Chronic mucocutaneous candidiasis

INTRODUCTION — Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of syndromes with the common features of chronic noninvasive Candida infections of the skin, nails, and mucous membranes that are usually resistant to topic treatment and absence of invasive fungal infections. The classic forms have associated autoimmune manifestations (most commonly endocrinopathies), and patients may have other microbial infections. Milder forms have oral candidiasis with or without associated staphylococcal skin infections. CMCC is caused by genetic defects in the immune system (figure 1).

The pathogenesis, clinical manifestations of identified genetic defects, differential diagnosis, and treatment of CMCC are reviewed here. A general discussion of Candida infections and their clinical manifestations is presented separately. (See "Overview of Candida infections" and "Candida infections in children" and "Esophageal candidiasis in adults".)

CLASSIC FORMS OF CMCC WITH ASSOCIATED AUTOIMMUNITY — CMCC traditionally refers to a heterogeneous group of patients who suffered persistent, noninvasive Candida infections of the skin, mucous membranes, and nails, as well as autoimmune manifestations, most commonly involving the endocrine system [1-5]. The classic forms of CMCC are caused by pathogenic variants in the autoimmune regulator gene (AIRE) and signal transducer and activator of transcription 1 gene (STAT1) (figure 1).

Classic CMCC is associated with a variety of additional clinical features:

●Autoimmune manifestations other than endocrinopathy, including autoimmune hemolytic anemia, immune thrombocytopenia purpura, autoimmune neutropenia, and rheumatoid arthritis [6,7].

●Various degrees of bone marrow failure with aplastic anemia [8,9].

●Neoplastic diseases, mostly involving the mouth and esophagus, and benign and malignant thymomas [10].

●Multiple abnormalities in the immune system including abnormal in vitro T cell proliferation to Candida antigen, humoral deficiencies, and increased susceptibility to bacterial and viral infections. (See 'Laboratory evaluation' below.)

Autoimmune regulator deficiency — Autoimmune regulator (AIRE) deficiency accounts for the majority of CMCC cases in distinct populations, such as the Finns and Sardinians, but only 20 to 40 percent of cases in other populations [11]. It is detected at a frequency of 1:9000 in Iranian Jews, 1:14,500 in Sardinians, and 1:25,000 in Finns. The AIRE gene is localized to chromosome 21q 22.3 [12]. The condition is transmitted in an autosomal recessive manner. More than 50 mutations have been described so far, with the most common mutation being R257X in the Finnish population.

Patients suffer chronic candidiasis as well as autoimmune polyendocrinopathy, most commonly hypoparathyroidism and adrenal insufficiency, and skin dystrophy, hence the name given to this disorder: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (MIM #240300). The disorder is also referred to as autoimmune polyendocrine syndrome type I (APS-I or APS1).

Pathogenesis of AIRE deficiency — Random rearrangement of antigen-specific receptor genes during lymphocyte maturation produces a diverse repertoire of receptors including some able to recognize the body's own antigens. To prevent autoimmunity, thymocytes expressing self-reactive T cell receptors (TCRs) are eliminated. This selection process is primarily mediated by stromal cells in the thymus that purge the repertoire of self-reactive TCRs [13]. A subpopulation of stromal cells, called medullary thymic epithelial cells (mTECs) [14], express a vast spectrum of peripheral tissue autoantigens. mTECs present these antigens to differentiating T cells, and only the cells that recognize the autoantigens with high affinity are clonally deleted [15]. Expression of many of these autoantigens is regulated by the transcription factor, AIRE [15,16]. Abnormal AIRE results in impaired clonal deletion, thus allowing T cells expressing autoreactive TCRs to expand to the periphery and induce autoimmunity [17,18]. AIRE transcripts have also been detected in secondary lymphoid organs, including monocyte/dendritic cells [19] and radiosensitive lymph node stromal cells [20]. Together, central and peripherally located AIRE are thought to play complementary roles in maintaining self-tolerance.

