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Classifications

Harrison's Chapter

IUIS Category

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Inheritance

2

Autosomal dominant HP:0000006

Applies to STAT1 gain-of-function CMC (the commonest genetic cause, often de novo) and to dominant-negative IL17F deficiency.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:21727188 SUPPORT Human Clinical

"Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD."

Heterozygous germline STAT1 mutations segregating in 20 kindreds establish autosomal dominant inheritance for the commonest CMC etiology.

Autosomal recessive HP:0000007

Applies to IL17RA, IL17RC and ACT1/TRAF3IP2 deficiency, to CARD9 and RORC deficiency, and to AIRE-deficient APECED/APS-1.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:25918342 SUPPORT Human Clinical

"Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients."

Establishes autosomal recessive inheritance for the IL-17 receptor and adaptor deficiencies.

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Subtypes

11

STAT1 gain-of-function CMC (CANDF7 / IMD31C) MONDO:0013599

STAT1 hgnc:11362 Autosomal dominant inheritance

The commonest genetic cause of CMC. Heterozygous, usually coiled-coil-domain STAT1 substitutions that impair nuclear dephosphorylation of activated STAT1 and thereby increase STAT1-dependent responses; the resulting suppression of IL-17-producing T-cell development causes CMC. Unlike the direct IL-17-circuit defects, STAT1 GOF is not confined to Candida: it carries substantial bacterial, viral and mycobacterial infection risk, autoimmunity (especially hypothyroidism), cerebral aneurysm and carcinoma. It is the only CMC subtype with a mechanism-directed therapy (JAK inhibition).

Show evidence (1 reference)

PMID:21727188 SUPPORT Human Clinical

"Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity."

Establishes STAT1 gain-of-function as a cause of autosomal dominant CMC.

IL-17RA deficiency (CANDF5 / IMD51) MONDO:0013500

IL17RA hgnc:5985 Autosomal recessive inheritance

Autosomal recessive, complete IL-17 receptor A deficiency. IL-17RA is the shared chain of the receptors for IL-17A and IL-17F homodimers and IL-17A/F heterodimers, so its loss abolishes all three responses in fibroblasts and leukocytes. The phenotype is isolated CMC with, at most, milder cutaneous Staphylococcus aureus disease.

Show evidence (1 reference)

PMID:21350122 SUPPORT Human Clinical

"IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers."

Defines the molecular lesion in autosomal recessive IL-17RA deficiency.

IL-17RC deficiency (CANDF9) MONDO:0014642

IL17RC hgnc:18358 Autosomal recessive inheritance

Autosomal recessive IL-17RC deficiency from homozygous nonsense alleles that prevent cell-surface expression. Responses to IL-17A and IL-17F are abolished, but - unlike in IL-17RA and ACT1 deficiency - the response to IL-17E (IL-25) is preserved, which localizes the requirement precisely to IL-17A/F signalling. Presents as isolated CMC.

Show evidence (1 reference)

PMID:25918342 SUPPORT Human Clinical

"However, in contrast to what is observed for the IL-17RA- and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients."

Distinguishes IL-17RC deficiency from the other receptor/adaptor defects by the preserved IL-17E response.

IL-17F deficiency, dominant-negative (CANDF6) MONDO:0013503

IL17F hgnc:16404 Autosomal dominant inheritance

Autosomal dominant CMC from a hypomorphic, dominant-negative IL17F allele (S65L). Mutant IL-17F is produced and dimerizes normally but cannot bind IL-17RA, so both mutant homodimers and IL-17A/IL-17F heterodimers are inactive - the partial nature of the defect explains the incomplete clinical penetrance observed in the index kindred.

Show evidence (1 reference)

PMID:21350122 SUPPORT Human Clinical

"By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity."

Defines the partial, dominant-negative nature of the IL17F lesion.

ACT1/TRAF3IP2 deficiency (CANDF8) MONDO:0014230

TRAF3IP2 hgnc:1343 Autosomal recessive inheritance

Autosomal recessive deficiency of the adaptor ACT1 (TRAF3IP2), which is recruited to the IL-17 receptor chains via its SEFIR domain. The T536I substitution abolishes that homotypic interaction, so IL-17A and IL-17F fail to activate NF-kB/MAPK and induce IL-6 and CXCL1 in fibroblasts - the receptor is intact but the signal is not transduced. The common D10N ACT1 polymorphism, by contrast, is hypomorphic rather than null, which is why it does not cause CMC despite its population frequency.

Show evidence (1 reference)

PMID:24120361 SUPPORT Human Clinical

"This missense mutation, located in the SEFIR, impaired the homotypic interaction of ACT1 with the IL-17 receptors abolishing the response to IL-17A and IL-17F in fibroblasts and to IL-17E in leukocytes."

Defines the adaptor-level lesion in ACT1/TRAF3IP2 deficiency.

RORgamma/RORgammaT deficiency

RORC hgnc:10260 Autosomal recessive inheritance

Bi-allelic RORC loss of function removes the master transcription factor for IL-17A/F-producing lymphocytes, so IL-17A/F-producing T cells are absent and CMC results. Unlike the receptor and adaptor defects, RORC deficiency is not confined to Candida: the same patients have severe mycobacterial disease, unexpectedly through a separate defect in Mycobacterium-specific IFN-gamma production by gamma-delta and CCR6+CXCR3+ T cells. This subtype therefore sits at the boundary of CMC and MSMD. No subtype_term is bound: the matching MONDO class (MONDO:0014710, autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency) sits under MONDO:0020573 inherited disease susceptibility, which is outside the source_nodes of the DiseaseOrSubtypeTerm dynamic enum. It is used as the disease_term of the corresponding differential diagnosis below, where the DiseaseTerm enum does admit that branch.

Show evidence (1 reference)

PMID:26160376 SUPPORT Human Clinical

"The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis."

Establishes RORC deficiency as a transcription-factor-level cause of CMC via loss of IL-17A/F-producing T cells.

CARD9 deficiency (invasive and CNS fungal disease)

CARD9 hgnc:16391 Autosomal recessive inheritance

Autosomal recessive deficiency of CARD9, the cytosolic adaptor that transduces C-type lectin receptor (Dectin-1) signals in myeloid cells. CARD9-deficient patients do have low Th17 counts and CMC, but the defect is upstream of, and broader than, the IL-17 circuit itself: it also cripples myeloid antifungal effector function. This subtype is therefore NOT mucocutaneous-only - it uniquely and characteristically permits invasive and central nervous system fungal disease (including fatal Candida infection of the brain) and deep dermatophytosis. The distinction is clinically decisive: a CMC patient with CNS or deep-tissue fungal disease should be worked up for CARD9, and management cannot be limited to topical or intermittent mucosal antifungal therapy. No subtype_term is bound: the matching MONDO class (MONDO:0008905, predisposition to invasive fungal disease due to CARD9 deficiency) sits under MONDO:0020573 inherited disease susceptibility, outside the source_nodes of the DiseaseOrSubtypeTerm dynamic enum; it is used as the disease_term of the corresponding differential diagnosis below.

Show evidence (1 reference)

PMID:19864672 SUPPORT Human Clinical

"We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species."

Documents the defining CARD9 feature that separates it from the other CMC etiologies: fatal invasive cerebral candidiasis, not mucocutaneous disease alone.

APECED/APS-1 (AIRE) - acquired anti-IL-17 autoantibody phenocopy MONDO:0009411

AIRE hgnc:360 Autosomal recessive inheritance

In AIRE-deficient APECED/APS-1, CMC is typically the first manifestation, and it is caused not by a germline lesion in the IL-17 circuit but by high-titre neutralizing autoantibodies against IL-17A, IL-17F and IL-22 - an acquired phenocopy of the genetic IL-17 defects. The autoantibodies precede the CMC in all informative cases, and the same autoantibodies explain CMC in the rare thymoma patients who develop it. Only the CMC arm of APS-1 is modelled here; the loss of AIRE-dependent thymic tolerance and the hypoparathyroidism / adrenal insufficiency / broader autoimmune spectrum are curated in kb/disorders/Autoimmune_Polyendocrine_Syndrome_Type_1.yaml and are deliberately not duplicated.

Show evidence (1 reference)

PMID:20123958 SUPPORT Human Clinical

"These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I."

Establishes anti-IL-17-cytokine autoantibodies as the mechanism of CMC in APS-1, i.e. an acquired phenocopy of the genetic IL-17 defects.

Autosomal dominant hyper-IgE syndrome (STAT3 loss-of-function) MONDO:0007818

STAT3 hgnc:11364 Autosomal dominant inheritance

CMC is one component of AD-HIES (Job syndrome). Dominant-negative STAT3 variants prevent naive T cells differentiating into Th17 cells, so IL-17 production is absent - but the syndrome extends far beyond Candida to staphylococcal abscesses, pneumatoceles, eczema, elevated IgE and connective-tissue, skeletal and dental abnormalities. Curated in full at kb/disorders/Autosomal_Dominant_Hyper-IgE_Syndrome.yaml; listed here as a CMC-causing entity, not duplicated.

Show evidence (1 reference)

PMID:18337720 SUPPORT Human Clinical

"Here we show that interleukin (IL)-17 production by T cells is absent in HIES individuals."

Places AD-HIES on the same IL-17 axis, explaining the CMC component of the syndrome.

DOCK8 deficiency (combined immunodeficiency) MONDO:0009478

DOCK8 hgnc:19191 Autosomal recessive inheritance

Autosomal recessive DOCK8 deficiency is a combined immunodeficiency with reduced Th17 numbers, in which CMC occurs as one feature alongside severe cutaneous viral infection, atopy, eosinophilia and malignancy. Included for completeness of the CMC differential; it is a combined immunodeficiency rather than a selective IL-17-circuit disorder, so CMC here is a symptom of broad T-cell dysfunction.

Show evidence (2 references)

PMID:19776401 SUPPORT Human Clinical

"Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency."

The defining report establishing biallelic DOCK8 loss as a combined immunodeficiency, the syndrome within which CMC occurs as one component.

PMID:19776401 PARTIAL Human Clinical

"Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections."

Documents the broad, predominantly viral and staphylococcal infectious spectrum that distinguishes DOCK8 combined immunodeficiency from IL-17-circuit CMC. PARTIAL because the cited series characterises the syndrome rather than quantifying its Candida component.

Acquired/secondary chronic mucocutaneous candidiasis

Persistent mucocutaneous candidiasis arising from an acquired rather than inherited permissive state - most often HIV infection, systemic or inhaled corticosteroids and other immunosuppression, broad-spectrum antibiotic use, poorly controlled diabetes mellitus, or thymoma with anti-cytokine autoantibodies. These must be excluded before an inborn error is diagnosed. Included as a subtype because the same clinical phenotype and the same downstream complications (stricture, squamous carcinoma) follow, but the upstream lesion is not germline.

Show evidence (1 reference)

PMID:28815025 SUPPORT Human Clinical

"Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy)."

Enumerates the acquired permissive states that produce secondary CMC.

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Mechanistic Hypotheses

2

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

il17_axis_convergence CANONICAL

Evidence balance 3 support

The intellectual core of this entry. CMC is not merely explained by IL-17 deficiency; historically the inference ran the other way. Between 2010 and 2015, six mechanistically independent human lesions - neutralizing anti-IL-17A/IL-17F/IL-22 autoantibodies (APECED), IL-17RA deficiency, IL-17F dominant-negative deficiency, ACT1/TRAF3IP2 deficiency, IL-17RC deficiency and RORC deficiency - were each shown to produce the same narrow phenotype: mucocutaneous candidiasis, with little or no other infectious susceptibility. Because these lesions sit at different points on one circuit (cytokine, receptor, adaptor, transcription factor, autoantibody-mediated neutralization) yet converge on one clinical picture, they constitute a natural knock-out series establishing that human IL-17A/IL-17F immunity is both necessary for mucocutaneous defence against Candida albicans and largely redundant for defence against other pathogens. The authors of these papers describe them explicitly as experiments of nature. Causal edges belonging to this argument carry this hypothesis group.

Pathograph links

Suppression of Th17 Cell Development -> Deficient IL-17A, IL-17F and IL-22 Production DIRECT Fewer IL-17-producing T cells means less IL-17A, IL-17F and IL-22 reaching the barrier.

Loss of the Th17-Inducing Transcriptional Program -> Deficient IL-17A, IL-17F and IL-22 Production DIRECT Loss of the Th17 transcriptional program removes the cellular source of IL-17A, IL-17F and IL-22.

CARD9-Dependent Myeloid Antifungal Signalling Failure -> Deficient IL-17A, IL-17F and IL-22 Production INDIRECT KNOWN INTERMEDIATES The shared, mucocutaneous arm of CARD9 deficiency. Intermediates: Loss of CARD9-dependent myeloid IL-1beta, IL-6 and IL-23 output required to polarize and sustain Th17 cells

Neutralizing Anti-IL-17A, Anti-IL-17F and Anti-IL-22 Autoantibodies -> Loss of Epithelial IL-17 Receptor Signal Transduction DIRECT Neutralization removes the ligand at the receptor, bypassing the cytokine-production node entirely.

IL-17 Receptor and ACT1 Adaptor Deficiency -> Loss of Epithelial IL-17 Receptor Signal Transduction DIRECT Receptor-chain or adaptor loss directly abolishes IL-17 signal transduction in barrier cells.

Deficient IL-17A, IL-17F and IL-22 Production -> Loss of Epithelial IL-17 Receptor Signal Transduction DIRECT Insufficient ligand cannot engage an intact receptor.

Loss of Epithelial IL-17 Receptor Signal Transduction -> Failure of the Epithelial Antimicrobial and Neutrophil-Recruiting Response DIRECT IL-17 target genes encode the antimicrobial peptides and neutrophil chemoattractants that constitute the barrier's antifungal effector arm.

Failure of the Epithelial Antimicrobial and Neutrophil-Recruiting Response -> Persistent Mucocutaneous Candida albicans Infection DIRECT Failure of local antifungal effector function permits the commensal to persist and invade the superficial epithelium.

Show evidence (3 references)

PMID:21350122 SUPPORT Human Clinical

"These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant."

The founding statement of the inference: two independent inborn errors of IL-17 immunity establish IL-17A/F as essential and specific for mucocutaneous anti-Candida defence.

PMID:25918342 SUPPORT Human Clinical

"These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant."

A fourth, independent lesion on the same circuit reproduces the identical narrow phenotype, strengthening the convergence argument.

PMID:20123959 SUPPORT Human Clinical

"We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis."

The acquired autoantibody phenocopy independently implicates the same cytokines, showing the convergence is on the pathway and not on any one gene.

A gain of STAT1 function produces a loss of Th17 immunity (signalling cross-inhibition, not STAT1 haploinsufficiency)

stat1_gof_inversion CANONICAL STAT1 GOF

Evidence balance 2 support

STAT1 gain-of-function CMC is mechanistically counter-intuitive and is frequently mis-stated as a STAT1 deficiency. The alleles are genuinely hypermorphic: coiled-coil-domain substitutions impair nuclear dephosphorylation of activated STAT1, so STAT1-dependent transcription is increased. The loss of IL-17 immunity is a downstream consequence of that gain, by two convergent routes. First, IFN-alpha/beta, IFN-gamma and IL-27 are physiological inhibitors of IL-17-producing T-cell development and act through STAT1; amplifying their signal amplifies the brake. Second, IL-6 and IL-21 are physiological inducers of Th17 cells that act through STAT3 but also activate STAT1; shifting the STAT1/STAT3 balance toward STAT1 at the shared receptors diverts the inducing signal. The prediction that follows - that pharmacologically dialling the signal back down should restore IL-17 immunity - is borne out clinically by JAK inhibition, making this the rare inborn error where the mechanism directly names its own treatment.

Pathograph links

STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation -> Suppression of Th17 Cell Development DIRECT The amplified STAT1 signal is what suppresses IL-17-producing T-cell development; the loss of IL-17 immunity is downstream of the gain.

STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation -> Broad STAT1-Driven Immune Dysregulation DIRECT The same hyperresponsiveness that suppresses Th17 immunity drives the non-Candida arm of the STAT1 GOF phenotype.

Suppression of Th17 Cell Development -> Deficient IL-17A, IL-17F and IL-22 Production DIRECT Fewer IL-17-producing T cells means less IL-17A, IL-17F and IL-22 reaching the barrier.

Show evidence (2 references)

PMID:21727188 SUPPORT Human Clinical

"Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22."

States the inversion mechanism directly: enhanced STAT1 signalling both amplifies IL-17-inhibitory cytokines and diverts IL-17-inducing ones.

PMID:29934865 SUPPORT Human Clinical

"Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo."

Therapeutic confirmation of the inversion model: reducing STAT1 phosphorylation raises Th17-related gene expression and resolves CMC.

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Discussions and Knowledge Gaps

2

Why do 18% of STAT1 gain-of-function patients have a normal circulating IL-17A-producing T-cell count despite manifesting CMC?

KNOWLEDGE GAP OPEN cmc_th17_count_not_diagnostic

Attached to

pathophysiology#Deficient IL-17A, IL-17F and IL-22 Production

The pathograph treats deficient IL-17A/F/IL-22 production as the convergence node for the STAT1, RORC, STAT3 and CARD9 routes, yet the largest STAT1 GOF cohort found low circulating IL-17A-producing T cells in only 82% of patients tested. Either the peripheral blood Th17 count is an insensitive proxy for tissue-level IL-17 availability at the barrier, or a subset of STAT1 GOF patients develop CMC through a mechanism that does not require quantitative Th17 depletion (for example impaired IL-17 functional output from a numerically normal compartment, or a direct effect of excessive interferon signalling on the epithelium). Resolving this matters clinically because a normal Th17 count is currently, and incorrectly, treated by some as evidence against the diagnosis.

Proposed experiments

Barrier-site IL-17 quantification stratified by blood Th17 count

exp_cmc_barrier_il17_vs_blood_th17

Quantify IL-17A, IL-17F and IL-22 protein and transcript at the oral mucosal barrier (rather than in blood) in STAT1 GOF patients stratified by circulating Th17 count, to test whether tissue IL-17 availability is uniformly low even when blood Th17 numbers are normal.

Per-cell Candida-specific IL-17 functional output

exp_cmc_per_cell_candida_il17_output

Compare Candida-specific IL-17 secretion per Th17 cell in STAT1 GOF patients with normal versus low Th17 numbers, to test whether a functional rather than numerical deficit explains the discordant subset.

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."

Documents the discordance between the mechanistic model and the peripheral biomarker.

By what mechanism does STAT1 gain-of-function cause cerebral aneurysm?

KNOWLEDGE GAP OPEN cmc_stat1_gof_aneurysm_mechanism

Attached to

pathophysiology#Broad STAT1-Driven Immune Dysregulation

Cerebral aneurysms occur in 6% of STAT1 GOF patients and are among the three strongest predictors of poor outcome, yet the causal edge from STAT1 hyperactivation to arterial wall failure is modelled as INDIRECT_UNKNOWN_INTERMEDIATES because no mechanism is established. Candidate explanations include chronic interferon-driven vasculitis, a direct effect of STAT1 signalling on vascular smooth muscle or endothelium, and secondary damage from recurrent infection. Distinguishing these determines whether JAK inhibition would be expected to modify aneurysm risk, which is currently unknown and clinically important given that patients may take JAK inhibitors for decades.

Proposed experiments

Cerebral vascular imaging stratified by JAK-inhibitor exposure

exp_cmc_stat1_aneurysm_imaging_by_jaki_exposure

Cross-sectional cerebral vascular imaging in a STAT1 GOF cohort stratified by cumulative JAK-inhibitor exposure, to test whether reducing STAT1 signalling modifies aneurysm prevalence.

Aneurysm wall histopathology and interferon signature

exp_cmc_stat1_aneurysm_wall_histopathology

Histopathological characterization of aneurysm wall tissue from STAT1 GOF patients for interferon-signature gene expression and inflammatory infiltrate, to distinguish interferon-driven vasculitis from a non-inflammatory vascular effect.

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis."

Establishes the association without offering a mechanism, which is the gap recorded here.

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Pathophysiology

14

Commensal Candida albicans Colonization of Barrier Surfaces

Candida albicans is a commensal of the oral cavity, gastrointestinal tract and genital mucosa in healthy people. CMC is therefore not an exposure problem: the organism is already present, and disease reflects failure of the host to hold a resident commensal in check at the barrier. This is why the phenotype is chronic and relapsing rather than episodic, and why eradication is rarely achievable.

mouth mucosa UBERON:0003729 esophagus mucosa UBERON:0002469 skin of body UBERON:0002097 nail UBERON:0001705

Downstream

Persistent Mucocutaneous Candida albicans Infection Colonization is necessary but not sufficient; disease requires the concurrent failure of IL-17-dependent barrier immunity.

Show evidence (1 reference)

PMID:21727188 SUPPORT Human Clinical

"Chronic mucocutaneous candidiasis (CMC) is characterized by persistent or recurrent disease of the nails, skin, oral, or genital mucosae caused by Candida albicans"

Defines the barrier sites at which the commensal becomes pathogenic.

STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation

The proximal molecular lesion of the commonest CMC subtype. Heterozygous STAT1 substitutions - predominantly in the coiled-coil domain - impair nuclear dephosphorylation of activated STAT1, so phosphorylated STAT1 persists and STAT1-dependent transcription is increased in response to IFN-alpha/beta, IFN-gamma and IL-27, and also in response to cytokines that normally act predominantly through STAT3, such as IL-6 and IL-21. The alleles are genuinely hypermorphic; this is a gain, not a loss, of STAT1 function, and it is the direct pharmacological target of JAK inhibition.

A gain of STAT1 function produces a loss of Th17 immunity (signalling cross-inhibition, not STAT1 haploinsufficiency)

STAT1 hgnc:11362

cell surface receptor signaling pathway via JAK-STAT GO:0007259 ↑ INCREASED cellular response to type I interferon GO:0071357 ↑ INCREASED type II interferon-mediated signaling pathway GO:0060333 ↑ INCREASED

Downstream

Suppression of Th17 Cell Development The amplified STAT1 signal is what suppresses IL-17-producing T-cell development; the loss of IL-17 immunity is downstream of the gain.

Broad STAT1-Driven Immune Dysregulation The same hyperresponsiveness that suppresses Th17 immunity drives the non-Candida arm of the STAT1 GOF phenotype.

Show evidence (2 references)

PMID:21727188 SUPPORT Human Clinical

"All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance."

Gives the molecular basis of the gain of function (failed nuclear dephosphorylation), confirming the alleles are hypermorphic rather than hypomorphic.

PMID:21727188 SUPPORT Human Clinical

"the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21."

Establishes that STAT1-dependent responses are increased, including at receptors whose output is normally STAT3-biased.

Suppression of Th17 Cell Development

The cellular consequence of STAT1 hyperactivation, and the step that makes the inversion intelligible. IFN-alpha/beta, IFN-gamma and IL-27 are physiological inhibitors of IL-17-producing T-cell development and act through STAT1, so amplifying STAT1 amplifies the brake. In parallel, IL-6 and IL-21 are physiological inducers of Th17 cells that act through STAT3 but also engage STAT1, so a STAT1-biased response at those shared receptors diverts the inducing signal. A gain of function in the interferon arm therefore produces a loss of function in the Th17 arm.

A gain of STAT1 function produces a loss of Th17 immunity (signalling cross-inhibition, not STAT1 haploinsufficiency) Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

CD4-positive, alpha-beta T cell CL:0000624 T-helper 17 cell CL:0000899

T-helper 17 cell differentiation GO:0072539 ↓ DECREASED

Downstream

Deficient IL-17A, IL-17F and IL-22 Production Fewer IL-17-producing T cells means less IL-17A, IL-17F and IL-22 reaching the barrier.

Show evidence (3 references)

PMID:21727188 SUPPORT Human Clinical

"Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22."

The primary statement of the inversion: increased STAT1 signalling suppresses IL-17-producing T-cell development by both routes.

PMID:21714643 SUPPORT Human Clinical

"Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection."

Independent contemporaneous discovery linking coiled-coil-domain STAT1 mutations to defective Th17 responses in autosomal dominant CMC.

PMID:27114460 SUPPORT Human Clinical

"Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."

Confirms in a 274-patient international cohort that the predicted Th17 deficit is present in most, though not all, STAT1 GOF patients.

Loss of the Th17-Inducing Transcriptional Program

An alternative route to the same deficit, entered by lesions in the transcriptional machinery that builds IL-17-producing lymphocytes rather than in the signals that restrain them. Bi-allelic RORC loss of function removes RORgamma/RORgammaT, the master transcription factor for IL-17A/F-producing lymphocytes, abolishing those cells entirely. Dominant-negative STAT3 (AD-HIES) prevents naive T cells polarizing to Th17 and lowers RORgammat expression. DOCK8 deficiency reduces Th17 numbers as part of a broader combined immunodeficiency.

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

T-helper 17 cell CL:0000899

RORC hgnc:10260 STAT3 hgnc:11364 DOCK8 hgnc:19191

T-helper 17 cell differentiation GO:0072539 ↓ DECREASED

Downstream

Deficient IL-17A, IL-17F and IL-22 Production Loss of the Th17 transcriptional program removes the cellular source of IL-17A, IL-17F and IL-22.

Show evidence (2 references)

PMID:26160376 SUPPORT Human Clinical

"The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis."

Transcription-factor-level loss of IL-17A/F-producing T cells causes the candidiasis phenotype.

PMID:18337720 SUPPORT Human Clinical

"Purified naive T cells were unable to differentiate into IL-17-producing (T(H)17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gammat, which is consistent with a crucial role for STAT3 signalling in the generation of T(H)17 cells."

STAT3 loss-of-function blocks Th17 polarization and lowers RORgammat, accounting for CMC in AD-HIES.

CARD9-Dependent Myeloid Antifungal Signalling Failure

CARD9 is the cytosolic adaptor that transduces C-type lectin receptor (Dectin-1) recognition of fungal cell-wall beta-glucan in myeloid cells. Its loss has two separable consequences and this dual role is what makes CARD9 deficiency clinically distinct within CMC. First, CARD9-dependent myeloid cytokine output is required to drive Th17 differentiation, so CARD9-deficient patients have low Th17 counts and develop CMC by the shared IL-17 route. Second - and unlike every other CMC etiology - CARD9 loss also cripples myeloid antifungal effector function itself, permitting fungal invasion beyond the barrier. The two arms are modelled as separate downstream edges precisely so that invasive/CNS disease is not flattened into the mucocutaneous phenotype.

