Hereditary Chronic Mucocutaneous Candidiasis (STAT1 Gain of Function, IL-17 Pathway Defects, CARD9)

Inborn errors of immunity with monogenic predisposition to mucocutaneous candidiasis and invasive fungal disease: STAT1 gain of function, IL-17RA, IL-17RC, IL-17F, ACT1 and JNK1 deficiencies, RORγT deficiency and CARD9 deficiency

Literature and regulatory information update: 7 November 2026.

0. Initial Reference Table

1. Introduction

Chronic mucocutaneous candidiasis (CMC) is defined by persistent or recurrent infection of the skin, nails and oral, oesophageal and genital mucosae by Candida species, above all Candida albicans, a usual commensal of the digestive tract [14, 30]. CMC is a sign of insufficient immunity: it occurs in acquired immunodeficiencies, such as human immunodeficiency virus (HIV) infection and poorly controlled diabetes, and in inborn errors of immunity (IEI) with profound T-cell defects, in which it is only one of many infections [21, 31]. This article covers the group of IEI in which CMC is the dominant manifestation or the gateway to diagnosis and in which a single gene explains the disease. The 2024 classification of the International Union of Immunological Societies (IUIS) groups these diseases in Table 6, among the defects of intrinsic and innate immunity, in the subtables "predisposition to mucocutaneous candidiasis" and "predisposition to invasive fungal diseases", and the accompanying phenotypic classification allows this group to be reached from the clinical picture [6, 32].

1.1 Historical overview

Patients with an apparently inherited form of CMC, without any other evident immunological phenotype, have been described since the late 1960s under the name chronic mucocutaneous candidiasis disease (CMCD); according to Boisson and colleagues, who cite the series of Canales (1969), Wells (1970 and 1972) and Kirkpatrick (1971), these patients frequently had staphylococcal skin infections and autoimmune thyroiditis, and the disease was not benign, being associated with mucocutaneous carcinomas and cerebral aneurysms [24]. In multiplex and consanguineous families, CMCD segregated sometimes as a dominant trait and sometimes as a recessive trait [14]. The pathophysiology began to be understood through the study of the syndromic forms: patients with autosomal dominant hyper-IgE syndrome due to dominant-negative STAT3 variants have few T cells producing IL-17A, IL-17F and IL-22, and patients with autoimmune polyendocrinopathy type 1 (APS-1) have neutralising autoantibodies against the same cytokines [14, 33]. These observations pointed to interleukin 17 (IL-17)-mediated immunity as the non-redundant mucosal defence against Candida [5].

1.2 Milestones of molecular discovery

The first gene was identified in 2009: in a five-generation consanguineous Iranian family, with four members with recurrent fungal infections and three deaths in adolescence (two from cerebral candidiasis), homozygosity mapping located the defect at 9q and found the homozygous variant Q295X in CARD9, the adaptor of dectin-1 signalling [9]. In 2011, Puel and colleagues described the first two aetiologies of isolated CMCD, autosomal recessive complete deficiency of IL-17 receptor A (IL-17RA) and autosomal dominant partial IL-17F deficiency [5]. In the same year, two independent groups identified heterozygous gain-of-function (GOF) variants of STAT1: Liu and colleagues, by exome sequencing, in 47 patients from 20 families with autosomal dominant CMCD, and van de Veerdonk and colleagues, by capture of 100 candidate genes, in 14 patients from five families [2, 34]. These were followed by ACT1 deficiency in 2013, deep dermatophytosis as a manifestation of CARD9 deficiency in 2013, IL-17RC deficiency and RORγT deficiency in 2015 and JNK1 haploinsufficiency in 2019 [7, 22, 24, 25, 30]. The discovery of the STAT1-GOF mechanism opened the way to treatment with Janus kinase (JAK) inhibitors, the subject of an international consensus of the European Society for Immunodeficiencies (ESID), the European Society for Blood and Marrow Transplantation (EBMT) and the European Reference Network ERN-RITA published in 2026 [27, 35].

1.3 Nomenclature and reclassifications

The literature distinguishes syndromic CMC, in which candidiasis is associated with other infections or with non-infectious manifestations and circulating Th17 cells are reduced (STAT1-GOF, dominant-negative STAT3, RORγT deficiency, ZNF341 deficiency), from isolated CMC, in which candidiasis is the predominant manifestation in an otherwise healthy individual (IL-17F, IL-17RA, IL-17RC and ACT1 deficiencies) [22]. STAT1-GOF was initially considered a cause of CMCD, but the international cohort of 274 patients showed a much broader phenotype, with bacterial, viral and invasive fungal infections, autoimmunity, aneurysms and carcinomas, and it is now regarded as a combined immunodeficiency with immune dysregulation [14, 15]. OMIM records STAT1-GOF as immunodeficiency 31C, distinct from the two loss-of-function diseases of the same gene (31A, autosomal dominant, and 31B, autosomal recessive) [4]. CARD9 deficiency is now classified by the IUIS under predisposition to invasive fungal diseases and not under CMC, because mucocutaneous candidiasis is present in only some patients [6, 16]. The common CLEC7A (dectin-1) variant Y238X, recorded in OMIM as familial candidiasis 4, is a susceptibility factor with incomplete penetrance, with an allele frequency of about 7–8%, and not a Mendelian cause of CMC [4]. The OMIM "familial candidiasis" (CANDF) names follow the order of discovery and not the gene, so the numerical designation does not indicate the mechanism [4]. The series also includes two loci without an identified gene: familial candidiasis 1 (OMIM 114580), autosomal dominant with or without thyroid disease, defined in an Alabama family in which four members had CMC and thyroid disease, five (including a concordant pair of monozygotic twins) only CMC and three only thyroid disease, with linkage to an interval of about 15 cM at 2p22.3-p21 (maximum lod score 3.82, with penetrance estimated at 0.8), which does not contain STAT1 (2q32.2); and familial candidiasis 3 (OMIM 607644), restricted to the fingernails and toenails, mapped to chromosome 11 [36, 37]. The form formerly called familial candidiasis 5 became immunodeficiency 51 when the cutaneous staphylococcal infections and bacterial respiratory infections of IL-17RA deficiency were recognised, and familial candidiasis 2 became immunodeficiency 103, reflecting the predominance of invasive fungal infections in CARD9 deficiency [11, 38].

1.4 Definition of the entities in this article

STAT1-GOF is the autosomal dominant disease caused by heterozygous STAT1 variants that increase STAT1-dependent signalling in a functional assay; demonstration of gain of function is part of the definition, because loss-of-function variants of the same gene cause opposite diseases [4, 35]. IL-17 pathway defects are single-gene diseases in which the cellular response to IL-17A and IL-17F is abolished (IL-17RA, IL-17RC, ACT1) or reduced (IL-17F, JNK1), with CMC as the main manifestation [6, 21]. RORγT deficiency is the autosomal recessive disease in which IL-17A/F-producing T cells are absent and interferon-γ (IFN-γ) production in response to mycobacteria is reduced, with CMC and mycobacterial disease in the same patient [7]. CARD9 deficiency is the autosomal recessive disease that predisposes previously healthy people to invasive fungal infections by Ascomycota, with CMC or superficial dermatophytosis in some cases [16]. APS-1, STAT3 hyper-IgE syndrome, ZNF341 deficiency, DOCK8 deficiency, Mendelian susceptibility to mycobacterial disease due to IL12RB1 or IL12B, acquired anti-IL-17/IL-22 autoantibodies and iatrogenic candidiasis due to IL-17 antagonists are differential diagnoses covered in section 6.

2. Molecular Genetics and Pathophysiology

2.1 The IL-23/IL-17 axis and mucosal defence against Candida

IL-17A and IL-17F, produced by Th17 cells and other lymphocytes, act as homodimers or as the IL-17A/F heterodimer on a receptor formed by the IL-17RA and IL-17RC chains; the signal passes through the adaptor ACT1 (encoded by TRAF3IP2), which binds the receptors through the SEFIR domain and, as a Lys63-linkage E3 ubiquitin ligase, ubiquitinates TRAF6 and activates nuclear factor κB (NF-κB) and the mitogen-activated protein kinases (MAPK) [4]. The response takes place mainly in epithelial cells, keratinocytes and fibroblasts, which produce β-defensins and other antimicrobial peptides and CXC chemokines that recruit neutrophils to the skin and mucosae [4, 21]. In mice with the homologous Ser65Leu substitution of IL-17F, CXC chemokine expression and neutrophil recruitment were reduced in oral candidiasis [4]. Human inborn errors show that IL-17A and IL-17F are essential for mucocutaneous immunity to C. albicans and, to a lesser extent, to Staphylococcus aureus, but largely redundant for systemic defence [5, 21]. Th17 differentiation depends on cytokines that signal through STAT3 (IL-6, IL-21, IL-23) and is inhibited by cytokines that signal through STAT1 (type I and II interferons and IL-27) [2, 35].

2.2 STAT1 gain of function

STAT1 (2q32.2; MANE transcript NM_007315.4) encodes signal transducer and activator of transcription 1, non-redundant in the signalling of type I, II and III interferons and IL-27; after phosphorylation at tyrosine 701, it forms homodimers (IFN-γ-activated factor, GAF), required for antimycobacterial immunity, or the ISGF3 complex with STAT2 and IRF9, required for antiviral immunity [4, 35]. GOF variants increase STAT1 phosphorylation and the responses to type I and II interferons and IL-27, and also STAT1 activation by cytokines that normally activate STAT3 (IL-6 and IL-21) [2]. Excess signalling by inhibitors of Th17 differentiation and the diversion of inducers towards STAT1 explain the reduction of T cells producing IL-17A, IL-17F and IL-22 and, thus, CMC; IL-27 also induces PD-L1 on naive T cells, another brake on Th17 differentiation [2, 35]. The molecular mechanism of gain of function remains under discussion: Liu and colleagues demonstrated persistence of phosphorylation in the presence of the kinase inhibitor staurosporine, indicating reduced nuclear dephosphorylation, and a structural model proposes that variants at the interface of the antiparallel dimer between the coiled-coil domain (CCD) and the DNA-binding domain (DBD) hinder phosphatase access (TCPTP/PTPN2 and SHP-2/PTPN11); other groups found increased total STAT1 with normal dephosphorylation, or premature nuclear import of phosphorylated STAT1, and a 2024 review keeps the two main hypotheses open [35, 39]. Systematic alanine scanning of 342 residues of the CCD and DBD predicted 100% of the known loss-of-function variants and 78.1% of the known gain-of-function variants [35]. Autoimmunity is attributed mainly to increased type I interferon signalling, which brings STAT1-GOF close to the interferonopathies; the mechanism of the mycobacterial and viral infections, paradoxical in a state of excess interferon signalling, has not been elucidated and has been related to T-cell exhaustion and refractory responses to IFN-γ [14, 35]. NK cells have reduced terminal maturation and cytotoxicity, and some patients have low memory B cells, low IgG2 and IgG4 or altered antibody specificity even with normal total IgG [14, 27, 35].

