite it being a recurrent candidal infection that affects a localized mucous membrane. Thus, one could rationally exclude these syndromes from the general picture of CMC.
  2. CMC with Endocrinopathy

    Endocrinopathy & CMC[28]

    Frequency % (N)
    Hypoparathyroidism 79% (68)
    Hypoadrenalism 72% (68)
    Ovary deficiency 60% (25)
    Gonadal failure 14% (28)
    Insulin-dependent Diabetes Mellitus 12% (68)
    Hypothyroidism 3% (68)

    CMC with endocrinopathy (or Candidal Endocrinopathy Syndrome) is the best characterized of the clinical varieties of CMC. It is thought to represent at least 50% of cases of CMC [461].
    The specific term “autoimmune polyendocrinopathy -candidiasis-ectodermal dystrophy (APECED)” has been used when the clinical picture combines multiple autoimmune endocrinopathies, chronic mucocutaneous candidiasis, and ectodermal dystrophies [27]. This entity is now a well-recognized autosomal recessive autoimmune disease that has been shown to be caused by mutations of a single gene named autoimmune regulator (AIRE) [1099, 1803]. The defective gene responsible for this condition was recently isolated, and several different mutations in AIRE gene have been identified [1, 253].

    This variety of CMC usually presents during infancy with persistent “diaper rash”. Cutaneous candidiasis becomes more extensive later on, and onychomycosis also occurs. The endocrine dysfunctions can manifest any time during life, and usually follow a sequential pattern [1196]

  3. Localized Chronic Mucocutaneous Candidiasis
    As described by Kirkpatrick, this form of CMC is characterized by impressive hyperkeratosis and cutaneous horn formation that usually affects both hands. It typically begins during childhood and a genetic pattern has not been identified. In addition, localized CMC is not associated with endocrinopathies and affects both sexes equally [327, 1198].
  4. Diffuse Chronic Mucocutaneous Candidiasis
    Within this category, Kirkpatrick has included patients with widespread mucocutaneous candidiasis with serpiginous borders and little hyperkeratosis. This form of CMC usually begins during late childhood or early adolescence. Although not associated with any specific inheritance pattern, there is one report of eight members of a family affected with a presumed autosomal dominant form of this disease [2402].
  5. Chronic Mucocutaneous Candidiasis And Thymoma
    This form of CMC begins during the third decade and has been associated with myasthenia gravis, hypogammaglobulinemia, red cell aplasia, aplastic anemia, and/or neutropenia [813, 1148, 1199, 1204, 1566, 1708]. However, most patients with thymoma do not have CMC. Rothberg et al. studied all possible cutaneous disorders in patients with thymoma and found only one case of CMC among 172 thymoma patients [1971].
  6. Chronic Mucocutaneous Candidiasis With Interstitial Keratitis
    Kirkpatrick has always included in his reviews a variety of CMC described by Okamoto et al. in which several families presented with CMC and severe interstitial keratitis [1681]. To the best of our knowledge, there have not been any further reports of this association.
  7. Chronic Mucocutaneous Candidiasis And “KID”
    Cases of CMC associated with the triad of keratitis, ichthyosis and deafness have also been described [987, 2097].

 

Diagnosis

From a diagnostic point of view, the evaluation of patients with suspected CMC is complex. Kirkpatrick has proposed the following age-based approach to the patient [1196].

Evaluation of patients with CMC. Adapted from [1196] 

Age of onset Test
Children < 1year old
  • CBC with differential
  • Lymphocyte phenotyping
  • T-Ly response to MT
Children > 1year old Previously listed tests, plus:

  • T-lymphocyte to Candida, tetanus and other antigens
  • Delayed cutaneous hypersensitivity testing with Candida, tetanus, mumps, etc.
  • Lymphokine production by antigen or mitogen-stimulated T cells
  • Antibodies against endocrine tissues
  • Endocrine function tests (Calcium, phosphate, TSH, cortisol)
Children with recurrent upper or lower respiratory tract infection
  • B lymphocyte counts
  • Serum IgG, IgA, IgM and IgE
  • IgG subclasses
  • Measurement of antibody response
Adults
  • CBC with differential
  • (A):HIV Antibody & Western blot
  • Lymphocyte phenotyping
  • Computed tomography of the chest to rule out thymoma

 

Therapy

Current therapy for CMC principally revolves around prolonged use of antifungal agents. However, there have also been attempts to ameliorate the underlying immune defect of CMC.

  1. Antifungal Therapy
    The availability of effective oral agents, especially the N/A(L):azole antifungal agents, has dramatically changed the life of patients living with CMC [1197]. Ketoconazole was the first agent to be extensively used for CMC and proved to be very successful when used either continuously or intermittently [714, 892, 1041, 1068, 1201, 1553, 1560]. However, liver toxicity soon was found to be a limitation [2241]. Itraconazole has also been used, although in fewer reports than for ketoconazole [345, 2249]. Fluconazole should also be effective, however there are only a few case reports describing its use [1006, 1989, 2097].
  2. Immunotherapy
    Given the underlying immunologic nature of CMC, immunologic treatments of various sorts have been attempted in selected patients:

    • Thymus transplantation was associated with clearance of CMC in patients with DiGeorge syndrome and other severe deficiencies in cell-mediated immunity [30, 453, 1200, 1329].
    • White blood cell transfusions yielded transient relief in patients with CMC [1202, 2278].
    • Transfusion of a Candida-specific transfer factor has been reported to be very successful (remission for > 10 years) when combined with antifungal therapy [165, 1204].
    • Reports of successful treatment with bone marrow transplantation have also been published [334, 546, 1054].