The Skin as a Window into Primary Immune Deficiency Diseases: Atopic Dermatitis and Chronic Mucocutaneous Candidiasis

Clinical Management Review

The Skin as a Window into Primary Immune Deficiency Diseases: Atopic Dermatitis and Chronic Mucocutaneous Candidiasis Heather Lehman, MD, and Christopher Gordon, DO Buffalo, NY

INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI: In Practice Web site: www.jaci-inpractice.org/. The accompanying tests may only be submitted online at www.jaciinpractice.org/. Fax or other copies will not be accepted. Date of Original Release: March 1, 2019. Credit may be obtained for these courses until February 28, 2020 Copyright Statement: Copyright Ó 2019-2021. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for 1.00

Primary immune deficiency diseases characteristically present with recurrent, severe, or unusual infections. These infections may often involve the skin, with mucocutaneous candidal infections seen in a variety of different primary immune deficiencies. Primary immune deficiencies may also present with noninfectious cutaneous complications, of which eczema is the most common. In a patient with suspected primary immune deficiency, the presence of eczema or candidal skin infections offers critical information about the underlying immune defect, either the presence of atopy or defect in the TH17 pathway, Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts of interest. Received for publication September 6, 2018; revised November 19, 2018; accepted for publication November 25, 2018. Corresponding author: Heather Lehman, MD, Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 1001 Main Street, 5th floor, Buffalo, NY 14203. E-mail: [email protected]. 2213-2198 Ó 2018 American Academy of Allergy, Asthma & Immunology https://doi.org/10.1016/j.jaip.2018.11.026

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AMA PRA Category 1 CreditÔ. Physicians should claim only the credit commensurate with the extent of their participation in the activity. List of Design Committee Members: Heather Lehman, MD, and Christopher Gordon, DO (authors); Robert S. Zeiger, MD, PhD (editor) Learning objectives: 1. To recognize the manifestations of primary immune deficiencies that commonly present with eczematous dermatitis. 2. To understand the inheritance patterns of genetic causes of chronic mucocutaneous candidiasis. 3. To differentiate the associated infections and noninfectious findings among the known genetic defects underlying chronic mucocutaneous candidiasis. 4. To describe an approach to diagnosis and treatment of chronic mucocutaneous candidiasis. Recognition of Commercial Support: This CME has not received external commercial support. Disclosure of Relevant Financial Relationships with Commercial Interests: The authors declare that they have no relevant conflicts of interest. R. S. Zeiger declares no relevant conflicts of interest.

respectively. These skin manifestations also are often early or heralding findings of the underlying immunologic disease. Therefore, awareness of associations between these skin findings and specific immune deficiencies may aide in the early detection and treatment of serious or life-threatening immunologic defects. This review specifically will focus on the primary immune deficiencies commonly associated with eczema or mucocutaneous candidiasis. Ó 2018 American Academy of Allergy, Asthma & Immunology (J Allergy Clin Immunol Pract 2019;7:788-98) Key words: Skin; PIDD; Atopic dermatitis; Chronic mucocutaneous candidiasis

Primary immune deficiency diseases (PIDDs) are a group of more than 350 genetic defects that lead to an aberrantly functioning immune system.1 Cutaneous manifestations are common in PIDD, affecting between 40% and 70% of patients with primary immunodeficiency.2,3 These skin findings in PIDD are often a presenting feature at the time of initial immune deficiency diagnosis in childhood.2-4 Skin infections are the most common cutaneous manifestation found in PIDD, and eczematous dermatitis is the

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Abbreviations used AD-HIES- Autosomal dominant hyper-IgE syndrome AIRE- Autoimmune regulator APECED- Autoimmune polyendocrinopathy, candidiasis, and ectodermal dysplasia AR-HIES- Autosomal recessive hyper-IgE syndrome CARD9- Caspase recruitment domain 9 CID- Combined immune deficiency CMCC- Chronic mucocutaneous candidiasis CMV- Cytomegalovirus DGS- DiGeorge syndrome DOCK8- Dedicator of cytokinesis 8 FOXP3- Forkhead box protein 3 GlcNAc-6-P- N-Acetylglucosamine-6-phosphate GM-CSF- Granulocyte-macrophage-colony stimulating factor GOF- Gain-of-function GVHD- Graft-versus-host disease HDAC- Histone deacetylase HPV- Human papillomavirus HSCT- Hematopoietic stem cell transplant HSV- Herpes simplex virus IPEX- Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked JAK- Janus kinase NF-kB- Nuclear factor-kB NK- Natural killer PGM3- Phosphoglucomutase 3 PIDD- Primary immune deficiency disease PRR- Pattern recognition receptor RORC- Retinoic aciderelated orphan receptor C SCID- Severe combined immunodeficiency SPINK5- Serine protease inhibitor of Kazal type 5 STAT- Signal transducer and activator factor of transcription TLR- Toll-like receptor WAS- Wiskott-Aldrich syndrome WASp- Wiskott-Aldrich syndrome protein

second most common skin finding reported in PIDD. This review will discuss 2 very important dermatologic manifestations of underlying immune deficiency: atopic dermatitis and mucocutaneous candidiasis.