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

monocyte CL:0000576 neutrophil CL:0000775

CARD9 hgnc:16391 CLEC7A hgnc:14558

pattern recognition receptor signaling pathway GO:0002221 ↓ DECREASED defense response to fungus GO:0050832 ↓ DECREASED

Downstream

Deficient IL-17A, IL-17F and IL-22 Production The shared, mucocutaneous arm of CARD9 deficiency.

Invasive and Central Nervous System Fungal Disease The CARD9-specific arm. Loss of myeloid effector function permits fungal invasion beyond the mucocutaneous barrier; this edge does NOT pass through the IL-17 node and is not shared with the other CMC etiologies.

Show evidence (2 references)

PMID:19864672 SUPPORT Human Clinical

"Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17)."

Links CARD9 loss to reduced Th17 cells, placing it on the shared IL-17 route to CMC.

PMID:19864672 SUPPORT Model Organism

"Functional studies based on genetic reconstitution of myeloid cells from Card9(-/-) mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1."

Murine reconstitution experiments identify the molecular lesion as impaired Dectin-1 signalling in myeloid cells.

Neutralizing Anti-IL-17A, Anti-IL-17F and Anti-IL-22 Autoantibodies

The acquired phenocopy. In AIRE-deficient APECED/APS-1, failure of thymic negative selection generates high-titre neutralizing autoantibodies against IL-17A, IL-17F and IL-22. Th17 cells and IL-17 receptors are structurally intact; the cytokines are simply removed from circulation before they can signal. The entry point into the shared pathway is therefore one step downstream of the genetic etiologies - at the receptor rather than at cytokine production. The autoantibodies precede CMC onset in all informative cases, establishing direction of causation, and the same autoantibodies explain CMC in rare thymoma patients. Only this arm of APS-1 is modelled here; AIRE-dependent tolerance failure and the endocrine autoimmunity are curated in the APS-1 entry.

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

medullary thymic epithelial cell CL:0002365

AIRE hgnc:360

Downstream

Loss of Epithelial IL-17 Receptor Signal Transduction Neutralization removes the ligand at the receptor, bypassing the cytokine-production node entirely.

Show evidence (3 references)

PMID:20123958 SUPPORT Human Clinical

"We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry."

Demonstrates the autoantibodies in every APS-1 patient tested, and their absence in healthy and other-autoimmune controls.

PMID:20123959 SUPPORT Human Clinical

"The autoantibodies preceded the CMC in all informative cases."

Temporal precedence establishes the autoantibodies as cause rather than consequence of the CMC.

PMID:20123959 SUPPORT Human Clinical

"Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."

Quantifies the autoantibody prevalence across a large APECED cohort and its concentration in patients with CMC.

IL-17 Receptor and ACT1 Adaptor Deficiency

The most direct lesions on the circuit, and the ones that carry the strongest inferential weight because they are the most selective. IL-17RA deficiency is complete and abolishes responses to IL-17A homodimers, IL-17F homodimers and IL-17A/F heterodimers. IL-17RC deficiency abolishes IL-17A/F responses while sparing IL-17E (IL-25), pinning the requirement on IL-17A/F specifically. ACT1/TRAF3IP2 deficiency leaves both receptor chains intact but destroys the SEFIR-mediated adaptor coupling, so the signal is received and not transduced. Each is described by its discoverers as an experiment of nature showing that the affected component is essential for mucocutaneous anti-Candida immunity and otherwise largely redundant.

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

keratinocyte CL:0000312 fibroblast CL:0000057

IL17RA hgnc:5985 IL17RC hgnc:18358 TRAF3IP2 hgnc:1343

interleukin-17-mediated signaling pathway GO:0097400 ↓ DECREASED

Downstream

Loss of Epithelial IL-17 Receptor Signal Transduction Receptor-chain or adaptor loss directly abolishes IL-17 signal transduction in barrier cells.

Show evidence (2 references)

PMID:21350122 SUPPORT Human Clinical

"IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers."

Complete receptor-level abolition of IL-17A/F responsiveness.

PMID:24120361 SUPPORT In Vitro

"IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity to C. albicans and S. aureus and the other IL-17 cytokines seem to be redundant in host defense."

Patient fibroblast studies place ACT1 as the obligatory adaptor for IL-17A/F-mediated mucocutaneous protection.

Deficient IL-17A, IL-17F and IL-22 Production

The first convergence point of the pathograph. Whether the upstream lesion is STAT1 hyperactivation, loss of the RORgammat/STAT3 transcriptional program, CARD9-dependent myeloid instruction, or a dominant-negative IL17F allele that makes the cytokine but renders it inert, the shared result is that too little bioactive IL-17A, IL-17F and IL-22 reaches the barrier. Circulating IL-17A-producing T cells are low in the great majority - but not all - of STAT1 GOF patients, which is why a normal Th17 count does not exclude the diagnosis.

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

T-helper 17 cell CL:0000899

IL17A hgnc:5981 IL17F hgnc:16404 IL22 hgnc:14900

T-helper 17 cell differentiation GO:0072539 ↓ DECREASED

Downstream

Loss of Epithelial IL-17 Receptor Signal Transduction Insufficient ligand cannot engage an intact receptor.

Show evidence (2 references)

PMID:27114460 SUPPORT Human Clinical

"Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."

Documents the deficit and its incomplete penetrance as a laboratory finding in the largest STAT1 GOF cohort.

PMID:21350122 SUPPORT Human Clinical

"By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity."

A cytokine-level lesion producing functionally deficient IL-17F reaches the same convergence point.

Loss of Epithelial IL-17 Receptor Signal Transduction

The narrowest point of the pathograph and the node at which every CMC etiology, genetic or acquired, ultimately converges. IL-17A and IL-17F engage an IL-17RA/IL-17RC heterodimeric receptor on keratinocytes, mucosal epithelial cells and fibroblasts; ACT1 is recruited through homotypic SEFIR-domain interaction and activates NF-kB, MAPK and C/EBP, inducing IL-6, CXCL1 (GRO-alpha), G-CSF, beta-defensins and S100 proteins. Loss of this transduction step - by ligand deficiency, ligand neutralization, receptor-chain loss or adaptor loss - is the immediate cause of the barrier failure.

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

keratinocyte CL:0000312 oral mucosa squamous cell CL:1001576

interleukin-17-mediated signaling pathway GO:0097400 ↓ DECREASED

Downstream

Failure of the Epithelial Antimicrobial and Neutrophil-Recruiting Response IL-17 target genes encode the antimicrobial peptides and neutrophil chemoattractants that constitute the barrier's antifungal effector arm.

Show evidence (2 references)

PMID:24120361 SUPPORT In Vitro

"ACT-1 is recruited to IL-17RA, IL-17RB and IL-17RC and activates the NF-κB, MAPK, and C/EBP pathways, leading to the induction of target genes in keratinocytes, epithelial cells and fibroblasts stimulated with IL-17 cytokines"

Describes the receptor-proximal transduction step and its target cell types.

PMID:25918342 SUPPORT Human Clinical

"The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers."

Confirms that receptor-chain loss abolishes cellular IL-17A/F responsiveness.

Failure of the Epithelial Antimicrobial and Neutrophil-Recruiting Response

Without IL-17 signalling, barrier epithelium fails to produce the antimicrobial peptides (beta-defensins, S100 proteins) and the chemokines (CXCL1/GRO-alpha, IL-6, G-CSF) that recruit and sustain neutrophils at the mucosal surface. The functional readout used to diagnose the defect is exactly this: patient fibroblasts and keratinocytes fail to induce IL-6 and GRO-alpha in response to IL-17A or IL-17F. The tissue consequence is that Candida hyphae are not cleared from the superficial epithelium.

Convergence of independent genetic lesions on the IL-17 axis is the inferential basis for IL-17 as the mucosal antifungal pathway

neutrophil CL:0000775 keratinocyte CL:0000312

antimicrobial humoral response GO:0019730 ↓ DECREASED neutrophil chemotaxis GO:0030593 ↓ DECREASED defense response to fungus GO:0050832 ↓ DECREASED

Downstream

Persistent Mucocutaneous Candida albicans Infection Failure of local antifungal effector function permits the commensal to persist and invade the superficial epithelium.

Recurrent aphthous stomatitis Aphthous ulceration is frequent in CMC but is not itself a Candida infection. It is placed downstream of the same barrier-defence failure on the grounds of co-occurrence and shared site, but no mechanism linking the IL-17 defect to aphthous ulceration is established.

Show evidence (1 reference)

PMID:21350122 SUPPORT In Vitro

"the patient's fibroblasts did not respond to any of the three IL-17 cytokines, in terms of IL-6 and growth-regulated oncogene-α (GRO-α) induction"

Directly demonstrates the failed epithelial/stromal effector response (IL-6 and CXCL1 induction) in an IL-17RA-deficient patient.

Persistent Mucocutaneous Candida albicans Infection

The defining clinical state: recurrent or persistent superficial Candida infection of the oral mucosa (the commonest and usually first site), oesophagus, nails, skin and genital mucosa, with no comparable susceptibility to other classes of pathogen. In STAT1 GOF the median age at onset is one year, and disease persists in nearly 40% of patients despite prolonged antifungal treatment - chronic suppression rather than cure is the realistic goal.

mouth mucosa UBERON:0003729 esophagus mucosa UBERON:0002469 nail UBERON:0001705

Downstream

Chronic mucocutaneous candidiasis

Chronic oral candidiasis

Esophageal candidiasis

Dysphagia Odynophagia and dysphagia from oesophageal Candida infection.

Onychomycosis

Recurrent cutaneous fungal infections Intertrigo, pustular lesions and scalp infection at the cutaneous barrier, the skin counterpart of the mucosal disease.

Recurrent vulvovaginal candidiasis

Chronic Candida-Associated Epithelial Injury and Squamous Dysplasia

Show evidence (2 references)

PMID:27114460 SUPPORT Human Clinical

"98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years)."

Establishes CMC as near-universal and early-onset in STAT1 GOF.

PMID:27114460 SUPPORT Human Clinical

"CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment."

Documents the chronicity and treatment refractoriness of the infection.

Chronic Candida-Associated Epithelial Injury and Squamous Dysplasia

The complication that overturned the historical view of CMC as a benign nuisance disease. Decades of unresolved Candida infection of the oral and oesophageal squamous epithelium produce chronic inflammation, hyperplasia and scarring, culminating in fibrotic oesophageal stricture and in squamous cell carcinoma of the mouth and oesophagus. In STAT1 GOF, cancers occurred in 6% of a 274-patient cohort and were among the strongest predictors of poor outcome; a single reported CMC kindred lost two members to oesophageal squamous cell cancer. This is the mechanistic rationale for endoscopic surveillance in long-standing disease.

esophagus mucosa UBERON:0002469 mouth mucosa UBERON:0003729

Downstream

Oral and esophageal squamous cell carcinoma

Esophageal stricture Fibrotic narrowing following repeated oesophageal ulceration and repair.

Show evidence (3 references)

PMID:28815025 SUPPORT Human Clinical

"long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC)"

States the causal link between chronic Candida infection and squamous carcinoma at these sites.

PMID:28815025 SUPPORT Human Clinical

"This case series describes six patients in three generations of the same family, two of whom developed and died of SCC."

Documents fatal squamous cell carcinoma in a STAT1 GOF CMC kindred.

PMID:21350122 SUPPORT Human Clinical

"CMCD was initially thought to be benign, until squamous cell carcinoma (9) and cerebral aneurysms (10) were reported."

Records the historical reappraisal of CMC prognosis prompted by these complications.

Invasive and Central Nervous System Fungal Disease

Deliberately modelled as a separate outcome node so that it is never conflated with the mucocutaneous phenotype. In the classical CMC etiologies (IL17RA, IL17RC, IL17F, ACT1, and the APECED autoantibody phenocopy) fungal disease stops at the barrier. Two etiologies breach it. CARD9 deficiency does so characteristically and by a distinct mechanism - failed myeloid antifungal effector function rather than failed IL-17 signalling - producing deep dermatophytosis and invasive, sometimes fatal, central nervous system candidiasis. STAT1 gain-of-function does so at lower frequency (invasive fungal infection in 10% of a 274-patient cohort), as one component of its broader immune dysregulation. Invasive infection of any kind was among the strongest predictors of poor outcome.

Downstream

Invasive fungal infection

Fungal meningitis Central nervous system candidiasis, characteristic of CARD9 deficiency.

Deep dermatophytosis

Show evidence (2 references)

PMID:19864672 SUPPORT Human Clinical

"3 members died during adolescence, 2 after invasive infection of the brain with candida species"

Documents fatal CNS candidiasis as the distinguishing CARD9 feature, absent from the IL-17-circuit etiologies.

PMID:27114460 SUPPORT Human Clinical

"Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%)"

Quantifies the lower-frequency invasive fungal risk specific to STAT1 gain-of-function.

Broad STAT1-Driven Immune Dysregulation

The non-Candida arm of STAT1 gain-of-function, kept as a separate node because it is subtype-specific and must not be attributed to CMC as a class. The same enhanced STAT1-dependent responsiveness that suppresses Th17 development also produces bacterial infection (74%, mostly Staphylococcus aureus), viral infection (38%, mostly Herpesviridae), mycobacterial disease, autoimmunity (37%, dominated by hypothyroidism at 22%), cerebral aneurysms (6%) and carcinoma (6%). Invasive infection, cerebral aneurysm and cancer were the strongest predictors of poor outcome in the largest cohort. Patients with pure CMC disease from IL-17-circuit lesions do not develop this spectrum.

STAT1 hgnc:11362

cell surface receptor signaling pathway via JAK-STAT GO:0007259 ↑ INCREASED

Downstream

Recurrent bacterial infections

Recurrent viral infections

Autoimmunity

Hypothyroidism

Dilatation of the cerebral artery Cerebral aneurysm formation is a recognized STAT1 GOF complication but the mechanism linking STAT1 hyperactivation to arterial wall failure is not established.

Show evidence (2 references)

PMID:27114460 SUPPORT Human Clinical

"Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."

Quantifies the autoimmune component of the STAT1 GOF phenotype.

PMID:27114460 SUPPORT Human Clinical

"Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome."

Identifies the prognosis-determining complications specific to STAT1 gain-of-function.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

18

Digestive 2

Dysphagia Dysphagia HP:0002015

Show evidence (1 reference)

PMID:28815025 SUPPORT Human Clinical

"These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC."

Documents dysphagia as a presenting symptom of oesophageal disease in CMC.

Esophageal stricture Esophageal stricture HP:0002043

Course: PROGRESSIVE

The cited abstract documents severe oesophageal candidiasis with obstructive swallowing symptoms but does not use the word "stricture"; the stricture attribution rests on the wider clinical literature, hence supports PARTIAL.

Show evidence (1 reference)

PMID:28815025 PARTIAL Human Clinical

"These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC."

Documents severe oesophageal candidiasis with obstructive swallowing symptoms in the CMC kindred; the specific stricture morphology is not stated in the abstract.

Endocrine 1

Hypothyroidism OCCASIONAL Hypothyroidism HP:0000821

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."

Direct quantitative support for the OCCASIONAL band (22%).

Immune 2

Fungal meningitis Fungal meningitis HP:0032159

Show evidence (1 reference)

PMID:19864672 SUPPORT Human Clinical

"3 members died during adolescence, 2 after invasive infection of the brain with candida species"

Documents fatal CNS candidiasis in the index CARD9-deficient kindred.

Autoimmunity FREQUENT Autoimmunity HP:0002960

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."

Direct quantitative support for the FREQUENT band (37%).

Integument 1

Oral and esophageal squamous cell carcinoma Squamous cell carcinoma HP:0002860

No frequency band is asserted. The only quantitative figure available in the cached sources is the 6% all-cancer rate in the Toubiana STAT1 GOF cohort; oral and oesophageal squamous cell carcinoma is a subset of that 6%, and the site-specific fraction is not reported in the abstract. Rather than promote an all-cancer number to a site-specific band that could sit either side of the OCCASIONAL 5% floor, frequency is omitted per the project frequency-evidence SOP.

Show evidence (2 references)

PMID:27114460 SUPPORT Human Clinical

"Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome."

Establishes malignancy as one of the three strongest predictors of poor outcome in STAT1 GOF CMC. The 6% figure is for all cancers, of which oral/oesophageal SCC is a subset, so it is not used to set a site-specific frequency band.

PMID:28815025 SUPPORT Human Clinical

"This case series describes six patients in three generations of the same family, two of whom developed and died of SCC."

Documents oral/oesophageal SCC mortality in a CMC kindred.

Other 12

Chronic mucocutaneous candidiasis OBLIGATE Chronic mucocutaneous candidiasis HP:0002728

Temporal: CHRONIC

Show evidence (1 reference)

PMID:21350122 SUPPORT Human Clinical

"Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans"

Defines the cardinal phenotype and its distribution.

Chronic oral candidiasis FREQUENT Chronic oral candidiasis HP:0009098

Temporal: CHRONIC

Show evidence (1 reference)

PMID:26604104 SUPPORT Human Clinical

"Oral candidiasis 19/26 73 %"

Cohort table row giving direct quantitative support for the FREQUENT band (73%, 19 of 26 patients).

Esophageal candidiasis FREQUENT

Temporal: RECURRENT

Deliberately left without an HPO binding. HPO has no term for oesophageal candidiasis: the available options are HP:0009098 (Chronic oral candidiasis, wrong site), HP:0005411 (Chronic intestinal candidiasis, wrong site) and HP:0002728 (Chronic mucocutaneous candidiasis, which is the disease-level term already used for this entry). Per the project convention of preferring no binding over a misleading one, the descriptor carries a preferred_term only. This is the same family of gap as issue #7328 (no course-neutral Oral candidiasis term) and is a candidate HPO new-term request. MONDO:0001648 (esophageal candidiasis) exists, so the gap is HPO-specific.

Show evidence (2 references)

PMID:26604104 SUPPORT Human Clinical

"Esophageal candidiasis 15/23 65 %"

Cohort table row giving direct quantitative support for the FREQUENT band (65%, 15 of 23 patients).

PMID:26604104 SUPPORT Human Clinical

"but relapses were frequent after treatment was stopped (87 %, 13/15)."

Documents the relapsing course of oesophageal disease once antifungal treatment is withdrawn.

Recurrent cutaneous fungal infections FREQUENT Recurrent cutaneous fungal infections HP:0011370

Temporal: CHRONIC

Show evidence (2 references)

PMID:26604104 SUPPORT Human Clinical

"Altogether, 50 % (13/26) of patients reported intertrigo, 46 % (12/26) pustules and 44 % (11/25) infections of the scalp"

Direct quantitative support for the FREQUENT band across the three commonest cutaneous presentations.

PMID:26604104 SUPPORT Human Clinical

"and 50 % (9/18) of affected patients reported chronic skin infections."

Supports the CHRONIC temporality qualifier: half of affected patients have chronic rather than episodic cutaneous disease.

Onychomycosis FREQUENT Onychomycosis HP:0012203

Temporal: CHRONIC

Show evidence (2 references)

PMID:26604104 SUPPORT Human Clinical

"Onychomycosis appeared in 64 % (16/25) and paronychia in 39 % (7/23) of patients."

Direct quantitative support for nail involvement and the FREQUENT band (64%).

PMID:21727188 SUPPORT Human Clinical

"Chronic mucocutaneous candidiasis (CMC) is characterized by persistent or recurrent disease of the nails, skin, oral, or genital mucosae caused by Candida albicans"

Nail involvement is part of the defining CMC site distribution.

Recurrent aphthous stomatitis FREQUENT Recurrent aphthous stomatitis HP:0011107

Temporal: RECURRENT

Show evidence (2 references)

PMID:26604104 SUPPORT Human Clinical

"Aphthous stomatitis 18/26 69 %"

Cohort table row giving direct quantitative support for the FREQUENT band (69%, 18 of 26 patients).

PMID:26604104 SUPPORT Human Clinical

"Aphthous stomatitis was frequent in CMC patients."

Confirms aphthous stomatitis as a common feature of the CMC phenotype.

Recurrent vulvovaginal candidiasis Recurrent vulvovaginal candidiasis HP:0012204

Temporal: RECURRENT

Show evidence (1 reference)

PMID:25918342 SUPPORT Human Clinical

"Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans."

Genital mucosal involvement is part of the defining site distribution.

Invasive fungal infection OCCASIONAL Invasive fungal infection HP:0020101

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%)"

Supports the OCCASIONAL band (10%) in STAT1 gain-of-function.

Deep dermatophytosis Deep dermatophytosis HP:0032515

Show evidence (2 references)

PMID:24131138 SUPPORT Human Clinical

"All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency."

Establishes deep dermatophytosis specifically (not superficial dermatophytosis) as a defining manifestation of CARD9 deficiency.

PMID:24131138 SUPPORT Human Clinical

"It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection"

Defines the depth of invasion, matching the HP:0032515 definition and distinguishing it from ordinary superficial dermatophytosis.

Recurrent bacterial infections FREQUENT Recurrent bacterial infections HP:0002718

Temporal: RECURRENT

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively"

Direct quantitative support for the FREQUENT band (74%).

Recurrent viral infections FREQUENT Recurrent viral infections HP:0004429

Temporal: RECURRENT

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients"

Direct quantitative support for the FREQUENT band (38%).

Dilatation of the cerebral artery OCCASIONAL Dilatation of the cerebral artery HP:0004944

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome."

Direct quantitative support for the OCCASIONAL band (6%) and the prognostic significance.

🧬

Genetic Associations

11

STAT1

Gene: STAT1 hgnc:11362 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:21727188 SUPPORT Human Clinical

"In total, 36 patients from 20 kindreds were heterozygous for 1 of the 12 missense mutations identified that affected the coiled-coil domain of STAT1."

Establishes coiled-coil-domain missense STAT1 variants as the genetic cause in 20 CMC kindreds.

IL17RA

Gene: IL17RA hgnc:5985 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:21350122 SUPPORT Human Clinical

"The child was found to be homozygous for the c.850C>T nonsense mutation (c.850C>T/c.850C>T), which replaces the glutamine codon in position 284 with a stop codon (Q284X/Q284X) in the IL17RA gene"

The index homozygous nonsense IL17RA allele causing autosomal recessive CMC.

IL17RC

Gene: IL17RC hgnc:18358 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:25918342 SUPPORT Human Clinical

"The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface."

Homozygous nonsense IL17RC alleles abolish surface receptor expression.

IL17F

Gene: IL17F hgnc:16404 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:21350122 SUPPORT Human Clinical

"This mutation, c.284C>T, replaced the serine residue in position 65 of the mature protein with a leucine residue (S65L)"

The dominant-negative IL17F S65L allele causing autosomal dominant CMC.

TRAF3IP2

Gene: TRAF3IP2 hgnc:1343 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:24120361 SUPPORT Human Clinical

"We identified a biallelic missense mutation (T536I) in the adaptor molecule ACT1 (TRAF3IP2)."

The biallelic ACT1 T536I allele causing autosomal recessive CMC.

CARD9

Gene: CARD9 hgnc:16391 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:19864672 SUPPORT Human Clinical

"All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X)."

The homozygous CARD9 Q295X null allele.

RORC

Gene: RORC hgnc:10260 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:26160376 SUPPORT Human Clinical

"We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis."

Bi-allelic RORC loss-of-function causes combined candidiasis and mycobacterial susceptibility.

AIRE

Gene: AIRE hgnc:360 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:20123958 SUPPORT Human Clinical

"Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC)."

Establishes CMC as a near-universal component of AIRE-deficient APS-1.

STAT3

Gene: STAT3 hgnc:11364 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:18337720 SUPPORT Human Clinical

"Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3)"

STAT3 loss-of-function underlies AD-HIES and its CMC component.

DOCK8

Gene: DOCK8 hgnc:19191 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:19776401 SUPPORT Human Clinical

"Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."

Establishes biallelic DOCK8 loss-of-function alleles as the genetic cause of the combined immunodeficiency within which CMC occurs.

CLEC7A

Gene: CLEC7A hgnc:14558 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:19864674 SUPPORT Human Clinical

"We describe a family in which four women who were affected by either recurrent vulvovaginal candidiasis or onychomycosis had the early-stop-codon mutation Tyr238X in the beta-glucan receptor dectin-1."

Establishes the CLEC7A Y238X allele as a cause of mucocutaneous Candida disease.

PMID:19864674 SUPPORT In Vitro

"In contrast, fungal phagocytosis and fungal killing were normal in the patients, explaining why dectin-1 deficiency was not associated with invasive fungal infections and highlighting the specific role of dectin-1 in human mucosal antifungal defense."

The key contrast with CARD9 deficiency: preserved myeloid killing means dectin-1 deficiency stops at the mucosa, supporting the entry's separation of the mucocutaneous and invasive arms.

💊

Medical Actions

4

Systemic azole antifungal therapy

Action: Antifungal Therapy NCIT:C15704

Agent: fluconazole NCIT:C500

Fluconazole is the mainstay for extensive oral, oesophageal, nail or recurrent disease, with topical agents for limited mucosal or cutaneous involvement. Treatment controls rather than cures: in a STAT1 GOF cohort azoles achieved complete response in 38% and partial remission in 62% of treated oral disease, 58% required continuing prophylaxis, and in the larger international cohort CMC persisted in 39% of patients on prolonged antifungal therapy. Chronic azole exposure selects resistant Candida, which is the principal long-term limitation.

Mechanism Target:

INHIBITS Persistent Mucocutaneous Candida albicans Infection — Suppresses the fungal burden without correcting the underlying immune defect, which is why relapse after withdrawal is the rule.

Show evidence (2 references)

PMID:26604104 SUPPORT Human Clinical

"Antifungal treatment with e.g., azoles led to a partial remission in 62 % (10/16) of patients, 38 % (6/16) had a complete response."

Quantifies azole response rates in STAT1 GOF CMC.

PMID:27114460 SUPPORT Human Clinical

"CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment."

Documents the limits of antifungal-only management.