2.3 Three diseases of the same gene: the direction of the effect decides the diagnosis

STAT1 causes three Mendelian diseases, and the direction of the functional change, not the presence of the variant, determines which one [4]. Heterozygous GOF variants cause immunodeficiency 31C (OMIM 614162), with CMC and autoimmunity [4]. Heterozygous dominant-negative loss-of-function variants cause immunodeficiency 31A (OMIM 614892), a Mendelian susceptibility to mycobacterial disease (MSMD) with incomplete penetrance, in which only the GAF arm (IFN-γ and IL-27) is impaired and the responses to IFN-α and IFN-λ1 are preserved; multifocal osteomyelitis is a representative manifestation [4, 35]. Biallelic loss-of-function variants, complete or hypomorphic, cause immunodeficiency 31B (OMIM 613796), with severe viral and mycobacterial infections and complete penetrance, curable by HCT in the complete form [35]. By 2020, 105 GOF variants, 4 complete recessive deficiency variants, 4 partial recessive deficiency variants and 10 dominant deficiency variants had been described [35]. ClinGen classifies the three gene-disease relationships as definitive (immunodeficiency 31B on 6 October 2024, MSMD due to partial deficiency on 20 November 2024 and immunodeficiency 31C on 17 December 2024) [4]. The practical consequence is that JAK inhibition is rational only in gain of function and would be harmful in loss of function [4, 27].

2.4 Variant spectrum of STAT1-GOF and genotype-phenotype correlations

GOF variants cluster in the CCD and DBD: in the 274-patient cohort, 62% of families had a variant in the CCD, 35% in the DBD and 1% in each of the transactivation, N-terminal and SH2 domains; in the 2020 review, 87.6% of variants were in the CCD and DBD and the CCD alone accounted for 52.6% of cases [14, 35]. In the 533-patient database assembled in 2025 (135 variants, 36 countries), 295 patients had a variant in the CCD, 191 in the DBD and 47 in the other domains; 15.2% of variants were de novo and known consanguinity was 1.7% [15]. Four variants recur through repeated mutation at the same site (hotspot) and not through a founder effect [35]. The following table presents them in validated HGVS nomenclature.

Source of HGVS validation: VariantValidator (GRCh38, MANE Select), accessed 7 November 2026 [12]. Several substitutions have been described at the same position 274 (R274Q, R274W, R274G), and the same applies to 24 residues [35]. DBD variants are associated with more systemic fungal, mycobacterial and viral infections, more bronchiectasis and shorter survival (p=0.0039), with a 1.5-fold higher risk of death; however, when patients with T385M are excluded, the DBD group no longer differs from the other domains, except for viral infection, indicating that the worse prognosis attributed to the domain is due mainly to this variant [15]. CCD variants are associated with less mycobacterial infection, autoimmunity, bronchiectasis and death [15]. None of the GOF variants described by 2020 was present in gnomAD (123,136 exomes), except T133A, inherited from an asymptomatic mother; GOF variants have lower allele frequencies and higher CADD scores than the common variants of the gene [35]. The clinical penetrance of CMC is very high: only 2% of the 274 patients (2.8% excluding probands) had never had CMC, at a median age of 32 years, and none of them was asymptomatic [14]. Intrafamilial variability and the incomplete penetrance of other manifestations justify the study of relatives [14, 19].

2.5 IL-17 pathway defects: IL-17RA, IL-17RC, IL-17F, ACT1 and JNK1

IL-17RA deficiency (IL17RA, 22q11.1, NM_014339.7) is autosomal recessive and complete: the 12 variants described in 21 patients, all homozygous, abolish the response of fibroblasts to IL-17A, IL-17F and IL-17A/F and the response of leucocytes to IL-17E/IL-25; eight create a stop codon before the transmembrane domain and prevent surface expression, but two (the missense p.D387N in the SEFIR domain and the frameshift p.Y591Sfs*29 in the SEFEX domain) produce a receptor present on the surface but non-functional, so detection of surface IL-17RA does not exclude the diagnosis [21]. IL17RA lies at 22q11.1, proximal to the 22q11.2 deletion region; two siblings homozygous for a 770 kb deletion encompassing IL17RA and CECR1 (ADA2) had combined IL-17RA and adenosine deaminase 2 deficiency, with Candida and Staphylococcus infections and refractory vasculitis, detected by array comparative genomic hybridisation [4, 21]. IL-17RC deficiency (IL17RC, 3p25.3, NM_153460.4) is autosomal recessive; the three initial patients were homozygous for nonsense variants that prevent surface expression, and a fourth, Japanese, patient had a homozygous duplication of exon 13; the defect for IL-17A/F is complete, but the response to IL-17E/IL-25 is preserved, unlike IL-17RA and ACT1 deficiency [4, 30]. IL-17F deficiency is autosomal dominant and partial: the heterozygous variant S65L, described in one family, produces IL-17F homodimers and IL-17A/F heterodimers with reduced but not abolished activity; OMIM records the relationship as provisional and the human evidence essentially comes down to that family [4, 5]. ACT1 deficiency (TRAF3IP2, 6q21, NM_147686.4) was described in two siblings homozygous for the missense T536I in the SEFIR domain, which abolishes the interaction of ACT1 with IL-17 receptors without altering homodimerisation or the interactions with CD40, HSP70 and HSP90; the same gene contains the common polymorphism D10N (rs33980500), associated with psoriasis and psoriatic arthritis with an odds ratio of 1.95, which reduces the IL-17 response without abolishing it and is not diagnostic [4, 24]. JNK1 haploinsufficiency (MAPK8), described in a three-generation French family with the splicing variant c.311+1G>A, combines autosomal dominant CMC with a connective tissue disease overlapping hypermobile Ehlers-Danlos syndrome, through reduced fibroblast responses to IL-17A/F and reduced c-Jun/ATF-2-dependent transforming growth factor β (TGF-β) signalling [6, 22]. The TRAF3IP2 and IL17F variants are cited in the protein nomenclature of the original articles, because their conversion to the MANE transcript was not confirmed in VariantValidator [12].

2.6 RORγT deficiency

RORC (1q21.3, NM_005060.4) encodes the nuclear receptor RORγ and the thymic isoform RORγT, master regulator of the differentiation of IL-17-producing T cells and of lymphoid organogenesis [4]. Biallelic loss-of-function variants in seven individuals from three families of different ethnic origins caused absence of IL-17A/F-producing T cells, with CMC, and, unexpectedly, markedly reduced IFN-γ production in response to mycobacteria by γδ T cells and CD4+CCR6+CXCR3+ αβ T cells, with mycobacterial disease [7]. The coexistence of CMC and disease due to BCG or environmental mycobacteria in the same child is the combination that should suggest this gene [4]. In ClinVar, RORC variants are dominated by variants of uncertain significance (134, against 21 pathogenic and 3 likely pathogenic), so an isolated heterozygous missense variant is not informative [4].

2.7 CARD9 deficiency

CARD9 (CARD9, 9q34.3, NM_052813.5) is a myeloid-cell adaptor downstream of the C-type lectin receptors (dectin-1, dectin-2, Mincle), which recognise carbohydrates of the fungal wall; after activation it forms the CBM complex with BCL10 and MALT1 and activates NF-κB and p38 MAPK, and through interaction with RASGRF1 and H-RAS it activates ERK [4, 23]. The deficiency causes reduced cytokine and chemokine production by macrophages, dendritic cells and mononuclear cells, defective killing of some fungi by neutrophils and deficient neutrophil recruitment to infected tissues; Th17 cells are reduced in most, but not all, patients [16]. A 2026 study showed that the defect also affects the intrinsic IL-17 immunity of CD4+ T cells and Candida-specific T cells, but not the fibroblast response to IL-17 [23]. In the review of 58 patients from 39 families, 49 were homozygous and 9 compound heterozygous for 22 variants, six of them recurrent owing to probable founder effects; no allele had been experimentally shown to be a complete loss of function, and mutant protein levels range from normal to absent, so a normal immunoblot does not exclude the diagnosis [4, 16]. The founder variants and reported associations are shown in the following table.

The first three HGVS conversions were validated in VariantValidator; c.820dup is presented as described by the authors [12, 41]. In the North African deep dermatophytosis series, 15 Algerian and Tunisian patients from seven families were homozygous for Q289X through a founder effect, with a common homozygous haplotype and a most recent common ancestor estimated at about 975 years ago [42], with recessive inheritance and complete clinical penetrance [25].

2.8 Phenocopies, modifiers and susceptibility variants

Neutralising autoantibodies against IL-17A, IL-17F and IL-22 reproduce the IL-17 pathway defect without a genetic cause in the axis itself: they were present, at high titres, in all 33 patients with APS-1 tested by multiplex cytometry, 29 of whom had CMC; by ELISA, 4 of 30 had anti-IL-17A antibodies, 10 anti-IL-17F and 12 anti-IL-22 [33]. Patients with thymoma and CMC may also have these autoantibodies [4, 31]. Anti-IL-17F autoantibodies, without anti-IL-17A or anti-IL-22, were also detected in 11 of 17 Japanese patients with STAT1-GOF, in whom production of IL-17A and IL-22, but not of IL-17F, was reduced [1, 37]. Therapeutic IL-17 antagonists produce an iatrogenic phenocopy: in the placebo-controlled period in psoriasis, bimekizumab (anti-IL-17A and IL-17F) was associated with oral candidiasis in 9% versus 0%, and secukinumab with mucocutaneous candida infections in 1.2% versus 0.3%, with a dose-dependent effect [4]. The CLEC7A variant Y238X reduces β-glucan binding and IL-17, TNF and IL-6 responses, was described in a family with recurrent vulvovaginal candidiasis and onychomycosis and is common in the population, so it should not be accepted as the cause of severe or invasive CMC [4]. In Mendelian susceptibility to mycobacterial disease due to IL-12Rβ1 deficiency, the lack of IL-23 signalling explains mild CMC (mainly recurrent thrush) in 23% of patients [4].

3. Clinical Spectrum and Manifestations by System

3.1 STAT1-GOF: the international cohort of 274 patients

The reference clinical portrait remains the cohort of the International STAT1-GOF Study Group, published in 2016: 274 patients from 167 families in 40 countries and 5 continents, 62% from Europe, with a male/female ratio of 1.03 and a median age of 22 years (1–71) at the time of the study; 61% were familial cases [14]. The figures of this cohort describe patients referred to immunology centres and studied in a reference laboratory, with probable ascertainment bias in favour of CMC, and they mix patients treated in very different ways; they are not population frequencies [14]. The table summarises the main manifestations.

In the systematic review of 533 patients published in 2025, which includes the 2016 cohort, CMC was present in 94.93%, autoimmunity in 24.58% and bronchiectasis in 24.77%, with survival declining with age [15]. The comparison shows the influence of method: the literature review depends on what each report describes and does not replace the standardised data of a cohort [15].

3.2 Skin, nails and mucosae

Oral candidiasis (thrush, glossitis, angular cheilitis, candidal gingivitis) is the most constant manifestation; in the 2026 Mexican cohort the oral mucosa was affected in all 30 patients and 90% had two or more sites [14, 43]. Skin lesions include pustules, annular plaques and intertrigo; onychomycosis with onychia and paronychia is often prolonged and deforms the nails, and in the Moroccan series it affected 7 of 12 patients [14, 20]. C. albicans was the species isolated in 95% of 147 isolates [14]. Vulvovaginal candidiasis and balanitis are probably under-reported, as the Mexican authors point out [43]. Hidradenitis suppurativa has been described in patients with STAT1-GOF and responded to JAK inhibition [27, 44].