ATOPIC DERMATITIS/ECZEMA IN PIDD Atopic or eczematous dermatitis is a common finding in the general population. It affects an estimated 10% to 20% of children in developed countries5 and 11% of children in the United States.6 It appears to be increasing in overall incidence and prevalence.7 In addition, higher rates of atopic dermatitis are observed in those affected by PIDD. In cohorts of pediatric PIDD populations, 13% to 22% have been affected by eczema.2-4 In 1 cohort, 75 patients with well-established severe atopic dermatitis underwent immune evaluation with 7.9% diagnosed with underlying PIDD.8 Eczema may be a presenting clinical manifestation of those immunodeficiencies presenting in the allergy clinic as well as the clinical immunology clinic. Several primary immunodeficiencies are also associated with the presence of infantile erythroderma, a severe exfoliative dermatitis affecting more than 90% of the body, which can be confused with a severe inflammatory eczema. Early diagnosis of immunodeficiency is crucial and

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therefore it is key to recognize the immunodeficiencies and additional clinical features that may present with atopic dermatitis or erythroderma.

Autosomal dominant hyper-IgE syndrome Early onset, severe eczema is a shared feature of both autosomal dominant and autosomal recessive forms of hyper-IgE syndrome (AD-HIES and AR-HIES). AD-HIES was originally described in 1966 as “Job syndrome.” It is a multisystem primary immunodeficiency syndrome of recurrent abscesses with Staphylococcus spp., sinopulmonary infections, and severe eczematous dermatitis.9,10 Mutations in the signal transducer and activator factor of transcription-3 (STAT3) were determined to be the cause of AD-HIES, first reported in 2007.11,12 The mutation is a dominant negative loss-of-function mutation, in which the abnormal gene product suppresses the function of the normal gene copy. STAT3 is a member of the Janus kinase (JAK)-STAT family of proteins. It is integral for the differentiation of naïve CD4þ T cells into TH17 cells. Therefore, patients with AD-HIES have a lack of TH17 cells leading to impaired IL-17/IL-22 production and signaling.13-15 Defective response to multiple cytokines, including IL-6 and IL-21, have also been reported.16,17 STAT3 is also key for maintenance of CD8þ T-cell memory. Likely related to this defect is an increased reactivation rate of varicella zoster virus and Epstein-Barr virus observed in AD-HIES.18,19 B-cell memory differentiation is also impacted and can result in derangements of specific antibody production, leading to the requirement of immunoglobulin replacement or prophylactic antibiotic use.20 Most patients with AD-HIES develop an early-onset (often in the first week of life) papulopustular eruption that begins on the face and scalp, but can become generalized.21 The rash morphology progresses to an eczematous dermatitis within the first year that can be lichenified.22,23 Colonization and infection with Staphylococcus aureus is strongly associated with this chronic dermatitis. Keratinocytes and bronchial epithelial cells normally produce antistaphylococcal factors, but require stimulation of TH17 cytokines to do so,24-26 which are impaired in patients with AD-HIES. In addition, approximately 80% of patients show some degree of impaired chemotactic effects of neutrophils.25,27,28 This may help explain the characteristic “cold” abscesses of some patients with STAT3 dominant negative mutation. Pneumonias can occur frequently and early in AD-HIES. In a French survey, the mean age at first infection was 10.5 months.29 Frequently, these infections are complicated by bronchiectasis, pneumatocele, and bronchopleural fistulae.10 Predisposition to other infections, including Pseudomonas, Aspergillus, and nontuberculous mycobacteria, has also been observed.29-32 Patients may actually report feeling well and are afebrile, despite serious infection. Patients with AD-HIES have elevated serum IgE levels with peak levels greater than 2000 IU/mL in the majority of cases, though normal IgE levels have been reported. Eosinophilia is observed in 93% of cases. Physical patient characteristics include facial asymmetry, large bulbous nose, prominent chin, higharched palate, and retained primary teeth. Other notable musculoskeletal features include scoliosis in 75% of patients.33 Vascular abnormalities such as Chiari I malformations are often detected. Recent studies have shown increased incidence of lacunar infarcts, coronary aneurysms, and coronary dilation.