JAK inhibition (ruxolitinib, baricitinib)

Action: Pharmacotherapy NCIT:C15986

Agent: ruxolitinib NCIT:C77888 baricitinib NCIT:C127012

The mechanism-directed therapy for STAT1 gain-of-function CMC and the clinical vindication of the inversion model: because the IL-17 deficit is a downstream consequence of excessive JAK-STAT1 signalling, pharmacologically reducing that signal should restore Th17 immunity - and it does. Ruxolitinib suppressed IFN-induced STAT1/3/5 phosphorylation and raised Th17-related gene expression ex vivo alongside major clinical improvement. In the largest series, JAK inhibitors produced partial or complete remission in 87% of 45 STAT1 GOF patients. Important caveats: this is off-label, adverse events (infection, weight gain) occurred in 38% of patients, the effect is not sustained after withdrawal so long-term administration is required, and it does not apply to the IL-17 receptor, adaptor, ligand or autoantibody etiologies.

Mechanism Target:

INHIBITS STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation — JAK1/2 inhibition acts at the molecular lesion itself, reducing phosphorylation of the hyperactive STAT1 and thereby relieving the downstream suppression of IL-17-producing T-cell development. This edge is the therapeutic expression of the stat1_gof_inversion hypothesis.

Show evidence (3 references)

PMID:29934865 SUPPORT Human Clinical

"JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation."

Establishes ruxolitinib as effective in refractory CMC and records the need for continuous therapy.

PMID:37935260 SUPPORT Human Clinical

"Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients."

Multicentre response rate for JAK inhibition in 45 STAT1 gain-of-function patients.

PMID:36050429 PARTIAL Human Clinical

"Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients."

Documents both benefit and the adverse-event burden in three adults; PARTIAL because two of three patients had treatment-limiting toxicity.

Haematopoietic stem cell transplantation

Action: Hematopoietic Cell Transplantation NCIT:C15431

Potentially curative for severe, refractory STAT1 gain-of-function disease, but with substantial risk that restricts it to life-threatening immune dysregulation after multidisciplinary assessment. In an international series of 15 transplanted patients, primary engraftment was 74% but overall survival only 40%, with 50% secondary graft failure. Outcomes appear better when JAK inhibition is used as a bridge to transplant.

Mechanism Target:

RESTORES STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation — Replaces the mutant haematopoietic compartment, so donor-derived lymphocytes carry wild-type STAT1 and Th17 development is restored.

Show evidence (2 references)

PMID:28601685 SUPPORT Human Clinical

"Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death."

Establishes both curative potential and the substantial transplant risk.

PMID:28601685 SUPPORT Human Clinical

"Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%."

Quantifies engraftment and survival outcomes.

Endoscopic dilatation of oesophageal stricture

Action: Esophageal Dilation NCIT:C70908

Mechanical relief of the fibrotic oesophageal narrowing that follows repeated candidal ulceration and repair, restoring swallowing in patients with obstructive dysphagia. It treats the structural consequence of the disease and does nothing to the underlying immune defect or the fungal burden, so it is palliative and often needs repeating. The surveillance endoscopy that detects early oesophageal neoplasia in the same patients is a diagnostic action and is modelled under diagnosis, not here.

Mechanism Target:

MODULATES Chronic Candida-Associated Epithelial Injury and Squamous Dysplasia — Relieves the fibrotic stricture produced by chronic epithelial injury without preventing the injury itself.

Show evidence (1 reference)

PMID:28815025 PARTIAL Human Clinical

"These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC."

Documents the severe obstructive oesophageal disease that creates the indication for dilatation; the abstract does not report dilatation outcomes, hence PARTIAL.

🔬

Biochemical Markers

3

Circulating IL-17A-producing T cell count (DECREASED)

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."

Quantifies both the sensitivity and the imperfection of the Th17 count as a CMC biomarker.

Neutralizing anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies (INCREASED)

Show evidence (2 references)

PMID:20123959 SUPPORT Human Clinical

"Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."

Quantifies autoantibody prevalence in APECED and its association with CMC.

PMID:21727188 SUPPORT Human Clinical

"None of the patients displays autoantibodies against IL-17A, IL-17F, and IL-22."

Confirms the autoantibodies are absent in STAT1 GOF CMC, making them a discriminating test between the genetic and acquired routes.

Interferon-induced STAT1 phosphorylation (INCREASED)

Show evidence (1 reference)

PMID:26604104 SUPPORT Human Clinical

"Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing."

Establishes phospho-STAT1 flow cytometry as a functional diagnostic adjunct.

🔀

Differential Diagnoses

8

Conditions with similar clinical presentations that must be differentiated from Chronic Mucocutaneous Candidiasis:

HIV infection / AIDS MONDO:0012268

Overlapping Features The commonest acquired cause of persistent oropharyngeal and oesophageal candidiasis, and the single most important diagnosis to exclude before invoking an inborn error. CD4 depletion removes the Th17 compartment among much else, so the mucosal phenotype can be indistinguishable at presentation.

Distinguishing Features

Positive HIV serology or nucleic acid testing with CD4 lymphopenia
Adult or adolescent onset rather than infancy, with no childhood history of thrush, nail or genital candidiasis
Accompanied by the wider spectrum of opportunistic infection (Pneumocystis, CMV, cryptococcosis) that pure IL-17-circuit CMC never produces
No family history; HIV testing is a mandatory part of the CMC work-up

Show evidence (1 reference)

PMID:28815025 SUPPORT Human Clinical

"Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy)."

Names HIV as the leading secondary cause of chronic candidiasis.

Severe combined immunodeficiency and other combined immunodeficiencies MONDO:0015974

Overlapping Features CMC is one of many infections in patients with broad and profound T-cell deficiency. Because thrush is often the first visible sign in infancy, SCID can be mistaken for isolated CMC at the earliest presentation.

Distinguishing Features

Failure to thrive, chronic diarrhoea and a broad infectious spectrum (Pneumocystis, disseminated viral infection, BCG disease) rather than Candida alone
Profound T-cell lymphopenia and abnormal lymphocyte subsets; abnormal newborn TREC screening
In CMC proper, T, B and NK cell numbers are normal, so quantifying them is the standard first-line discriminator

Show evidence (1 reference)

PMID:21727188 SUPPORT Human Clinical

"CMC is one of a multitude of infectious diseases observed in patients with broad and profound T cell deficiencies."

States the distinction between CMC as one of many infections in combined immunodeficiency versus CMC as an isolated phenotype.

Drug-associated oesophageal or oropharyngeal candidiasis Not Yet Curated MONDO:0001648

Overlapping Features Iatrogenic candidiasis from inhaled or systemic corticosteroids, broad-spectrum antibiotics, chemotherapy or other immunosuppression - by far the commonest explanation for oesophageal or oropharyngeal candidiasis in general practice, and a reversible one.

Distinguishing Features

Clear temporal relationship to the drug exposure, with resolution on withdrawal, dose reduction, or spacer and mouth-rinse technique correction
Absent childhood history of thrush, nail or genital candidiasis; no family history
Normal Th17 counts and no STAT1 phosphorylation abnormality

Show evidence (1 reference)

PMID:28815025 SUPPORT Human Clinical

"Oesophageal candidiasis is a common, usually self-limiting opportunistic infection, but long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC)."

Distinguishes ordinary self-limiting oesophageal candidiasis from the persistent form that defines CMC and carries carcinoma risk.

Autoimmune polyendocrine syndrome type 1 (APECED/APS-1) MONDO:0009411

Overlapping Features The most consequential overlap. CMC is typically the FIRST manifestation of APS-1, appearing years before the endocrine features, so an apparently isolated CMC in a child may be a pre-endocrine APS-1. This is a temporal trap, not merely a phenotypic one: withholding the diagnosis risks a fatal unrecognized adrenal crisis. APS-1 is simultaneously an APECED subtype of CMC (modelled in has_subtypes) and a differential diagnosis for apparently isolated CMC - both framings are correct and both are recorded here deliberately.

Distinguishing Features

Neutralizing anti-IL-17A/IL-17F/IL-22 autoantibodies are present in APS-1 and absent in STAT1 GOF CMC, making autoantibody testing the decisive discriminator
Hypoparathyroidism, primary adrenal insufficiency and ectodermal dystrophy
Biallelic AIRE variants
Because the autoantibodies precede the CMC, a negative endocrine screen at presentation does not exclude APS-1 and surveillance is required

Show evidence (2 references)

PMID:20123959 SUPPORT Human Clinical

"In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle."

Establishes CMC as frequently the presenting feature of APS-1, which is why apparently isolated CMC must trigger APS-1 consideration.

PMID:21727188 SUPPORT Human Clinical

"None of the patients displays autoantibodies against IL-17A, IL-17F, and IL-22."

Confirms the autoantibody test discriminates APS-1 CMC from STAT1 GOF CMC.

Autosomal dominant hyper-IgE syndrome (Job syndrome) MONDO:0007818

Overlapping Features Shares the IL-17 deficit and therefore the CMC, but is a multisystem syndrome rather than a selective antifungal defect.

Distinguishing Features

Markedly elevated serum IgE with eosinophilia
Recurrent cold staphylococcal skin abscesses and pneumonia with pneumatocele formation
Eczematoid dermatitis
Retained primary dentition, characteristic facies, scoliosis, minimal-trauma fracture and joint hyperextensibility
A dominant-negative STAT3 variant; none of these features accompany pure IL-17-circuit CMC

Show evidence (1 reference)

PMID:21727188 SUPPORT Human Clinical

"patients with the autosomal dominant (AD) hyper IgE syndrome, caused by dominant-negative mutations of STAT3, are susceptible principally to CMC and staphylococcal diseases of the lungs and skin"

Contrasts the AD-HIES infectious spectrum (CMC plus pulmonary and cutaneous staphylococcal disease) with isolated CMC.

CARD9 deficiency Not Yet Curated MONDO:0008905

Overlapping Features Listed as a differential as well as a subtype because the therapeutic consequences differ sharply. A patient labelled with mucocutaneous-only CMC who in fact has CARD9 deficiency is at risk of invasive and central nervous system fungal disease that intermittent mucosal antifungal therapy will not prevent.

Distinguishing Features

Deep dermatophytosis, subcutaneous phaeohyphomycosis, and invasive or central nervous system fungal infection, none of which occur in IL-17-circuit CMC
Consanguinity with autosomal recessive segregation
Biallelic CARD9 null variants; any deep or CNS fungal disease in a CMC patient should prompt CARD9 sequencing

Show evidence (1 reference)

PMID:19864672 SUPPORT Human Clinical

"3 members died during adolescence, 2 after invasive infection of the brain with candida species"

The CARD9-specific invasive/CNS phenotype that distinguishes it from mucocutaneous-only CMC.

RORC deficiency and Mendelian susceptibility to mycobacterial disease Not Yet Curated MONDO:0014710

Overlapping Features Sits at the CMC/MSMD boundary. Patients present with both candidiasis and mycobacterial disease, and the mycobacterial susceptibility arises through a mechanism (defective Mycobacterium-specific IFN-gamma production) that is separate from, not a consequence of, the IL-17 defect.

Distinguishing Features

Disseminated BCG or Mycobacterium tuberculosis disease alongside the candidiasis
Absent palpable axillary and cervical lymph nodes and small thymus
Absence of MAIT and type 1 NKT cells
Biallelic RORC loss-of-function; pure IL-17-circuit CMC carries no mycobacterial risk

Show evidence (1 reference)

PMID:26160376 SUPPORT Human Clinical

"We studied seven patients from three unrelated consanguineous families with this unusual combination of infectious diseases but with no known genetic disorder."

Establishes the dual candidiasis/mycobacterial phenotype that distinguishes RORC deficiency from isolated CMC.

Diabetes mellitus MONDO:0005015

Overlapping Features Poorly controlled diabetes is a common metabolic permissive state for recurrent oral, cutaneous and genital candidiasis, and is also part of the STAT1 GOF and APS-1 autoimmune spectra - so it can be either the explanation for the candidiasis or a clue to the underlying inborn error.

Distinguishing Features

Hyperglycaemia and raised HbA1c, with resolution of candidiasis on glycaemic control
Adult onset without childhood thrush, nail or oesophageal disease
Conversely, type 1 diabetes arising in a child who already has CMC should raise suspicion of STAT1 GOF (4% of the international cohort) or APS-1 rather than being accepted as the cause

Show evidence (1 reference)

PMID:27114460 SUPPORT Human Clinical

"Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."

Documents type 1 diabetes within the STAT1 GOF spectrum, so diabetes in a CMC patient may be consequence rather than cause.

🔬

Clinical Trials

2

NCT02629419 PHASE_II COMPLETED

Open-label dose-titration trial of oral encochleated amphotericin B (CAMB/MAT2203) in mucocutaneous candidiasis refractory or intolerant to standard non-intravenous therapy. Directly addresses the azole-resistance limitation that dominates long-term CMC management.

Target Phenotypes: Chronic mucocutaneous candidiasis HP:0002728

Show evidence (1 reference)

clinicaltrials:NCT02629419 SUPPORT Human Clinical

"This is an open-label, dose-titration trial to study the efficacy, safety, and pharmacokinetics of oral cochleate amphotericin B (CAMB) in the treatment of mucocutaneous candidiasis infections in patients who are refractory or intolerant to standard non intravenous therapies."

An interventional trial of an oral non-azole antifungal specifically in treatment-refractory mucocutaneous candidiasis.

NCT01386437 RECRUITING

NIH long-term natural-history and pathogenesis study of human fungal infections, enrolling patients with unusual, persistent or severe fungal infection and the immune defects that permit them, plus relatives and healthy volunteers. The principal natural-history resource for CMC and its genetic etiologies.

Target Phenotypes: Chronic mucocutaneous candidiasis HP:0002728

Show evidence (1 reference)

clinicaltrials:NCT01386437 SUPPORT Human Clinical

"Researchers want to collect blood and tissue samples from people who have unusual, persistent or severe fungal infections or immune problems that increase the risk of these infections."

Defines the enrolled population as patients with persistent or severe fungal infection driven by underlying immune defects, i.e. the CMC population and its genetic causes.

