Chronic Mucocutaneous Candidiasis

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Chronic mucocutaneous candidiasis

Author: Chaim M Roifman, CM, MD, FRCPC, FCACB
Section Editor: Jordan S Orange, MD, PhD
Deputy Editor: Elizabeth TePas, MD, MS
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2019. | This topic last updated: Mar 26, 2019.
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 "Clinical manifestations of oropharyngeal and esophageal candidiasis".)
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].
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● 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-7A 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 deficiency' and
"Combined immunodeficiencies" 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 due to underlying disease states, environmental exposures,
and miscellaneous causes" 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, a combined immunodeficiency, 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
"Combined immunodeficiencies", section on 'Interleukin 2 receptor alpha chain (CD25) deficiency'.)
● 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", section on 'Dedicator of cytokinesis 8 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", section on 'IL-12 receptor beta1 deficiency' 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
"Treatment of oropharyngeal and esophageal candidiasis" 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 "Evaluation and treatment of hypomagnesemia" 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 primary immunodeficiency".)
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].
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● 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: Primary immunodeficiencies".)
SUMMARY
● 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.)
● 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.)
● 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.)
● 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.)

● Management includes antifungal therapy and treatment of associated endocrine and autoimmune
abnormalities. (See 'Treatment' above.)
ACKNOWLEDGMENT
The editorial staff at UpToDate would like to acknowledge E Richard Stiehm, MD, who contributed as a
Section Editor to an earlier version of this topic review.
Use of UpToDate is subject to the Subscription and License Agreement.
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Topic 13569 Version 26.0

GRAPHICS
Inborn errors of IL-17 immunity
Phagocytes recognize Candida albicans via pattern recognition receptors and produce proinflammatory cytokines, such as IL-6
and IL-23. These proinflammatory cytokines activate T cells via STAT3 and upregulate RORγT expression, leading to production
of IL-17A, IL-17F, and IL-22. Impairment in IL-23-induced STAT3-mediated signaling in AD HIES and AR IL-12Rβ1 and IL-12p40
deficiencies cause syndromic CMCC. Neutralizing autoantibodies against IL-17A, IL-17F, and IL-22 in patients with APECED
impair IL-17 signaling, underlying syndromic CMCC. Patients with AR RORγT deficiency show developmental defects of Th17
cells, resulting in syndromic CMCC. They also develop MSMD, probably caused by impairment of IFN-γ production associated
with mycobacterial infections. AD STAT1 gain-of-function was originally identified as a genetic etiology of CMCCD. However, it
can be categorized as syndromic CMCC based on its broad clinical manifestations. The majority of patients with GOF-STAT1
display a decreased frequency of IL-17-producing cells. Defects in four genes (encoding IL-17F, IL-17RA, IL-17RC, and ACT1)
that are directly involved in IL-17 signaling have been identified in patients with CMCCD.
APECED: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; IL: interleukin; CARD9: caspase recruitment domain-
containing protein 9; ACT1: activator 1; BCL10: B cell CLL/lymphoma 10; MALT: mucosa-associated lymphoid tissue; NF-kB: nuclear
factor kappa B; AP-1: activator protein 1; TGF-β: transforming growth factor beta; RORγT: retinoic acid-related orphan receptor gamma
T; STAT3: signal transducer and activator of transcription 3; STAT1: signal transducer and activator of transcription 1; TYK2: tyrosine
kinase 2; JAK2: Janus kinase 2; NK: natural killer; AD: autosomal dominant; HIES: hyperimmunoglobulin E syndrome; AR: autosomal
recessive; CMCC: chronic mucocutaneous candidiasis; Th17: T helper type 17; MSMD: Mendelian susceptibility to mycobacterial disease;
IFN-γ: interferon gamma; CMCCD: chronic mucocutaneous candidiasis disease; GOF: gain of function.
* Syndromic CMCC-related molecules and neutralizing antibodies (APECED).
¶ CMCCD-related molecules.
From: Okada S, Puel A, Casanova JL, Kobayashi M. Chronic mucocutaneous candidiasis disease associated with inborn errors of IL-17
immunity. Clin Transl Immunology 2016; 5(12):e114. https://onlinelibrary.wiley.com/doi/abs/10.1038/cti.2016.71. Copyright © 2016
Australasian Society for Immunology. Reproduced with permission of John Wiley & Sons Inc. This image has been provided by or is
owned by Wiley. Further permission is needed before it can be downloaded to PowerPoint, printed, shared or emailed. Please contact
Wiley's permissions department either via email: permissions@wiley.com or use the RightsLink service by clicking on the 'Request
Permission' link accompanying this article on Wiley Online Library (http://onlinelibrary.wiley.com).
Graphic 117876 Version 1.0