Pathogenic variants in the AIRE gene lead to multiorgan autoimmunity [18]. The endocrine system is most commonly involved. The severity of the inflammation and the organs/systems targeted vary with genetic background (human leukocyte antigen [HLA]-DR). As examples, HLA-DRB1*15-DQB1*0602 appears protective against type 1 diabetes mellitus [21,22], while HLA-DRB1*04-DQB1*0302 is associated with alopecia and HLA-DRB1*DQ1*0602 is associated with adrenal failure [23]. Autoimmunity is associated with increased levels of autoantibodies against proteins made specifically by the affected organs [24,25]. Deletion of B cells with anti-CD20 antibody resulted in improvement of autoimmunity in AIRE-deficient mice, suggesting that antigen presentation by B cells and autoantibodies are important in the pathogenesis of CMCC [26]. While success of rituximab treatment was demonstrated in patients with pulmonary disease [27] and type 1 diabetes mellitus [28] associated with AIRE deficiency, its application in autoimmune tubulointerstitial nephritis has had mixed results so far [29,30].

Autoantibodies against interleukin (IL) 17 and IL-22 were identified in the serum of patients with AIRE deficiency, suggesting that susceptibility to Candida infections also has an autoimmune basis [31-33]. One study suggested that IL-17A autoantibodies were correlated with disease severity [34]. Another study found impaired T helper cell type 17 (Th17) responses to Candida in patients with AIRE deficiency and other types of CMCC [35].

Susceptibility to candidal infections in patients with AIRE deficiency may result from both abnormal adaptive and innate immunity. Dectin-1 is a beta-glucan receptor involved in the innate immune response to candidal infection. AIRE associates with components of the Dectin-1 signaling pathway, including Dectin-1, Syk, and caspase recruitment domain-containing protein 9 (CARD9) [36]. The trace constitutive association increases with stimulation of the Dectin-1 pathway, resulting in production of tumor necrosis factor (TNF) alpha. TNF-alpha production after stimulation of the Dectin-1 pathway is reduced in patients with AIRE deficiency. (See 'Dectin-1 deficiency' below and 'Differential diagnosis' below.)

Clinical features of AIRE deficiency/APECED — AIRE deficiency/autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is known for its wide variation in clinical presentation and course of disease, even among affected family members carrying an identical genetic aberration [11,37,38]. This clinical heterogeneity can lead to a significant delay in diagnosis [39]. The first manifestation of the disease can start between the ages of two months to >18 years of age [37].

The classic triad is mucocutaneous candidiasis, hypoparathyroidism, and adrenal failure [37]:

●Chronic, or sometimes recurrent, candidal infection of the oral cavity, nails, and skin, and less frequently the esophagus, vagina, and gastrointestinal tract, is the presenting feature in 60 percent of patients and affects all patients by the time they are 40 years old. Skin lesions are frequently raised and sometimes disfiguring. Similarly, affected nail beds result in structurally malformed nails. These changes are probably due to a combination of infection and an exaggerated inflammatory (autoimmune) response (picture 1 and picture 2). Candida albicans is the most common species to cause infection.

●Hypoparathyroidism is the most common endocrine abnormality in this disease and the second most common feature in AIRE deficiency, occurring at presentation in approximately 30 percent of patients. More than 80 percent of patients are eventually afflicted. Hypoparathyroidism appears earlier and is more common in females than males. The resultant hypocalcemia and hypomagnesemia are sometimes hard to control and may lead to seizures.

●Adrenal failure is the third most common feature in the disease. It occurs in only approximately 5 percent at presentation but occurs in more than 60 percent of cases by the age of 15 years.

Other manifestations are less common [37,38]:

●Other endocrinopathies include type 1 diabetes mellitus, hypothyroidism, growth hormone deficiency, Addison's disease, ovarian failure (appears to coexist with adrenal failure), and male hypogonadism.