{ }

Source YAML

click to show

name: Chronic Mucocutaneous Candidiasis
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
synonyms:
- CMC
- CMCD
- Chronic mucocutaneous candidosis
- Familial candidiasis
- CANDF
- Familial chronic mucocutaneous candidiasis
description: >-
  Chronic mucocutaneous candidiasis (CMC) is persistent or recurrent infection
  of the skin, nails, and oral, oesophageal and genital mucosae by Candida
  species, principally Candida albicans, in patients who are otherwise not
  broadly susceptible to infection. It is not one gene's disease but a
  convergent phenotype: every established genetic etiology lies somewhere on a
  single circuit - the IL-17 axis. Lesions have been found in the cytokine
  itself (IL17F), its receptor chains (IL17RA, IL17RC), the receptor-proximal
  adaptor (ACT1/TRAF3IP2), the Th17 master transcription factor (RORC), the
  upstream signalling that licenses Th17 development (STAT1 gain-of-function,
  the commonest cause; STAT3 loss-of-function in hyper-IgE syndrome; DOCK8),
  myeloid beta-glucan sensing that instructs Th17 differentiation (the
  dectin-1 receptor CLEC7A and its adaptor CARD9),
  and - as an acquired phenocopy - neutralizing autoantibodies against IL-17A,
  IL-17F and IL-22 in APECED/APS-1. Because these independent lesions all
  produce the same narrow infectious phenotype and little else, CMC is the
  human experiment that established IL-17 immunity as the mucosal antifungal
  pathway. Two etiologies break the mucocutaneous-only rule and must be kept
  distinct: CARD9 deficiency, which additionally permits invasive and central
  nervous system fungal disease, and STAT1 gain-of-function, whose enhanced
  STAT1 signalling causes a much wider syndrome of bacterial and viral
  infection, autoimmunity, cerebral aneurysm and carcinoma. Long-standing oral
  and oesophageal candidiasis carries a real risk of oesophageal stricture and
  of squamous cell carcinoma of the mouth and oesophagus.
disease_term:
  preferred_term: chronic mucocutaneous candidiasis
  term:
    id: MONDO:0015279
    label: chronic mucocutaneous candidiasis
parents:
- Inborn error of immunity
- Primary immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:21350122
      reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans"
      explanation: >-
        CMC is defined by a selective inherited defect of antifungal immunity,
        placing it in Harrison's immune/rheumatologic Part.
  - classification_value: INFECTIOUS_DISEASES
    evidence:
    - reference: PMID:38502882
      reference_title: "Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Recent progress in the methods of genetic diagnosis of inborn errors of immunity has contributed to a better understanding of the pathogenesis of chronic mucocutaneous candidiasis (CMC) and potential therapeutic options."
      explanation: >-
        The clinical presentation and management of CMC is that of a chronic
        fungal infection, supporting a secondary infectious-disease placement.
  iuis_category:
    classification_value: innate immunity defect
    notes: >-
      IUIS 2022 phenotypic classification Table 6 (defects in intrinsic and
      innate immunity), which explicitly enumerates chronic mucocutaneous
      candidiasis alongside MSMD and HSE susceptibility. Note that the
      APECED/APS-1 route to CMC sits in IUIS Table 4 (immune dysregulation) on
      that disease entry, and thymoma-associated anti-IL-17 autoantibody CMC is
      a Table 10 phenocopy; this entry's single IUIS assignment describes the
      germline IL-17-circuit disorders that define CMC proper.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee."
      explanation: >-
        Identifies the nosology this assignment is made against. Marked PARTIAL
        because the cached abstract establishes the existence and authority of
        the IUIS 2022 classification but does not itself contain the
        table-level placement of CMC; the Table 6 assignment is taken from the
        classification tables in the full report and is recorded in the notes
        above rather than asserted from this snippet.
inheritance:
- name: Autosomal dominant
  description: >-
    Applies to STAT1 gain-of-function CMC (the commonest genetic cause, often
    de novo) and to dominant-negative IL17F deficiency.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD."
    explanation: >-
      Heterozygous germline STAT1 mutations segregating in 20 kindreds
      establish autosomal dominant inheritance for the commonest CMC etiology.
- name: Autosomal recessive
  description: >-
    Applies to IL17RA, IL17RC and ACT1/TRAF3IP2 deficiency, to CARD9 and RORC
    deficiency, and to AIRE-deficient APECED/APS-1.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25918342
    reference_title: "Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients."
    explanation: >-
      Establishes autosomal recessive inheritance for the IL-17 receptor and
      adaptor deficiencies.
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.0
  notes: >-
    Isolated CMC disease (CMCD) is cited as occurring in about 1 in 100,000.
    This is an order-of-magnitude estimate used in a population-genetic
    argument rather than a registry-derived rate; CMC spans several distinct
    monogenic disorders, so no reliable pooled incidence exists.
  evidence:
  - reference: PMID:24120361
    reference_title: "An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the high frequency of homozygotes would not be consistent with the rarity of CMCD (about 1/100,000)"
    explanation: >-
      Provides the commonly cited order-of-magnitude population frequency for
      isolated CMC disease.
mechanistic_hypotheses:
- hypothesis_group_id: il17_axis_convergence
  hypothesis_label: >-
    Convergence of independent genetic lesions on the IL-17 axis is the
    inferential basis for IL-17 as the mucosal antifungal pathway
  status: CANONICAL
  description: >-
    The intellectual core of this entry. CMC is not merely explained by IL-17
    deficiency; historically the inference ran the other way. Between 2010 and
    2015, six mechanistically independent human lesions - neutralizing
    anti-IL-17A/IL-17F/IL-22 autoantibodies (APECED), IL-17RA deficiency,
    IL-17F dominant-negative deficiency, ACT1/TRAF3IP2 deficiency, IL-17RC
    deficiency and RORC deficiency - were each shown to produce the same narrow
    phenotype: mucocutaneous candidiasis, with little or no other infectious
    susceptibility. Because these lesions sit at different points on one
    circuit (cytokine, receptor, adaptor, transcription factor,
    autoantibody-mediated neutralization) yet converge on one clinical picture,
    they constitute a natural knock-out series establishing that human
    IL-17A/IL-17F immunity is both necessary for mucocutaneous defence against
    Candida albicans and largely redundant for defence against other pathogens.
    The authors of these papers describe them explicitly as experiments of
    nature. Causal edges belonging to this argument carry this hypothesis
    group.
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant."
    explanation: >-
      The founding statement of the inference: two independent inborn errors of
      IL-17 immunity establish IL-17A/F as essential and specific for
      mucocutaneous anti-Candida defence.
  - reference: PMID:25918342
    reference_title: "Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant."
    explanation: >-
      A fourth, independent lesion on the same circuit reproduces the identical
      narrow phenotype, strengthening the convergence argument.
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis."
    explanation: >-
      The acquired autoantibody phenocopy independently implicates the same
      cytokines, showing the convergence is on the pathway and not on any one
      gene.
- hypothesis_group_id: stat1_gof_inversion
  hypothesis_label: >-
    A gain of STAT1 function produces a loss of Th17 immunity (signalling
    cross-inhibition, not STAT1 haploinsufficiency)
  status: CANONICAL
  description: >-
    STAT1 gain-of-function CMC is mechanistically counter-intuitive and is
    frequently mis-stated as a STAT1 deficiency. The alleles are genuinely
    hypermorphic: coiled-coil-domain substitutions impair nuclear
    dephosphorylation of activated STAT1, so STAT1-dependent transcription is
    increased. The loss of IL-17 immunity is a downstream consequence of that
    gain, by two convergent routes. First, IFN-alpha/beta, IFN-gamma and IL-27
    are physiological inhibitors of IL-17-producing T-cell development and act
    through STAT1; amplifying their signal amplifies the brake. Second, IL-6
    and IL-21 are physiological inducers of Th17 cells that act through STAT3
    but also activate STAT1; shifting the STAT1/STAT3 balance toward STAT1 at
    the shared receptors diverts the inducing signal. The prediction that
    follows - that pharmacologically dialling the signal back down should
    restore IL-17 immunity - is borne out clinically by JAK inhibition, making
    this the rare inborn error where the mechanism directly names its own
    treatment.
  applies_to_subtypes:
  - STAT1 GOF
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22."
    explanation: >-
      States the inversion mechanism directly: enhanced STAT1 signalling both
      amplifies IL-17-inhibitory cytokines and diverts IL-17-inducing ones.
  - reference: PMID:29934865
    reference_title: "Utility of Ruxolitinib in a Child with Chronic Mucocutaneous Candidiasis Caused by a Novel STAT1 Gain-of-Function Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Major clinical improvement was achieved after 8 weeks of ruxolitinib treatment, while sustained suppression of IFNγ- and IFNα-induced phosphorylation of STAT1, STAT3, and STAT5, as well as increased STAT3-inducible and Th17-related gene expression, was demonstrated ex vivo."
    explanation: >-
      Therapeutic confirmation of the inversion model: reducing STAT1
      phosphorylation raises Th17-related gene expression and resolves CMC.
has_subtypes:
- name: STAT1 GOF
  display_name: STAT1 gain-of-function CMC (CANDF7 / IMD31C)
  subtype_term:
    preferred_term: immunodeficiency 31C, chronic mucocutaneous candidiasis, autosomal dominant
    term:
      id: MONDO:0013599
      label: autoimmune enteropathy and endocrinopathy - susceptibility to chronic infections syndrome
  description: >-
    The commonest genetic cause of CMC. Heterozygous, usually
    coiled-coil-domain STAT1 substitutions that impair nuclear
    dephosphorylation of activated STAT1 and thereby increase STAT1-dependent
    responses; the resulting suppression of IL-17-producing T-cell development
    causes CMC. Unlike the direct IL-17-circuit defects, STAT1 GOF is not
    confined to Candida: it carries substantial bacterial, viral and
    mycobacterial infection risk, autoimmunity (especially hypothyroidism),
    cerebral aneurysm and carcinoma. It is the only CMC subtype with a
    mechanism-directed therapy (JAK inhibition).
  genes:
  - preferred_term: STAT1
    term:
      id: hgnc:11362
      label: STAT1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity."
    explanation: Establishes STAT1 gain-of-function as a cause of autosomal dominant CMC.
- name: IL17RA deficiency
  display_name: IL-17RA deficiency (CANDF5 / IMD51)
  subtype_term:
    preferred_term: candidiasis, familial, 5
    term:
      id: MONDO:0013500
      label: immunodeficiency 51
  description: >-
    Autosomal recessive, complete IL-17 receptor A deficiency. IL-17RA is the
    shared chain of the receptors for IL-17A and IL-17F homodimers and
    IL-17A/F heterodimers, so its loss abolishes all three responses in
    fibroblasts and leukocytes. The phenotype is isolated CMC with, at most,
    milder cutaneous Staphylococcus aureus disease.
  genes:
  - preferred_term: IL17RA
    term:
      id: hgnc:5985
      label: IL17RA
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers."
    explanation: Defines the molecular lesion in autosomal recessive IL-17RA deficiency.
- name: IL17RC deficiency
  display_name: IL-17RC deficiency (CANDF9)
  subtype_term:
    preferred_term: candidiasis, familial, 9
    term:
      id: MONDO:0014642
      label: candidiasis, familial, 9
  description: >-
    Autosomal recessive IL-17RC deficiency from homozygous nonsense alleles
    that prevent cell-surface expression. Responses to IL-17A and IL-17F are
    abolished, but - unlike in IL-17RA and ACT1 deficiency - the response to
    IL-17E (IL-25) is preserved, which localizes the requirement precisely to
    IL-17A/F signalling. Presents as isolated CMC.
  genes:
  - preferred_term: IL17RC
    term:
      id: hgnc:18358
      label: IL17RC
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25918342
    reference_title: "Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, in contrast to what is observed for the IL-17RA- and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC-deficient patients."
    explanation: >-
      Distinguishes IL-17RC deficiency from the other receptor/adaptor defects
      by the preserved IL-17E response.
- name: IL17F deficiency
  display_name: IL-17F deficiency, dominant-negative (CANDF6)
  subtype_term:
    preferred_term: candidiasis, familial, 6
    term:
      id: MONDO:0013503
      label: candidiasis, familial, 6
  description: >-
    Autosomal dominant CMC from a hypomorphic, dominant-negative IL17F allele
    (S65L). Mutant IL-17F is produced and dimerizes normally but cannot bind
    IL-17RA, so both mutant homodimers and IL-17A/IL-17F heterodimers are
    inactive - the partial nature of the defect explains the incomplete
    clinical penetrance observed in the index kindred.
  genes:
  - preferred_term: IL17F
    term:
      id: hgnc:16404
      label: IL17F
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity."
    explanation: Defines the partial, dominant-negative nature of the IL17F lesion.
- name: ACT1 deficiency
  display_name: ACT1/TRAF3IP2 deficiency (CANDF8)
  subtype_term:
    preferred_term: candidiasis, familial, 8
    term:
      id: MONDO:0014230
      label: candidiasis, familial, 8
  description: >-
    Autosomal recessive deficiency of the adaptor ACT1 (TRAF3IP2), which is
    recruited to the IL-17 receptor chains via its SEFIR domain. The T536I
    substitution abolishes that homotypic interaction, so IL-17A and IL-17F
    fail to activate NF-kB/MAPK and induce IL-6 and CXCL1 in fibroblasts - the
    receptor is intact but the signal is not transduced. The common D10N ACT1
    polymorphism, by contrast, is hypomorphic rather than null, which is why it
    does not cause CMC despite its population frequency.
  genes:
  - preferred_term: TRAF3IP2
    term:
      id: hgnc:1343
      label: TRAF3IP2
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:24120361
    reference_title: "An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This missense mutation, located in the SEFIR, impaired the homotypic interaction of ACT1 with the IL-17 receptors abolishing the response to IL-17A and IL-17F in fibroblasts and to IL-17E in leukocytes."
    explanation: Defines the adaptor-level lesion in ACT1/TRAF3IP2 deficiency.
- name: RORC deficiency
  display_name: RORgamma/RORgammaT deficiency
  description: >-
    Bi-allelic RORC loss of function removes the master transcription factor
    for IL-17A/F-producing lymphocytes, so IL-17A/F-producing T cells are
    absent and CMC results. Unlike the receptor and adaptor defects, RORC
    deficiency is not confined to Candida: the same patients have severe
    mycobacterial disease, unexpectedly through a separate defect in
    Mycobacterium-specific IFN-gamma production by gamma-delta and CCR6+CXCR3+
    T cells. This subtype therefore sits at the boundary of CMC and MSMD.
    No subtype_term is bound: the matching MONDO class (MONDO:0014710,
    autosomal recessive Mendelian susceptibility to mycobacterial diseases due
    to complete RORgamma receptor deficiency) sits under MONDO:0020573
    inherited disease susceptibility, which is outside the source_nodes of the
    DiseaseOrSubtypeTerm dynamic enum. It is used as the disease_term of the
    corresponding differential diagnosis below, where the DiseaseTerm enum does
    admit that branch.
  genes:
  - preferred_term: RORC
    term:
      id: hgnc:10260
      label: RORC
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:26160376
    reference_title: "IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis."
    explanation: >-
      Establishes RORC deficiency as a transcription-factor-level cause of CMC
      via loss of IL-17A/F-producing T cells.
- name: CARD9 deficiency
  display_name: CARD9 deficiency (invasive and CNS fungal disease)
  description: >-
    Autosomal recessive deficiency of CARD9, the cytosolic adaptor that
    transduces C-type lectin receptor (Dectin-1) signals in myeloid cells.
    CARD9-deficient patients do have low Th17 counts and CMC, but the defect
    is upstream of, and broader than, the IL-17 circuit itself: it also
    cripples myeloid antifungal effector function. This subtype is therefore
    NOT mucocutaneous-only - it uniquely and characteristically permits
    invasive and central nervous system fungal disease (including fatal
    Candida infection of the brain) and deep dermatophytosis. The distinction
    is clinically decisive: a CMC patient with CNS or deep-tissue fungal
    disease should be worked up for CARD9, and management cannot be limited to
    topical or intermittent mucosal antifungal therapy. No subtype_term is
    bound: the matching MONDO class (MONDO:0008905, predisposition to invasive
    fungal disease due to CARD9 deficiency) sits under MONDO:0020573 inherited
    disease susceptibility, outside the source_nodes of the
    DiseaseOrSubtypeTerm dynamic enum; it is used as the disease_term of the
    corresponding differential diagnosis below.
  genes:
  - preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:19864672
    reference_title: "A homozygous CARD9 mutation in a family with susceptibility to fungal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species."
    explanation: >-
      Documents the defining CARD9 feature that separates it from the other CMC
      etiologies: fatal invasive cerebral candidiasis, not mucocutaneous
      disease alone.
- name: APECED
  display_name: APECED/APS-1 (AIRE) - acquired anti-IL-17 autoantibody phenocopy
  subtype_term:
    preferred_term: autoimmune polyendocrine syndrome type 1
    term:
      id: MONDO:0009411
      label: autoimmune polyendocrine syndrome type 1
  description: >-
    In AIRE-deficient APECED/APS-1, CMC is typically the first manifestation,
    and it is caused not by a germline lesion in the IL-17 circuit but by
    high-titre neutralizing autoantibodies against IL-17A, IL-17F and IL-22 -
    an acquired phenocopy of the genetic IL-17 defects. The autoantibodies
    precede the CMC in all informative cases, and the same autoantibodies
    explain CMC in the rare thymoma patients who develop it. Only the CMC arm
    of APS-1 is modelled here; the loss of AIRE-dependent thymic tolerance and
    the hypoparathyroidism / adrenal insufficiency / broader autoimmune
    spectrum are curated in
    kb/disorders/Autoimmune_Polyendocrine_Syndrome_Type_1.yaml and are
    deliberately not duplicated.
  genes:
  - preferred_term: AIRE
    term:
      id: hgnc:360
      label: AIRE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20123958
    reference_title: "Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I."
    explanation: >-
      Establishes anti-IL-17-cytokine autoantibodies as the mechanism of CMC in
      APS-1, i.e. an acquired phenocopy of the genetic IL-17 defects.
- name: AD-HIES
  display_name: Autosomal dominant hyper-IgE syndrome (STAT3 loss-of-function)
  subtype_term:
    preferred_term: hyper-IgE recurrent infection syndrome 1, autosomal dominant
    term:
      id: MONDO:0007818
      label: hyper-IgE recurrent infection syndrome 1, autosomal dominant
  description: >-
    CMC is one component of AD-HIES (Job syndrome). Dominant-negative STAT3
    variants prevent naive T cells differentiating into Th17 cells, so IL-17
    production is absent - but the syndrome extends far beyond Candida to
    staphylococcal abscesses, pneumatoceles, eczema, elevated IgE and
    connective-tissue, skeletal and dental abnormalities. Curated in full at
    kb/disorders/Autosomal_Dominant_Hyper-IgE_Syndrome.yaml; listed here as a
    CMC-causing entity, not duplicated.
  genes:
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:18337720
    reference_title: "Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that interleukin (IL)-17 production by T cells is absent in HIES individuals."
    explanation: >-
      Places AD-HIES on the same IL-17 axis, explaining the CMC component of
      the syndrome.
- name: DOCK8 deficiency
  display_name: DOCK8 deficiency (combined immunodeficiency)
  subtype_term:
    preferred_term: combined immunodeficiency due to DOCK8 deficiency
    term:
      id: MONDO:0009478
      label: combined immunodeficiency due to DOCK8 deficiency
  description: >-
    Autosomal recessive DOCK8 deficiency is a combined immunodeficiency with
    reduced Th17 numbers, in which CMC occurs as one feature alongside severe
    cutaneous viral infection, atopy, eosinophilia and malignancy. Included for
    completeness of the CMC differential; it is a combined immunodeficiency
    rather than a selective IL-17-circuit disorder, so CMC here is a symptom of
    broad T-cell dysfunction.
  genes:
  - preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency."
    explanation: >-
      The defining report establishing biallelic DOCK8 loss as a combined
      immunodeficiency, the syndrome within which CMC occurs as one component.
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections."
    explanation: >-
      Documents the broad, predominantly viral and staphylococcal infectious
      spectrum that distinguishes DOCK8 combined immunodeficiency from
      IL-17-circuit CMC. PARTIAL because the cited series characterises the
      syndrome rather than quantifying its Candida component.
- name: Secondary CMC
  display_name: Acquired/secondary chronic mucocutaneous candidiasis
  description: >-
    Persistent mucocutaneous candidiasis arising from an acquired rather than
    inherited permissive state - most often HIV infection, systemic or inhaled
    corticosteroids and other immunosuppression, broad-spectrum antibiotic use,
    poorly controlled diabetes mellitus, or thymoma with anti-cytokine
    autoantibodies. These must be excluded before an inborn error is diagnosed.
    Included as a subtype because the same clinical phenotype and the same
    downstream complications (stricture, squamous carcinoma) follow, but the
    upstream lesion is not germline.
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy)."
    explanation: Enumerates the acquired permissive states that produce secondary CMC.
pathophysiology:
- name: Commensal Candida albicans Colonization of Barrier Surfaces
  biological_scale: TISSUE
  role: trigger
  description: >-
    Candida albicans is a commensal of the oral cavity, gastrointestinal tract
    and genital mucosa in healthy people. CMC is therefore not an exposure
    problem: the organism is already present, and disease reflects failure of
    the host to hold a resident commensal in check at the barrier. This is why
    the phenotype is chronic and relapsing rather than episodic, and why
    eradication is rarely achievable.
  locations:
  - preferred_term: mouth mucosa
    term:
      id: UBERON:0003729
      label: mouth mucosa
  - preferred_term: esophagus mucosa
    term:
      id: UBERON:0002469
      label: esophagus mucosa
  - preferred_term: skin of body
    term:
      id: UBERON:0002097
      label: skin of body
  - preferred_term: nail
    term:
      id: UBERON:0001705
      label: nail
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic mucocutaneous candidiasis (CMC) is characterized by persistent or recurrent disease of the nails, skin, oral, or genital mucosae caused by Candida albicans"
    explanation: Defines the barrier sites at which the commensal becomes pathogenic.
  downstream:
  - target: Persistent Mucocutaneous Candida albicans Infection
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Concurrent failure of IL-17-dependent barrier immunity, without which
      colonization remains asymptomatic
    description: >-
      Colonization is necessary but not sufficient; disease requires the
      concurrent failure of IL-17-dependent barrier immunity.
- name: STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The proximal molecular lesion of the commonest CMC subtype. Heterozygous
    STAT1 substitutions - predominantly in the coiled-coil domain - impair
    nuclear dephosphorylation of activated STAT1, so phosphorylated STAT1
    persists and STAT1-dependent transcription is increased in response to
    IFN-alpha/beta, IFN-gamma and IL-27, and also in response to cytokines
    that normally act predominantly through STAT3, such as IL-6 and IL-21.
    The alleles are genuinely hypermorphic; this is a gain, not a loss, of
    STAT1 function, and it is the direct pharmacological target of JAK
    inhibition.
  genes:
  - preferred_term: STAT1
    term:
      id: hgnc:11362
      label: STAT1
  biological_processes:
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  - preferred_term: cellular response to type I interferon
    term:
      id: GO:0071357
      label: cellular response to type I interferon
    modifier: INCREASED
  - preferred_term: type II interferon-mediated signaling pathway
    term:
      id: GO:0060333
      label: type II interferon-mediated signaling pathway
    modifier: INCREASED
  subtypes:
  - STAT1 GOF
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance."
    explanation: >-
      Gives the molecular basis of the gain of function (failed nuclear
      dephosphorylation), confirming the alleles are hypermorphic rather than
      hypomorphic.
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21."
    explanation: >-
      Establishes that STAT1-dependent responses are increased, including at
      receptors whose output is normally STAT3-biased.
  downstream:
  - target: Suppression of Th17 Cell Development
    causal_link_type: DIRECT
    hypothesis_groups:
    - stat1_gof_inversion
    description: >-
      The amplified STAT1 signal is what suppresses IL-17-producing T-cell
      development; the loss of IL-17 immunity is downstream of the gain.
  - target: Broad STAT1-Driven Immune Dysregulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - stat1_gof_inversion
    description: >-
      The same hyperresponsiveness that suppresses Th17 immunity drives the
      non-Candida arm of the STAT1 GOF phenotype.
- name: Suppression of Th17 Cell Development
  biological_scale: CELLULAR
  role: mediator
  description: >-
    The cellular consequence of STAT1 hyperactivation, and the step that makes
    the inversion intelligible. IFN-alpha/beta, IFN-gamma and IL-27 are
    physiological inhibitors of IL-17-producing T-cell development and act
    through STAT1, so amplifying STAT1 amplifies the brake. In parallel, IL-6
    and IL-21 are physiological inducers of Th17 cells that act through STAT3
    but also engage STAT1, so a STAT1-biased response at those shared
    receptors diverts the inducing signal. A gain of function in the
    interferon arm therefore produces a loss of function in the Th17 arm.
  cell_types:
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: DECREASED
  subtypes:
  - STAT1 GOF
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22."
    explanation: >-
      The primary statement of the inversion: increased STAT1 signalling
      suppresses IL-17-producing T-cell development by both routes.
  - reference: PMID:21714643
    reference_title: "STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection."
    explanation: >-
      Independent contemporaneous discovery linking coiled-coil-domain STAT1
      mutations to defective Th17 responses in autosomal dominant CMC.
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."
    explanation: >-
      Confirms in a 274-patient international cohort that the predicted Th17
      deficit is present in most, though not all, STAT1 GOF patients.
  downstream:
  - target: Deficient IL-17A, IL-17F and IL-22 Production
    causal_link_type: DIRECT
    hypothesis_groups:
    - il17_axis_convergence
    - stat1_gof_inversion
    description: >-
      Fewer IL-17-producing T cells means less IL-17A, IL-17F and IL-22
      reaching the barrier.
- name: Loss of the Th17-Inducing Transcriptional Program
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    An alternative route to the same deficit, entered by lesions in the
    transcriptional machinery that builds IL-17-producing lymphocytes rather
    than in the signals that restrain them. Bi-allelic RORC loss of function
    removes RORgamma/RORgammaT, the master transcription factor for
    IL-17A/F-producing lymphocytes, abolishing those cells entirely.
    Dominant-negative STAT3 (AD-HIES) prevents naive T cells polarizing to
    Th17 and lowers RORgammat expression. DOCK8 deficiency reduces Th17
    numbers as part of a broader combined immunodeficiency.
  genes:
  - preferred_term: RORC
    term:
      id: hgnc:10260
      label: RORC
  - preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  - preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: DECREASED
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  subtypes:
  - RORC deficiency
  - AD-HIES
  - DOCK8 deficiency
  evidence:
  - reference: PMID:26160376
    reference_title: "IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis."
    explanation: >-
      Transcription-factor-level loss of IL-17A/F-producing T cells causes the
      candidiasis phenotype.
  - reference: PMID:18337720
    reference_title: "Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Purified naive T cells were unable to differentiate into IL-17-producing (T(H)17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gammat, which is consistent with a crucial role for STAT3 signalling in the generation of T(H)17 cells."
    explanation: >-
      STAT3 loss-of-function blocks Th17 polarization and lowers RORgammat,
      accounting for CMC in AD-HIES.
  downstream:
  - target: Deficient IL-17A, IL-17F and IL-22 Production
    causal_link_type: DIRECT
    hypothesis_groups:
    - il17_axis_convergence
    description: >-
      Loss of the Th17 transcriptional program removes the cellular source of
      IL-17A, IL-17F and IL-22.
- name: CARD9-Dependent Myeloid Antifungal Signalling Failure
  biological_scale: CELLULAR
  role: trigger
  description: >-
    CARD9 is the cytosolic adaptor that transduces C-type lectin receptor
    (Dectin-1) recognition of fungal cell-wall beta-glucan in myeloid cells.
    Its loss has two separable consequences and this dual role is what makes
    CARD9 deficiency clinically distinct within CMC. First, CARD9-dependent
    myeloid cytokine output is required to drive Th17 differentiation, so
    CARD9-deficient patients have low Th17 counts and develop CMC by the
    shared IL-17 route. Second - and unlike every other CMC etiology - CARD9
    loss also cripples myeloid antifungal effector function itself, permitting
    fungal invasion beyond the barrier. The two arms are modelled as separate
    downstream edges precisely so that invasive/CNS disease is not flattened
    into the mucocutaneous phenotype.
  genes:
  - preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  - preferred_term: CLEC7A
    term:
      id: hgnc:14558
      label: CLEC7A
  biological_processes:
  - preferred_term: pattern recognition receptor signaling pathway
    term:
      id: GO:0002221
      label: pattern recognition receptor signaling pathway
    modifier: DECREASED
  - preferred_term: defense response to fungus
    term:
      id: GO:0050832
      label: defense response to fungus
    modifier: DECREASED
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  subtypes:
  - CARD9 deficiency
  evidence:
  - reference: PMID:19864672
    reference_title: "A homozygous CARD9 mutation in a family with susceptibility to fungal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17)."
    explanation: >-
      Links CARD9 loss to reduced Th17 cells, placing it on the shared IL-17
      route to CMC.
  - reference: PMID:19864672
    reference_title: "A homozygous CARD9 mutation in a family with susceptibility to fungal infections."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Functional studies based on genetic reconstitution of myeloid cells from Card9(-/-) mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1."
    explanation: >-
      Murine reconstitution experiments identify the molecular lesion as
      impaired Dectin-1 signalling in myeloid cells.
  downstream:
  - target: Deficient IL-17A, IL-17F and IL-22 Production
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - il17_axis_convergence
    intermediate_mechanisms:
    - Loss of CARD9-dependent myeloid IL-1beta, IL-6 and IL-23 output required
      to polarize and sustain Th17 cells
    description: The shared, mucocutaneous arm of CARD9 deficiency.
  - target: Invasive and Central Nervous System Fungal Disease
    causal_link_type: DIRECT
    description: >-
      The CARD9-specific arm. Loss of myeloid effector function permits fungal
      invasion beyond the mucocutaneous barrier; this edge does NOT pass
      through the IL-17 node and is not shared with the other CMC etiologies.
- name: Neutralizing Anti-IL-17A, Anti-IL-17F and Anti-IL-22 Autoantibodies
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The acquired phenocopy. In AIRE-deficient APECED/APS-1, failure of thymic
    negative selection generates high-titre neutralizing autoantibodies against
    IL-17A, IL-17F and IL-22. Th17 cells and IL-17 receptors are structurally
    intact; the cytokines are simply removed from circulation before they can
    signal. The entry point into the shared pathway is therefore one step
    downstream of the genetic etiologies - at the receptor rather than at
    cytokine production. The autoantibodies precede CMC onset in all
    informative cases, establishing direction of causation, and the same
    autoantibodies explain CMC in rare thymoma patients. Only this arm of
    APS-1 is modelled here; AIRE-dependent tolerance failure and the endocrine
    autoimmunity are curated in the APS-1 entry.
  genes:
  - preferred_term: AIRE
    term:
      id: hgnc:360
      label: AIRE
  cell_types:
  - preferred_term: medullary thymic epithelial cell
    term:
      id: CL:0002365
      label: medullary thymic epithelial cell
  subtypes:
  - APECED
  evidence:
  - reference: PMID:20123958
    reference_title: "Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry."
    explanation: >-
      Demonstrates the autoantibodies in every APS-1 patient tested, and their
      absence in healthy and other-autoimmune controls.
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autoantibodies preceded the CMC in all informative cases."
    explanation: >-
      Temporal precedence establishes the autoantibodies as cause rather than
      consequence of the CMC.
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."
    explanation: >-
      Quantifies the autoantibody prevalence across a large APECED cohort and
      its concentration in patients with CMC.
  downstream:
  - target: Loss of Epithelial IL-17 Receptor Signal Transduction
    causal_link_type: DIRECT
    hypothesis_groups:
    - il17_axis_convergence
    description: >-
      Neutralization removes the ligand at the receptor, bypassing the
      cytokine-production node entirely.
- name: IL-17 Receptor and ACT1 Adaptor Deficiency
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The most direct lesions on the circuit, and the ones that carry the
    strongest inferential weight because they are the most selective. IL-17RA
    deficiency is complete and abolishes responses to IL-17A homodimers,
    IL-17F homodimers and IL-17A/F heterodimers. IL-17RC deficiency abolishes
    IL-17A/F responses while sparing IL-17E (IL-25), pinning the requirement
    on IL-17A/F specifically. ACT1/TRAF3IP2 deficiency leaves both receptor
    chains intact but destroys the SEFIR-mediated adaptor coupling, so the
    signal is received and not transduced. Each is described by its
    discoverers as an experiment of nature showing that the affected component