3.3 Oesophagus and digestive tract

Recurrent oesophageal candidiasis leads to dysphagia and stricture: in the 274-patient cohort, 97% of the 31 patients with digestive complications had a history of recurrent oesophageal candidiasis, and carcinomas were more frequent in patients with previous oesophagitis (10% versus 2%; p=0.002) [14]. The authors recommend sequential oesophageal biopsies in patients with oesophagitis and dysphagia [14]. Autoimmune enteropathy, inflammatory bowel disease and autoimmune hepatitis are part of the dysregulation spectrum; autoimmune hepatitis began before adulthood in six patients of the cohort, and a 2026 review describes, besides the autoimmune hepatitis pattern, probably underdiagnosed vascular and portal hypertension phenotypes [14, 45]. Severe enteropathy with dependence on parenteral nutrition may respond to JAK inhibitors [46].

3.4 Respiratory infections and lung

Lower respiratory infections affect almost half of patients, with recurrent lobar pneumonia, bronchitis and interstitial pneumonia; Streptococcus pneumoniae, Pseudomonas aeruginosa, Haemophilus influenzae and S. aureus were the most frequent agents [14]. Bronchiectasis developed in 21%, with superinfection by P. aeruginosa in 19% and by non-tuberculous mycobacteria in 7% [14]. Respiratory susceptibility is related to low IgA, IgG2 or IgG4 and to a deficient response to protein antigens, and to a qualitative immunoglobulin defect even without hypogammaglobulinaemia [14, 27].

3.5 Invasive fungal, mycobacterial and viral infections

Invasive fungal infections include endemic mycoses (histoplasmosis, coccidioidomycosis, talaromycosis) that depend on geography: in Mexico, 20% of the 30 patients had an invasive fungal infection, at a median age of 16.5 years, including disseminated histoplasmosis [14, 43]. Mycobacteria carry greater weight in regions with endemic tuberculosis: in Morocco, 42% of the 12 patients had a mycobacterial infection, mainly tuberculosis, and in Mexico 24% of the 25 BCG-vaccinated patients had BCG disease and 23% had tuberculosis; in Brazil, a mother and daughter with STAT1 p.(Arg274Gln) had lepromatous leprosy [20, 43, 47]. Viral infections are mainly due to herpesviruses; severe varicella, recurrent shingles in childhood, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viraemias, severe disease due to live viral vaccines and progressive multifocal leucoencephalopathy are part of the spectrum [14, 45].

3.6 Autoimmunity and endocrinopathies

Autoimmune thyroiditis with hypothyroidism is the most frequent autoimmune manifestation (22% of the 274 patients, 62% women); it is followed by type 1 diabetes, autoimmune cytopenias, vitiligo, alopecia, lupus, autoimmune hepatitis and coeliac disease [14]. In 19% of patients with autoimmunity there was more than one autoimmune disease [14]. In a patient with p.(Thr385Met), CMC and hypogammaglobulinaemia since the age of 15 and type 1 diabetes at 17, ruxolitinib 10 mg twice daily resolved the CMC and autoimmunity and allowed insulin to be stopped 12 months after initiation (21 months after the diagnosis of diabetes), with euglycaemia maintained for more than one year of follow-up [1]. A subgroup presents with a picture similar to IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked), with severe enteropathy, endocrinopathies and growth retardation [46, 48]. The overlap with APS-1 is large — CMC, thyroiditis, diabetes, hepatitis, vitiligo, alopecia — but hypoparathyroidism and adrenal insufficiency, typical of APS-1, are not part of the usual picture of STAT1-GOF [14].

3.7 Aneurysms, vasculopathy and nervous system

Aneurysms, in 6% of patients and diagnosed at a median age of 23 years, are mainly cerebral and multiple (basilar trunk, vertebral arteries, intracranial carotids), but also of the abdominal aorta, iliac arteries and pulmonary arteries; half of the symptomatic patients had a haemorrhage, and aneurysmal haemorrhage caused 15% of deaths, at a median age of 9 years [14]. The real frequency is probably underestimated, because only 42 patients had imaging and systematic screening in 25 asymptomatic patients was normal, whereas two aneurysms were detected only by screening [14]. Cerebral vasculitis, epilepsy and cognitive impairment have been described in minorities [14]. Cerebral aneurysms did not respond to JAK inhibitors during follow-up of a paediatric series [49].

3.8 Neoplasms

Squamous cell carcinomas of the oral mucosa, oesophagus, larynx and skin are the typical neoplasm, linked to chronic candidiasis and inflammation; cancer risk in the cohort was 5.8% versus 1.1% expected for age, and death from cancer occurred at a median age of 43 years [14]. In the Moroccan series, a 52-year-old man had squamous cell carcinoma of the lower lip; the A267V variant was associated with more tumours in the 533-patient database [15, 20].

3.9 Other haematological and systemic manifestations

Aplastic anaemia, pure red cell aplasia, haemophagocytic lymphohistiocytosis (HLH), infection-triggered macrophage activation syndrome, myocarditis and mineral bone disease have been described; in the Mexican cohort there was macrophage activation syndrome in two patients [19, 27, 43]. Growth retardation affects 12% in the international cohort and 61% of patients who proceeded to HCT, which reflects the severity of this subpopulation [14, 28].

3.10 IL-17 pathway defects

In IL-17RA deficiency, all 21 patients had their first CMC episode before 6 months (intertrigo, scalp, thrush, anogenital candidiasis, nails), 14 had staphylococcal skin infections (abscesses, folliculitis, furunculosis, crusted pustules of the face and scalp) and 8 had recurrent bacterial respiratory infections (otitis, sinusitis, bronchitis, lobar pneumonia); none had autoimmune endocrinopathy, aneurysms or carcinomas, and ages ranged from 2 to 35 years [21]. A family with four affected members aged 11 to 37 years had raised IgG [4]. IL-17RC deficiency produces isolated CMC from childhood, without staphylococcal infections, in four described patients (8, 12 and 37 years, and an infant with onset at 3 months) [4, 30]. ACT1 deficiency manifested in two siblings with thrush, recurrent staphylococcal blepharitis and transient atopic dermatitis; the IUIS adds folliculitis and macroglossia [6, 24]. In the two Algerian siblings, children of consanguineous parents and homozygous for p.T536I, the brother developed at 8 years macrocheilitis with chronic progressive macroglossia and recurrent oral candidiasis, and the sister had from early childhood bilateral blepharitis and folliculitis decalvans due to S. aureus, occasional thrush and onychomycosis due to Candida parapsilosis; the infantile dermatitis, described as atopic in the article abstract and as seborrhoeic in the clinical report and in OMIM, resolved in 6 weeks with topical treatment, and neither had psoriasis [24, 50]. IL-17F deficiency was described in one family with CMC and, less frequently, S. aureus infection [4, 5]. In that Argentinian family, the heterozygous variant p.Ser65Leu was present in all affected members and also in two asymptomatic female relatives, aged 9 months and 21 years, indicating incomplete penetrance; OMIM keeps the gene-phenotype relationship as provisional because there is only one family [51]. JNK1 haploinsufficiency combines CMC with Ehlers-Danlos-like skin and joint hyperextensibility [22]. The authors of the IL-17RA study propose a continuum of severity, milder in IL-17F and IL-17RC deficiencies and more severe in ACT1 and IL-17RA deficiencies, which also respond to IL-17E; in a review of 31 patients with isolated IL-17 pathway CMC there were no cancers, but the number is too small to exclude risk [4, 21].

3.11 RORγT deficiency

The seven described patients had CMC and mycobacterial disease (BCG or environmental mycobacteria) [7]. OMIM, based on the clinical report, records that all were vaccinated with BCG in infancy and that most developed disseminated mycobacterial disease, with CMC of variable severity in six of the seven; it adds the absence of palpable axillary and cervical lymph nodes, a small thymus and, in some patients, hepatosplenomegaly, and in the laboratory a slight reduction of T cells, absence of type 1 NKT cells and MAIT cells and very low levels of type 3 innate lymphoid cells, with normal B and NK cells [17]. These findings reproduce the phenotype of the Rorc-/- mouse, with no peripheral and mesenteric lymph nodes or Peyer's patches and 74.4% fewer thymocytes [17]. Orphanet classifies the disease in the Mendelian susceptibility to mycobacterial disease group [8].

3.12 CARD9 deficiency

CARD9 deficiency is characterised by invasive fungal disease due to Ascomycota in previously healthy children and adults, without increased susceptibility to bacteria, viruses, parasites or mycobacteria [16]. In the review of 58 patients from 39 families and 14 countries, invasive disease began between 3.5 and 52 years; 20 of the 52 patients with invasive disease also had superficial infections; 6 had only CMC or superficial dermatophytosis at last follow-up (19–50 years); in 50 of the 52 patients a single fungus was involved [16]. Manifestations include candidiasis of the central nervous system (CNS), with a marked predilection, deep dermatophytosis with invasion of the dermis, subcutaneous tissue, lymph nodes and sometimes the brain, subcutaneous and invasive phaeohyphomycosis and extrapulmonary aspergillosis [4, 25]. In the North African series of 17 patients with deep dermatophytosis, four died with active disease at 28, 29, 37 and 39 years, and the survivors (37–75 years) had no other serious infections [25]. The 2025 systematic review found a mean age of 33.43 ± 19.12 years (1–91), onset in childhood or adolescence in 58%, skin, CNS and lymph nodes as the most affected sites, Trichophyton and Candida as the most frequently isolated fungi, 18 anatomical sites and 19 fungal genera, and 32.82% invasive infections defined by the EORTC/MSG criteria [40].

3.13 Natural history and treated disease

STAT1-GOF cohorts mix untreated patients, patients treated with antifungals, with immunosuppressants, with JAK inhibitors and transplanted patients; none describes pure natural history [14, 15]. In the 2016 cohort, only one patient had received ruxolitinib; the frequencies of autoimmunity, aneurysms and cancer therefore essentially describe disease without targeted treatment [14]. In later cohorts, JAK inhibitors modified CMC and the dysregulation manifestations, but there are as yet no long-term data on their influence on the incidence of aneurysms, carcinomas or invasive infections [19, 27]. In CARD9 deficiency, relapse of invasive disease in 44 of 45 patients who had responded to treatment shows that the treated history is that of a chronic relapsing disease [16].

4. Clinical Recognition and Warning Signs

4.1 When to suspect

The French National Diagnosis and Care Protocol (PNDS) for inherited immune deficiencies includes among the warning signs, in children, infections by opportunistic or usually non-pathogenic agents, such as "recurrent or invasive candidiasis" ("candidoses récidivantes ou invasives"), and, in adults, "persistent mucocutaneous mycosis" ("mycose cutanéo-muqueuse persistante"); recurrent mucocutaneous candidiasis also appears among the infections with an unusual course that justify immunological evaluation [52]. In the PNDS table of agents, Candida points to a cellular immunity defect and invasive Candida to a phagocytic cell defect [52]. The following table summarises the clinical contexts that, in the sources consulted, should point towards each entity.

Diagnostic delay is frequent: in the clinical case in section 10, CMC from the age of 16 was attributed for decades to the glycaemic control of type 1 diabetes [26]. Recurrent candidiasis in a diabetic patient with adequate glycaemia, the association of several endocrine autoimmune diseases and a family history of onychomycosis or thyroiditis should prompt referral to clinical immunology [26].