●Other autoimmune manifestations include vitiligo and alopecia areata, which affects more than 30 percent of patients after the age of 20 years and can progress to universal baldness. Pernicious anemia affects more than 20 percent of patients after the age of 30 years. Hepatitis is rare.

●Complications presumed due to chronic Candida infection include keratoconjunctivitis, which may lead to blindness, esophageal stricture, and squamous cell carcinoma of the mouth and esophagus [40,41].

●Antibody deficiency to polysaccharide antigens may occur.

●Other oral and gastrointestinal manifestations include enamel abnormalities, chronic diarrhea, and constipation [37].

●Other ocular features reported include cortical lenticular opacities and chronic iridocyclitis [42].

●Pulmonary disease, interstitial nephritis, and encephalopathy may also occur [38].

AIRE deficiency may also present with unusual features [37]. Young children, even in their first year of life, may present with fever and periodic rash, dry eyes [42], exocrine pancreatic insufficiency [43], or renal involvement, including hypokalemia, hypertension, or tubular interstitial nephritis [44,45].

Forty to 80 percent of patients in North America present with clinical features uncommon in European cohorts, including urticaria, enteritis, pneumonitis, and Sjögren-like syndrome [46]. This is most likely due to the predominance of a Scandinavian founder mutation in this population.

Signal transducer and activator of transcription (STAT1) dysfunction — STAT1 is a critical transcription factor downstream of interferon (IFN) receptor signaling. Upon ligation of IFN-gamma to its receptor, Janus kinase (JAK) 1/2 tyrosine kinases are activated, leading to phosphorylation of the receptor, docking and dimerization of STAT1 molecules, and release of dimerized STAT1. Once dimerized STAT1 translocates to the nucleus, it binds to recognized sites and subsequently drives IFN-triggered gene transcription of antiviral and proinflammatory proteins [47].

Monoallelic mutations in the STAT1 gene were first identified in a cohort of patients with presumed autosomal dominant CMCC [48]. The proposed mechanism of these mutations is a gain of function caused by impaired nuclear dephosphorylation of STAT1 [49-53]. These events lead to impaired IFN-mediated gene expression [54]. STAT1 gain-of-function mutations frequently result in decreased production of IFN-gamma, IL-17, and IL-22, suggesting a defect in T helper cell type 1 (Th1) and Th17 responses [55]. Other immune aberrations reported in these patients include progressive lymphopenia, reduced responses to mitogens and antigens [56], hypogammaglobulinemia [52,56,57], and impaired natural killer (NK) cell function [58].

The clinical spectrum of manifestations in patients with STAT1 dysfunction is wide but most commonly includes oral thrush as well as fungal skin and nail infections [48,57,59]. Microbial infections including sinusitis, pneumonia, and folliculitis are also common [60,61]. Viral infections with herpes viruses, papillomavirus, and JC virus are less common. However, these viral infections can be life threatening in a subset of patients who gradually develop a profound combined immunodeficiency that may also predispose them to invasive fungal infections such as coccidioidomycosis, histoplasmosis, and mucormycosis [49-51,56,60,62,63].

Up to half of patients with STAT1 dysfunction have hypothyroidism, inflammatory bowel disease (IBD)-like disease, or autoimmune cytopenias [56,60]. Rarely, some patients suffer severe and repeated strokes caused by cerebral vasculitis and multiple aneurysms, mainly in medium-size vessels (Moyamoya-like disease) [48,52,53,60,64].

Patients with severe cutaneous involvement have an increased risk of developing skin cancer [52]. Other patients with a progressive decline in immunity are at increased risk of developing chronic lung disease or overwhelming viral or fungal infections.

Other STAT1 mutations that cause loss of expression and loss of function produce different phenotypes, such as susceptibility to mycobacterial and viral infections or combined immunodeficiency. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'STAT1 defects' and "Combined immunodeficiencies: An overview" and 'Laboratory evaluation' below.)