Oral candidiasis (thrush) in a patient with chronic

mucocutaneous candidiasis (CMCC)

Candidal onychomycosis in a patient with chronic

mucocutaneous candidiasis (CMCC)

Contributor Disclosures
Chaim M Roifman, CM, MD, FRCPC, FCACB Nothing to disclose Jordan S Orange, MD, PhD Consultant/Advisory
Boards: ADMA Biologics; Shire/CSL Behring; Grifols [Therapeutic immune globulin (IVIG, SCIG)]. Elizabeth TePas,
MD, MS Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
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10/23/2019 Chronic mucocutaneous candidiasis - UpToDate

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CLASSIC FORMS OF CMCC WITH ASSOCIATED AUTOIMMUNITY

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

● Autoimmune manifestations other than endocrinopathy, including autoimmune hemolytic anemia,

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

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Patients suffer chronic candidiasis as well as autoimmune polyendocrinopathy, most commonly

Pathogenesis of AIRE deficiency — Random rearrangement of antigen-specific receptor genes

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Clinical features of AIRE deficiency/APECED — AIRE deficiency/autoimmune polyendocrinopathy-

Other manifestations are less common [37,38]:

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● Antibody deficiency to polysaccharide antigens may occur.

Signal transducer and activator of transcription (STAT1) dysfunction — STAT1 is a critical

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IL-17 PATHWAY IMMUNE DEFICIENCIES

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OTHER GENETIC DEFECTS

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ROR-gamma t deficiency — Retinoic acid-binding receptor-related orphan receptor gamma (ROR-

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SOCIETY GUIDELINE LINKS

● Chronic mucocutaneous candidiasis (CMCC) is a heterogeneous group of syndromes with common

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Use of UpToDate is subject to the Subscription and License Agreement.

6. Herrod HG. Chronic mucocutaneous candidiasis in childhood and complications of non-Candida

https://www.uptodate.com/contents/chronic-mucocutaneous-candidiasis/print?search=chronic mucocutaneous candidiasis&source=search_res… 12/25

11. Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. Clinical variation of autoimmune

12. Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in

22. Karvonen M, Viik-Kajander M, Moltchanova E, et al. Incidence of childhood type 1 diabetes

29. Kluger N, Kataja J, Aho H, et al. Kidney involvement in autoimmune polyendocrinopathy-candidiasis-

37. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin

38. Capalbo D, Improda N, Esposito A, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal

https://www.uptodate.com/contents/chronic-mucocutaneous-candidiasis/print?search=chronic mucocutaneous candidiasis&source=search_res… 14/25

42. Merenmies L, Tarkkanen A. Chronic bilateral keratitis in autoimmune polyendocrinopathy-

43. Ward L, Paquette J, Seidman E, et al. Severe autoimmune polyendocrinopathy-candidiasis-

44. Ulinski T, Perrin L, Morris M, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal

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73. Wu J, Katrekar A, Honigberg LA, et al. Identification of substrates of human protein-tyrosine

74. Gjörloff-Wingren A, Saxena M, Williams S, et al. Characterization of TCR-induced receptor-proximal

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87. Jouault T, Ibata-Ombetta S, Takeuchi O, et al. Candida albicans phospholipomannan is sensed

93. Meager A, Visvalingam K, Peterson P, et al. Anti-interferon autoantibodies in autoimmune

96. Nahum A, Roifman CM, et al, 2010, personal communication.

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118. Kamai Y, Maebashi K, Kudoh M, et al. Characterization of mechanisms of fluconazole resistance in

121. Padeh S, Theodor R, Jonas A, Passwell JH. Severe malabsorption in autoimmune

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128. Ballow M, Hyman LR. Combination immunotherapy in chronic mucocutaneous candidiasis.

Topic 13569 Version 26.0

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Inborn errors of IL-17 immunity

Graphic 117876 Version 1.0

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Oral candidiasis (thrush) in a patient with chronic

Graphic 59947 Version 1.0

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