4.2 Warning and emergency signs

Emergencies include sudden headache, focal neurological signs or seizures in a patient with STAT1-GOF (ruptured aneurysm or vasculitis), fever with meningeal or neurological signs in a patient with CARD9 deficiency (CNS candidiasis), progressive dysphagia or weight loss (oesophageal stricture or carcinoma), fever and cytopenia with hepatosplenomegaly (HLH or disseminated infection) and extensive varicella or herpes [14, 16, 48]. Fever, general malaise and inflammatory lymphadenopathy weeks after BCG vaccination (regional BCGitis) justify specialist evaluation, unlike isolated local BCGitis, which heals without treatment [52].

4.3 Newborn screening

The sources consulted do not describe newborn screening for any of the diseases in this article; the French PNDS mentions only newborn screening for severe combined immunodeficiency by quantification of T-cell receptor excision circles (TREC), aimed at profound defects of T-cell production. Presymptomatic detection is made by studying the relatives of an index case [14, 52].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Criteria

There are no validated formal clinical criteria for these diseases. Diagnosis is molecular and functional: a pathogenic biallelic variant in a recessive gene (IL17RA, IL17RC, TRAF3IP2, RORC, CARD9) or a heterozygous variant with a demonstrated functional effect in a dominant gene (STAT1, IL17F, MAPK8), in a patient with a compatible phenotype [4, 6]. To accept a gene as a cause of IEI, the IUIS requires a monogenic genotype absent in individuals without the phenotype, a causal relationship confirmed by a cellular phenotype and, whenever possible, correction of the functional defect [6].

5.2 Initial evaluation of CMC

Before accepting a genetic defect, the evaluation includes HIV serology, serum immunoglobulins and lymphocyte subsets, thyroid and adrenal function, APS-1 autoantibodies (anti-interferon-ω and anti-IFN-α antibodies) and neutralising anti-IL-17A, IL-17F and IL-22 antibodies [4, 33]. Mycological tests document the infection: culture and species identification of Candida from oral, oesophageal, cutaneous or nail lesions and antifungal susceptibility testing, to detect azole resistance and non-albicans species [4, 31]. The general approach to IEI recommends a three-generation pedigree, vaccination history including BCG, full blood count, immunoglobulins, T, B and NK subsets, vaccine responses and tests of neutrophil function and innate pathways when indicated [13].

5.3 Guiding immunological tests

The count of IL-17A-producing T cells is low in 82% of tested patients with STAT1-GOF, but not in all; a normal count does not exclude the diagnosis [14]. In RORγT deficiency, IL-17A/F T cells are absent and IFN-γ production in response to mycobacteria is reduced; it is the combination of the two findings that is specific [4]. In CARD9 deficiency, routine immunology (immunoglobulins, subsets, oxidative burst) is usually normal, cytokine production in response to C-type lectin agonists and to inactivated fungi is reduced, and Th17 cells are low in most patients [4, 16]. In IL-17RA, IL-17RC and ACT1 deficiencies, lymphocyte subsets are normal and assays of the fibroblast response to IL-17A/F (and of the leucocyte response to IL-17E) exist only in specialised laboratories; these assays do not distinguish between genes of the same complex and do not differentiate a genetic defect from anti-IL-17 autoantibodies [4, 21]. In STAT1-GOF, immunophenotyping shows low CD4+ in 28%, CD8+ in 16%, CD19+ in 19%, memory B in 49% and NK in 25% of tested patients [35].

5.4 Molecular tests in order

The first-line test is a next-generation sequencing IEI gene panel, or exome sequencing, that includes STAT1, IL17RA, IL17RC, IL17F, TRAF3IP2, MAPK8, RORC, CARD9, AIRE, STAT3, ZNF341, DOCK8, IL12RB1 and IL12B; the French PNDS mentions panels with more than 480 genes and Oxford Desk Reference recommends storing DNA when the defect is not defined [13, 52]. Copy-number analysis is part of the study, because IL-17RA deficiency may result from a homozygous deletion at 22q11.1 detectable by microarray [4]. In families with a known variant, targeted Sanger sequencing is sufficient for relatives [21].

5.5 Functional confirmation of STAT1-GOF

Confirmation of gain of function is indispensable for novel variants or variants of uncertain significance, because it determines the disease and the treatment [4, 27]. Methods include leucocyte immunoblotting showing increased phosphorylated STAT1 after IFN-γ, flow cytometry in CD14+ monocytes stimulated with IFN-γ and staurosporine, described as a simple functional screen, transient expression assays with a GAS luciferase reporter and flow cytometry of phosphorylated STAT1 after IL-6, IFN-α or IL-27 [4, 26, 48]. Interpretation is made together with the molecular result and by specialised laboratories [4]. The functional assay allowed the variant of uncertain significance in the case in section 10 to be reclassified as pathogenic (criteria PS3, PM6, PP2 and PP4) [26].

5.6 Limitations of the tests

A negative panel does not exclude the diagnosis: deep intronic variants, structural variants and variants in genes not yet described escape most panels, and about half of the patients with CMCD studied before 2016 had no identified genetic aetiology [14, 24]. Sequencing alone does not distinguish gain from loss of function in STAT1: the same position may have changes with different effects, and interpretation depends on the functional assay [4, 35]. In CARD9, the presence of normal-sized protein does not exclude the deficiency [4]. In IL17RA, surface expression does not exclude the deficiency [21]. In RORC, variants of uncertain significance dominate ClinVar [4]. The proportion of variants detectable by a panel is not equivalent to clinical sensitivity, which has not been estimated for these diseases [14].

5.7 Report content and classification

The report should state the gene, the transcript with version (for example NM_007315.4 for STAT1 and NM_052813.5 for CARD9), the variant in HGVS c. and p. nomenclature, the zygosity, the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and, for STAT1, whether the functional effect was demonstrated and in which direction [12, 26]. Family segregation helps to interpret variants of uncertain significance in recessive genes, in which healthy parents and siblings should be heterozygous or homozygous for the normal allele [21].

5.8 Diagnostic algorithm

The algorithm proposed from the sources consulted follows four steps. First, confirm CMC by mycology and exclude acquired causes (HIV, uncontrolled diabetes, corticosteroids, IL-17 antagonists, thymoma) [4, 31]. Second, characterise the associated phenotype (autoimmunity, other infections, mycobacteria, invasive infection, IgE, ectodermal and endocrine abnormalities) and request the guiding immunological tests and anti-interferon and anti-IL-17/IL-22 antibodies [4, 14]. Third, request a panel or exome with copy-number analysis [4]. Fourth, functionally confirm novel variants of STAT1 and of dominant genes and perform segregation studies in the recessive forms [4, 21].

5.9 Prenatal and preimplantation diagnosis

When the familial variant is known, prenatal diagnosis by molecular analysis of chorionic villi or amniocytes and preimplantation genetic diagnosis are technically possible; Oxford Desk Reference recommends considering cord blood storage from unaffected siblings, a potential source of stem cells, and sending cord blood for immunophenotyping when there has been no prenatal diagnosis [13].

6. Differential Diagnosis

6.1 Comparative table

6.2 The main differential diagnoses

APS-1 is the closest differential diagnosis of STAT1-GOF: both combine CMC with endocrine autoimmunity, and the overlap includes thyroiditis, diabetes, hepatitis, vitiligo and alopecia [14]. APS-1 is distinguished by hypoparathyroidism, adrenal insufficiency, enamel hypoplasia and CMC as the only infection, and in the laboratory by anti-IFN-ω and anti-IFN-α autoantibodies, present in all patients, and by anti-IL-17F and anti-IL-22 autoantibodies [33]; isolated anti-IL-17F does not discriminate, because it has also been found in STAT1-GOF [1]. STAT1-GOF is distinguished by bacterial, herpetic and mycobacterial infections, endemic mycoses, aneurysms and dominant inheritance [14]. Both diseases respond to JAK inhibition, which does not obviate molecular diagnosis, because genetic counselling and surveillance differ [27].

The hyper-IgE syndromes (due to dominant-negative STAT3 and to ZNF341 deficiency) share the reduction of Th17 cells and CMC, but are distinguished by the neonatal rash, eczema, "cold" staphylococcal abscesses, pneumonia with pneumatoceles, very high IgE and abnormalities of connective tissue, skeleton and dentition [6, 22]. DOCK8 deficiency combines raised IgE with severe cutaneous viral infections and allergy [6].

Among the genetic causes of CMC, the pattern of infections points to the gene: isolated candidiasis suggests an IL-17 pathway defect; candidiasis with staphylococcal skin infections suggests IL-17RA or ACT1; candidiasis with mycobacteria suggests RORγT, IL-12Rβ1 or STAT1-GOF; invasive fungal disease due to a single Ascomycota in a healthy patient suggests CARD9 [4, 7, 16, 21]. Loss-of-function STAT1 deficiency is the mirror image of STAT1-GOF: the same gene causes susceptibility to mycobacteria and viruses without CMC, and JAK inhibition would be harmful [4, 35].

The IPEX-like picture of STAT1-GOF, with enteropathy, endocrinopathies and growth retardation, enters the differential diagnosis of the Tregopathies: in the 2018 transplant series, some patients had an IPEX-like phenotype, isolated or with combined immunodeficiency [48]. Early oral candidiasis with growth retardation, diarrhoea and opportunistic infections in the first months points to severe combined immunodeficiency, a therapeutic emergency [13]. In biotinidase deficiency, mucocutaneous candidiasis frequently accompanies dermatitis and alopecia, and in two patients with extensive CMC the in vitro and in vivo responses to Candida antigen were absent; correction with biotin distinguishes this treatable cause [53].

In adult-onset forms, testing for anti-cytokine autoantibodies and thymoma is mandatory before concluding that there is a genetic defect, and the drug history (IL-17 antagonists, corticosteroids) excludes iatrogenic causes [4, 31]. Diabetes is a frequent cause of candidiasis, but persistence of the infection with good glycaemic control, the association with other autoimmune diseases and a family history should rule out the simple explanation [26].

7. Treatments and Risk Management Strategies

7.1 Principles and organisation of care

No medicine is authorised for any of the diseases in this article: antifungals are prescribed under the indication of the infection and Janus kinase (JAK) inhibitors are used outside the indications of the summary of product characteristics (SmPC), with the informed consent of the patient or family [4, 27]. Management has four components: treatment and prevention of candidiasis and other infections; treatment of immune dysregulation in STAT1-GOF; surveillance of the complications that determine mortality (invasive infections, aneurysms, carcinomas); and, in selected patients, definitive correction by haematopoietic cell transplantation (HCT) [14, 27]. The authors of the international cohort consider that STAT1-GOF should not be regarded as benign and should be followed up in experienced centres, and the French national protocol organises care in reference and competence centres with national multidisciplinary consultation meetings [14, 52]. The 2026 consensus recommends coordination with infectious diseases and clinical pharmacy, given the complexity of interactions and infectious risks [27].

7.2 Antifungals: treatment of episodes and long-term suppression

Oral azoles are first line in all forms of chronic mucocutaneous candidiasis (CMC). In the cohort of 274 patients with STAT1-GOF, 74% required long-term antifungal therapy, mainly systemic, with fluconazole as first line followed by itraconazole or posaconazole; in IL-17RA deficiency, the combination of oral fluconazole and topical nystatin controlled or prevented episodes [14, 21]. The 2016 Infectious Diseases Society of America (IDSA) guideline is the dosing reference for mucosal candidiasis: it does not specifically address inborn errors of the IL-17 pathway, but it indicates fluconazole as initial therapy for CMC and states that most of these patients require long-term suppression and frequently develop azole-refractory infections, to be treated as in patients with AIDS [31]. The 2025 global guideline of the European Confederation of Medical Mycology (ECMM) refers the recommendations on mucocutaneous candidiasis to its appendix and recommends therapeutic drug monitoring of triazoles and echinocandins, when available, in populations at risk of extreme exposure [54].