IL-17 PATHWAY IMMUNE DEFICIENCIES — T cell immunity is critical for host defense against superficial as well as invasive fungal infections. A deficit in interleukin (IL) 17-producing T cell is associated with a growing number of conditions characterized by a susceptibility to bacterial and fungal infections [65]. There are six IL-17 cytokines (IL-17 A through F) that bind to five distinct receptors (IL-17 RA through RE). These receptors form homodimers or heterodimers in combinations that recognize a distinct cytokine. Ligation of these receptors induces the recruitment of the adaptor ACT1 (nuclear factor kappa-B activator 1, also called TRAF3-interacting protein 2 [TRAF3IP2]), which is required for downstream signaling (figure 1). (See "The adaptive cellular immune response: T cells and cytokines", section on 'Th17'.)

Mutations in the genes for IL-17RA, IL-17RC, IL-17F, and ACT1 are all associated with various degrees of mucocutaneous candidiasis. Their phenotype is not strictly limited to superficial Candida infections, and, frequently, their more prominent features are severe infections with Staphylococcus aureus or Mycobacteria [65,66].

IL-17RA deficiency — Interleukin 17 receptor alpha (IL-17RA) is the common subunit for all five members of the IL-17R family [67]. Most patients described so far with autosomal recessive IL-17RA deficiency are of Middle Eastern, Japanese, or South American origins. Analysis of a large cohort of 21 patients revealed that oral thrush was present in all patients followed by scalp and skin Candida infections. Nail involvement was recorded in only approximately 20 percent of these patients. Staphylococcal skin infections in the forms of pustules, folliculitis, and furunculosis were prevalent. Other infections included pneumonia sinusitis, otitis, and pulmonary tuberculosis. Eczema was also reported in some patients.

IL-17RC deficiency — A few patients of Turkish descent with homozygous mutations in interleukin 17 receptor C (IL-17RC) have been reported. Patients presented at a young age predominantly with oral candidiasis and pustular skin lesions [68].

IL-17F deficiency — Mucosal candidiasis was found in several members of an extended family from Argentina. Affected individuals were found to carry a heterozygous mutation in the interleukin 17F (IL17F) gene, suggesting autosomal dominant inheritance. However, two healthy individuals in this family had an identical monoallelic variant [65].

ACT1 deficiency — Two adult siblings born to consanguineous Algerian parents were reported to have homozygous mutations in the ACT1 (nuclear factor kappa-B activator 1, also called TRAF3-interacting protein 2 [TRAF3QP2]) gene. One patient suffered macro-cheilitis, while his sibling had S. aureus blepharitis and folliculitis. Both had repeated episodes of oral thrush [69].

OTHER GENETIC DEFECTS — Other genetic aberrations are associated with far smaller numbers of cases and are frequently found in a single family. These genetic defects are all disease modifiers. In some cases, inheritance may involve the effect of multiple genes, as is seen in some patients with lymphoid phosphatase (Lyp) [70] and Dectin-1 [71] mutations.

Lyp mutation — The protein tyrosine phosphatase nonreceptor-type 22 (PTPN22) gene localized to 1p13 encodes Lyp [72]. The substrates of Lyp include the kinases Lck, Fyn, Zap-70, and the CD3-zeta chain of the T cell receptor (TCR) [73]. In accordance with this observation, Lyp overexpression downregulates TCR signaling, while Lyp deficiency enhances T cell activation. Lyp also interacts with the Src family negative regulatory kinase, Csk. Lyp and Csk act in tandem to negatively regulate activation of Src kinases [74]. The interaction between Lyp and Csk is lost in the R620W mutation of Lyp since the arginine at this position is necessary for Csk-SH3 domain recognition of protein-rich areas of Lyp. This mutation is also believed to result in gain of function that alters TCR signaling, resulting in possible compromised central as well as peripheral tolerance [75,76]. This variant probably acts as a disease modifier, altering expression of another gene, although this gene is not known.