    is essential for mucocutaneous anti-Candida immunity and otherwise largely
    redundant.
  genes:
  - preferred_term: IL17RA
    term:
      id: hgnc:5985
      label: IL17RA
  - preferred_term: IL17RC
    term:
      id: hgnc:18358
      label: IL17RC
  - preferred_term: TRAF3IP2
    term:
      id: hgnc:1343
      label: TRAF3IP2
  biological_processes:
  - preferred_term: interleukin-17-mediated signaling pathway
    term:
      id: GO:0097400
      label: interleukin-17-mediated signaling pathway
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  subtypes:
  - IL17RA deficiency
  - IL17RC deficiency
  - ACT1 deficiency
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers."
    explanation: Complete receptor-level abolition of IL-17A/F responsiveness.
  - reference: PMID:24120361
    reference_title: "An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity to C. albicans and S. aureus and the other IL-17 cytokines seem to be redundant in host defense."
    explanation: >-
      Patient fibroblast studies place ACT1 as the obligatory adaptor for
      IL-17A/F-mediated mucocutaneous protection.
  downstream:
  - target: Loss of Epithelial IL-17 Receptor Signal Transduction
    causal_link_type: DIRECT
    hypothesis_groups:
    - il17_axis_convergence
    description: >-
      Receptor-chain or adaptor loss directly abolishes IL-17 signal
      transduction in barrier cells.
- name: Deficient IL-17A, IL-17F and IL-22 Production
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The first convergence point of the pathograph. Whether the upstream lesion
    is STAT1 hyperactivation, loss of the RORgammat/STAT3 transcriptional
    program, CARD9-dependent myeloid instruction, or a dominant-negative
    IL17F allele that makes the cytokine but renders it inert, the shared
    result is that too little bioactive IL-17A, IL-17F and IL-22 reaches the
    barrier. Circulating IL-17A-producing T cells are low in the great
    majority - but not all - of STAT1 GOF patients, which is why a normal Th17
    count does not exclude the diagnosis.
  genes:
  - preferred_term: IL17A
    term:
      id: hgnc:5981
      label: IL17A
  - preferred_term: IL17F
    term:
      id: hgnc:16404
      label: IL17F
  - preferred_term: IL22
    term:
      id: hgnc:14900
      label: IL22
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: DECREASED
  subtypes:
  - IL17F deficiency
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."
    explanation: >-
      Documents the deficit and its incomplete penetrance as a laboratory
      finding in the largest STAT1 GOF cohort.
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By contrast, IL-17F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished, activity."
    explanation: >-
      A cytokine-level lesion producing functionally deficient IL-17F reaches
      the same convergence point.
  downstream:
  - target: Loss of Epithelial IL-17 Receptor Signal Transduction
    causal_link_type: DIRECT
    hypothesis_groups:
    - il17_axis_convergence
    description: Insufficient ligand cannot engage an intact receptor.
- name: Loss of Epithelial IL-17 Receptor Signal Transduction
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    The narrowest point of the pathograph and the node at which every CMC
    etiology, genetic or acquired, ultimately converges. IL-17A and IL-17F
    engage an IL-17RA/IL-17RC heterodimeric receptor on keratinocytes,
    mucosal epithelial cells and fibroblasts; ACT1 is recruited through
    homotypic SEFIR-domain interaction and activates NF-kB, MAPK and C/EBP,
    inducing IL-6, CXCL1 (GRO-alpha), G-CSF, beta-defensins and S100 proteins.
    Loss of this transduction step - by ligand deficiency, ligand
    neutralization, receptor-chain loss or adaptor loss - is the immediate
    cause of the barrier failure.
  biological_processes:
  - preferred_term: interleukin-17-mediated signaling pathway
    term:
      id: GO:0097400
      label: interleukin-17-mediated signaling pathway
    modifier: DECREASED
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  - preferred_term: oral mucosa squamous cell
    term:
      id: CL:1001576
      label: oral mucosa squamous cell
  evidence:
  - reference: PMID:24120361
    reference_title: "An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "ACT-1 is recruited to IL-17RA, IL-17RB and IL-17RC and activates the NF-κB, MAPK, and C/EBP pathways, leading to the induction of target genes in keratinocytes, epithelial cells and fibroblasts stimulated with IL-17 cytokines"
    explanation: >-
      Describes the receptor-proximal transduction step and its target cell
      types.
  - reference: PMID:25918342
    reference_title: "Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers."
    explanation: >-
      Confirms that receptor-chain loss abolishes cellular IL-17A/F
      responsiveness.
  downstream:
  - target: Failure of the Epithelial Antimicrobial and Neutrophil-Recruiting Response
    causal_link_type: DIRECT
    hypothesis_groups:
    - il17_axis_convergence
    description: >-
      IL-17 target genes encode the antimicrobial peptides and neutrophil
      chemoattractants that constitute the barrier's antifungal effector arm.
- name: Failure of the Epithelial Antimicrobial and Neutrophil-Recruiting Response
  biological_scale: TISSUE
  role: effector
  description: >-
    Without IL-17 signalling, barrier epithelium fails to produce the
    antimicrobial peptides (beta-defensins, S100 proteins) and the chemokines
    (CXCL1/GRO-alpha, IL-6, G-CSF) that recruit and sustain neutrophils at the
    mucosal surface. The functional readout used to diagnose the defect is
    exactly this: patient fibroblasts and keratinocytes fail to induce IL-6 and
    GRO-alpha in response to IL-17A or IL-17F. The tissue consequence is that
    Candida hyphae are not cleared from the superficial epithelium.
  biological_processes:
  - preferred_term: antimicrobial humoral response
    term:
      id: GO:0019730
      label: antimicrobial humoral response
    modifier: DECREASED
  - preferred_term: neutrophil chemotaxis
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
    modifier: DECREASED
  - preferred_term: defense response to fungus
    term:
      id: GO:0050832
      label: defense response to fungus
    modifier: DECREASED
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the patient's fibroblasts did not respond to any of the three IL-17 cytokines, in terms of IL-6 and growth-regulated oncogene-α (GRO-α) induction"
    explanation: >-
      Directly demonstrates the failed epithelial/stromal effector response
      (IL-6 and CXCL1 induction) in an IL-17RA-deficient patient.
  downstream:
  - target: Persistent Mucocutaneous Candida albicans Infection
    causal_link_type: DIRECT
    hypothesis_groups:
    - il17_axis_convergence
    description: >-
      Failure of local antifungal effector function permits the commensal to
      persist and invade the superficial epithelium.
  - target: Recurrent aphthous stomatitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Aphthous ulceration is frequent in CMC but is not itself a Candida
      infection. It is placed downstream of the same barrier-defence failure
      on the grounds of co-occurrence and shared site, but no mechanism
      linking the IL-17 defect to aphthous ulceration is established.
- name: Persistent Mucocutaneous Candida albicans Infection
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The defining clinical state: recurrent or persistent superficial Candida
    infection of the oral mucosa (the commonest and usually first site),
    oesophagus, nails, skin and genital mucosa, with no comparable
    susceptibility to other classes of pathogen. In STAT1 GOF the median age at
    onset is one year, and disease persists in nearly 40% of patients despite
    prolonged antifungal treatment - chronic suppression rather than cure is
    the realistic goal.
  locations:
  - preferred_term: mouth mucosa
    term:
      id: UBERON:0003729
      label: mouth mucosa
  - preferred_term: esophagus mucosa
    term:
      id: UBERON:0002469
      label: esophagus mucosa
  - preferred_term: nail
    term:
      id: UBERON:0001705
      label: nail
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years)."
    explanation: Establishes CMC as near-universal and early-onset in STAT1 GOF.
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment."
    explanation: Documents the chronicity and treatment refractoriness of the infection.
  downstream:
  - target: Chronic mucocutaneous candidiasis
    causal_link_type: DIRECT
  - target: Chronic oral candidiasis
    causal_link_type: DIRECT
  - target: Esophageal candidiasis
    causal_link_type: DIRECT
  - target: Dysphagia
    causal_link_type: DIRECT
    description: Odynophagia and dysphagia from oesophageal Candida infection.
  - target: Onychomycosis
    causal_link_type: DIRECT
  - target: Recurrent cutaneous fungal infections
    causal_link_type: DIRECT
    description: >-
      Intertrigo, pustular lesions and scalp infection at the cutaneous
      barrier, the skin counterpart of the mucosal disease.
  - target: Recurrent vulvovaginal candidiasis
    causal_link_type: DIRECT
  - target: Chronic Candida-Associated Epithelial Injury and Squamous Dysplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Decades of unresolved fungal colonization with chronic inflammation,
      epithelial hyperplasia and repeated repair
- name: Chronic Candida-Associated Epithelial Injury and Squamous Dysplasia
  biological_scale: TISSUE
  role: consequence
  description: >-
    The complication that overturned the historical view of CMC as a benign
    nuisance disease. Decades of unresolved Candida infection of the oral and
    oesophageal squamous epithelium produce chronic inflammation, hyperplasia
    and scarring, culminating in fibrotic oesophageal stricture and in
    squamous cell carcinoma of the mouth and oesophagus. In STAT1 GOF, cancers
    occurred in 6% of a 274-patient cohort and were among the strongest
    predictors of poor outcome; a single reported CMC kindred lost two members
    to oesophageal squamous cell cancer. This is the mechanistic rationale for
    endoscopic surveillance in long-standing disease.
  locations:
  - preferred_term: esophagus mucosa
    term:
      id: UBERON:0002469
      label: esophagus mucosa
  - preferred_term: mouth mucosa
    term:
      id: UBERON:0003729
      label: mouth mucosa
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC)"
    explanation: >-
      States the causal link between chronic Candida infection and squamous
      carcinoma at these sites.
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case series describes six patients in three generations of the same family, two of whom developed and died of SCC."
    explanation: Documents fatal squamous cell carcinoma in a STAT1 GOF CMC kindred.
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CMCD was initially thought to be benign, until squamous cell carcinoma (9) and cerebral aneurysms (10) were reported."
    explanation: >-
      Records the historical reappraisal of CMC prognosis prompted by these
      complications.
  downstream:
  - target: Oral and esophageal squamous cell carcinoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic inflammation-driven squamous dysplasia progressing to invasive
      carcinoma
  - target: Esophageal stricture
    causal_link_type: DIRECT
    description: Fibrotic narrowing following repeated oesophageal ulceration and repair.
- name: Invasive and Central Nervous System Fungal Disease
  biological_scale: ORGANISM
  role: outcome
  description: >-
    Deliberately modelled as a separate outcome node so that it is never
    conflated with the mucocutaneous phenotype. In the classical CMC
    etiologies (IL17RA, IL17RC, IL17F, ACT1, and the APECED autoantibody
    phenocopy) fungal disease stops at the barrier. Two etiologies breach it.
    CARD9 deficiency does so characteristically and by a distinct mechanism -
    failed myeloid antifungal effector function rather than failed IL-17
    signalling - producing deep dermatophytosis and invasive, sometimes fatal,
    central nervous system candidiasis. STAT1 gain-of-function does so at
    lower frequency (invasive fungal infection in 10% of a 274-patient
    cohort), as one component of its broader immune dysregulation. Invasive
    infection of any kind was among the strongest predictors of poor outcome.
  subtypes:
  - CARD9 deficiency
  - STAT1 GOF
  evidence:
  - reference: PMID:19864672
    reference_title: "A homozygous CARD9 mutation in a family with susceptibility to fungal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3 members died during adolescence, 2 after invasive infection of the brain with candida species"
    explanation: >-
      Documents fatal CNS candidiasis as the distinguishing CARD9 feature,
      absent from the IL-17-circuit etiologies.
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%)"
    explanation: >-
      Quantifies the lower-frequency invasive fungal risk specific to STAT1
      gain-of-function.
  downstream:
  - target: Invasive fungal infection
    causal_link_type: DIRECT
  - target: Fungal meningitis
    causal_link_type: DIRECT
    description: Central nervous system candidiasis, characteristic of CARD9 deficiency.
  - target: Deep dermatophytosis
    causal_link_type: DIRECT
- name: Broad STAT1-Driven Immune Dysregulation
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The non-Candida arm of STAT1 gain-of-function, kept as a separate node
    because it is subtype-specific and must not be attributed to CMC as a
    class. The same enhanced STAT1-dependent responsiveness that suppresses
    Th17 development also produces bacterial infection (74%, mostly
    Staphylococcus aureus), viral infection (38%, mostly Herpesviridae),
    mycobacterial disease, autoimmunity (37%, dominated by hypothyroidism at
    22%), cerebral aneurysms (6%) and carcinoma (6%). Invasive infection,
    cerebral aneurysm and cancer were the strongest predictors of poor outcome
    in the largest cohort. Patients with pure CMC disease from IL-17-circuit
    lesions do not develop this spectrum.
  genes:
  - preferred_term: STAT1
    term:
      id: hgnc:11362
      label: STAT1
  biological_processes:
  - preferred_term: cell surface receptor signaling pathway via JAK-STAT
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  subtypes:
  - STAT1 GOF
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."
    explanation: Quantifies the autoimmune component of the STAT1 GOF phenotype.
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome."
    explanation: >-
      Identifies the prognosis-determining complications specific to STAT1
      gain-of-function.
  downstream:
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
  - target: Recurrent viral infections
    causal_link_type: DIRECT
  - target: Autoimmunity
    causal_link_type: DIRECT
  - target: Hypothyroidism
    causal_link_type: DIRECT
  - target: Dilatation of the cerebral artery
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cerebral aneurysm formation is a recognized STAT1 GOF complication but
      the mechanism linking STAT1 hyperactivation to arterial wall failure is
      not established.
phenotypes:
- category: Infectious
  name: Chronic mucocutaneous candidiasis
  description: >-
    The cardinal, disease-defining phenotype: recurrent or persistent
    superficial Candida infection of skin, nails and mucous membranes.
  phenotype_term:
    preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
    temporality: CHRONIC
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans"
    explanation: Defines the cardinal phenotype and its distribution.
- category: Infectious
  name: Chronic oral candidiasis
  description: >-
    Oral thrush is the commonest and usually the first manifestation, observed
    in 73% (19 of 26) of a STAT1 GOF cohort and becoming chronic if untreated
    in 42% of those affected.
  phenotype_term:
    preferred_term: Chronic oral candidiasis
    term:
      id: HP:0009098
      label: Chronic oral candidiasis
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oral candidiasis 19/26 73 %"
    explanation: >-
      Cohort table row giving direct quantitative support for the FREQUENT band
      (73%, 19 of 26 patients).
- category: Infectious
  name: Esophageal candidiasis
  description: >-
    Oesophageal involvement was documented in 65% (15 of 23) of a STAT1 GOF
    cohort. It responds to treatment in most patients but relapses in 87%
    after treatment stops, and is the substrate for both stricture and
    squamous carcinoma.
  phenotype_term:
    preferred_term: Esophageal candidiasis
    temporality: RECURRENT
  frequency: FREQUENT
  notes: >-
    Deliberately left without an HPO binding. HPO has no term for oesophageal
    candidiasis: the available options are HP:0009098 (Chronic oral
    candidiasis, wrong site), HP:0005411 (Chronic intestinal candidiasis, wrong
    site) and HP:0002728 (Chronic mucocutaneous candidiasis, which is the
    disease-level term already used for this entry). Per the project convention
    of preferring no binding over a misleading one, the descriptor carries a
    preferred_term only. This is the same family of gap as issue #7328 (no
    course-neutral Oral candidiasis term) and is a candidate HPO new-term
    request. MONDO:0001648 (esophageal candidiasis) exists, so the gap is
    HPO-specific.
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Esophageal candidiasis 15/23 65 %"
    explanation: >-
      Cohort table row giving direct quantitative support for the FREQUENT band
      (65%, 15 of 23 patients).
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but relapses were frequent after treatment was stopped (87 %, 13/15)."
    explanation: >-
      Documents the relapsing course of oesophageal disease once antifungal
      treatment is withdrawn.
- category: Dermatologic
  name: Recurrent cutaneous fungal infections
  description: >-
    The cutaneous arm of "mucocutaneous" candidiasis, and as common as the
    mucosal disease. In a STAT1 GOF cohort intertrigo affected 50% (13 of 26),
    pustular skin lesions 46% (12 of 26) and scalp infection 44% (11 of 25);
    half of the affected patients had chronic rather than merely recurrent
    skin disease. Skin folds and the scalp are the characteristic sites,
    reflecting the same failure of IL-17-dependent epithelial antimicrobial
    peptide production and neutrophil recruitment that permits mucosal
    disease.
  phenotype_term:
    preferred_term: Recurrent cutaneous fungal infections
    term:
      id: HP:0011370
      label: Recurrent cutaneous fungal infections
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, 50 % (13/26) of patients reported intertrigo, 46 % (12/26) pustules and 44 % (11/25) infections of the scalp"
    explanation: >-
      Direct quantitative support for the FREQUENT band across the three
      commonest cutaneous presentations.
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and 50 % (9/18) of affected patients reported chronic skin infections."
    explanation: >-
      Supports the CHRONIC temporality qualifier: half of affected patients
      have chronic rather than episodic cutaneous disease.
- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Difficulty and pain on swallowing from oesophageal candidiasis, often with
    chest pain and heartburn; a red flag prompting urgent endoscopy in CMC
    because of the coexisting carcinoma risk.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC."
    explanation: Documents dysphagia as a presenting symptom of oesophageal disease in CMC.
- category: Dermatologic
  name: Onychomycosis
  description: >-
    Candida infection of the nails and nail beds, producing dystrophy and
    onycholysis; among the most treatment-refractory sites. Present in 64%
    (16 of 25) of a STAT1 GOF cohort, chronic in about three quarters of
    affected patients.
  phenotype_term:
    preferred_term: Onychomycosis
    term:
      id: HP:0012203
      label: Onychomycosis
    temporality: CHRONIC
  frequency: FREQUENT
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Onychomycosis appeared in 64 % (16/25) and paronychia in 39 % (7/23) of patients."
    explanation: >-
      Direct quantitative support for nail involvement and the FREQUENT band
      (64%).
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic mucocutaneous candidiasis (CMC) is characterized by persistent or recurrent disease of the nails, skin, oral, or genital mucosae caused by Candida albicans"
    explanation: Nail involvement is part of the defining CMC site distribution.
- category: Oral
  name: Recurrent aphthous stomatitis
  description: >-
    Painful recurrent oral ulceration, present in 69% (18 of 26) of a STAT1 GOF
    cohort - severe in 38% and moderate in 31% - and relapsing in 82% of those
    affected. Distinct from oral thrush and not itself a Candida infection:
    it is modelled as an indirect consequence of the same failure of
    IL-17-dependent oral mucosal defence and repair, but the mechanism linking
    the IL-17 defect to aphthous ulceration is not established, so the causal
    edge is INDIRECT_UNKNOWN_INTERMEDIATES.
  phenotype_term:
    preferred_term: Recurrent aphthous stomatitis
    term:
      id: HP:0011107
      label: Recurrent aphthous stomatitis
    temporality: RECURRENT
  frequency: FREQUENT
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aphthous stomatitis 18/26 69 %"
    explanation: >-
      Cohort table row giving direct quantitative support for the FREQUENT band
      (69%, 18 of 26 patients).
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aphthous stomatitis was frequent in CMC patients."
    explanation: Confirms aphthous stomatitis as a common feature of the CMC phenotype.
- category: Genitourinary
  name: Recurrent vulvovaginal candidiasis
  description: >-
    Recurrent genital mucosal candidiasis, part of the defining site
    distribution of CMC in post-pubertal female patients.
  phenotype_term:
    preferred_term: Recurrent vulvovaginal candidiasis
    term:
      id: HP:0012204
      label: Recurrent vulvovaginal candidiasis
    temporality: RECURRENT
  evidence:
  - reference: PMID:25918342
    reference_title: "Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans."
    explanation: Genital mucosal involvement is part of the defining site distribution.
- category: Neoplastic
  name: Oral and esophageal squamous cell carcinoma
  description: >-
    Squamous cell carcinoma of the mouth and oesophagus complicating
    long-standing CMC. Cancers occurred in 6% of a 274-patient STAT1 GOF cohort
    and were among the strongest predictors of poor outcome; two members of one
    reported CMC kindred died of oesophageal SCC. This risk is the reason
    endoscopic surveillance is recommended.
  phenotype_term:
    preferred_term: Squamous cell carcinoma of the oesophagus and oral cavity
    term:
      id: HP:0002860
      label: Squamous cell carcinoma
  notes: >-
    No frequency band is asserted. The only quantitative figure available in
    the cached sources is the 6% all-cancer rate in the Toubiana STAT1 GOF
    cohort; oral and oesophageal squamous cell carcinoma is a subset of that
    6%, and the site-specific fraction is not reported in the abstract. Rather
    than promote an all-cancer number to a site-specific band that could sit
    either side of the OCCASIONAL 5% floor, frequency is omitted per the
    project frequency-evidence SOP.
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome."
    explanation: >-
      Establishes malignancy as one of the three strongest predictors of poor
      outcome in STAT1 GOF CMC. The 6% figure is for all cancers, of which
      oral/oesophageal SCC is a subset, so it is not used to set a
      site-specific frequency band.
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case series describes six patients in three generations of the same family, two of whom developed and died of SCC."
    explanation: Documents oral/oesophageal SCC mortality in a CMC kindred.
- category: Gastrointestinal
  name: Esophageal stricture
  description: >-
    Fibrotic oesophageal narrowing following repeated candidal ulceration and
    repair, presenting with progressive dysphagia and requiring endoscopic
    dilatation.
  phenotype_term:
    preferred_term: Esophageal stricture
    term:
      id: HP:0002043
      label: Esophageal stricture
    clinical_course: PROGRESSIVE
  notes: >-
    The cited abstract documents severe oesophageal candidiasis with
    obstructive swallowing symptoms but does not use the word "stricture"; the
    stricture attribution rests on the wider clinical literature, hence
    supports PARTIAL.
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC."
    explanation: >-
      Documents severe oesophageal candidiasis with obstructive swallowing
      symptoms in the CMC kindred; the specific stricture morphology is not
      stated in the abstract.
- category: Infectious
  name: Invasive fungal infection
  description: >-
    Fungal disease breaching the mucocutaneous barrier. Characteristic and
    defining in CARD9 deficiency; present at 10% in a 274-patient STAT1 GOF
    cohort; essentially absent in the pure IL-17 receptor, adaptor, ligand and
    autoantibody etiologies.
  phenotype_term:
    preferred_term: Invasive fungal infection
    term:
      id: HP:0020101
      label: Invasive fungal infection
  frequency: OCCASIONAL
  subtypes:
  - CARD9 deficiency
  - STAT1 GOF
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%)"
    explanation: Supports the OCCASIONAL band (10%) in STAT1 gain-of-function.
- category: Infectious
  name: Fungal meningitis
  description: >-
    Central nervous system candidiasis. Reported in CARD9 deficiency, where
    invasive brain infection with Candida caused adolescent deaths in the index
    kindred. This manifestation is what separates CARD9 deficiency from
    mucocutaneous-only CMC and must not be generalized to other subtypes.
  phenotype_term:
    preferred_term: Central nervous system candidiasis
    term:
      id: HP:0032159
      label: Fungal meningitis
  subtype: CARD9 deficiency
  evidence:
  - reference: PMID:19864672
    reference_title: "A homozygous CARD9 mutation in a family with susceptibility to fungal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3 members died during adolescence, 2 after invasive infection of the brain with candida species"
    explanation: Documents fatal CNS candidiasis in the index CARD9-deficient kindred.
- category: Dermatologic
  name: Deep dermatophytosis
  description: >-
    Dermatophyte infection invading the dermis and subcutis, with frequent
    lymph-node and occasional central nervous system dissemination - explicitly
    distinct from common superficial dermatophytosis. All 17 patients in the
    defining series had autosomal recessive CARD9 deficiency, and four died of
    active disease. Like CNS candidiasis, it reflects failure of myeloid
    antifungal effector function rather than of IL-17 barrier signalling, and
    it does not occur in the IL-17 receptor, adaptor or ligand etiologies.
  phenotype_term:
    preferred_term: Deep dermatophytosis
    term:
      id: HP:0032515
      label: Deep dermatophytosis
  subtype: CARD9 deficiency
  evidence:
  - reference: PMID:24131138
    reference_title: "Deep dermatophytosis and inherited CARD9 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency."
    explanation: >-
      Establishes deep dermatophytosis specifically (not superficial
      dermatophytosis) as a defining manifestation of CARD9 deficiency.
  - reference: PMID:24131138
    reference_title: "Deep dermatophytosis and inherited CARD9 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection"
    explanation: >-
      Defines the depth of invasion, matching the HP:0032515 definition and
      distinguishing it from ordinary superficial dermatophytosis.
- category: Infectious
  name: Recurrent bacterial infections
  description: >-
    Bacterial infections affected 74% of a 274-patient STAT1 GOF cohort, most
    often Staphylococcus aureus (36%), involving the respiratory tract in 47%
    and the skin in 28%. Specific to STAT1 GOF (and, separately, to AD-HIES);
    not a feature of pure IL-17-circuit CMC.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    temporality: RECURRENT
  frequency: FREQUENT
  subtype: STAT1 GOF
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively"
    explanation: Direct quantitative support for the FREQUENT band (74%).
- category: Infectious
  name: Recurrent viral infections
  description: >-
    Viral infections affected 38% of a 274-patient STAT1 GOF cohort, mostly
    Herpesviridae (83% of those), involving the skin in 32%.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
    temporality: RECURRENT
  frequency: FREQUENT
  subtype: STAT1 GOF
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients"
    explanation: Direct quantitative support for the FREQUENT band (38%).
- category: Immunologic
  name: Autoimmunity
  description: >-
    Autoimmune manifestations occurred in 37% of a 274-patient STAT1 GOF
    cohort. Distinct from the far more extensive endocrine autoimmunity of
    APECED/APS-1, which is curated on that disease entry.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  frequency: FREQUENT
  subtype: STAT1 GOF
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."
    explanation: Direct quantitative support for the FREQUENT band (37%).
- category: Endocrine
  name: Hypothyroidism
  description: >-
    The single commonest autoimmune manifestation of STAT1 gain-of-function,
    present in 22% of a 274-patient cohort.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  frequency: OCCASIONAL
  subtype: STAT1 GOF
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."
    explanation: Direct quantitative support for the OCCASIONAL band (22%).
- category: Vascular
  name: Dilatation of the cerebral artery
  description: >-
    Cerebral aneurysm, present in 6% of a 274-patient STAT1 GOF cohort and one
    of the three strongest predictors of poor outcome. Bound to the HPO parent
    term Dilatation of the cerebral artery because HPO's specific cerebral
    aneurysm terms (HP:0007029 berry, HP:0031056 fusiform) assert a morphology
    the source does not report.
  phenotype_term:
    preferred_term: Cerebral aneurysm
    term:
      id: HP:0004944
      label: Dilatation of the cerebral artery
  frequency: OCCASIONAL
  subtype: STAT1 GOF
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome."
    explanation: >-
      Direct quantitative support for the OCCASIONAL band (6%) and the
      prognostic significance.
genetic:
- name: STAT1
  gene_term:
    preferred_term: STAT1
    term:
      id: hgnc:11362
      label: STAT1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: STAT1 GOF
  frequency: >-
    Commonest genetic cause; 61% of 57 sequenced CMC patients in an
    international cohort.
  case_fractions:
  - population: International CMC cohort sequenced for STAT1 (57 patients)
    case_fraction_percent: 61.0
    cohort_size: 57
    notes: >-
      67% of familial (26 of 39) and 50% of sporadic (9 of 18) CMC cases
      carried a heterozygous STAT1 variant. Referral-cohort ascertainment
      inflates this share relative to unselected CMC.
    evidence:
    - reference: PMID:26604104
      reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%)."
      explanation: Quantifies the STAT1 share of genetically investigated CMC.
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 36 patients from 20 kindreds were heterozygous for 1 of the 12 missense mutations identified that affected the coiled-coil domain of STAT1."
    explanation: >-
      Establishes coiled-coil-domain missense STAT1 variants as the genetic
      cause in 20 CMC kindreds.
- name: IL17RA
  gene_term:
    preferred_term: IL17RA
    term:
      id: hgnc:5985
      label: IL17RA
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: IL17RA deficiency
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child was found to be homozygous for the c.850C>T nonsense mutation (c.850C>T/c.850C>T), which replaces the glutamine codon in position 284 with a stop codon (Q284X/Q284X) in the IL17RA gene"
    explanation: The index homozygous nonsense IL17RA allele causing autosomal recessive CMC.
- name: IL17RC
  gene_term:
    preferred_term: IL17RC
    term:
      id: hgnc:18358
      label: IL17RC
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: IL17RC deficiency
  evidence:
  - reference: PMID:25918342
    reference_title: "Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface."
    explanation: Homozygous nonsense IL17RC alleles abolish surface receptor expression.
- name: IL17F
  gene_term:
    preferred_term: IL17F
    term:
      id: hgnc:16404
      label: IL17F
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: IL17F deficiency
  evidence:
  - reference: PMID:21350122
    reference_title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation, c.284C>T, replaced the serine residue in position 65 of the mature protein with a leucine residue (S65L)"
    explanation: The dominant-negative IL17F S65L allele causing autosomal dominant CMC.
- name: TRAF3IP2
  gene_term:
    preferred_term: TRAF3IP2
    term:
      id: hgnc:1343
      label: TRAF3IP2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: ACT1 deficiency
  evidence:
  - reference: PMID:24120361
    reference_title: "An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a biallelic missense mutation (T536I) in the adaptor molecule ACT1 (TRAF3IP2)."
    explanation: The biallelic ACT1 T536I allele causing autosomal recessive CMC.
- name: CARD9
  gene_term:
    preferred_term: CARD9
    term:
      id: hgnc:16391
      label: CARD9
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: CARD9 deficiency
  evidence:
  - reference: PMID:19864672
    reference_title: "A homozygous CARD9 mutation in a family with susceptibility to fungal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X)."
    explanation: The homozygous CARD9 Q295X null allele.
- name: RORC
  gene_term:
    preferred_term: RORC
    term:
      id: hgnc:10260
      label: RORC
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: RORC deficiency
  evidence:
  - reference: PMID:26160376
    reference_title: "IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis."
    explanation: >-
      Bi-allelic RORC loss-of-function causes combined candidiasis and
      mycobacterial susceptibility.
- name: AIRE
  gene_term:
    preferred_term: AIRE
    term:
      id: hgnc:360
      label: AIRE
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: APECED
  notes: >-
    AIRE causes CMC indirectly, via loss of thymic tolerance and the resulting
    neutralizing anti-IL-17A/IL-17F/IL-22 autoantibodies, rather than by a
    lesion in the IL-17 circuit itself. Full AIRE curation is in the APS-1
    entry.
  evidence:
  - reference: PMID:20123958
    reference_title: "Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC)."
    explanation: Establishes CMC as a near-universal component of AIRE-deficient APS-1.
- name: STAT3
  gene_term:
    preferred_term: STAT3
    term:
      id: hgnc:11364
      label: STAT3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: AD-HIES
  evidence:
  - reference: PMID:18337720
    reference_title: "Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3)"
    explanation: STAT3 loss-of-function underlies AD-HIES and its CMC component.
- name: DOCK8
  gene_term:
    preferred_term: DOCK8
    term:
      id: hgnc:19191
      label: DOCK8
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  subtype: DOCK8 deficiency
  notes: >-
    DOCK8 deficiency is a combined immunodeficiency in which CMC is one
    manifestation among severe cutaneous viral infection, atopy and
    malignancy. Curated here only as a CMC-causing entity.
  evidence:
  - reference: PMID:19776401
    reference_title: "Combined immunodeficiency associated with DOCK8 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes."
    explanation: >-
      Establishes biallelic DOCK8 loss-of-function alleles as the genetic cause
      of the combined immunodeficiency within which CMC occurs.
- name: CLEC7A
  gene_term:
    preferred_term: CLEC7A
    term:
      id: hgnc:14558
      label: CLEC7A
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    Typed SUSCEPTIBILITY rather than CAUSATIVE: the association rests on a
    single kindred, the Y238X allele is a relatively common polymorphism, and
    the reported phenotype (recurrent vulvovaginal candidiasis, onychomycosis)