The fluconazole dose stated in the Portuguese SmPC for CMC (50–100 mg/day) is lower than the IDSA dose for moderate to severe oropharyngeal candidiasis (100–200 mg/day); the reference is the guideline dose, and the SmPC dose is given for comparison [31, 55]. Prolonged exposure selects resistant strains: in the STAT1-GOF cohort there was clinical resistance to at least one antifungal in 78 of the 202 patients on long-term treatment (39%) and in 8 of the 53 on intermittent treatment (15%), resistance to more than one antifungal in 10%, and in vitro azole resistance in 98% of the strains tested; resistance was associated with recurrent pneumonia (51% versus 25%), systemic fungal infection (17% versus 7%) and mortality (21% versus 7%) [14]. These patients moved to second or third line with voriconazole, echinocandins, terbinafine or liposomal amphotericin B, with toxicity and with the practical limitation of the intravenous route [14]. Culture with species identification and susceptibility testing before switching drugs, and attention to non-albicans species, are part of follow-up [4, 31]. Rezafungin, a once-weekly echinocandin, was used successfully in a patient with STAT1-GOF and azole-resistant CMC [27]. Oral encochleated amphotericin B (MAT2203) was evaluated in a phase 2a trial in four patients with mucocutaneous candidiasis refractory to or intolerant of standard oral therapies, completed in 2022, and a review describes it as effective and well tolerated in azole-resistant CMC [58, 59].

Adverse effects of fluconazole to monitor include liver injury, rare but sometimes severe, anaphylactic reactions and exfoliative skin disorders, with discontinuation if a rash attributable to the drug appears in a superficial infection [56]. Azoles are CYP3A4 inhibitors (posaconazole, strong) or dual CYP2C9 and CYP3A4 inhibitors (fluconazole) and increase exposure to ruxolitinib, tofacitinib and upadacitinib; the adjustments are given in section 7.4 [27, 60]. Besides azoles, care of the skin, nails and mouth and oral and denture hygiene are part of treatment, and topical antifungals and antiseptic mouthwashes remain an option, although the corresponding statement of the 2026 consensus did not reach the agreement threshold [4, 27, 31].

7.3 Prevention of bacterial, viral and Pneumocystis infections

In the 274-patient cohort, 66 (24%) received antibacterial prophylaxis, mainly with co-trimoxazole, for recurrent lower respiratory infections or cutaneous staphylococcal disease, and 30% of patients with recurrent pneumonia (14% of the total) received intravenous immunoglobulin [14]. The 2026 consensus recommends considering replacement immunoglobulin in patients with recurrent sinopulmonary infections, lung disease or impaired B-cell immunity (agreement 87.5%; level of evidence 4; grade of recommendation C); in the largest cohort treated with JAK inhibitors, 53% of patients with STAT1-GOF were receiving immunoglobulin, and the altered antibody specificity, even without hypogammaglobulinaemia, supports this option [27]. Antibiotic prophylaxis with co-trimoxazole or azithromycin in patients with recurrent infections or bronchiectasis is supported by clinical experience, but the corresponding statement did not reach the agreement threshold for reasons of wording [27]. Antiviral prophylaxis should be considered in patients with recurrent or difficult-to-treat HSV or VZV infections (agreement 100%; level of evidence 2b; grade B), and Pneumocystis jirovecii prophylaxis in selected patients, particularly with impaired T-cell immunity (level 4; grade C); in the largest cohort, 51% of patients with STAT1-GOF received pneumocystis prophylaxis and 20% antiviral prophylaxis [27]. In IL-17RA deficiency, staphylococcal and respiratory infections respond to antibiotics but recur [21].

7.4 Janus kinase inhibitors in STAT1-GOF

7.4.1 Rationale and published results

JAK inhibitors are small molecules that occupy the ATP-binding site of the kinase domain and prevent STAT phosphorylation, reducing signalling of type I and II interferons, IL-6 and IL-4/IL-13 while preserving part of the defence mechanisms [27]. Ruxolitinib preferentially inhibits JAK1 and JAK2, baricitinib JAK1 and JAK2 with lower potency, tofacitinib JAK1 and JAK3, and upadacitinib is JAK1-selective [44, 46, 59]. In STAT1-GOF, treatment reduces phosphorylated STAT1, normalises the expression of interferon-stimulated genes, reduces T-cell apoptosis, corrects Th1 polarisation and increases Th17 cells, with improvement of candidiasis; NK-cell maturation and cytotoxicity improve only partly and neutrophils maintain their pro-inflammatory programme [19, 35]. In a longitudinal study of two patients, immune recovery began in the first week, with increased T-cell receptor repertoire diversity, but was incomplete and the NK-cell defect persisted in one of them [19].

The clinical evidence is retrospective. In the 2018 international series, 11 of the 17 patients had STAT1-GOF; 14 of the 17 improved and candidiasis resolved in the responding patients with STAT1-GOF; two patients with enteropathy dependent on parenteral nutrition no longer needed it [46]. In the paediatric series of 10 children (median age 8.5 years; ruxolitinib in 9 and baricitinib in 1; median follow-up 18 months), 9 had a partial or complete response and the immune deficiency and dysregulation activity score (IDDA) fell from 15.99 to 7.55 (p=0.0078) [49]. In the ESID and EBMT cohort of 69 patients (45 with STAT1-GOF; ruxolitinib in 80%), there was partial or complete remission of symptoms in 87% of patients with STAT1-GOF; adverse events, mainly infection and weight gain, occurred in 38% and were mostly grade I to II and transient; at last follow-up 52 of the 69 patients remained on treatment [61]. Time to response depends on the manifestation: cytopenias in 1 to 2 weeks, candidiasis in 1 to 8 weeks, dermatitis in 2 to 4 weeks, aphthae and enteropathy in 6 to 12 weeks, keratitis, autoimmune hepatitis and pulmonary hypertension in 3 to 8 months; cerebral aneurysms showed no response during follow-up [49]. About a quarter of patients resolve candidiasis with the JAK inhibitor and can stop systemic antifungal therapy, which avoids interactions (agreement 100%; level 4; grade C) [27]. Cases have been published of response of autoimmune hepatitis resistant to conventional treatment, hidradenitis suppurativa and recent-onset type 1 diabetes, and also of failures with worsening fungal infection in patients already severely infected [44, 46, 62].

7.4.2 Indications, contraindications and pre-treatment assessment

The 2026 consensus establishes that treatment should be considered in patients with immune dysregulation and genetic or functional evidence of increased activation of one or more JAK-STAT pathways (agreement 100%; level 2b; grade B), and that CMC is not a contraindication to starting (agreement 100%; level 2b; grade B) [27]. It recommends caution in active or previous neoplasia, cardiovascular disease, thromboembolic disease or its risk factors, risk of tuberculosis or endemic mycoses, pulmonary hypertension and renal impairment (glomerular filtration rate below 30 mL/min/1.73 m²) or hepatic impairment (enzymes five times above the upper limit of normal); active severe or opportunistic infections should be controlled before starting [27]. Vasculitis and non-infectious, non-thrombotic vasculopathy may be manifestations of the disease itself and do not contraindicate treatment [27]. The baseline assessment includes the history of infections, neoplasms and immunosuppressants, physical examination, vaccination status, medication review (organic anion transporter 3 inhibitors, such as probenecid, and CYP450 inhibitors or inducers, such as clarithromycin and rifampicin), full blood count with differential, liver and renal function, lipid profile, infectious screening including nucleic acid amplification tests when appropriate (hepatitis B and C, HSV, HIV, Epstein-Barr virus, cytomegalovirus, VZV and tuberculosis), lymphocyte subsets and immunoglobulins; serology is unreliable in these patients, owing to impaired antibody function and replacement immunoglobulin [27]. Baseline imaging comprises chest radiography, abdominal ultrasound, electrocardiogram and echocardiogram, chest computed tomography in patients with pulmonary involvement and brain magnetic resonance imaging with a vasculitis protocol [27].

7.4.3 Choice of drug, dose and adjustments

The consensus does not recommend a particular inhibitor or dose (level 2b; grade B) and lists as factors in the choice age, interactions, comorbidities, local availability and experience, cost, the possibility of drug-level monitoring, patient preference, tolerance and toxicity profile [27]. The starting dose may follow the recommendations for other indications or published experience, with escalation or shortening of the interval according to response and, when available, with pharmacokinetic support [27]. In the largest cohort, the median ruxolitinib dose in STAT1-GOF was 15 mg/m²/day (4.5–40 mg/m²/day), 82% of patients took two daily doses and 9% needed three, guided by drug-level monitoring [61]. In the paediatric series, starting doses were lower: median 0.28 mg/kg/day (0.2–0.6) and median maximum dose 0.6 mg/kg/day (0.25–0.78); the authors propose, in the absence of prospective data, starting at 0.3–0.5 mg/kg/day in two doses and increasing by 0.1–0.2 mg/kg/day every 2 to 4 weeks until clinical effect, without exceeding the suggested maximum of 50 mg/m²/day in children [49]. The 2018 series used 0.4–2 mg/kg/day or 15 mg/m² per dose twice daily, with escalation from half the target dose and increases of 25% per week [46]. Baricitinib was used in adults at 2 mg/day increasing to 2 mg twice daily, and in a child at 4 mg/day without response after two months, with complete remission of candidiasis after switching to ruxolitinib [19, 49]. All these doses are outside the approved indications.

Dose reduction is indicated for grade 3 cytopenia not attributable to the disease (haemoglobin below 6.5 g/dL, platelets below 25 × 10⁹/L, neutrophils below 0.5 × 10⁹/L), elevation of transaminases, alkaline phosphatase or bilirubin above 2.5 times the upper limit of normal, any other toxicity above grade 3, creatinine clearance below 30 mL/min (half the dose) and chronic or recurrent viral infections [27]. With strong CYP3A4 inhibitors, such as posaconazole, or dual CYP2C9 and CYP3A4 inhibitors, such as fluconazole, the dose should be reduced by about 50%; the European SmPC and the US label of ruxolitinib recommend the same adjustment and advise avoiding combination with fluconazole at doses above 200 mg per day [27, 60, 63]. In the transplant cohort, 13 of the 20 patients pre-treated with ruxolitinib were receiving an azole at the same time, with an estimated doubling of ruxolitinib exposure [28]. Tofacitinib and upadacitinib are metabolised mainly by CYP3A4, whereas baricitinib is eliminated by renal transporters [27]. Switching inhibitor should be considered for incomplete response, interactions or organ toxicity attributed to the drug, and almost all patients who switched improved [27]. Discontinuation should be gradual, over two to four weeks, because of the risk of a withdrawal syndrome, although in one cohort 12 of 18 patients stopped abruptly without symptoms; sustained remission after discontinuation has been described in a patient treated for 48 months for candidiasis [27].