Six patients with CMCC who carried a R620W mutation of PTPN22 all had oral or skin candidiasis, similar to patients with AIRE mutations, but none had enamel defects [70]. The most common endocrine abnormalities were hypothyroidism and gonadal failure. None had hypoparathyroidism, the most common endocrine abnormality in autoimmune regulator (AIRE) deficiency. A unique finding seen in five of the patients with the R620W Lyp mutant was chronic lung disease, including bronchiectasis. This is probably due to antibody deficiency in four of the six patients, another manifestation almost nonexistent in AIRE deficiency. The R620W mutant is also associated with a variety of autoimmune disorders including rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus (SLE), and Addison's disease [77-84].

Dectin-1 deficiency — C. albicans is recognized by the innate immune system through pattern-recognition receptors, such as the toll-like receptors (TLRs) and lectin-like receptors [85]. TLR2, TLR4, and mannose receptors recognize mannans, Candida cell wall components [71,85-87]. These receptors collaborate with the beta-glucan receptor Dectin-1 (MIM *606264) in stimulation of cytokine production [88]. Dectin-1 enhances TLR2 and TLR4 induced cytokine production, such as tumor necrosis factor (TNF). In its absence, mice have increased susceptibility to C. albicans and Pneumocystis jirovecii infections [89,90].

A family with Dectin-1 deficiency was identified in which affected members had a homozygous single nucleotide polymorphism (SNP) in exon 6 that caused a change of amino acid 238 from tyrosine to a stop codon [71]. These patients suffered vulvovaginitis and onychomycosis but did not have invasive candidiasis, other major infections, or autoimmune manifestations. It therefore appears that Dectin-1 deficiency leads to a pure susceptibility to mucosal and skin, but not invasive, fungal infection. However, the allelic frequency of these Dectin-1 variants are common and therefore probably represent modifying or predisposing variants rather than directly pathogenic variants.

Toll-like receptor 3 defect (L412F mutant) — TLR3 plays a role in initiating adaptive immune responses, suppressing autoimmune disorders, and protecting against viral infection. Fourteen patients with no identified mutations in the other genes known to cause CMCC were found to carry the TLR3 L412F mutant that renders TLR3 dysfunctional [91]. This variant probably acts as a disease modifier, although the modified gene is unknown. These patients were previously classified as a distinct clinical subgroup, CMCC with autoimmunity and combined immunodeficiency.

The one patient who was homozygous for this variant had more severe disease with treatment-resistant oral and esophageal candidiasis; cytomegalovirus (CMV)-induced hepatitis, viremia, and pneumonitis; recurrent sinopulmonary infections; chronic lung disease with bronchiectasis; and thrombocytopenia, hemolytic anemia, and neutropenia.

Patients heterozygous for the TLR3 variant all had chronic candidiasis, and most had nail dystrophy, similar to other forms of CMCC. However, these patients also had severe chronic infections (mainly sinopulmonary), often leading to chronic lung disease and bronchiectasis. In addition, they had a high frequency of severe viral infections, particularly CMV, autoimmune disorders (eg, cytopenias), and endocrine abnormalities (eg, hypothyroidism). Rarely, these patients develop bone marrow failure, possibly due to CMV infections.

Immune evaluation reveals antibody deficiency as well as abnormal in vitro proliferative responses to mitogens. Interferon (IFN) gamma production was decreased in response to stimulation with a TLR3 ligand.

ROR-gamma t deficiency — Retinoic acid-binding receptor-related orphan receptor gamma (ROR-gamma t) is a transcription factor that regulates the T helper type 17 (Th17) subset. Biallelic loss-of-function mutations in the RORC gene were identified in seven patients from three unrelated kindreds [92]. These patients presented with both CMCC and disseminated Bacillus Calmette-Guérin (BCG) infection. Interleukin (IL) 17 producing cells were absent in these patients, and there was an impaired leukocyte response to Mycobacterium due to a defect in IFN-gamma production by circulating T cells.