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These coronary abnormalities have been associated with an increased risk of myocardial infarction.10,34 In contrast to AR-HIES, anaphylaxis is rare and food allergies are not a major concern in AD-HIES.35 Compared with patients with atopic dermatitis with similarly elevated IgE, both food allergy and food-induced anaphylaxis in AD-HIES were significantly lower (38% vs 58% and 8% vs 33%, respectively).36 Life expectancy is into the fifth or sixth decade with infection as the most common cause of death.10

DOCK8 deficiency The majority of cases of AR-HIES are attributed to dedicator of cytokinesis 8 (DOCK8) mutations.37 AR-HIES is similar in presentation to AD-HIES with elevated serum IgE levels, eosinophilia, eczematous dermatitis, and recurrent sinopulmonary and skin infections. Patients present with early onset dermatitis with classic atopic distribution and appearance.35 They often lack the pustular eruption observed in AD-HIES during the neonatal period.23 Another somewhat unique characteristic of DOCK8 deficiency is the increased frequency of multiple severe food allergies and asthma.35 DOCK8 deficiency can also be clinically distinguished from AD-HIES by severe cutaneous viral infections with herpes simplex virus (HSV), varicella zoster virus, molluscum contagiosum virus, and human papillomavirus (HPV).38 This susceptibility to these viral infections is likely due to associated impairment of natural killer (NK) cell development.38 CD4þ, CD8þ T cells, and plasmacytoid dendritic cells are also reduced in number. This results in profound decrease in production of IFN-a in response to viral infections through Toll-like receptor 9 (TLR9). A reduction in memory B cells has been found and is likely an explanation for the elevated risk of recurrent sinopulmonary infections observed due to specific antibody deficiency.38,39 Compared with AD-HIES, mucocutaneous candidiasis is observed less frequently in DOCK8 deficiency. However, this population is at higher risk of malignancy, particularly squamous cell carcinoma related to HPV infection sites and lymphoma. Later in life, malignancy becomes a frequent cause of death.10 Treatment of the dermatitis in AD-HIES and DOCK8 deficiency is quite difficult due to concurrent cutaneous viral infections and superimposed bacterial infections with S. aureus. Use of sodium hypochlorite baths and occasionally systemic antibiotics is recommended based on the literature published regarding the treatment of general atopic dermatitis population.40 Given reduced life expectancy, allogeneic hematopoietic stem cell transplant (HSCT) is often a pursued treatment.41 Cutaneous viral infections and dermatitis improve after transplant.42 Phosphoglucomutase 3 deficiency First described in 2014, phosphoglucomutase 3 (PGM3) deficiency results in a syndrome associated with atopic dermatitis, recurrent infections, and elevated IgE levels. It has been considered another cause of AR-HIES in addition to DOCK8 deficiency. PGM3 protein catalyzes the conversion of N-acetylglucosamine-6-phosphate (GlcNAc-6-P) into GlcNAc-1-P in the synthesis of uridine diphosphate-GlcNAc, a critical component of the glycosylation pathway. All patients described have had atopic dermatitis as a feature. These patients were also described as having other significant atopic diseases including asthma and

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allergies. Similar to DOCK8 deficiency, a susceptibility to cutaneous bacterial and viral infections (HSV, cytomegalovirus [CMV]) was observed. Frequent sinopulmonary infections are reported with complications including pneumatocele development and bronchiectasis. One series of 3 patients with PGM3 deficiency had a more severe immunophenotype of T-B-NKþ severe combined immunodeficiency (SCID) along with skeletal anomalies in 2 of these 3 patients.43 Setting PGM3 deficiency apart from AD-HIES and DOCK8 deficiency is the observed neurologic impairment including developmental delay, ataxia, myoclonus, dysarthria, and sensorineural hearing loss. Another potentially unique cutaneous finding of PGM3 deficiency is leukocytoclastic vasculitis. Chronic mucocutaneous candidiasis can also develop, but with more variability than in AD-HIES.44,45

