History
Patients present with recurrent or persistent superficial candidal infections of the oral cavity (thrush) or intertriginous or periorificial areas. Infants often present with recalcitrant thrush, candidal diaper dermatitis, or both. More extensive scaling of skin lesions and thickened nails and red, swollen periungual tissues can follow these infections.
Systemic candidiasis and invasive fungal dermatitis, although rare, usually occur in premature infants, particularly those with extremely low birth weight.
Persistent and refractory candidal infections, which characterize chronic mucocutaneous candidiasis (CMC), must be distinguished from the more common and treatment-responsive overgrowth of Candida that occurs in the setting of systemic antibiotic therapy, local/systemic corticosteroid treatment, or hyperglycemia in persons with diabetes mellitus.
Physical Examination
Chronic mucocutaneous candidiasis (CMC) is diagnosed based on physical examination findings, potassium chloride (KOH) preparation results, fungal culture, and a history of recurrent and refractory candidiasis infections. Oral examination may reveal the white adherent plaques of thrush or the angular cheilitis of perlèche. Oral involvement may extend to the esophagus, but further extension is extremely uncommon. Nails may be markedly thickened, fragmented, and discolored, with significant edema and erythema of the surrounding periungual tissue, simulating clubbing (see first image below). Skin lesions more frequently are acral and characterized by erythematous, hyperkeratotic, serpiginous plaques (see second image below). The scalp may be involved with similar hyperkeratotic plaques, which can result in scarring alopecia (see third image below).
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.
A subset of CMC patients has recurrent or severe noncandidal infections, [7] including those from viral, bacterial, and other fungal pathogens. Some patients with CMC have low serum iron levels and decreased iron stores, possibly related to decreased iron absorption. Iron replacement should be initiated in these patients. Several patients reportedly have improved after parenteral iron therapy.
Several classifications exist for CMC. The authors categorize CMC based on its association with other conditions.
CMC without endocrinopathy
This category comprises a spectrum of clinical presentations. Inheritance may be autosomal recessive or dominant, but many cases are sporadic. It is estimated that around half the patients with isolated CMC have a signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation leading to impaired IL-17 immunity. [8, 9] Onset is in childhood, and no associated endocrine or autoimmune disorders are observed.
CMC with endocrinopathy
APECED
CMC may occur as part of autoimmune polyendocrinopathy syndrome type 1 (Online Mendelian Inheritance in Man #240300), also known as APECED. [10, 11, 12, 13, 14]
APECED is characterized by at least 2 of the following: CMC, hypoparathyroidism, and Addison disease. Other autoimmune disorders may be associated, such as, type 1 diabetes, autoimmune thyroiditis, Graves disease, alopecia areata, vitiligo, hypogonadism, biliary cirrhosis, hepatitis, idiopathic thrombocytopenic purpura, and pernicious anemia.
APECED is inherited in an autosomal recessive fashion and usually manifests early in childhood. It is caused by mutations in the autoimmune regulator gene (AIRE) on 21q22.3, which encodes a protein that plays an important role in establishing and maintaining tolerance in the thymus. [15] Autoantibodies against IL-17A, IL-17F, and/or IL-22 underlie the development of CMC in these patients. [16, 17] A study found that APECED patients have defective receptor-mediated Candida internalization, leading to altered Candida-specific immune responses. [10]
Candidiasis is often the first manifestation of APECED, appearing before age 5 years in most cases, followed by manifestations of the other endocrine and nonendocrine conditions, including ectodermal dysplasia. Ectodermal dysplasia manifestations include dental enamel hypoplasia and pitted nail dystrophy. Keratopathy and calcifications of the tympanic membrane also may occur.
A 2006 review of 18 APECED patients found candidiasis in all patients as the presenting symptom, and researchers concluded that ectodermal dystrophy usually only occurs as a secondary phenomenon. [15]
No correlation exists between the severity of the endocrinopathy and the severity of the candidal infections. Treatment of the underlying endocrinopathy does not usually improve candidal infections.
Thyroid disease
CMC may be associated with thyroid disease. An autosomal dominant CMC associated with thyroid disease has been mapped to 2p. [18] Hypothyroidism was also noted in patients with Toll-like receptor 3 defect (L412F mutant), which is involved in the suppression of autoimmune disorders, adaptive immune response, and defense against viral infections. [19]
CMC with thymoma
Patients in this subgroup typically present after the third decade of life. These patients are at increased risk of myasthenia gravis and bone marrow abnormalities. As in APECED patients, autoantibodies to IL-17A, IL-17F, and/or IL-22 are implicated in this subgroup. [16, 20]
CMC with other conditions
CMC may be seen in patients with autosomal dominant hyperimmunoglobulin E syndrome, autosomal dominant signal transducer and activator of transcription 1 (STAT1) gain-of-function, autosomal recessive deficiencies of IL-12 receptor β1 (IL-12Rβ1), autosomal recessive caspase recruitment domain-containing protein 9 (CARD9), or retinoic acid–related orphan receptor γT (RORγT). [21] The shared process among these conditions in the context of CMC is impaired IL-17 immunity.
Patients with autosomal dominant hyperimmunoglobulin E syndrome present with CMC as well as recurrent staphylococcal infections. T lymphocytes producing IL-17 and IL-22 are significantly decreased, which may be explained by impaired STAT3 signaling of IL-6, IL-21, and IL-23. [22, 23, 24]
In addition to CMC, patients with autosomal recessive CARD9 present with invasive fungal infections and deep dermatophytosis due to impaired neutrophil- and IL-17–producing T-lymphocyte cell defenses. [25, 26]
Nontuberculous mycobacterial infections are the most prominent feature in patients with IL-12Rβ1 deficiency, but milder cases of CMC are also observed. T-helper cells involved in the Th1 pathway, as well as macrophages, contain genetic defects that increase susceptibility to intracellular pathogens. Among other immune-signaling pathway defects such as human JNK1-dependent MAPK signaling pathway and autosomal recessive ACT1 deficiency caused by a mutation of TRAF3IP2 variant, patients have shown decreased circulating T cells producing IL-17A and IL-22. [23, 27, 28, 29]
Recurrent oral candidiasis is not uncommon in patients with HIV infection.
Complications
Because of compromised immunity, patients often develop secondary infections. Among other bacterial infections, respiratory and skin infections due to Staphylococcus aureus are frequently encountered. Patients often display viral infections with Herpesviridae causing oral or genital sores and, less commonly, invasive fungal infections due to Candida organisms. Nine patients affected by chronic mucocutaneous candidiasis with heterozygous STAT1 mutations were found to have developed bronchiectasis, chronic lung disease, and early severe reflux disease. [30] A 2016 study reported invasive infections, cerebral aneurysms, and cancers as the strongest predictors of poor outcomes. [31]
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Thickened, fragmented, hyperkeratotic nails and erythematous periungual skin. Courtesy of Walter Reed Army Medical Center.
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Crusted hyperkeratotic plaques on and around the nose. Courtesy of Walter Reed Army Medical Center.
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Crusted hyperkeratotic plaques on eyebrow, forehead, and scalp. Courtesy of Walter Reed Army Medical Center.