DIAGNOSIS — The diagnosis of CMCC is primarily based upon clinical features including chronic, noninvasive candidiasis of the skin and mucous membranes associated with autoimmune manifestations, most commonly endocrinopathies. Most patients are diagnosed during childhood, but some are not identified until adulthood. If a STAT1 defect is suspected, STAT1 function should be tested in freshly obtained peripheral blood lymphocytes. The diagnosis is confirmed by identifying a disease-causing mutation (figure 1). If interleukin (IL) 17 pathway-related defects are suspected but the significance of the genetic abnormalities is unclear, evaluation of cytokine function and cytokine receptor responses may clinically be valuable. (See 'Classic forms of CMCC with associated autoimmunity' above and 'IL-17 pathway immune deficiencies' above and 'Other genetic defects' above.)

LABORATORY EVALUATION — All patients with chronic candidiasis should be evaluated for a suspected primary immunodeficiency. This should include a complete blood count with differential; immunoglobulin levels including immunoglobulin E (IgE) level; T, B, and natural killer (NK) cell subsets; and T cell function. (See "Laboratory evaluation of the immune system" and "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)

The only definitive laboratory test for the diagnosis of CMCC is the genetic analysis of relevant genes. However, autoantibodies against interferon (IFN) alpha and IFN-omega are consistently high in patients with AIRE mutations [93,94]. Measurement of autoantibodies against IFN-omega and well as interleukin (IL) 17A, IL-17F, and IL-22 can help differentiate CMCC due to genetic causes from autoimmune mimics. (See 'Differential diagnosis' below.)

Other laboratory findings are less definitive but can aid in the diagnosis. These include standard laboratory tests to evaluate for endocrine disorders, such as hypoparathyroidism and adrenal insufficiency that are associated with CMCC. A blood count can reveal anemia, either due to iron deficiency (hypochromic, microcytic) or due to vitamin B12 deficiency (megaloblastic). Both may be caused by malabsorption and parietal cell atrophy. Liver function should also be screened because hepatitis is rarely associated with CMCC.

Evaluation of the immune system may identify a selective inability to respond in vitro (T cell proliferation) or in vivo (cutaneous delayed-type hypersensitivity) to Candida, especially in patients with AIRE deficiency [95]. In other patients, lymphopenia and more extensive abnormalities in in vitro antigenic and mitogenic responses are identified. In one cohort, 20 percent of patients with non-autoimmune regulator (AIRE) deficiency CMCC had reduced number and/or function of circulating T cells [96]. Patients with STAT1 mutation in the DNA-binding domain may have a gradual decline of T, B, and NK cells [58], as well as deteriorating T cell function.

Humoral immunity may also be affected in patients with non-AIRE deficiency CMCC and includes low immunoglobulin G2 (IgG2) and IgG4, hypogammaglobulinemia, and an inadequate response to vaccination with polysaccharide antigens (eg, unconjugated pneumococcal vaccine) [56,97,98].

Serum Candida antibodies are not of value in the diagnosis of CMCC, nor are skin or serum IgE tests for Candida.

DIFFERENTIAL DIAGNOSIS — Chronic candidiasis can be encountered in many types of primary immunodeficiencies. Most commonly, profound primary or secondary T cell deficiencies predispose to susceptibility to Candida. Patients with severe combined immunodeficiency (SCID) and acquired immunodeficiency almost invariably present with oral thrush and/or with other cutaneous Candida infections. However, unlike patients with CMCC, Candida infections in these disorders can become invasive with systemic spread. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "Secondary immunodeficiency induced by biologic therapies".)