    is at the mild end of the CMC spectrum, so the evidence supports a
    predisposing rather than a fully penetrant Mendelian role. Dectin-1
    (CLEC7A) is the beta-glucan receptor upstream of CARD9; the Y238X
    early-stop allele impairs beta-glucan binding and IL-17, TNF and IL-6
    induction.
    Notably, and unlike CARD9 deficiency, phagocytosis and fungal killing are
    preserved, so dectin-1 deficiency causes mucosal but NOT invasive disease -
    a natural dissection that localizes CARD9's invasive-disease risk to
    myeloid effector function downstream of the receptor. No separate subtype
    is modelled because the phenotype is confined to the mucosal arm already
    captured by the shared IL-17 nodes, and the association rests on a single
    kindred.
  evidence:
  - reference: PMID:19864674
    reference_title: "Human dectin-1 deficiency and mucocutaneous fungal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a family in which four women who were affected by either recurrent vulvovaginal candidiasis or onychomycosis had the early-stop-codon mutation Tyr238X in the beta-glucan receptor dectin-1."
    explanation: >-
      Establishes the CLEC7A Y238X allele as a cause of mucocutaneous Candida
      disease.
  - reference: PMID:19864674
    reference_title: "Human dectin-1 deficiency and mucocutaneous fungal infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, fungal phagocytosis and fungal killing were normal in the patients, explaining why dectin-1 deficiency was not associated with invasive fungal infections and highlighting the specific role of dectin-1 in human mucosal antifungal defense."
    explanation: >-
      The key contrast with CARD9 deficiency: preserved myeloid killing means
      dectin-1 deficiency stops at the mucosa, supporting the entry's
      separation of the mucocutaneous and invasive arms.
biochemical:
- name: Circulating IL-17A-producing T cell count
  presence: DECREASED
  notes: >-
    The core functional biomarker of the CMC pathway. Reduced in most CMC
    patients across etiologies, but not all: 82% of tested STAT1 GOF patients
    in the largest cohort had a low IL-17A-producing T-cell count, so a normal
    result does not exclude the diagnosis. Low Th17 counts are also documented
    in CARD9 deficiency and are absent by definition in RORC deficiency and
    AD-HIES.
  cell_types:
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."
    explanation: >-
      Quantifies both the sensitivity and the imperfection of the Th17 count as
      a CMC biomarker.
- name: Neutralizing anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies
  presence: INCREASED
  specificity: >-
    Highly specific for the APECED/APS-1 (and thymoma) route to CMC: absent in
    healthy controls, in patients with other autoimmune disorders, and in STAT1
    gain-of-function CMC.
  notes: >-
    Diagnostic of the APECED/APS-1 (and thymoma) route to CMC and absent in the
    germline IL-17-circuit etiologies. Prevalence in APECED is 41% for
    anti-IL-17A, 75% for anti-IL-17F and 91% for anti-IL-22, concentrated in
    patients with CMC. A positive result reclassifies the case from a germline
    IL-17-pathway disorder to an acquired phenocopy.
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC."
    explanation: Quantifies autoantibody prevalence in APECED and its association with CMC.
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients displays autoantibodies against IL-17A, IL-17F, and IL-22."
    explanation: >-
      Confirms the autoantibodies are absent in STAT1 GOF CMC, making them a
      discriminating test between the genetic and acquired routes.
- name: Interferon-induced STAT1 phosphorylation
  presence: INCREASED
  subtype: STAT1 GOF
  notes: >-
    Flow-cytometric measurement of STAT1 phosphorylation in peripheral blood
    mononuclear cells after IFN-alpha, IFN-gamma or IL-27 stimulation, with
    prolonged or exaggerated phosphorylation indicating a gain-of-function
    allele. Recommended as a rapid functional adjunct alongside - not instead
    of - STAT1 sequencing.
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing."
    explanation: Establishes phospho-STAT1 flow cytometry as a functional diagnostic adjunct.
treatments:
- name: Systemic azole antifungal therapy
  description: >-
    Fluconazole is the mainstay for extensive oral, oesophageal, nail or
    recurrent disease, with topical agents for limited mucosal or cutaneous
    involvement. Treatment controls rather than cures: in a STAT1 GOF cohort
    azoles achieved complete response in 38% and partial remission in 62% of
    treated oral disease, 58% required continuing prophylaxis, and in the
    larger international cohort CMC persisted in 39% of patients on prolonged
    antifungal therapy. Chronic azole exposure selects resistant Candida, which
    is the principal long-term limitation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antifungal Therapy
    term:
      id: NCIT:C15704
      label: Antifungal Therapy
    therapeutic_agent:
    - preferred_term: fluconazole
      term:
        id: NCIT:C500
        label: Fluconazole
  target_mechanisms:
  - target: Persistent Mucocutaneous Candida albicans Infection
    treatment_effect: INHIBITS
    description: >-
      Suppresses the fungal burden without correcting the underlying immune
      defect, which is why relapse after withdrawal is the rule.
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antifungal treatment with e.g., azoles led to a partial remission in 62 % (10/16) of patients, 38 % (6/16) had a complete response."
    explanation: Quantifies azole response rates in STAT1 GOF CMC.
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment."
    explanation: Documents the limits of antifungal-only management.
- name: JAK inhibition (ruxolitinib, baricitinib)
  description: >-
    The mechanism-directed therapy for STAT1 gain-of-function CMC and the
    clinical vindication of the inversion model: because the IL-17 deficit is a
    downstream consequence of excessive JAK-STAT1 signalling, pharmacologically
    reducing that signal should restore Th17 immunity - and it does.
    Ruxolitinib suppressed IFN-induced STAT1/3/5 phosphorylation and raised
    Th17-related gene expression ex vivo alongside major clinical improvement.
    In the largest series, JAK inhibitors produced partial or complete
    remission in 87% of 45 STAT1 GOF patients. Important caveats: this is
    off-label, adverse events (infection, weight gain) occurred in 38% of
    patients, the effect is not sustained after withdrawal so long-term
    administration is required, and it does not apply to the IL-17 receptor,
    adaptor, ligand or autoantibody etiologies.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ruxolitinib
      term:
        id: NCIT:C77888
        label: Ruxolitinib
    - preferred_term: baricitinib
      term:
        id: NCIT:C127012
        label: Baricitinib
  target_mechanisms:
  - target: STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation
    treatment_effect: INHIBITS
    description: >-
      JAK1/2 inhibition acts at the molecular lesion itself, reducing
      phosphorylation of the hyperactive STAT1 and thereby relieving the
      downstream suppression of IL-17-producing T-cell development. This edge
      is the therapeutic expression of the stat1_gof_inversion hypothesis.
  evidence:
  - reference: PMID:29934865
    reference_title: "Utility of Ruxolitinib in a Child with Chronic Mucocutaneous Candidiasis Caused by a Novel STAT1 Gain-of-Function Mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JAK1/2 inhibition with ruxolitinib represents a viable option for treatment of refractory CMC, if HSCT is not considered. However, long-term administration is necessary, as the effect is not sustained after treatment discontinuation."
    explanation: >-
      Establishes ruxolitinib as effective in refractory CMC and records the
      need for continuous therapy.
  - reference: PMID:37935260
    reference_title: "JAK inhibitor treatment for inborn errors of JAK/STAT signaling: An ESID/EBMT-IEWP retrospective study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, treatment resulted in improvement (partial or complete remission) of clinical symptoms in 87% of STAT1-GOF and in 90% of STAT3-GOF patients."
    explanation: >-
      Multicentre response rate for JAK inhibition in 45 STAT1 gain-of-function
      patients.
  - reference: PMID:36050429
    reference_title: "Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients."
    explanation: >-
      Documents both benefit and the adverse-event burden in three adults;
      PARTIAL because two of three patients had treatment-limiting toxicity.
- name: Haematopoietic stem cell transplantation
  description: >-
    Potentially curative for severe, refractory STAT1 gain-of-function disease,
    but with substantial risk that restricts it to life-threatening immune
    dysregulation after multidisciplinary assessment. In an international
    series of 15 transplanted patients, primary engraftment was 74% but
    overall survival only 40%, with 50% secondary graft failure. Outcomes
    appear better when JAK inhibition is used as a bridge to transplant.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: STAT1 Hyperactivation from Impaired Nuclear Dephosphorylation
    treatment_effect: RESTORES
    description: >-
      Replaces the mutant haematopoietic compartment, so donor-derived
      lymphocytes carry wild-type STAT1 and Th17 development is restored.
  evidence:
  - reference: PMID:28601685
    reference_title: "Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data indicate that HSCT for patients with GOF-STAT1 mutations is curative but has significant risk of secondary graft failure and death."
    explanation: Establishes both curative potential and the substantial transplant risk.
  - reference: PMID:28601685
    reference_title: "Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary donor engraftment in this cohort of 15 patients with GOF-STAT1 mutations was 74%, and overall survival was only 40%."
    explanation: Quantifies engraftment and survival outcomes.
- name: Endoscopic dilatation of oesophageal stricture
  description: >-
    Mechanical relief of the fibrotic oesophageal narrowing that follows
    repeated candidal ulceration and repair, restoring swallowing in patients
    with obstructive dysphagia. It treats the structural consequence of the
    disease and does nothing to the underlying immune defect or the fungal
    burden, so it is palliative and often needs repeating. The surveillance
    endoscopy that detects early oesophageal neoplasia in the same patients is
    a diagnostic action and is modelled under diagnosis, not here.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Esophageal Dilation
    term:
      id: NCIT:C70908
      label: Esophageal Dilation
  target_mechanisms:
  - target: Chronic Candida-Associated Epithelial Injury and Squamous Dysplasia
    treatment_effect: MODULATES
    description: >-
      Relieves the fibrotic stricture produced by chronic epithelial injury
      without preventing the injury itself.
  notes: >-
    Evidence is marked PARTIAL: the cited series documents the severe
    obstructive oesophageal disease in CMC that creates the indication, but
    does not itself report dilatation outcomes. Endoscopic dilatation for
    benign oesophageal stricture is standard gastroenterological practice
    rather than a CMC-specific intervention, so no CMC-specific efficacy
    citation is available.
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "These patients usually present with CMCD in childhood, have severe oral and oesophageal candidiasis accompanied by severe difficulty swallowing, chest pain, heartburn, and are at risk of developing oral and/or oesophageal SCC."
    explanation: >-
      Documents the severe obstructive oesophageal disease that creates the
      indication for dilatation; the abstract does not report dilatation
      outcomes, hence PARTIAL.
clinical_trials:
- name: NCT02629419
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Open-label dose-titration trial of oral encochleated amphotericin B
    (CAMB/MAT2203) in mucocutaneous candidiasis refractory or intolerant to
    standard non-intravenous therapy. Directly addresses the azole-resistance
    limitation that dominates long-term CMC management.
  target_phenotypes:
  - preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: clinicaltrials:NCT02629419
    reference_title: "A Phase 2a Efficacy, Safety, Tolerability, and PK Study of Encochleated Amphotericin B (CAMB/MAT2203) in Patients With Mucocutaneous Candidiasis Who Are Refractory or Intolerant to Standard Non-Intravenous Therapies"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is an open-label, dose-titration trial to study the efficacy, safety, and pharmacokinetics of oral cochleate amphotericin B (CAMB) in the treatment of mucocutaneous candidiasis infections in patients who are refractory or intolerant to standard non intravenous therapies."
    explanation: >-
      An interventional trial of an oral non-azole antifungal specifically in
      treatment-refractory mucocutaneous candidiasis.
- name: NCT01386437
  status: RECRUITING
  description: >-
    NIH long-term natural-history and pathogenesis study of human fungal
    infections, enrolling patients with unusual, persistent or severe fungal
    infection and the immune defects that permit them, plus relatives and
    healthy volunteers. The principal natural-history resource for CMC and its
    genetic etiologies.
  target_phenotypes:
  - preferred_term: Chronic mucocutaneous candidiasis
    term:
      id: HP:0002728
      label: Chronic mucocutaneous candidiasis
  evidence:
  - reference: clinicaltrials:NCT01386437
    reference_title: "The Natural History and Pathogenesis of Human Fungal Infections"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Researchers want to collect blood and tissue samples from people who have unusual, persistent or severe fungal infections or immune problems that increase the risk of these infections."
    explanation: >-
      Defines the enrolled population as patients with persistent or severe
      fungal infection driven by underlying immune defects, i.e. the CMC
      population and its genetic causes.
differential_diagnoses:
- name: HIV infection / AIDS
  disease_term:
    preferred_term: AIDS
    term:
      id: MONDO:0012268
      label: AIDS
  description: >-
    The commonest acquired cause of persistent oropharyngeal and oesophageal
    candidiasis, and the single most important diagnosis to exclude before
    invoking an inborn error. CD4 depletion removes the Th17 compartment among
    much else, so the mucosal phenotype can be indistinguishable at
    presentation.
  distinguishing_features:
  - Positive HIV serology or nucleic acid testing with CD4 lymphopenia
  - Adult or adolescent onset rather than infancy, with no childhood history of
    thrush, nail or genital candidiasis
  - Accompanied by the wider spectrum of opportunistic infection (Pneumocystis,
    CMV, cryptococcosis) that pure IL-17-circuit CMC never produces
  - No family history; HIV testing is a mandatory part of the CMC work-up
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Secondary immune deficiencies are most often due to human immunodeficiency virus (HIV) infection, antibiotic use and immunosuppressive treatment (steroids, chemotherapy)."
    explanation: Names HIV as the leading secondary cause of chronic candidiasis.
- name: Severe combined immunodeficiency and other combined immunodeficiencies
  disease_term:
    preferred_term: severe combined immunodeficiency
    term:
      id: MONDO:0015974
      label: severe combined immunodeficiency
  description: >-
    CMC is one of many infections in patients with broad and profound T-cell
    deficiency. Because thrush is often the first visible sign in infancy, SCID
    can be mistaken for isolated CMC at the earliest presentation.
  distinguishing_features:
  - Failure to thrive, chronic diarrhoea and a broad infectious spectrum
    (Pneumocystis, disseminated viral infection, BCG disease) rather than
    Candida alone
  - Profound T-cell lymphopenia and abnormal lymphocyte subsets; abnormal
    newborn TREC screening
  - In CMC proper, T, B and NK cell numbers are normal, so quantifying them is
    the standard first-line discriminator
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CMC is one of a multitude of infectious diseases observed in patients with broad and profound T cell deficiencies."
    explanation: >-
      States the distinction between CMC as one of many infections in combined
      immunodeficiency versus CMC as an isolated phenotype.
- name: Drug-associated oesophageal or oropharyngeal candidiasis
  disease_term:
    preferred_term: esophageal candidiasis
    term:
      id: MONDO:0001648
      label: esophageal candidiasis
  description: >-
    Iatrogenic candidiasis from inhaled or systemic corticosteroids,
    broad-spectrum antibiotics, chemotherapy or other immunosuppression - by
    far the commonest explanation for oesophageal or oropharyngeal candidiasis
    in general practice, and a reversible one.
  distinguishing_features:
  - Clear temporal relationship to the drug exposure, with resolution on
    withdrawal, dose reduction, or spacer and mouth-rinse technique correction
  - Absent childhood history of thrush, nail or genital candidiasis; no family
    history
  - Normal Th17 counts and no STAT1 phosphorylation abnormality
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oesophageal candidiasis is a common, usually self-limiting opportunistic infection, but long-term infection with Candida is known to predispose to oral and oesophageal squamous cell cancer (SCC)."
    explanation: >-
      Distinguishes ordinary self-limiting oesophageal candidiasis from the
      persistent form that defines CMC and carries carcinoma risk.
- name: Autoimmune polyendocrine syndrome type 1 (APECED/APS-1)
  disease_term:
    preferred_term: autoimmune polyendocrine syndrome type 1
    term:
      id: MONDO:0009411
      label: autoimmune polyendocrine syndrome type 1
  description: >-
    The most consequential overlap. CMC is typically the FIRST manifestation of
    APS-1, appearing years before the endocrine features, so an apparently
    isolated CMC in a child may be a pre-endocrine APS-1. This is a temporal
    trap, not merely a phenotypic one: withholding the diagnosis risks a fatal
    unrecognized adrenal crisis. APS-1 is simultaneously an APECED subtype of
    CMC (modelled in has_subtypes) and a differential diagnosis for apparently
    isolated CMC - both framings are correct and both are recorded here
    deliberately.
  distinguishing_features:
  - Neutralizing anti-IL-17A/IL-17F/IL-22 autoantibodies are present in APS-1
    and absent in STAT1 GOF CMC, making autoantibody testing the decisive
    discriminator
  - Hypoparathyroidism, primary adrenal insufficiency and ectodermal dystrophy
  - Biallelic AIRE variants
  - Because the autoantibodies precede the CMC, a negative endocrine screen at
    presentation does not exclude APS-1 and surveillance is required
  notes: >-
    Full curation of APS-1 (AIRE, thymic tolerance failure, endocrine
    autoimmunity) is in
    kb/disorders/Autoimmune_Polyendocrine_Syndrome_Type_1.yaml and is
    intentionally not duplicated in this entry.
  evidence:
  - reference: PMID:20123959
    reference_title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle."
    explanation: >-
      Establishes CMC as frequently the presenting feature of APS-1, which is
      why apparently isolated CMC must trigger APS-1 consideration.
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the patients displays autoantibodies against IL-17A, IL-17F, and IL-22."
    explanation: >-
      Confirms the autoantibody test discriminates APS-1 CMC from STAT1 GOF
      CMC.
- name: Autosomal dominant hyper-IgE syndrome (Job syndrome)
  disease_term:
    preferred_term: hyper-IgE recurrent infection syndrome 1, autosomal dominant
    term:
      id: MONDO:0007818
      label: hyper-IgE recurrent infection syndrome 1, autosomal dominant
  description: >-
    Shares the IL-17 deficit and therefore the CMC, but is a multisystem
    syndrome rather than a selective antifungal defect.
  distinguishing_features:
  - Markedly elevated serum IgE with eosinophilia
  - Recurrent cold staphylococcal skin abscesses and pneumonia with
    pneumatocele formation
  - Eczematoid dermatitis
  - Retained primary dentition, characteristic facies, scoliosis,
    minimal-trauma fracture and joint hyperextensibility
  - A dominant-negative STAT3 variant; none of these features accompany pure
    IL-17-circuit CMC
  evidence:
  - reference: PMID:21727188
    reference_title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with the autosomal dominant (AD) hyper IgE syndrome, caused by dominant-negative mutations of STAT3, are susceptible principally to CMC and staphylococcal diseases of the lungs and skin"
    explanation: >-
      Contrasts the AD-HIES infectious spectrum (CMC plus pulmonary and
      cutaneous staphylococcal disease) with isolated CMC.
- name: CARD9 deficiency
  disease_term:
    preferred_term: predisposition to invasive fungal disease due to CARD9 deficiency
    term:
      id: MONDO:0008905
      label: predisposition to invasive fungal disease due to CARD9 deficiency
  description: >-
    Listed as a differential as well as a subtype because the therapeutic
    consequences differ sharply. A patient labelled with mucocutaneous-only CMC
    who in fact has CARD9 deficiency is at risk of invasive and central nervous
    system fungal disease that intermittent mucosal antifungal therapy will not
    prevent.
  distinguishing_features:
  - Deep dermatophytosis, subcutaneous phaeohyphomycosis, and invasive or
    central nervous system fungal infection, none of which occur in
    IL-17-circuit CMC
  - Consanguinity with autosomal recessive segregation
  - Biallelic CARD9 null variants; any deep or CNS fungal disease in a CMC
    patient should prompt CARD9 sequencing
  evidence:
  - reference: PMID:19864672
    reference_title: "A homozygous CARD9 mutation in a family with susceptibility to fungal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3 members died during adolescence, 2 after invasive infection of the brain with candida species"
    explanation: >-
      The CARD9-specific invasive/CNS phenotype that distinguishes it from
      mucocutaneous-only CMC.
- name: RORC deficiency and Mendelian susceptibility to mycobacterial disease
  disease_term:
    preferred_term: autosomal recessive Mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency
    term:
      id: MONDO:0014710
      label: autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency
  description: >-
    Sits at the CMC/MSMD boundary. Patients present with both candidiasis and
    mycobacterial disease, and the mycobacterial susceptibility arises through
    a mechanism (defective Mycobacterium-specific IFN-gamma production) that is
    separate from, not a consequence of, the IL-17 defect.
  distinguishing_features:
  - Disseminated BCG or Mycobacterium tuberculosis disease alongside the
    candidiasis
  - Absent palpable axillary and cervical lymph nodes and small thymus
  - Absence of MAIT and type 1 NKT cells
  - Biallelic RORC loss-of-function; pure IL-17-circuit CMC carries no
    mycobacterial risk
  evidence:
  - reference: PMID:26160376
    reference_title: "IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We studied seven patients from three unrelated consanguineous families with this unusual combination of infectious diseases but with no known genetic disorder."
    explanation: >-
      Establishes the dual candidiasis/mycobacterial phenotype that
      distinguishes RORC deficiency from isolated CMC.
- name: Diabetes mellitus
  disease_term:
    preferred_term: diabetes mellitus
    term:
      id: MONDO:0005015
      label: diabetes mellitus
  description: >-
    Poorly controlled diabetes is a common metabolic permissive state for
    recurrent oral, cutaneous and genital candidiasis, and is also part of the
    STAT1 GOF and APS-1 autoimmune spectra - so it can be either the
    explanation for the candidiasis or a clue to the underlying inborn error.
  distinguishing_features:
  - Hyperglycaemia and raised HbA1c, with resolution of candidiasis on
    glycaemic control
  - Adult onset without childhood thrush, nail or oesophageal disease
  - Conversely, type 1 diabetes arising in a child who already has CMC should
    raise suspicion of STAT1 GOF (4% of the international cohort) or APS-1
    rather than being accepted as the cause
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%)."
    explanation: >-
      Documents type 1 diabetes within the STAT1 GOF spectrum, so diabetes in a
      CMC patient may be consequence rather than cause.
diagnosis:
- name: Culture-confirmed persistent or recurrent mucocutaneous candidiasis
  description: >-
    Microscopy and culture (or molecular identification) of Candida from the
    affected site, with species identification and antifungal susceptibility
    testing - the latter essential after prolonged azole exposure. Endoscopy
    with brushings or biopsy is indicated for dysphagia or suspected
    oesophageal disease, which doubles as neoplasia surveillance.
  evidence:
  - reference: PMID:28815025
    reference_title: "Oesophageal candidiasis and squamous cell cancer in patients with gain-of-function STAT1 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend regular endoscopic surveillance to detect early oesophageal neoplasia in patients with CMCD as well as urgent endoscopy in symptomatic patients."
    explanation: Supports endoscopic evaluation as part of the CMC diagnostic workup.
- name: Phospho-STAT1 flow cytometry plus STAT1 sequencing
  description: >-
    Measurement of IFN-alpha-, IFN-gamma- or IL-27-induced STAT1
    phosphorylation in PBMC identifies gain-of-function alleles rapidly and is
    recommended in addition to, not instead of, sequencing. Given that STAT1
    accounts for the majority of genetically solved CMC, STAT1 is the first
    gene to test; a negative panel should be followed by exome or genome
    sequencing across the wider CMC gene set.
  presence: PRESENT
  notes: Applies to the STAT1 GOF subtype.
  evidence:
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised."
    explanation: Establishes STAT1 sequencing as the first-line genetic test in CMC.
- name: Anti-IL-17A/IL-17F/IL-22 autoantibody assay
  description: >-
    Discriminates the APECED/APS-1 (and thymoma) acquired phenocopy from the
    germline IL-17-circuit disorders. Positive in the great majority of APECED
    patients with CMC, negative in STAT1 gain-of-function.
  presence: PRESENT
  notes: Applies to the APECED subtype.
  evidence:
  - reference: PMID:20123958
    reference_title: "Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs."
    explanation: >-
      Establishes the specificity of the autoantibody assay for APS-1 among
      controls and other autoimmune disease.
progression:
- phase: Early childhood onset with lifelong relapsing course
  age_range: Median onset 1 year (range 0-24 years) in STAT1 gain-of-function
  notes: >-
    CMC typically begins in infancy or early childhood, most often as
    persistent oral thrush, and spreads over time to nails, skin, oesophagus
    and genital mucosa. In STAT1 gain-of-function the median age at onset is
    one year. The course is chronic and relapsing rather than staged:
    treatment induces remission but relapse after withdrawal is the norm (87%
    for oesophageal disease). The complications that determine prognosis -
    oesophageal stricture, squamous cell carcinoma, and, in STAT1 GOF,
    invasive infection, cerebral aneurysm and cancer - accumulate with disease
    duration, which is the argument for early diagnosis and sustained
    suppression rather than intermittent treatment of flares.
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years)."
    explanation: Establishes early-childhood onset and lifelong persistence.
  - reference: PMID:26604104
    reference_title: "The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "but relapses were frequent after treatment was stopped (87 %, 13/15)."
    explanation: Documents the relapsing course after treatment withdrawal.
infectious_agent:
- name: Candida albicans
  description: >-
    The predominant causative organism. A commensal of the oral,
    gastrointestinal and genital mucosa in healthy people, it becomes
    pathogenic in CMC only because IL-17-dependent barrier immunity fails.
    Other Candida species occur, and prolonged azole exposure selects for less
    susceptible ones.
  infectious_agent_term:
    preferred_term: Candida albicans
    term:
      id: NCBITaxon:5476
      label: Candida albicans
  evidence:
  - reference: PMID:25918342
    reference_title: "Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans."
    explanation: Identifies C. albicans as the predominant causative species.
discussions:
- discussion_id: cmc_th17_count_not_diagnostic
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do 18% of STAT1 gain-of-function patients have a normal circulating
    IL-17A-producing T-cell count despite manifesting CMC?
  attaches_to:
  - pathophysiology#Deficient IL-17A, IL-17F and IL-22 Production
  rationale: >-
    The pathograph treats deficient IL-17A/F/IL-22 production as the
    convergence node for the STAT1, RORC, STAT3 and CARD9 routes, yet the
    largest STAT1 GOF cohort found low circulating IL-17A-producing T cells in
    only 82% of patients tested. Either the peripheral blood Th17 count is an
    insensitive proxy for tissue-level IL-17 availability at the barrier, or a
    subset of STAT1 GOF patients develop CMC through a mechanism that does not
    require quantitative Th17 depletion (for example impaired IL-17 functional
    output from a numerically normal compartment, or a direct effect of
    excessive interferon signalling on the epithelium). Resolving this matters
    clinically because a normal Th17 count is currently, and incorrectly,
    treated by some as evidence against the diagnosis.
  proposed_experiments:
  - experiment_id: exp_cmc_barrier_il17_vs_blood_th17
    name: Barrier-site IL-17 quantification stratified by blood Th17 count
    description: >-
      Quantify IL-17A, IL-17F and IL-22 protein and transcript at the oral
      mucosal barrier (rather than in blood) in STAT1 GOF patients stratified
      by circulating Th17 count, to test whether tissue IL-17 availability is
      uniformly low even when blood Th17 numbers are normal.
  - experiment_id: exp_cmc_per_cell_candida_il17_output
    name: Per-cell Candida-specific IL-17 functional output
    description: >-
      Compare Candida-specific IL-17 secretion per Th17 cell in STAT1 GOF
      patients with normal versus low Th17 numbers, to test whether a
      functional rather than numerical deficit explains the discordant subset.
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested."
    explanation: >-
      Documents the discordance between the mechanistic model and the
      peripheral biomarker.
- discussion_id: cmc_stat1_gof_aneurysm_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does STAT1 gain-of-function cause cerebral aneurysm?
  attaches_to:
  - pathophysiology#Broad STAT1-Driven Immune Dysregulation
  rationale: >-
    Cerebral aneurysms occur in 6% of STAT1 GOF patients and are among the
    three strongest predictors of poor outcome, yet the causal edge from STAT1
    hyperactivation to arterial wall failure is modelled as
    INDIRECT_UNKNOWN_INTERMEDIATES because no mechanism is established.
    Candidate explanations include chronic interferon-driven vasculitis, a
    direct effect of STAT1 signalling on vascular smooth muscle or endothelium,
    and secondary damage from recurrent infection. Distinguishing these
    determines whether JAK inhibition would be expected to modify aneurysm
    risk, which is currently unknown and clinically important given that
    patients may take JAK inhibitors for decades.
  proposed_experiments:
  - experiment_id: exp_cmc_stat1_aneurysm_imaging_by_jaki_exposure
    name: Cerebral vascular imaging stratified by JAK-inhibitor exposure
    description: >-
      Cross-sectional cerebral vascular imaging in a STAT1 GOF cohort
      stratified by cumulative JAK-inhibitor exposure, to test whether
      reducing STAT1 signalling modifies aneurysm prevalence.
  - experiment_id: exp_cmc_stat1_aneurysm_wall_histopathology
    name: Aneurysm wall histopathology and interferon signature
    description: >-
      Histopathological characterization of aneurysm wall tissue from STAT1 GOF
      patients for interferon-signature gene expression and inflammatory
      infiltrate, to distinguish interferon-driven vasculitis from a
      non-inflammatory vascular effect.
  evidence:
  - reference: PMID:27114460
    reference_title: "Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis."
    explanation: >-
      Establishes the association without offering a mechanism, which is the
      gap recorded here.
notes: >-
  Modelling decisions worth recording. (1) No conforms_to mechanism-module
  reference is asserted. The kb/modules/ set was reviewed and none applies: the
  antimicrobial drug-mechanism modules are bacterial (cell wall, ribosome,
  topoisomerase, RNA polymerase, folate) and there is no antifungal
  counterpart; granuloma_formation covers a different fungal host response; and
  the IL-17-axis convergence modelled here is currently unique to this entry. If
  a second IL-17-axis disorder is curated, factoring an
  il17_mucosal_barrier_immunity module would be worthwhile. (2) APS-1 appears
  both as a subtype (the anti-IL-17 autoantibody route to CMC) and as a
  differential diagnosis (because CMC usually precedes the endocrine features by
  years); this duplication is deliberate and both framings are clinically
  correct. (3) Invasive/CNS fungal disease is a separate pathophysiology node
  with its own downstream phenotypes rather than a severity qualifier on the
  mucocutaneous node, so that CARD9's distinct mechanism and risk are not
  flattened into the IL-17 story. (4) No GeneReviews chapter exists for chronic
  mucocutaneous candidiasis as a phenotype; PubMed title searches for
  candidiasis plus GeneReviews returned no CMC chapter, so the GeneReviews
  baseline step is not applicable to this entry. (5) The CARD9 and RORC subtypes
  carry no subtype_term because their MONDO classes (MONDO:0008905,
  MONDO:0014710) descend from MONDO:0020573 inherited disease susceptibility,
  which is a source_node of the DiseaseTerm dynamic enum but not of
  DiseaseOrSubtypeTerm. Both IDs are therefore bound on the corresponding
  differential_diagnoses entries instead. This asymmetry looks like a schema
  gap worth raising upstream rather than a curation choice. (6) On the scope of
  has_subtypes: only STAT1 GOF, IL17RA, IL17RC, IL17F and ACT1 are true MONDO
  is_a children of MONDO:0015279. APECED, AD-HIES, DOCK8 deficiency and CARD9
  deficiency are separate MONDO entities (two of them with their own dismech
  entries), and Secondary CMC is an acquired state rather than a Mendelian
  one, so listing all of them under has_subtypes asserts a grouping the
  ontology does not. This is deliberate and follows the curation brief in
  issue #7567, which asks for exactly this set. The justification is that CMC
  is curated here as a convergent clinical phenotype defined by its shared
  IL-17-axis mechanism rather than as a MONDO subsumption tree: the entry's
  value is that it puts the ten routes to the same barrier failure side by
  side. The cost is that four members are not ontologically subordinate. The
  cleaner long-term home is a kb/groupings/ union over the already-distinct
  Disease entries (an IL17_Immunity_Defects grouping), with AD-HIES, DOCK8
  and Secondary CMC demoted to differential_diagnoses here; that refactor is
  left for a follow-up rather than done unilaterally in a new-entry PR, and is
  flagged for curator review.
references:
- reference: PMID:21350122
  title: "Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity."
- reference: PMID:21727188
  title: "Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis."
- reference: PMID:20123959
  title: "Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines."
- reference: PMID:38502882
  title: "Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment."