7.4.4 Monitoring and risks

Monitoring includes, at each visit, the dose and concomitant medication, response and new manifestations, infections and adverse events, physical examination with weight, height, body mass index and blood pressure, full blood count, liver and renal function, lipids, coagulation and inflammatory markers, faecal calprotectin in patients with digestive inflammation, testing for viral nucleic acids in blood (Epstein-Barr virus, cytomegalovirus, HSV, adenovirus) and, when accessible, drug levels; annual abdominal ultrasound, low-dose chest tomography and brain magnetic resonance imaging with a vasculitis protocol every two to three years and an annual electrocardiogram complete the schedule [27]. In the largest cohort, visits took place every one to two weeks in the first three months and thereafter at a median of ten weeks [61]. The ruxolitinib label requires a full blood count before starting and every two to four weeks until the dose is stable, lipid assessment at 8 to 12 weeks and enquiry about a history of tuberculosis, herpes simplex, shingles and hepatitis B, with testing for latent infection in higher-risk patients [63]. The risks listed on the label are cytopenias, serious bacterial, mycobacterial, fungal and viral infections, symptom exacerbation after interruption, non-melanoma skin cancer (with periodic skin examination), dyslipidaemia, major adverse cardiovascular events, thrombosis and secondary malignancies [63]. In patients with STAT1-GOF, VZV reactivation is the most frequent concern: two paediatric patients developed shingles on ruxolitinib and were treated with an antiviral and temporary interruption, one of them resuming the drug without further complications; in the 2018 series, two patients without prophylaxis had shingles, and one who did not resume treatment had a severe relapse of candidiasis followed by P. jirovecii and Cryptococcus pneumonia [27, 46]. Progressive multifocal leucoencephalopathy has been described among the infectious complications of JAK inhibition in these patients [45]. Treatment should be stopped in pregnancy and breastfeeding, acute venous thrombosis unrelated to the disease, cardiovascular events, uncontrolled neoplasia, anaphylaxis to the drug, active severe infections, including latent tuberculosis and opportunistic infections, and severe organ dysfunction not attributable to the disease [27].

7.5 Haematopoietic cell transplantation

HCT is the only option with curative potential in STAT1-GOF and historical results were unfavourable. In the first international series, with 15 patients, primary donor engraftment occurred in 74%, overall survival was 40%, secondary graft failure reached 50% and event-free survival at 100 days was 10%, with pre-transplant haemophagocytic lymphohistiocytosis contributing to the poor outcome; only one patient had received a JAK inhibitor before the procedure [48]. In the joint cohort of the EBMT and the Primary Immune Deficiency Treatment Consortium published in 2025, with 36 patients and 40 procedures between 2010 and 2023 in 14 countries, overall survival was 72.2% and event-free survival 55.6% [28]. The median age was 0.8 years at first symptoms, 7 years at diagnosis and 11 years at first transplant (range 1–33 years); the indications were combined immunodeficiency (39%), autoimmunity or an IPEX-like picture (28%) and severe infections (33%) [28]. Conditioning was myeloablative in 60% of procedures and reduced-intensity myeloablative in 25%; non-myeloablative conditioning, used in six procedures because of poor clinical condition, very young age or previous failure, had a worse outcome; serotherapy was given in 90% (antithymocyte globulin in 23 and alemtuzumab in 13, the latter associated with better survival) [28]. The probability of engraftment at 100 days was 87.2% for neutrophils and 74.3% for platelets above 20 × 10⁹/L; 64% of patients achieved durable full chimerism after the first transplant; acute graft-versus-host disease occurred in 45% of procedures, grade III or IV in 15%, and graft failure in 15% [28]. Of the ten deaths, six resulted from post-transplant infection, two from severe graft-versus-host disease, one from cerebral aneurysm haemorrhage and one from pulmonary microangiopathy [28].

Prior treatment with ruxolitinib was associated with better event-free survival (73% versus 30%; p=0.0044) and a trend towards better overall survival (84% versus 54%; p=0.067); in the multivariable analysis with year of transplant and serotherapy as covariates, only ruxolitinib pre-treatment remained associated with event-free survival (hazard ratio 0.286; 95% CI 0.092–0.894; p=0.031) [28]. The authors' hypothesis is that prior control of immune dysregulation, with reduction of interferon-γ in the peri-transplant period, reduces graft failure and inflammatory complications; in one patient emapalumab (anti-interferon-γ antibody) was used in conditioning, with a good outcome at more than one year [28]. Patients with a haematopoietic cell transplantation-specific comorbidity index of 1 or more had worse event-free survival [28]. The 2026 consensus therefore recommends considering bridging with a JAK inhibitor in all patients with a planned transplant, maintaining the same dose and surveillance, performing the transplant ideally after a stable complete or partial response, not delaying an indicated transplant when there is no response after three to six months and especially if there is a risk of organ damage, tapering the inhibitor from the start of conditioning and stopping it before infusion, and reintroducing it or using corticosteroids if withdrawal symptoms appear after engraftment [27]. HCT is not an established treatment in IL-17 pathway defects, in which disease is restricted to the mucocutaneous barriers, and its value in CARD9 deficiency remains uncertain [4, 16].

7.6 Gene therapy

The first strategy for gene correction of a dominant gain-of-function disease causing immunodeficiency was published in 2026, at the preclinical stage [64]. The aim is an autologous alternative to allogeneic transplantation. CRISPR/Cas-mediated homology-directed repair strategies, universal or mutation-specific, proved limited: efficiency below 25%, low cell viability and absence of allelic specificity, that is, inability to correct the mutant allele without affecting the normal one [64]. Adenine base editing corrected the recurrent p.(Thr385Met) variant with an efficiency above 90% in patients' T cells and haematopoietic stem cells, without significant genomic aberrations at the target site or off target [64]. Correction restored total STAT1 expression (p<0.0217), STAT1 phosphorylation (p<0.0056) and the expression of interferon-stimulated genes, with OAS1 as the readout (p=0.0005), and improved IL-17 production (p<0.0001); the edited stem cells retained multilineage differentiation capacity and sustained engraftment, with persistence of the corrected allele at 16 weeks in humanised immunodeficient mice [64]. There is no registered gene therapy trial in this disease; the level of evidence is preclinical and translation to the patient depends on safety and efficacy studies that have not yet begun [64, 65]. A Belgian observational study, recruiting since the end of 2025, includes among its objectives the ex vivo assessment of gene correction in mononuclear cells from patients with STAT1-GOF, without administration to patients [65].

7.7 Immunomodulators and second-line approaches

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) have been used to increase the differentiation of IL-17-producing T cells: in the cohort of 274 patients with STAT1-GOF, one patient received GM-CSF, interferon-α and acitretin without relevant improvement, five received G-CSF with marked improvement of the lesions in only one, and one received interferon-γ from 6 to 15 years of age with no effect on the candidiasis [14]. In CARD9 deficiency, adjuvant recombinant GM-CSF produced complete remission of central nervous system candidiasis refractory to antifungals in one patient, and GM-CSF or G-CSF have been suggested in persistent or relapsing central nervous system infection; the label of sargramostim includes no fungal or immunodeficiency indication, so use is off-label and supported by isolated cases [4]. Interferon-γ-1b has a label limited to chronic granulomatous disease and severe malignant osteopetrosis, and its use in Mendelian susceptibility to mycobacterial disease is off-label, mechanistically rational in defects of production of the cytokine and not in defects of its receptor [4]. In patients with STAT1-GOF and severe autoimmunity, conventional immunosuppression was used in six patients of the cohort with a good response and without severe infectious complications, and rituximab in two patients with systemic Epstein-Barr virus infection that was not controlled [14]. In the IL-17 pathway deficiencies, there is no indication for immunosuppression or immunomodulation, because the defect is confined to IL-17A/F-dependent mucocutaneous immunity; JAK inhibition, effective in STAT1-GOF, acts on a different mechanism and is not transferable [4].

7.8 CARD9 deficiency: treatment of invasive fungal disease

Treatment is empirical and consists of prolonged antifungal therapy directed at the fungus actually isolated, combined with debridement or surgical removal of the fungal masses when feasible; as invasive disease relapsed in 44 of 45 patients who had responded to initial treatment, prolonged secondary prophylaxis and indefinite follow-up form part of care [16]. The choice of antifungal follows the identification and susceptibility of the fungus, with voriconazole, itraconazole, posaconazole, terbinafine, amphotericin B or echinocandins according to the agent [31, 40]. The systematic review of cases indicates that early diagnosis and early initiation of the antifungal improve the prognosis, and that mortality is concentrated in infections of the central nervous system, the blood and the viscera; 13 of the 82 patients analysed died [40]. Adjuvant therapy with myeloid growth factors has been used in refractory cases, and the role of HSCT remains undetermined [4, 40].

7.9 Regulatory table

7.10 Trials and developments of the last twelve months

The first controlled trial registered in these diseases is a phase 1/2 basket study of upadacitinib against placebo in patients aged 12 to 65 years with activating variants of STAT1, STAT3, STAT5B, STAT6 or JAK1, with 30 planned participants at three centres in the United States; the registration was published on 26 June 2026, the start was planned for October 2026 and completion for August 2028, and the primary outcomes are time to first disease reactivation, the proportion of patients with adverse events of special interest and the proportion with organ toxicity [68]. The Belgian study of ex vivo assessment of JAK inhibitors and of gene correction has been recruiting since December 2025, with 20 planned adult participants [65]. An expanded access programme made itacitinib available to one patient with STAT1-GOF and aplastic anaemia [27]. The natural history study of immune defects with fungal infections of the National Institute of Allergy and Infectious Diseases continues to recruit, with 1200 planned participants [69]. The publications of the last twelve months include the international consensus on JAK inhibitors (August 2026), the transplantation cohort of 36 patients (July 2025), correction by base editing in a preclinical model (August 2026), the genotype-phenotype analysis of 533 patients (November 2025), the study of immune reconstitution under a JAK inhibitor (October 2026), the Moroccan cohort of 12 patients (August 2026), the Mexican cohort of 30 patients (October 2026) and the review of hepatic manifestations (February 2026) [15, 19, 20, 27, 28, 43, 45, 64]. No new regulatory authorisation applies to these diseases.

7.11 Agents and situations to avoid

BCG vaccine and the other live attenuated vaccines are contraindicated: the French protocol states that BCG is contraindicated in disorders of innate immunity and that live vaccines are formally contraindicated in profound cellular deficiency, and the US label of BCG vaccine contraindicates it in congenital immunodeficiency [4, 52]. In RORγT deficiency and in Mendelian susceptibility to mycobacterial disease, BCG vaccination should be avoided in the affected or at-risk child, and siblings should be tested before neonatal vaccination [4]. In the STAT1-GOF cohort, severe disease due to live viral vaccines occurred in two patients, so the decision on each vaccine must be discussed with the reference immunologist; yellow fever vaccine is a particular problem for travel, because some countries do not accept waivers [14, 52]. During treatment with JAK inhibitors, live vaccines should be avoided or given at least four weeks before initiation, inactivated influenza vaccine is recommended for the patient and household contacts, and recombinant zoster vaccines follow the usual schedule [27]. Therapeutic antagonists of IL-17 and IL-23 are not advised because they worsen susceptibility to Candida; the label of ustekinumab expressly warns of serious infections due to mycobacteria, salmonella and BCG in patients with genetic IL-12/IL-23 deficiency [4]. In patients with CARD9 deficiency, occupational or domestic exposure to decaying plant matter and to soil is a plausible route of infection by saprophytic fungi, although the sources consulted do not quantify this risk [16].