A number of other primary immunodeficiencies can result in candidiasis, but common to all of these conditions is the presence of other major clinical features not present in CMCC [99]:

●Caspase recruitment domain-containing protein 9 (CARD9) plays a positive regulatory role in cell apoptosis and nuclear factor (NF)-kappa B activation and is involved in antifungal immunity [100]. Autosomal recessive forms of CARD9 deficiency, a phagocytic disorder with variable presentation, have been identified in several kindreds and individual patients [101-106]. Manifestations include meningoencephalitis and invasive brain infections due to Candida species, CMCC, disseminated infections with Exophiala and Phialophora species, superficial (cutaneous) dermatophytosis, and deep dermatophytosis with involvement of the skin, scalp, nails, lymph nodes, and brain. Multifocal-to-coalescing granulomatous dermatitis is seen on skin biopsy in patients with deep dermatophytosis. CARD9 levels (measured by flow cytometry) in monocyte-derived dendritic cells are low to absent, depending upon the specific mutation. The specific mechanisms underlying increased susceptibility to fungal disease in these patients remain unclear.

●CD25 deficiency can cause persistent oral and esophageal candidiasis. However, patients also have a variable array of other manifestations, including bacterial, viral, and other fungal infections; enteropathy; primary biliary cholangitis; and eczema. (See "IPEX: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked", section on 'IPEX-like syndromes'.)

●Patients with hyperimmunoglobulin E (hyper-IgE) syndrome due to signal transducer and activator of transcription 3 (STAT3) mutation frequently have mucocutaneous candidiasis as a result of impaired T helper cell type 17 (Th17) function [107-109]. However, deep staphylococcal abscesses, Aspergillus infections, and dysmorphic features are also prominent features. (See "Autosomal dominant hyperimmunoglobulin E syndrome".)

●Dedicator of cytokinesis 8 (DOCK8) deficiency can cause mucocutaneous candidiasis but is also associated with recurrent respiratory tract infections, cutaneous viral infections, S. aureus skin infections, atopic disease, hepatic disorders, and cancer, along with eosinophilia and elevated IgE [110]. (See "Combined immunodeficiencies: Specific defects", section on 'DOCK8 deficiency'.)

●Ataxia-telangiectasia can also present with oral thrush, but these patients also develop neurologic abnormalities including progressive cerebellar ataxia and abnormal eye movements, as well as oculocutaneous telangiectasias [109]. (See "Ataxia-telangiectasia".)

●The primary manifestations in patients with interleukin (IL) 12 receptor beta1 (IL12RB1) mutations are disseminated Salmonella and nontuberculous mycobacterial (NTM) infections or disseminated Bacillus Calmette-Guérin (BCG) infection. These patients can also have oral candidiasis, although, unlike typical cases of CMCC, few have esophageal involvement, cutaneous lesions are rare, and some patients have disseminated candidiasis [111]. The majority have risk factors for candidal infections, such as antibiotic treatment for mycobacterial infections. To a lesser degree, some patients with IL-12p40 deficiency, another disorder with increased susceptibility to mycobacterial disease, have either oral thrush or disseminated candidiasis [112]. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects" and "Mendelian susceptibility to mycobacterial diseases: Specific defects", section on 'IL-12 p40 deficiency'.)

Autoimmune disease can mimic the genetic causes of CMCC. Autoantibodies against IL-17A, IL-17F, and IL-22 produced by Th17 cells have been identified in thymoma patients with CMCC [32].

Chronic candidiasis is also seen in patients with diabetes mellitus, human immunodeficiency virus (HIV) infection, or in patients treated with systemic or inhaled glucocorticoids [113] or prolonged courses of antibiotics [114]. (See "Glucocorticoid effects on the immune system".)

TREATMENT — Management includes antifungal therapy and treatment of associated endocrine and autoimmune abnormalities.