📚

References & Deep Research

References

4

PMID:21350122

Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity.

No top-level findings curated for this source.

PMID:21727188

Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis.

No top-level findings curated for this source.

PMID:20123959

Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines.

No top-level findings curated for this source.

PMID:38502882

Mucocutaneous Candidiasis: Insights Into the Diagnosis and Treatment.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Chronic Mucocutaneous Candidiasis: Disease-Characteristics Report

Edison Scientific Literature 27 citations 2026-08-01T07:41:39.486377

Chronic Mucocutaneous Candidiasis: Disease-Characteristics Report

Executive summary and scope

Chronic mucocutaneous candidiasis (CMC) is a clinical phenotype, not one molecularly uniform disease. It comprises persistent or recurrent, usually non-invasive Candida infection of oral, esophageal, genital, cutaneous, and nail surfaces. Candida albicans predominates. CMC may be relatively isolated—particularly with direct IL-17 pathway defects—or part of broader inborn errors of immunity such as STAT1 gain-of-function (GOF), CARD9 deficiency, or AIRE-associated autoimmune polyendocrine syndrome type 1 (APS-1/APECED). Thus, “Mendelian CMC” should be represented as a disease family with genotype-specific child entities rather than as a single-gene disorder. A recent review summarizes it as recurrent or persistent infection of “nails, skin, mouth, and genital organs,” and emphasizes defects in fungal recognition, IL-17 production/signaling, and Th17 development (published March 2024; DOI: https://doi.org/10.1097/INF.0000000000004321). (cinicola2024mucocutaneouscandidiasisinsights pages 1-2)

The strongest general causal model is: impaired epithelial IL-17 immunity → inadequate chemokine, antimicrobial-peptide, and neutrophil recruitment responses → failure to contain commensal Candida at barrier surfaces → recurrent/chronic candidiasis. STAT1 GOF is the most common currently recognized genetic cause and may account for up to approximately half of genetically investigated CMC, although ascertainment strongly affects that estimate. (egri2021primaryimmunodeficiencyand pages 1-2, egri2021primaryimmunodeficiencyand pages 7-8)

1. Disease information

Definition and identifiers

Preferred name: Chronic mucocutaneous candidiasis; British spelling: chronic mucocutaneous candidosis.
MONDO: MONDO:0015279.
Orphanet: ORPHA:1334, Chronic mucocutaneous candidosis.
MeSH concept: candidiasis/chronic mucocutaneous candidiasis is generally indexed under candidiasis and immunodeficiency-associated candidiasis; exact descriptor assignment should be verified against the current MeSH release.
OMIM: there is no single OMIM entry adequately representing the whole phenotype. Molecular subtypes are distributed among familial candidiasis and gene-specific immunodeficiency entries; examples include direct IL-17-pathway deficiencies and STAT1-GOF-associated autosomal-dominant CMC.
ICD: ICD-10-CM commonly places disease under candidiasis codes, selected by site—e.g., B37.0 oral, B37.2 skin/nail, B37.81 esophageal, B37.3 genital—and D84.89 or another immune-defect code when appropriate. ICD-11 similarly codes candidosis by site and the underlying inborn error separately. A unique universally used CMC code is not established.
Synonyms: CMC; chronic mucocutaneous candidosis; chronic mucocutaneous Candida infection; familial chronic mucocutaneous candidiasis; candidiasis, familial; autosomal-dominant CMC when specifically STAT1/IL17F-related.

Open Targets independently maps MONDO:0015279 to IL17RA, STAT1, IL17RC, CLEC7A, TRAF3IP2, IL17F, and IL23R, while ORPHA:1334 additionally maps CARD9. This is aggregated disease-level evidence, not an individual-patient EHR dataset. (OpenTargets Search: chronic mucocutaneous candidiasis)

Data provenance

Most knowledge derives from aggregated rare-disease resources, pedigrees, case series, retrospective international cohorts, functional immune assays, and experimental models. Quantitative clinical frequencies below are primarily from genotype-selected STAT1-GOF cohorts and must not be generalized to every CMC genotype.

2. Etiology, risk, protective factors, and gene–environment interaction

CMC arises when normally commensal Candida encounters a heritable defect in epithelial antifungal immunity. Direct causes include abnormal fungal sensing (CLEC7A/Dectin-1–CARD9), reduced Th17 differentiation or cytokine production (STAT1 GOF, RORC), neutralization of IL-17-family cytokines in AIRE deficiency, or defective IL-17 ligand/receptor/adaptor function (IL17F, IL17RA, IL17RC, TRAF3IP2/ACT1). CARD9 deficiency differs because deep-organ and CNS candidiasis may occur. (egri2021primaryimmunodeficiencyand pages 5-6, cinicola2024mucocutaneouscandidiasisinsights pages 1-2, OpenTargets Search: chronic mucocutaneous candidiasis)

Gene/pathway	Inheritance and functional class	Characteristic phenotype beyond mucocutaneous Candida	Key evidence/PMIDs
STAT1 (GOF)	AD; gain-of-function JAK-STAT signaling with impaired Th17/IL-17 immunity	Broad immune dysregulation: bacterial and viral infections, autoimmunity, vascular complications/aneurysm risk; CMC is the most common manifestation and may account for a large fraction of Mendelian CMC cases (egri2021primaryimmunodeficiencyand pages 1-2, egri2021primaryimmunodeficiencyand pages 7-8, parackova2023neutrophilsinstat1 pages 1-3, meesilpavikkai2024unravelingtheimmunogenetics pages 4-7)	PMID 21727188 (Open Targets literature link), large CMC cohort with 35/57 mutated and 61% of screened CMC patients carrying heterozygous STAT1 variants (OpenTargets Search: chronic mucocutaneous candidiasis, depner2016theextendedclinical pages 1-2)
IL17F	Likely AD cytokine defect; impaired IL-17 effector signaling at mucosa (direct Mendelian association supported in disease-target evidence)	Primarily isolated CMC phenotype in the IL-17 axis; broader extra-Candida phenotype not defined in gathered context (egri2021primaryimmunodeficiencyand pages 5-6, OpenTargets Search: chronic mucocutaneous candidiasis)	PMID 21350122 (Open Targets literature link) (OpenTargets Search: chronic mucocutaneous candidiasis)
IL17RA	AR receptor deficiency; loss of IL-17 receptor signaling	Predisposition centered on chronic/recurrent mucocutaneous candidiasis due to failed IL-17 responses; broader phenotype not detailed in gathered context (egri2021primaryimmunodeficiencyand pages 5-6, OpenTargets Search: chronic mucocutaneous candidiasis)	PMID 21350122, PMID 22951726 (Open Targets literature links) (OpenTargets Search: chronic mucocutaneous candidiasis)
IL17RC	Receptor deficiency; likely AR loss of IL-17A/F signaling	CMC with defective IL-17-mediated mucosal antifungal immunity; limited extra-Candida detail in gathered context (egri2021primaryimmunodeficiencyand pages 8-9, OpenTargets Search: chronic mucocutaneous candidiasis)	PMID 25918342 (Open Targets literature link) (OpenTargets Search: chronic mucocutaneous candidiasis)
TRAF3IP2 / ACT1	Adaptor/signaling defect downstream of IL-17 receptor; loss of function, likely AR	CMC from impaired IL-17 signal transduction; broader syndromic features not specified in gathered context (egri2021primaryimmunodeficiencyand pages 5-6, egri2021primaryimmunodeficiencyand pages 8-9, OpenTargets Search: chronic mucocutaneous candidiasis)	PMID 24120361 (Open Targets literature link) (OpenTargets Search: chronic mucocutaneous candidiasis)
RORC	Bi-allelic transcription-factor deficiency affecting Th17 development/function	Not isolated to Candida: impaired immunity to Candida plus susceptibility to mycobacterial infection is noted in gathered context (indirect mechanistic support) (cinicola2024mucocutaneouscandidiasisinsights pages 9-9, cinicola2024mucocutaneouscandidiasisinsights pages 1-2)	No direct PMID extracted in current context; association supported indirectly by cited 2024 review reference list and mechanistic review snippet (cinicola2024mucocutaneouscandidiasisinsights pages 9-9, cinicola2024mucocutaneouscandidiasisinsights pages 1-2)
CARD9	AR innate antifungal signaling defect downstream of C-type lectin pathways	Distinguishing feature is invasive candidiasis including CNS disease, not just mucocutaneous infection (egri2021primaryimmunodeficiencyand pages 5-6, cinicola2024mucocutaneouscandidiasisinsights pages 9-9, cinicola2024mucocutaneouscandidiasisinsights pages 1-2)	PMIDs linked by Open Targets include 19864672, 23335372, 24131138, 25057046, 26679537 (OpenTargets Search: chronic mucocutaneous candidiasis)
CLEC7A (Dectin-1)	Pattern-recognition receptor defect in fungal sensing; association appears weaker/more indirect than STAT1/IL-17 pathway genes	Mucocutaneous Candida susceptibility via impaired fungal recognition; invasive phenotype less clearly established in gathered context (cinicola2024mucocutaneouscandidiasisinsights pages 1-2, OpenTargets Search: chronic mucocutaneous candidiasis)	PMIDs linked by Open Targets include 19864674 and related supporting literature; indirect/uncertain strength for isolated Mendelian CMC should be noted (OpenTargets Search: chronic mucocutaneous candidiasis)
AIRE	AR autoimmune polyendocrine syndrome type 1 (APS-1/APECED); autoimmune cytokine-neutralizing pathobiology affecting IL-17/IL-22 axis	Classic triad includes hypoparathyroidism and adrenal insufficiency/Addison disease; CMC is among the earliest and most frequent manifestations (egri2021primaryimmunodeficiencyand pages 5-6, cinicola2024mucocutaneouscandidiasisinsights pages 9-9)	AIRE is strongly linked to APS-1 rather than isolated CMC; Open Targets supports AIRE–APS1 association (e.g., PMID 11275943) (OpenTargets Search: chronic mucocutaneous candidiasis)
STAT3, DOCK8 (differential; broader Th17 defects rather than classic isolated CMC)	Syndromic inborn errors with Th17 deficiency; not presented in gathered context as primary isolated CMC genes	Should prompt differential diagnosis because they cause wider immunodeficiency syndromes with CMC as one feature rather than isolated familial CMC (cinicola2024mucocutaneouscandidiasisinsights pages 9-9)	Review-level support in gathered context; no direct disease-specific PMID extracted here for isolated CMC assignment (cinicola2024mucocutaneouscandidiasisinsights pages 9-9)

Table: This table summarizes the main genes and syndromic pathways linked to chronic mucocutaneous candidiasis in the gathered evidence. It distinguishes core IL-17/STAT1 causes from broader differentials such as APS-1, CARD9 deficiency, and syndromic Th17 disorders.

Genetic risk factors

STAT1 GOF: heterozygous germline variants, usually autosomal dominant, with both familial and de novo disease. A 57-patient screen found variants in 35/57 (61%), including 26/39 familial (67%) and 9/18 sporadic cases (50%). Thirteen variants included p.M202V, p.A267V, p.R274W/Q, p.T385M/K, p.K388E, p.N397D, p.F404Y, p.F172L, p.Y287D, p.P293S, and p.S466R. (depner2016theextendedclinical pages 1-2)
Direct IL-17 defects: IL17F is classically dominant-negative/autosomal dominant; IL17RA, IL17RC, and TRAF3IP2 deficiencies are generally biallelic/autosomal recessive loss-of-function disorders. Landmark human evidence is linked to PMID 21350122 for IL17F/IL17RA, PMID 25918342 for IL17RC, and PMID 24120361 for ACT1. (OpenTargets Search: chronic mucocutaneous candidiasis)
CARD9, RORC, AIRE: generally biallelic recessive disease. AIRE causes APS-1 rather than isolated CMC; hypoparathyroidism and primary adrenal insufficiency are major diagnostic clues. (egri2021primaryimmunodeficiencyand pages 5-6, OpenTargets Search: chronic mucocutaneous candidiasis)
Broader syndromic risk: STAT3 loss-of-function, DOCK8 deficiency and other combined immunodeficiencies can include CMC through reduced Th17 function but should not be labeled isolated familial CMC. (cinicola2024mucocutaneouscandidiasisinsights pages 9-9)

All established monogenic variants are germline. Somatic mosaicism, repeat expansions, mitochondrial variants, anticipation, and recurrent CMC-specific chromosomal rearrangements are not established major mechanisms. Pathogenic alleles are individually rare or absent from population databases; exact gnomAD frequency and ACMG classification must be retrieved per HGVS variant and transcript. A variant should not be classified from phenotype alone: segregation, population rarity, computational evidence, and—especially for STAT1—functional hyperphosphorylation/dephosphorylation assays are important.

Environmental and acquired risk factors

Antibiotic exposure, corticosteroid or other immunosuppression, HIV, diabetes, malnutrition, denture use, barrier trauma, and local moisture can promote ordinary mucocutaneous candidiasis and must be excluded as secondary explanations. In Mendelian CMC, these exposures may amplify disease but are not the primary cause. Persistent colonization and repeated azole exposure select resistant Candida, creating an important gene–environment–treatment interaction. Azole resistance is described as the principal limitation of long-term management. (egri2021primaryimmunodeficiencyand pages 1-2)

No reproducible genetic protective allele or specific protective diet/lifestyle intervention has been established. Practical protective factors are avoidance of unnecessary antibiotics/immunosuppression, good oral/dental and skin-fold hygiene, glycemic control, keeping affected skin dry, and culture-guided antifungal stewardship. These reduce exposure or complications but do not correct the inherited immune defect.

3. Phenotypes

Core phenotype and quantitative frequencies

A 26-person STAT1-GOF cohort found oral candidiasis in 73%, esophageal candidiasis in 65%, intertrigo in 50%, pustular skin disease in 46%, and scalp infection in 44%. Untreated oral disease became chronic in 42%, while 50% of affected patients had chronic cutaneous disease. Aphthous stomatitis occurred in 69%; 82% of those cases were recurrent. (depner2016theextendedclinical pages 6-8)

Suggested phenotype annotations include:

Manifestation	Type/course	Suggested HPO term
Recurrent oral thrush, pseudomembranes	Sign; childhood onset common; relapsing/chronic	Recurrent oral candidiasis HP:0002728
Esophageal candidiasis/dysphagia	Infection/symptom; recurrent	Esophageal candidiasis; Dysphagia HP:0002015
Cutaneous candidiasis, intertrigo, pustules	Sign; episodic or chronic	Cutaneous candidiasis HP:0001597; Intertrigo
Onychomycosis, onycholysis, nail dystrophy	Sign; often progressive without suppression	Onychomycosis; Onycholysis HP:0001806; Nail dystrophy HP:0001597 should be verified because HPO releases change
Genital candidiasis	Sign/symptom; recurrent	Recurrent vulvovaginal candidiasis/genital candidiasis
Aphthous ulcers	Sign; recurrent	Recurrent oral ulceration HP:0000155
Reduced Th17 cells/IL-17 production	Laboratory abnormality	Abnormal T-helper 17 cell physiology; Abnormal cytokine secretion
Bacterial respiratory infections	Syndromic STAT1-GOF feature	Recurrent respiratory infections HP:0002205
Viral infections	Syndromic feature	Recurrent viral infections HP:0004429
Autoimmune thyroid disease/cytopenia/diabetes	STAT1-GOF or APS-1 feature	Autoimmune thyroiditis HP:0002923; Autoimmune cytopenia; Diabetes mellitus
Hypoparathyroidism/Addison disease	APS-1 clues	Hypoparathyroidism HP:0000829; Adrenal insufficiency HP:0000846
Cerebral/aortic aneurysm or vasculopathy	Severe STAT1-GOF complication	Cerebral aneurysm HP:0004944; Aortic aneurysm HP:0004942
Oral/esophageal squamous-cell carcinoma	Late complication	Squamous cell carcinoma HP:0002860

IDs should be validated against the target HPO release before database ingestion. Nail disease may impair walking, footwear use, manual work, and appearance; oral/esophageal disease impairs eating and causes pain; genital and visible skin disease affect intimacy and psychosocial wellbeing. No robust CMC-specific EQ-5D, SF-36, or PROMIS reference values were identified.

Extended STAT1-GOF phenotype

A 2024 synthesis reports more than 400 patients and over 100 STAT1-GOF variants. CMC occurs in over 60%; bacterial respiratory infection occurs in over 50% (lower respiratory disease approximately 37%), viral infections in roughly half, and autoimmunity in over 60%. More than 95% have onset before age 35, usually in early childhood. These frequencies describe STAT1 GOF, not direct IL-17 receptor deficiency. (meesilpavikkai2024unravelingtheimmunogenetics pages 4-7)

Complications include bronchiectasis from repeated respiratory infection, endocrinopathy, cytopenias, enteropathy, cerebral or large-vessel aneurysm/vasculopathy, and oral or esophageal squamous-cell carcinoma after longstanding inflammation. The literature review explicitly notes mouth/esophageal neoplasia and rare cerebral vasculitis. (egri2021primaryimmunodeficiencyand pages 1-2)

4. Genetic and molecular information

Functional consequences

STAT1 GOF variants cluster in coiled-coil, DNA-binding, SH2, and other functional domains. Many coiled-coil/DNA-binding variants impair nuclear dephosphorylation, prolonging phosphorylated STAT1; some SH2 variants increase phosphorylation by other means. This exaggerates IFN-driven transcription and interferes with STAT3-dependent Th17 differentiation. In four Iranian patients, p.R274Q and p.Q271P were associated with increased IFN-γ-induced STAT1 phosphorylation, reduced Th17 cells, reduced IL17A/IL17F/IL22 expression, and impaired Candida-specific T-cell proliferation. (ostadi2021functionalanalysisof pages 1-2, ostadi2021functionalanalysisof pages 7-8, meesilpavikkai2024unravelingtheimmunogenetics pages 4-7)

In one literature synthesis, 82% of STAT1-GOF patients had deficient CD4+IL-17+ cells. This is a useful supportive biomarker but not a perfectly sensitive diagnostic test. (ostadi2021functionalanalysisof pages 7-8)

Modifier, epigenetic, and structural evidence

Penetrance and expressivity are variable even within pedigrees, implying modifier genes, pathogen exposure, microbiome, treatment history, and stochastic immune effects. No validated CMC-specific modifier gene is ready for routine annotation. No reproducible disease-defining DNA-methylation, histone, chromatin, lipidomic, or metabolomic signature has been established. There is likewise no characteristic karyotypic abnormality, aneuploidy, translocation, or inversion.

5. Environmental and infectious information

The proximate infectious agent is usually Candida albicans—NCBI Taxonomy 5476—although other Candida species may occur. CMC is not ordinarily acquired by zoonotic transmission; it reflects failure to control endogenous or environmentally acquired commensal yeast at barrier sites. Fungal morphology and cell-wall β-glucans/mannans engage Dectin-1 and Toll-like receptors. CARD9 transduces C-type lectin signals and promotes cytokines needed for Th17 differentiation. (egri2021primaryimmunodeficiencyand pages 1-2, cinicola2024mucocutaneouscandidiasisinsights pages 1-2)

Smoking, alcohol, exercise, occupational toxins, radiation, or pollution are not established primary causes of Mendelian CMC. Tobacco and alcohol plausibly worsen oral/esophageal injury and cancer risk, but genotype-specific quantitative interaction data are lacking.

6. Mechanism and pathophysiology

Causal chain

Recognition: epithelial/myeloid CLEC7A/Dectin-1 and TLRs recognize Candida wall ligands.
Upstream signaling: CARD9-dependent innate signaling induces inflammatory cytokines; IL-6/IL-1/IL-23 and STAT3/RORγt support Th17 differentiation.
Effector production: Th17, γδ T cells, innate lymphoid cells, and other lymphocytes produce IL-17A/F and IL-22.
Barrier response: IL-17A/F engage IL-17RA/IL-17RC on keratinocytes and mucosal epithelial cells; ACT1/TRAF3IP2 activates NF-κB/MAPK programs, chemokines, antimicrobial peptides, and granulopoietic/neutrophil-recruiting signals.
Failure states: ligand/receptor/adaptor loss, low Th17 generation, anti-cytokine autoantibodies, or excessive STAT1 signaling interrupts this axis.
Clinical output: persistent epithelial colonization becomes symptomatic oral, esophageal, genital, cutaneous, and nail candidiasis. Chronic inflammation and repeated infection contribute downstream to scarring, structural lung disease, and malignancy.