7.12 Pregnancy, breastfeeding, perioperative care and transition

JAK inhibitors have few data in pregnancy: the consensus recommends effective contraception in women of childbearing potential and does not recommend breastfeeding during treatment, because some of these drugs pass into milk; treatment should be stopped in pregnancy and during breastfeeding [27]. The label of ruxolitinib notes the absence of studies in pregnant women, adverse developmental outcomes in animals with maternal toxicity, and recommends stopping breastfeeding during treatment and for the following two weeks [63]. In the systematic review of the consensus, two patients with STAT1-GOF stopped baricitinib on becoming pregnant [27]. Fluconazole at doses of 400 to 800 mg daily during the first trimester has been associated with a pattern of congenital anomalies (brachycephaly, facial dysmorphism, calvarial abnormalities, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis and congenital heart disease), and epidemiological studies suggest a risk of spontaneous abortion and of anomalies with 150 mg as a single or repeated dose in the first trimester; the label recommends avoiding fluconazole in pregnancy, except in severe or potentially fatal fungal infections, and effective contraception during treatment with 400 to 800 mg daily and for about one week after the last dose [56]. Pregnancy in a patient with CMC therefore requires the antifungal to be chosen together with infectious diseases and obstetrics, with preference for topical agents when they are sufficient [56]. In the perioperative setting, the sources consulted describe no precautions specific to these diseases, beyond considering the presence of cerebral aneurysms in STAT1-GOF and the infectious risk; procedures on fungal masses in CARD9 deficiency form part of treatment [14, 16]. Transition to adult care should maintain follow-up by clinical immunology, surveillance for the complications of section 11 and education on adherence and warning signs, in a disease in which mortality is concentrated in young adulthood [13, 14].

7.13 Table of studies and trials

All the clinical studies listed are retrospective or descriptive, without a concurrent comparison group and without random allocation; there is no completed controlled trial in any of these diseases, and the only registered comparative trial has not yet begun [27, 68]. The response rates of 87% to 90% refer to clinical improvement assessed by the treating physicians, with heterogeneous criteria between centres, highly variable doses and short follow-up; they do not measure survival or the incidence of complications [27, 61]. The comparison between the 40% survival of the first transplantation series and the 72.2% of the 2025 cohort is not a direct comparison of treatments: the two populations differ in era, conditioning regimens, serotherapy and severity, and seven patients from the first series were included again in the second; the multivariable analysis sought to correct for the effect of the year of transplantation and of alemtuzumab, but the number of patients is small [28, 48]. The differences in relative risk between STAT1 variants come from a review of the literature, with selective reporting of the most severe cases and unequal clinical information between reports [15]. The results of base editing are preclinical and allow no prediction of efficacy or safety in the patient [64].

8. Reproductive Options and Family Counselling

8.1 Recurrence risks

In STAT1-GOF, inheritance is autosomal dominant: an affected parent has a 50% probability of transmitting the variant in each pregnancy, regardless of sex [14]. In the 533-patient database, 15.2% of variants were de novo, so the risk for siblings of a sporadic case with negative parental testing is low, but not zero, because germline mosaicism has not been excluded; the sources consulted do not quantify this risk [15]. The penetrance of candidiasis is almost complete, but expressivity varies within families: in the international cohort, 61% of cases were familial and signs and symptoms varied between and within families [14]. A variant inherited from a parent with minimal or absent manifestations cannot be excluded: the only gain-of-function variant present in gnomAD was inherited from an asymptomatic mother [35]. In the case described in section 10, maternal inheritance was presumed from the mother's history of thyroiditis and onychomycosis; she was not tested [26].

In IL-17RA, IL-17RC, ACT1, RORγT and CARD9 deficiencies, inheritance is autosomal recessive, with a 25% risk in each pregnancy of a carrier couple, 50% healthy carriers and 25% non-carriers; the healthy parents and siblings tested in the published series were heterozygous or homozygous for the normal allele, with complete clinical penetrance in homozygotes [21, 25]. Consanguinity is frequent in these forms: 11 of the 12 families with IL-17RA deficiency were consanguineous, and the North African p.(Gln289Ter) and East Asian founder variants in CARD9 imply an increased risk in those populations [21, 25, 41]. In IL-17F deficiency and JNK1 haploinsufficiency, inheritance is autosomal dominant [5, 22].

8.2 Cascade testing and asymptomatic relatives

Testing relatives has immediate practical value in three situations. First, in diseases with mycobacterial risk (RORγT deficiency, Mendelian susceptibility to mycobacterial disease, STAT1-GOF), identifying affected siblings before BCG vaccination prevents disseminated disease due to a live vaccine [4, 52]. Second, in STAT1-GOF, identifying carriers allows surveillance of the complications in section 11 to be started before symptoms appear, with the caveat that the presence of the variant does not predict with certainty which manifestations the relative will have [14, 19]. Third, in the recessive forms, knowledge of carrier status informs reproductive planning and, in consanguineous families, targeted screening of the partner [21]. Testing an asymptomatic minor is justified when there is an immediate medical benefit, such as the contraindication of live vaccines or the start of surveillance, and should be accompanied by a genetics clinic consultation, in line with the French protocol, which assigns to the geneticist the explanation of the mode of transmission and family counselling [52].

8.3 Prenatal, preimplantation and perinatal options

When the familial variant has been characterised, prenatal diagnosis by molecular analysis of chorionic villi or amniocytes is technically possible, as is preimplantation genetic diagnosis; in diseases in which available treatment is effective in reducing morbidity, the decision is sensitive to the expected prognosis, which varies widely between the entities in this article and between variants of the same gene [13, 15]. The general approach to inborn errors of immunity recommends considering, in severe forms in which transplantation may be needed, the collection and storage of umbilical cord blood from unaffected siblings, a potential source of stem cells, and sending cord blood for immunophenotyping when there has been no prenatal diagnosis [13]. The absence of an identified gene in about half of the patients with inherited chronic mucocutaneous candidiasis studied before 2016 limits counselling for many families, which is then based on the observed segregation pattern [14].

8.4 Content of the consultation

The consultation should explain the mode of transmission and the recurrence risk, the variability of expression, the difference between identifying the variant and predicting the disease, the availability of cascade testing and its practical consequences (live vaccines, surveillance), the existence of effective symptomatic treatment and of off-label targeted treatment in STAT1-GOF, the need for long-term follow-up in an experienced centre and the patient support resources listed in section 9 [13, 27, 52]. In families with a variant of uncertain significance, it should be explained that the classification may change with the functional assay, as happened in the case in section 10 [26].

9. Special Considerations: Population Diversity and Epidemiology

9.1 What is and is not known about frequency

There is no validated population estimate for any of the diseases in this article. Orphanet classifies the worldwide point prevalence of chronic mucocutaneous candidiasis (ORPHA:1334, all causes) as "unknown", with an assigned and non-validated class; the STAT1-related entity (ORPHA:391487) has the class below 1 per 1,000,000 in Europe and a record of five cases or families, very outdated compared with the more than 660 published patients; complete RORγ deficiency (ORPHA:477857) has the same prevalence class and seven recorded cases [3, 8, 18]. The available figures are counts of described cases, dependent on access to molecular diagnosis: more than 660 patients with STAT1-GOF and more than 135 variants in 2026, about 100 patients with CARD9 deficiency, 21 patients with IL-17RA deficiency in 2016 (plus a family of four and two siblings with a deletion), 4 patients with IL-17RC deficiency, one family with ACT1 deficiency, one with IL-17F deficiency, three families with RORγT deficiency and one family with JNK1 haploinsufficiency [4, 7, 19–24, 30]. STAT1-GOF is the most frequent genetic cause of inherited chronic mucocutaneous candidiasis: about half of the approximately 400 patients with chronic mucocutaneous candidiasis disease studied in the Paris and New York reference laboratory had gain-of-function STAT1 variants, according to unpublished data cited by the authors of the international cohort [14].

9.2 Europe and North America

The international cohort of 274 patients with STAT1-GOF had 62% of patients in Europe, with centres in France, the United Kingdom, Germany, the Netherlands, Spain, Italy, Hungary, Poland, Czechia, Sweden, Switzerland, Turkey, Russia, Ukraine and Estonia, as well as centres in the United States, Canada, Latin America, North Africa, the Middle East, India, Japan and Australia [14]. The 533-patient database brings together cases from 36 countries [15]. The 2025 transplant cohort covers 14 countries in Europe, North America, South America, the Middle East and Asia [28]. In the IL-17 pathway defects, the published patients come from Morocco, Turkey, Japan, Saudi Arabia, Algeria, Argentina, Italy, France and Sri Lanka [4, 21, 30].

9.3 Founder populations and geographical effects

In CARD9 deficiency, two founder variants structure the epidemiology. The p.(Gln289Ter) variant was found in the homozygous state in 15 Algerian and Tunisian patients from seven unrelated families, through a founder effect, and in the following twelve years it was described in six more patients, three of them in Spain, Turkey and Argentina, and the others in the same North African countries; it is associated with deep dermatophytosis and infection by Trichophyton and dematiaceous fungi [25, 40]. The c.820dup variant, described by the authors in that nomenclature, occurs in patients from China, Japan and South Korea, who share a 10 kb haplotype derived from a common ancestor who lived less than four thousand years ago; OMIM records it as the insertion c.819insG (Asp274fsTer60), homozygous in three unrelated Chinese patients with subcutaneous phaeohyphomycosis and a shared founder haplotype [42]; Phialophora phaeohyphomycosis is frequent in Chinese patients and did not occur in the five Japanese and Korean patients studied, a difference the authors attribute to environmental factors [41]. The p.(Gln295Ter) variant was that of the initial Iranian family and is associated with Candida infection [9, 40]. The four recurrent STAT1 variants result from repeated mutation at hotspots and not from founder effects [35].

Geography shapes the phenotype through endemic diseases. In Morocco, 42% of the 12 patients with STAT1-GOF had a mycobacterial infection, mainly pulmonary, pleuropulmonary or lymph node tuberculosis, and autoimmunity was less frequent than in Western cohorts; the mean onset of candidiasis was at 4 years and two patients died [20]. In Mexico, among 30 patients from 17 families and 13 centres, 24% of the 25 BCG-vaccinated patients had BCG disease, 23% had tuberculosis, 20% had an invasive fungal infection (including disseminated histoplasmosis and cryptococcosis), autoinflammation affected 50% and autoimmunity 40%, and seven patients (23%) died [43]. In Brazil, a mother and daughter with the p.(Arg274Gln) variant had lepromatous leprosy in addition to candidiasis, with raised total and phosphorylated STAT1 in CD4+ T cells and reduced IL-17A transcripts [47]. The sources consulted contain no data from Portugal.

9.4 Special populations

In children, the disease manifests early (candidiasis in the first year in STAT1-GOF and before 6 months in IL-17RA deficiency), with the addition of growth retardation, feeding difficulties due to oral and oesophageal candidiasis and dental problems; most transplanted patients had growth retardation and chronic lung disease before the procedure [14, 21, 28]. In adults, the complications that determine mortality appear: carcinomas, aneurysms, bronchiectasis and invasive infections, with death from cancer at a median age of 43 years and from infection at a median age of 17 years [14]. In CARD9 deficiency, invasive disease may begin in adulthood and has been described with onset up to 52 years of age, so genetic investigation should not be limited to children [16]. Patients with recurrent vulvovaginal candidiasis and people with genital candidiasis may under-report symptoms, as the authors of the Mexican cohort observed [43].