Candidiasis usually clears with treatment with a member of the azole family, although chronic suppressive therapy is often required to prevent recurrences [115-117]. Fluconazole is the preferred treatment. It has good activity against C. albicans, is easy to administer, has few side effects, and is relatively inexpensive. Drug resistance may occur with suppressive therapy [118]. The dose can be escalated if increasing resistance is an issue, but ultimately another azole agent will need to be used. Itraconazole, voriconazole, or posaconazole can be tried, in that order. Liver function should be carefully monitored while patients are on systemic therapy with these drugs. Amphotericin has been successfully used in severe cases [119]. Antifungal therapy for mucocutaneous candidiasis is discussed in greater detail separately. (See "Oropharyngeal candidiasis in adults" and "Pharmacology of azoles".)

Endocrine abnormalities should be treated with replacement therapy, when possible [37,114]. In cases of hypoparathyroidism, calcium levels should be carefully monitored, and calcium supplementation should be given. Frequently, magnesium must be given to avoid seizures that can be caused by hypomagnesemia [37]. (See "Treatment of hypocalcemia" and "Hypomagnesemia: Evaluation and treatment" and "Treatment of adrenal insufficiency in children" and "Treatment of adrenal insufficiency in adults".)

Antibody deficiency, if severe, should be treated with immune globulin replacement [97]. (See "Immune globulin therapy in inborn errors of immunity".)

The experience in controlling severe autoimmune manifestations in CMCC is limited to single case reports that suggest potentially effective treatments:

●Prednisone 60 mg/day for two weeks was effective in resolving autoimmune panniculitis [120].

●Prednisone, tacrolimus, and mycophenolate mofetil, which were given to prevent renal transplant rejection, reversed multiple autoimmune manifestations and reduced levels of autoantibodies [44].

●Prednisone in combination with azathioprine was effective in improving autoimmune hepatitis [11,21].

●Severe malabsorption was reversed with a pulse of methylprednisolone followed by oral methotrexate maintenance therapy [121].

●Long-term clinical remission was reported after continuous therapy with granulocyte-colony stimulating factor (G-CSF) [122].

●Oral candidiasis and alopecia areata resolved on ruxolitinib, an oral Janus kinase (Jak) family protein kinase inhibitor [123].

●Recurrent oral and esophageal C. albicans infections and oral and vaginal ulcers were prevented with baricitinib, an oral JAK 1/2 inhibitor [124].

●There are two reports of successful hematopoietic cell transplantation in patients with CMCC and severe autoimmune disease [9,125].

Transplantation of thymus tissue [126-128] and human leukocyte antigen (HLA)-matched peripheral blood leukocyte infusions [129,130] were attempted therapies before effective oral antifungal drugs became available. Both showed limited and short-lived clinical improvement and are no longer used.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of syndromes with common features including chronic, noninvasive Candida infections of the skin, nails, and mucous membranes and associated autoimmune manifestations (most commonly endocrinopathies). (See 'Introduction' above.)

●Genetics – CMCC is caused by genetic defects in the immune system, including those affecting autoimmune regulator (AIRE), signal transducer and activator of transcription 1 (STAT1), the interleukin (IL) 17 pathway, lymphoid phosphatase (Lyp), beta-glucan receptor Dectin-1, and Toll-like receptor 3 (TLR3). However, the genetic defect has not been identified in all patients, and inheritance may involve multiple genes in some cases. (See 'Autoimmune regulator deficiency' above and 'IL-17 pathway immune deficiencies' above and 'Other genetic defects' above.)

●Diagnosis – The diagnosis of CMCC is primarily based upon clinical features including chronic, noninvasive candidiasis of the skin and mucous membranes associated with autoimmune manifestations and can be confirmed in most patients by genetic testing. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of CMCC includes primary and secondary immunodeficiencies that affect T cell function, including combined immunodeficiencies, such as CD25 deficiency, and severe combined immunodeficiency (SCID). Chronic candidiasis is also seen in patients treated with systemic or inhaled glucocorticoids or prolonged courses of antibiotics. (See 'Differential diagnosis' above.)

●Treatment – Management includes antifungal therapy and treatment of associated endocrine and autoimmune abnormalities. (See 'Treatment' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.