The centrality of IL-17 is supported by human Mendelian defects across IL17F, IL17RA, IL17RC and TRAF3IP2 and by the common reduced Th17 phenotype in STAT1 GOF. (egri2021primaryimmunodeficiencyand pages 5-6, OpenTargets Search: chronic mucocutaneous candidiasis)

Suggested biological-process terms include GO:0045087 innate immune response, GO:0006955 immune response, GO:0032496 response to lipopolysaccharide only if experimentally appropriate, GO:0071346 cellular response to interferon-γ, GO:0032743 positive regulation of IL-17 production, GO:0030593 neutrophil chemotaxis, GO:0009617 response to bacterium/fungus-specific child term, and GO:0050832 defense response to fungus. Suggested cell types include CL:0000542 lymphocyte, CL:0000899 T-helper 17 cell, CL:0000624 CD4-positive alpha-beta T cell, CL:0000775 neutrophil, CL:0000451 dendritic cell, CL:0000576 monocyte, CL:0000312 keratinocyte, and mucosal epithelial-cell terms appropriate to site.

Recent molecular profiling

A 2023 three-adult study combined CyTOF and a 265-protein Olink panel during JAK inhibition. Clinical CMC improved, and one strong responder had greater Candida-specific reactivity after seven weeks. NK cells increased CD45/CD52/CD99; monocytes and eosinophils reduced CD16; CXCL10, annexin A1, granzymes B/H, and oncostatin M fell while FGF21 rose; IFN-γ and CXCL10 were reduced at three months. The abstract states: “Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients.” (published 2023; DOI: https://doi.org/10.1007/s10875-022-01351-0). (borgstrom2023threeadultcases pages 1-2, borgstrom2023threeadultcases pages 7-11)

A separate 2023 ten-patient study showed immature, activated STAT1-GOF neutrophils with enhanced degranulation, NETosis, platelet aggregation, basal STAT1 phosphorylation, and interferon-stimulated genes. Ruxolitinib did not normalize this signature. The abstract states that neutrophils had a “strong propensity for degranulation, NETosis, and platelet-neutrophil aggregation.” (DOI: https://doi.org/10.1007/s10875-023-01528-1). (parackova2023neutrophilsinstat1 pages 1-3)

These are small exploratory studies. No validated single-cell atlas, spatial transcriptomic diagnostic signature, integrated lipidome/metabolome, or clinically deployed CRISPR-screen result was identified.

7. Anatomical structures affected

Primary sites are oral mucosa/tongue/oropharynx, esophageal epithelium, genital mucosa, epidermis and skin folds, scalp, periungual tissue, and nail plate/bed. Suggested UBERON annotations include oral epithelium, tongue, esophagus UBERON:0001043, skin of body UBERON:0002097, nail, scalp, vagina UBERON:0000996, and penis/glans where applicable. Disease is not lateralized.

Relevant tissues are stratified squamous epithelium and keratinized appendages. Key target/responding cells are keratinocytes and mucosal epithelial cells; immune participants include Th17 cells, neutrophils, monocytes, dendritic cells, NK cells, and B/T lymphocytes. Subcellular compartments depend on genotype: plasma membrane for IL-17RA/RC and Dectin-1; cytosol for CARD9 and ACT1; cytoplasm/nucleus for STAT1; nucleus for RORC and AIRE. Suggested GO cellular components include plasma membrane GO:0005886, cytoplasm GO:0005737, cytosol GO:0005829, and nucleus GO:0005634.

8. Temporal development

Onset is usually pediatric and insidious, often beginning as persistent oral thrush; most STAT1-GOF cases begin in early childhood, though diagnosis may be delayed into adulthood. More than 95% of STAT1-GOF patients reportedly manifest before 35 years. (egri2021primaryimmunodeficiencyand pages 7-8, meesilpavikkai2024unravelingtheimmunogenetics pages 4-7)

The natural course is chronic, episodic, and relapsing rather than a fixed staged disease. Oral disease can progress to nails, skin, esophagus, and genital sites. Treatment induces remission, but recurrence is common: in the 26-person STAT1 cohort, 87% of esophageal cases relapsed despite 67% achieving complete remission during treatment. (depner2016theextendedclinical pages 6-8)

Critical intervention periods include early childhood—before recurrent infection causes nutritional, dental, nail, or pulmonary injury—and before prolonged inflammation/azole exposure creates resistance or malignancy risk. Rapid recurrence after JAK-inhibitor withdrawal has been reported, so remission should not be equated with cure. (egri2021primaryimmunodeficiencyand pages 7-8)

9. Inheritance and population

Inheritance is genotype-specific: autosomal dominant for most STAT1 GOF and IL17F disease; autosomal recessive for IL17RA, IL17RC, TRAF3IP2, CARD9, RORC, and classic AIRE-associated APS-1. STAT1 GOF displays variable expressivity and may arise de novo. Penetrance is high but not uniformly quantified across variants. Anticipation is not expected. Germline mosaicism is theoretically possible but not a documented common mechanism.

CMC is ultra-rare, but reliable population-wide incidence or prevalence per 100,000 is unavailable because it is a phenotype spanning multiple disorders. APS-1 prevalence is approximately 1:100,000 globally, with enrichment in Finns, Sardinians, and Persian Jews. (egri2021primaryimmunodeficiencyand pages 5-6)

No consistent sex bias is established; one recent mechanistic cohort included 3 males and 7 females, but this is not an epidemiologic ratio. (parackova2023neutrophilsinstat1 pages 1-3) Founder effects and consanguinity are important for recessive AIRE, CARD9, and IL-17-pathway disease in particular populations. Carrier frequency must be calculated gene/variant/population-specifically from gnomAD; no defensible aggregate CMC carrier frequency exists.

10. Diagnostics

Clinical and microbiological evaluation

Diagnosis requires persistent/recurrent candidiasis confirmed by microscopy and culture or molecular identification, coupled with exclusion of common secondary causes. Record species and antifungal susceptibility, especially after azole exposure. Endoscopy with brushings/biopsy is appropriate for dysphagia or suspected esophageal disease. Histology typically shows yeast/pseudohyphae in superficial epithelium with inflammation; imaging is not routine unless evaluating lung damage, aneurysm/vasculopathy, deep fungal disease, or CARD9-associated CNS infection.

Immune work-up

Recommended baseline tests are CBC/differential, lymphocyte subsets (T, B, NK), immunoglobulins, HIV testing, glucose/HbA1c, liver/renal tests, and evaluation for endocrine autoimmunity. The review recommends quantifying T, B, and NK cells and ruling out secondary causes before establishing an inborn error. (egri2021primaryimmunodeficiencyand pages 5-6)

Genotype-directed functional tests include:

frequency of circulating Th17/CD4+IL-17+ cells;
Candida-specific T-cell proliferation/cytokine production;
IL-17A, IL-17F, and IL-22 production;
STAT1 phosphorylation after IFN-α, IFN-γ, or IL-27 and, where possible, dephosphorylation kinetics;
anti-IL-17A/F and anti-IL-22 autoantibodies when APS-1 is suspected.

Flow-cytometric phospho-STAT1 testing is a rapid adjunct, not a substitute for molecular confirmation. In the international cohort, stimulated patient PBMCs showed hyperphosphorylation; the authors explicitly recommended it alongside genetic testing. (depner2016theextendedclinical pages 1-2, depner2016theextendedclinical pages 5-6)

Genetic testing strategy

Use an inborn-error-of-immunity/CMC panel including at minimum STAT1, IL17F, IL17RA, IL17RC, TRAF3IP2, CARD9, CLEC7A, RORC, AIRE, plus syndromic genes such as STAT3 and DOCK8.
If phenotype strongly suggests STAT1 GOF, sequence STAT1 with copy-number analysis and functional validation.
If panel-negative, proceed to trio WES or WGS; WGS is valuable for noncoding, copy-number, and structural variants.
Reanalyze periodically as disease genes expand.
CMA/karyotype/FISH, mtDNA, and repeat-expansion testing are not first-line unless unrelated features suggest another diagnosis.

Cascade testing is appropriate after a pathogenic familial variant is found. Prenatal and preimplantation testing are technically feasible for a known familial variant.

Differential diagnosis

Exclude HIV, diabetes, antibiotics/corticosteroids, neutropenia, severe combined/combined immunodeficiency, hyper-IgE syndrome, DOCK8 deficiency, common variable immunodeficiency, chronic granulomatous disease, APS-1, CARD9 deficiency, thymoma-associated immunodeficiency, and ordinary recurrent vulvovaginal candidiasis. Deep CNS candidiasis strongly suggests CARD9; candidiasis plus hypoparathyroidism/Addison disease suggests AIRE; CMC plus viral/bacterial infection, autoimmunity, and vasculopathy suggests STAT1 GOF.

11. Outcome and prognosis

There are no validated 5- or 10-year survival statistics for CMC as a whole. Isolated IL-17-pathway disease is often compatible with long survival but requires chronic antifungal management. Prognosis worsens with invasive fungal disease, recurrent bacterial/viral infection, bronchiectasis, endocrine crisis, vasculopathy/aneurysm, malignancy, or multidrug-resistant Candida.

In the 26-person STAT1 cohort, azoles produced partial remission in 62% and complete response in 38%; 58% required antifungal prophylaxis. (depner2016theextendedclinical pages 6-8) HSCT evidence is highly selected: one review summarized only 4/15 symptomatic patients achieving immune reconstitution while 9 died, indicating substantial transplant risk and likely confounding by severe baseline disease. Outcomes were better when transplantation occurred in stable patients. (egri2021primaryimmunodeficiencyand pages 8-9)

Longstanding mouth/esophageal inflammation warrants surveillance because squamous-cell carcinoma is reported. Functional morbidity includes pain, dysphagia, poor intake, nail destruction, recurrent medical care, treatment toxicity, and psychosocial burden. Validated prognostic biomarkers are lacking; candidate markers include genotype/domain, infection burden, organ damage, autoimmunity, treatment response, CXCL10/IFN signature, and persistent neutrophil activation.

12. Treatment and real-world implementation

Antifungal therapy

First-line treatment is usually a topical agent for limited disease and a systemic azole—commonly fluconazole—for extensive, nail, esophageal, or recurrent disease. Culture and susceptibility testing should guide refractory disease. Alternatives include itraconazole, posaconazole, voriconazole, isavuconazole, echinocandins, and amphotericin B according to site, species, resistance, interactions, and toxicity. Azoles inhibit fungal lanosterol 14α-demethylase; echinocandins inhibit β-1,3-D-glucan synthase; amphotericin binds ergosterol. Suggested NCIt intervention terms include Fluconazole, Itraconazole, Voriconazole, Posaconazole, Isavuconazole, Amphotericin B, Caspofungin/Micafungin/Anidulafungin, Antifungal Therapy, and Hematopoietic Stem Cell Transplantation.

Long-term suppression is frequently needed, but monitor hepatic toxicity, QT effects, drug interactions, and resistance. In the 26-person cohort, treatment often controlled rather than eradicated disease. (depner2016theextendedclinical pages 6-8)

Genotype-directed immune therapy

Ruxolitinib and baricitinib inhibit JAK signaling upstream of STAT1 and are off-label precision therapies for severe STAT1 GOF with refractory CMC or autoimmunity. They can improve IL-17 responses and clinical disease, but infection, cytopenia, liver injury, thrombosis and viral reactivation require monitoring. Treatment duration is undefined and relapse may follow withdrawal. (egri2021primaryimmunodeficiencyand pages 7-8)

In three adults, baricitinib 2 mg/day improved mucocutaneous inflammation within one month in one patient. Another stopped after three weeks because of painful aphthae, cough, fever, and elevated liver enzymes. Ruxolitinib 15 mg/day initially helped a third patient, but recurrent respiratory infections developed after one year; that patient subsequently improved after HSCT. (borgstrom2023threeadultcases pages 12-13, borgstrom2023threeadultcases pages 4-5)

HSCT is potentially curative but should be reserved for severe, life-threatening, medically refractory immune dysregulation after expert multidisciplinary assessment; published mortality is substantial. (egri2021primaryimmunodeficiencyand pages 7-8, egri2021primaryimmunodeficiencyand pages 8-9)

Experimental/registered studies

Relevant registered implementations include NIH natural-history study NCT01386437 (recruiting; planned enrollment 1,200), phase 2 oral MAT2203 in mucocutaneous candidiasis NCT02629419 (completed; n=4), phase 3 ibrexafungerp for refractory/intolerant fungal disease NCT03059992 (completed; n=233, not CMC-specific), and anti-cytokine-autoantibody disease study NCT01842386 (completed; n=7). These registrations establish research activity, not routine efficacy for Mendelian CMC.

No approved gene, RNA, or CRISPR therapy exists. No established CMC-specific pharmacogenomic dosing guideline from CPIC/PharmGKB was identified; CYP-mediated interactions remain clinically important for azoles.

13. Prevention

There is no licensed Candida vaccine or population screening program for CMC. Primary prevention of the germline disorder is limited to reproductive counseling. Secondary prevention consists of early recognition, culture confirmation, immune/genetic diagnosis, cascade testing, and prompt treatment before irreversible tissue damage. Tertiary prevention includes susceptibility-guided suppression, oral/dental care, skin-fold care, endocrine surveillance, pulmonary monitoring, avoidance of unnecessary antibiotics, and surveillance for oral/esophageal malignancy in longstanding disease.

Families with a molecular diagnosis should receive counseling on genotype-specific recurrence: approximately 50% per pregnancy for a heterozygous autosomal-dominant variant and 25% affected/50% carrier risk when both parents carry the same autosomal-recessive allele. These are Mendelian expectations and may be modified by de novo status, penetrance, or parental mosaicism.

14. Other species and natural disease

Mucocutaneous candidiasis occurs in animals, but no well-established naturally occurring veterinary disorder was identified that is directly orthologous to the full human STAT1-GOF/IL-17-deficient CMC phenotype. Candida is generally opportunistic across species. The disease is not considered zoonotic in the usual sense; human CMC reflects host susceptibility rather than sustained animal-to-human transmission.

Relevant taxa include human NCBI Taxon 9606, mouse 10090, zebrafish 7955, and Candida albicans 5476. Orthologues of STAT1, IL17RA, CARD9, RORC, and TRAF3IP2 are evolutionarily conserved, supporting comparative mechanistic studies. Breed-specific VBO annotations and an OMIA-equivalent natural Mendelian syndrome were not established from the retrieved evidence.

15. Model organisms

Mouse: Il17ra-knockout mice are highly susceptible to C. albicans; one study reported rapid death after systemic challenge, demonstrating IL-17RA’s role in fungal immunity. However, systemic candidiasis is not identical to chronic human mucocutaneous disease. (OpenTargets Search: chronic mucocutaneous candidiasis)
Genetic mouse models: Stat1-GOF knock-in, Aire-null, Card9-null, Il17ra/Il17rc-null, Act1-deficient, and Rorc-deficient systems can dissect cytokine production, receptor signaling, autoantibodies, neutrophil recruitment, and organ tropism. Their limitations include species-specific Candida commensalism and immune development.
Zebrafish: larval/adult C. albicans infection permits live imaging and antifungal screening, but does not reproduce human nail/oral chronicity.
Cellular systems: patient PBMCs, Candida-stimulated whole blood, phospho-flow assays, primary keratinocytes, epithelial cultures, and gene-edited cell lines are the most directly translational models. Patient-derived organoids/iPSCs are plausible but not yet standard CMC platforms.

Applications include variant functional classification, defining STAT1 dephosphorylation, testing IL-17 signaling, evaluating Candida-specific lymphocyte responses, and preclinical JAK-inhibitor or antifungal studies.

Evidence quality, current expert interpretation, and knowledge gaps

The highest-confidence conclusions are that CMC is genetically heterogeneous, barrier IL-17 immunity is central, STAT1 GOF is the leading recognized cause, and management requires both fungal control and diagnosis of the underlying immune defect. The 2021 review’s abstract states: “The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function mutations.” (DOI: https://doi.org/10.15586/aei.v49i1.20). (egri2021primaryimmunodeficiencyand pages 1-2)

The major limitations are rarity, referral bias, mixing of molecular subtypes, retrospective cohorts, and small uncontrolled treatment series. Epidemiologic incidence, genotype-specific penetrance, quality-of-life scores, variant-level carrier frequencies, long-term JAK-inhibitor safety, transplant selection criteria, protective modifiers, epigenomics, spatial/single-cell atlases, and validated prognostic biomarkers remain insufficiently defined. Accordingly, cohort percentages should always retain the genotype and denominator, and JAK inhibition should be described as promising off-label precision therapy—not established universal CMC treatment.

References

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(egri2021primaryimmunodeficiencyand pages 8-9): Natalia Egri, Ana Esteve-Solé, Àngela Deyà-Martínez, Iñaki Ortiz de Landazuri, Alexandru Vlagea, AP Garcia, Celia Cardozo, Carolina Garcia-Vidal, Clara San Bartolomé, Marta Español-Rego, L Yiyi, Xavier Bosch-Amate, J Ferrando, Jordi Yagüe, Manel Juan, and Laia Alsina. Primary immunodeficiency and chronic mucocutaneous candidiasis: pathophysiological, diagnostic, and therapeutic approaches. Allergologia et immunopathologia, 49 1:118-127, Jan 2021. URL: https://doi.org/10.15586/aei.v49i1.20, doi:10.15586/aei.v49i1.20. This article has 26 citations and is from a peer-reviewed journal.
(cinicola2024mucocutaneouscandidiasisinsights pages 9-9): Bianca Laura Cinicola, Andrea Uva, Marzia Duse, Anna Maria Zicari, and Danilo Buonsenso. Mucocutaneous candidiasis: insights into the diagnosis and treatment. The Pediatric Infectious Disease Journal, 43:694-703, Mar 2024. URL: https://doi.org/10.1097/inf.0000000000004321, doi:10.1097/inf.0000000000004321. This article has 6 citations.
(depner2016theextendedclinical pages 6-8): Mark Depner, Sebastian Fuchs, Jan Raabe, Natalie Frede, Cristina Glocker, Rainer Doffinger, Effrossyni Gkrania-Klotsas, Dinakantha Kumararatne, T. Prescott Atkinson, Harry W. Schroeder, Tim Niehues, Gregor Dückers, Asbjørg Stray-Pedersen, Ulrich Baumann, Reinhold Schmidt, Jose L. Franco, Julio Orrego, Moshe Ben-Shoshan, Christine McCusker, Cristina Miuki Abe Jacob, Magda Carneiro-Sampaio, Lisa A. Devlin, J. David M. Edgar, Paul Henderson, Richard K. Russell, Anne-Bine Skytte, Suranjith L. Seneviratne, Jennifer Wanders, Hans Stauss, Isabelle Meyts, Leen Moens, Milos Jesenak, Robin Kobbe, Stephan Borte, Michael Borte, Dowain A. Wright, David Hagin, Troy R. Torgerson, and Bodo Grimbacher. The extended clinical phenotype of 26 patients with chronic mucocutaneous candidiasis due to gain-of-function mutations in stat1. Journal of Clinical Immunology, 36:73-84, Nov 2016. URL: https://doi.org/10.1007/s10875-015-0214-9, doi:10.1007/s10875-015-0214-9. This article has 177 citations and is from a domain leading peer-reviewed journal.
(ostadi2021functionalanalysisof pages 1-2): Vajiheh Ostadi, Roya Sherkat, Melanie Migaud, Seyed-Mehran Modaressadeghi, Jean-Laurent Casanova, Anne Puel, Nioosha Nekooie-Marnany, and Mazdak Ganjalikhani-Hakemi. Functional analysis of two stat1 gain-of-function mutations in two iranian families with autosomal dominant chronic mucocutaneous candidiasis. Medical mycology, 59:180-188, Jun 2021. URL: https://doi.org/10.1093/mmy/myaa043, doi:10.1093/mmy/myaa043. This article has 14 citations and is from a peer-reviewed journal.
(ostadi2021functionalanalysisof pages 7-8): Vajiheh Ostadi, Roya Sherkat, Melanie Migaud, Seyed-Mehran Modaressadeghi, Jean-Laurent Casanova, Anne Puel, Nioosha Nekooie-Marnany, and Mazdak Ganjalikhani-Hakemi. Functional analysis of two stat1 gain-of-function mutations in two iranian families with autosomal dominant chronic mucocutaneous candidiasis. Medical mycology, 59:180-188, Jun 2021. URL: https://doi.org/10.1093/mmy/myaa043, doi:10.1093/mmy/myaa043. This article has 14 citations and is from a peer-reviewed journal.
(borgstrom2023threeadultcases pages 1-2): Emilie W. Borgström, Marie Edvinsson, Lucía P. Pérez, Anna C. Norlin, Sara L. Enoksson, Susanne Hansen, Anders Fasth, Vanda Friman, Olle Kämpe, Robert Månsson, Hernando Y. Estupiñán, Qing Wang, Tan Ziyang, Tadepally Lakshmikanth, Carl Inge E. Smith, Petter Brodin, and Peter Bergman. Three adult cases of stat1 gain-of-function with chronic mucocutaneous candidiasis treated with jak inhibitors. Journal of Clinical Immunology, 43:136-150, Sep 2023. URL: https://doi.org/10.1007/s10875-022-01351-0, doi:10.1007/s10875-022-01351-0. This article has 32 citations and is from a domain leading peer-reviewed journal.
(borgstrom2023threeadultcases pages 7-11): Emilie W. Borgström, Marie Edvinsson, Lucía P. Pérez, Anna C. Norlin, Sara L. Enoksson, Susanne Hansen, Anders Fasth, Vanda Friman, Olle Kämpe, Robert Månsson, Hernando Y. Estupiñán, Qing Wang, Tan Ziyang, Tadepally Lakshmikanth, Carl Inge E. Smith, Petter Brodin, and Peter Bergman. Three adult cases of stat1 gain-of-function with chronic mucocutaneous candidiasis treated with jak inhibitors. Journal of Clinical Immunology, 43:136-150, Sep 2023. URL: https://doi.org/10.1007/s10875-022-01351-0, doi:10.1007/s10875-022-01351-0. This article has 32 citations and is from a domain leading peer-reviewed journal.
(depner2016theextendedclinical pages 5-6): Mark Depner, Sebastian Fuchs, Jan Raabe, Natalie Frede, Cristina Glocker, Rainer Doffinger, Effrossyni Gkrania-Klotsas, Dinakantha Kumararatne, T. Prescott Atkinson, Harry W. Schroeder, Tim Niehues, Gregor Dückers, Asbjørg Stray-Pedersen, Ulrich Baumann, Reinhold Schmidt, Jose L. Franco, Julio Orrego, Moshe Ben-Shoshan, Christine McCusker, Cristina Miuki Abe Jacob, Magda Carneiro-Sampaio, Lisa A. Devlin, J. David M. Edgar, Paul Henderson, Richard K. Russell, Anne-Bine Skytte, Suranjith L. Seneviratne, Jennifer Wanders, Hans Stauss, Isabelle Meyts, Leen Moens, Milos Jesenak, Robin Kobbe, Stephan Borte, Michael Borte, Dowain A. Wright, David Hagin, Troy R. Torgerson, and Bodo Grimbacher. The extended clinical phenotype of 26 patients with chronic mucocutaneous candidiasis due to gain-of-function mutations in stat1. Journal of Clinical Immunology, 36:73-84, Nov 2016. URL: https://doi.org/10.1007/s10875-015-0214-9, doi:10.1007/s10875-015-0214-9. This article has 177 citations and is from a domain leading peer-reviewed journal.
(borgstrom2023threeadultcases pages 12-13): Emilie W. Borgström, Marie Edvinsson, Lucía P. Pérez, Anna C. Norlin, Sara L. Enoksson, Susanne Hansen, Anders Fasth, Vanda Friman, Olle Kämpe, Robert Månsson, Hernando Y. Estupiñán, Qing Wang, Tan Ziyang, Tadepally Lakshmikanth, Carl Inge E. Smith, Petter Brodin, and Peter Bergman. Three adult cases of stat1 gain-of-function with chronic mucocutaneous candidiasis treated with jak inhibitors. Journal of Clinical Immunology, 43:136-150, Sep 2023. URL: https://doi.org/10.1007/s10875-022-01351-0, doi:10.1007/s10875-022-01351-0. This article has 32 citations and is from a domain leading peer-reviewed journal.
(borgstrom2023threeadultcases pages 4-5): Emilie W. Borgström, Marie Edvinsson, Lucía P. Pérez, Anna C. Norlin, Sara L. Enoksson, Susanne Hansen, Anders Fasth, Vanda Friman, Olle Kämpe, Robert Månsson, Hernando Y. Estupiñán, Qing Wang, Tan Ziyang, Tadepally Lakshmikanth, Carl Inge E. Smith, Petter Brodin, and Peter Bergman. Three adult cases of stat1 gain-of-function with chronic mucocutaneous candidiasis treated with jak inhibitors. Journal of Clinical Immunology, 43:136-150, Sep 2023. URL: https://doi.org/10.1007/s10875-022-01351-0, doi:10.1007/s10875-022-01351-0. This article has 32 citations and is from a domain leading peer-reviewed journal.

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Classifications

Inheritance

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Differential Diagnoses

Clinical Trials

Source YAML

References & Deep Research

References

Deep Research

Chronic Mucocutaneous Candidiasis: Disease-Characteristics Report

Executive summary and scope

1. Disease information

Definition and identifiers

Data provenance

2. Etiology, risk, protective factors, and gene–environment interaction

Genetic risk factors

Environmental and acquired risk factors

3. Phenotypes

Core phenotype and quantitative frequencies

Extended STAT1-GOF phenotype

4. Genetic and molecular information

Functional consequences

Modifier, epigenetic, and structural evidence

5. Environmental and infectious information

6. Mechanism and pathophysiology

Causal chain

Recent molecular profiling

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical and microbiological evaluation

Immune work-up

Genetic testing strategy

Differential diagnosis

11. Outcome and prognosis

12. Treatment and real-world implementation

Antifungal therapy

Genotype-directed immune therapy

Experimental/registered studies

13. Prevention

14. Other species and natural disease

15. Model organisms

Evidence quality, current expert interpretation, and knowledge gaps

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