9.5 Reference network and patient resources

The relevant European Reference Network is ERN-RITA, dedicated to rare immunological diseases, which endorsed the 2026 consensus on JAK inhibitors [27, 29]. The European patient registry is maintained by ESID, and in France clinical, therapeutic and genetic data are collected in the CEREDIH registry [52, 70]. The international patient organisation is IPOPI, which took part in drawing up the consensus [27, 71]. In Portugal there is the Associação Portuguesa de Doentes com Imunodeficiências Primárias (APDIP, Portuguese Association of Patients with Primary Immunodeficiencies) [72]. The general approach to inborn errors of immunity also refers to the United Kingdom organisations dedicated to primary immunodeficiencies [13]. The natural history study of immune defects with predisposition to fungal infections, conducted in the United States, remains open to patients [69].

10. Illustrative Clinical Case

The case described by Sparanese and colleagues in 2025 illustrates diagnostic delay and the response to targeted treatment [26]. The patient was a 54-year-old woman, the only child of non-consanguineous parents of European ancestry, with type 1 diabetes diagnosed at 14 years and Hashimoto's thyroiditis at 20 years. Since the age of 16 she had had chronic mucocutaneous candidiasis requiring oral antifungal therapy almost every month to resolve, with several tongue scrapings positive for Candida albicans; in young adulthood recurrent vaginal candidiasis was added. At 36 years, dysphagia and odynophagia led to upper endoscopy, which showed oesophageal candidiasis and a stricture, treated by dilatation. She had one episode of paronychia requiring intravenous antifungal therapy and onychomycosis of several nails. Her mother had Hashimoto's thyroiditis and recurrent fungal nail infections, and died at 74 years with no cause established at autopsy.

For years the infections were attributed to glycaemic control and the patient was referred to nutrition, but the infections persisted with control reported as adequate. At 48 years, urticaria after fluconazole prompted referral to allergy and clinical immunology for suspected drug allergy; it was the constellation of chronic mucocutaneous candidiasis, type 1 diabetes and autoimmune hypothyroidism that led to investigation for an inborn error of immunity. Initial tests showed haemoglobin 100 g/L (reference 115–165), lymphocytes 1.4 × 10⁹/L (1.5–4.0), CD3+ 0.69 × 10⁹/L (1.0–3.6), CD4+ 0.46 × 10⁹/L (0.5–1.8), CD8+ 0.20 × 10⁹/L, CD19+ 0.34 × 10⁹/L, NK cells 13%, phytohaemagglutinin stimulation index 4.13 (1.4 or above), IgG 14.4 g/L, IgA 3.1 g/L, IgM 0.99 g/L, IgE 3 kIU/L, antitetanus antibodies 4.75 IU/mL, non-reactive varicella-zoster virus-specific IgG, thyroid-stimulating hormone 0.70 mIU/L, free thyroxine 26.2 pmol/L and glycated haemoglobin 7.7%.

The clinical inborn errors of immunity panel identified the heterozygous variant STAT1 c.842A>G, p.(Glu281Gly), absent from population databases (gnomAD v4.0) and initially classified as a variant of uncertain significance; validation of the nomenclature on the MANE transcript confirms NM_007315.4:c.842A>G, NP_009330.1:p.(Glu281Gly) [12, 26]. To confirm gain of function, peripheral blood mononuclear cells from the patient and from healthy controls were stimulated with recombinant IL-6 and phosphorylated STAT1 was measured by flow cytometry at 15, 30, 60 and 120 minutes: the patient had raised values at all time points and delayed dephosphorylation relative to controls. With the functional result, the variant was reclassified as pathogenic under the PS3, PM6, PP2 and PP4 criteria of the American College of Medical Genetics and Genomics. Ruxolitinib 5 mg twice daily was started, with the intention of titrating according to effect; at five months there was a progressive rise in lymphocyte counts and improvement of candidiasis.

The publication contains no clinical figures; the laboratory data cited are in Table 1 of the article, which was consulted [26]. The management in this report is not routine. The 2026 international consensus, published after the case, recommends clinical, laboratory and imaging baseline assessment before starting a JAK inhibitor, including infectious screening by nucleic acid amplification, chest radiography, abdominal ultrasound, electrocardiogram, echocardiogram and brain magnetic resonance imaging with a vasculitis protocol; the starting dose of 5 mg twice daily corresponds to the label starting dose for acute graft-versus-host disease and is below the median used in the largest cohort of patients with STAT1-GOF [27, 61, 63]. Non-reactive varicella-zoster virus serology, in a patient about to receive a JAK inhibitor, is of practical interest because of the risk of severe disease due to a live vaccine and the recommendation of antiviral prophylaxis in patients with reactivations; the report does not describe the management adopted [14, 27]. The case also illustrates the risk of attributing recurrent candidiasis solely to diabetes and of failing to recognise the significance of several endocrine autoimmune diseases combined with a refractory infection [26].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

In STAT1-GOF, mortality in the international cohort was 12% (34 of 274 patients), at a median age of 30 years (1–58). The causes were severe infection in 13 patients (38%; disseminated BCG, histoplasmosis, coccidioidomycosis, cytomegalovirus, Staphylococcus aureus septicaemia or bacterial lower respiratory infection), at a median age of 17 years; cancer in 8 (24%), at a median age of 43 years; cerebral haemorrhage due to aneurysm in 5 (15%), at a median age of 9 years; fulminant hepatitis in 2 and transplant complications in 3 [14]. Cumulative survival at 60 years was 31% in patients who developed invasive infection, cancer or symptomatic aneurysm, versus 87% in those who had none of these three complications, which are the predictors of poor outcome [14]. Abnormalities of lymphocyte subsets (low CD4+ or CD19+) were associated with higher mortality (19% versus 6% and 25% versus 7%) [14]. In the review of 533 patients, infection was the cause of death in 41% of the 56 deaths, at a mean age of 15.4 years, followed by neoplasia and intracranial haemorrhage; the p.(Thr385Met) variant conferred the worst survival and p.(Arg274Gln) the best [15]. In the regional cohorts, 2 of 12 patients died in Morocco and 7 of 30 in Mexico (23%) [20, 43].

In IL-17 pathway defects, no deaths or carcinomas have been described in the published series, and the patients followed up reached adulthood with disease limited to the mucocutaneous barriers; the review of 31 patients with isolated IL-17 pathway candidiasis found no cancers, but the number is too small to exclude risk, and the carcinoma risk associated with chronic candidiasis requires clinical surveillance [4, 21]. In CARD9 deficiency, 10 of the 58 patients in the 2018 review died of fungal disease between 12 and 39 years, and 81% were alive at last scheduled follow-up, aged 6.5 to 75 years; invasive disease relapsed in 44 of 45 patients who had responded to treatment [16]. In the systematic review of cases, 13 of 82 patients died, mainly with infection of the central nervous system, blood or viscera [40].

11.2 Surveillance table

The intervals in this table match those given in section 7: full blood count every two to four weeks until the JAK inhibitor dose is stable, lipids at eight to twelve weeks, brain imaging and chest tomography every two to three years and an annual electrocardiogram [27, 63].

11.3 Practical follow-up

Follow-up is by clinical immunology, in collaboration with infectious diseases, dermatology, gastroenterology, endocrinology, respiratory medicine and, for transplant candidates, the transplant unit [13, 27]. Patients with antifungal resistance should be seen more often, because resistance marks a more severe phenotype and higher mortality [14]. In CARD9 deficiency, relapse is the rule and follow-up is indefinite, with attention to central nervous system infection [16]. The long-term complications of inborn errors of immunity in general — bronchiectasis, autoimmunity, lymphoproliferation and neoplasia — apply to these patients and justify continued surveillance beyond the control of candidiasis [13].

12. Summary and Final Considerations

Persistent or recurrent chronic mucocutaneous candidiasis, especially when it begins in childhood, resists treatment or recurs in relatives, is a sign of an inborn error of immunity and should lead to genetic investigation once acquired causes have been excluded. The common mechanism is failure of IL-17-mediated immunity at the mucocutaneous barriers, which may result from the absence of IL-17-producing T cells or from the inability of tissues to respond to these cytokines. The most frequent monogenic cause is STAT1 gain of function, autosomal dominant, in which excess interferon signalling suppresses Th17 differentiation; candidiasis is almost constant, but the picture goes far beyond it, with bacterial, herpetic, mycobacterial and invasive fungal infections, endocrine and hepatic autoimmunity, enteropathy, bronchiectasis, cerebral aneurysms and squamous cell carcinomas, and it is these latter complications, not candidiasis, that determine mortality. IL-17RA, IL-17RC, IL-17F and ACT1 deficiencies and JNK1 haploinsufficiency produce isolated candidiasis, with staphylococcal skin infections in the forms that also lose the response to IL-17E and with connective tissue disease in the JNK1 form. RORγT deficiency combines candidiasis and mycobacterial disease in the same patient, and CARD9 deficiency causes invasive fungal disease due to fungi of the phylum Ascomycota, with a predilection for the central nervous system and deep dermatophytosis, in previously healthy people.

Diagnosis rests on a gene panel or exome with copy-number analysis, interpreted with the phenotype and, for dominant genes, with a functional assay demonstrating the direction of the effect: in STAT1, the same gene causes opposite diseases through gain and loss of function, and the distinction decides treatment. A negative panel does not exclude the diagnosis, a normal count of IL-17-producing T cells does not exclude STAT1 gain of function, the presence of the receptor on the cell surface does not exclude IL-17RA deficiency and the presence of normal-sized protein does not exclude CARD9 deficiency. Before accepting a genetic cause, it is mandatory to exclude the neutralising anti-IL-17 autoantibodies of autoimmune polyendocrinopathy type 1 and thymoma and candidiasis caused by therapeutic IL-17 antagonists.

Treatment of candidiasis is antifungal, with fluconazole as first line, doses and durations defined by the mucosal candidiasis guidelines and long-term suppression in most patients; the price of this suppression is the selection of azole-resistant strains, which in the international cohort affected four in ten patients treated continuously and was associated with more severe disease and higher mortality. In STAT1 gain of function, Janus kinase inhibition is the first mechanism-directed treatment: it improves candidiasis and the dysregulation manifestations in the great majority of patients in the retrospective series, with a 2026 international consensus defining indications, prior assessment, starting doses, adjustments for interaction with azoles, surveillance and discontinuation, but with no completed controlled trial and with infectious and cardiovascular risks that require surveillance. Haematopoietic cell transplantation, with historically poor results, now achieves overall survival of 72% and event-free survival of 56% when preceded by JAK inhibition, which has become the recommended bridge. Correction of the recurrent p.(Thr385Met) variant by base editing has been demonstrated in patient cells and in an animal model, with no clinical trial yet started.

Any of these diseases requires long-term follow-up in an experienced centre, with surveillance that goes beyond candidiasis: thyroid function and blood glucose, immunoglobulins, brain imaging for aneurysms in STAT1 gain of function, chest imaging for bronchiectasis, oncological surveillance of the oral mucosa and oesophagus and, in patients on JAK inhibitors, the consensus monitoring schedule. Family counselling depends on the gene: dominant with almost complete penetrance for candidiasis but variable expressivity in STAT1 gain of function, recessive with a 25% risk and frequently in a context of consanguinity or a founder variant in the other forms. Testing relatives has immediate consequences, because it avoids BCG vaccination in the forms with mycobacterial risk and allows surveillance to begin before symptoms appear.

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