IPEX Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is an often fatal, X-linked recessive condition caused by loss-of-function mutations in forkhead box protein 3 (FOXP3). Foxp3 is fundamental to the function of CD4þ T-regulatory lymphocytes. Lack of functional regulatory T cells leads to immune dysregulation including autoimmune disease. Affecting males, IPEX typically presents during the first few months of life with a triad of severe dermatitis, insulin-dependent diabetes mellitus and other autoimmune phenomena, and intractable diarrhea.46 The primary skin manifestation is severe eczematous dermatitis. Other less common cutaneous manifestations include erythroderma, urticaria, psoriasiform dermatitis, pemphigoid nodularis, cheilitis, onychodystrophy, and alopecia universalis.46-48 IgE and eosinophil levels are often elevated along with increased incidence of food allergies.49,50 Antibodies to organ-specific antigens have been documented as likely explanation for autoimmune manifestations observed in IPEX syndrome.51 Impaired skin barrier and gut epithelium leads to infections. In addition, immunosuppressive drugs used to manage autoimmune disease can increase susceptibility to infection. In a cohort of 50 patients afflicted with IPEX, more than 50% experienced significant infections, including sepsis, meningitis, pneumonia, and osteomyelitis.52 The most commonly reported pathogens are Enterococcus spp., Staphylococcus spp., CMV, and Candida spp.53 Currently, the only potential curative treatment is hematopoietic stem cell transplant. A retrospective, multicenter review published in 2018 identified 96 patients with IPEX and demonstrated similar overall survival rates for individuals managed with chronic immune suppression compared with those who underwent HSCT, although there was greater mortality in the HSCT group in the peritransplant period.54 The disease progressed in individuals managed with chronic immune suppression, resulting in lower long-term, disease-free survival. Wiskott-Aldrich syndrome Wiskott-Aldrich syndrome (WAS) is an X-linked disorder due to mutations in the WAS gene, encoding the Wiskott-Aldrich syndrome protein (WASp). WASp, only expressed by hematopoietic cells, plays a key role for actin cytoskeleton remodeling that is vital for immunologic synapse formation between T cells and antigen-presenting cells.55 Mutations lead to

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dysregulation of lymphocyte and NK cell migration and homing functions.56 The classic phenotype of Wiskott-Aldrich includes thrombocytopenia with small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. However, there is a broad spectrum of phenotypic presentations of WAS mutations, ranging from severe eczema with associated bacterial and viral infection with the risk of malignancy (B-cell lymphoma or leukemia), to a mild form of isolated thrombocytopenia (X-linked thrombocytopenia).57,58 The high variability in presentation is due to many possible mutations in the WAS gene resulting in variable effects on protein expression.58 Isolated Xlinked congenital neutropenia has been described due to gain-offunction (GOF) mutations in the GTPase-binding domain of WASp.59 Eczema affected 81% of patients with WAS in 1 large multiinstitutional case series, and typically presents during their first year of life.60 Immunologic findings include defective antibody responses to vaccines with normal IgG and normal-to-high IgE and IgA, low IgM levels, reduced NK cell cytotoxicity, decreased function of regulatory Treg cells, and impaired chemotaxis of phagocytic cells.49,61-63 Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are frequent microbial agents isolated in WAS, manifesting as sinopulmonary infections, meningitis, and colitis. Recommended antimicrobial therapy is prophylactic trimethoprim-sulfamethoxazole and acyclovir. Some patients require immune globulin replacement at higher rates typically owing to an increased catabolic rate observed in WAS.64 HSCT can be completed in hopes of curative treatment. For autoimmune cytopenias, rituximab has been used with effectiveness. Those with increased bleeding risk can be treated with splenectomy; however, this can increase the risk of severe infection.65

DiGeorge syndrome DiGeorge syndrome (DGS) is a disorder characterized by a constellation of signs and symptoms associated with defective development of the pharyngeal pouch system. It is caused by a heterozygous chromosomal deletion at 22q11.2. Most patients with DGS have mildly-impaired T-cell production and normal humoral immunity. Other abnormalities include cleft palate, heart defects, dysmorphism, and hypoparathyroidism.66 Less than 1% of patients with 22q11.2 deletion have “complete DGS” with profoundly decreased T-cell counts consistent with T-BþNKþ SCID. Only a small subset of patients with complete DSG develop atypical complete DGS, with oligoclonal T-cell expansion resulting in inflammatory manifestations resembling those of Omenn syndrome. Skin findings include a papular or eczematous dermatitis that can be diffuse and erythrodermic.67-69 Omenn syndrome Hypomorphic mutations in various SCID genes may lead to Omenn syndrome due to the expansion of an oligoclonal, activated T-cell population. The classic presentation of Omenn syndrome is the development of exfoliative erythroderma associated with diffuse alopecia, lymphadenopathy, hepatosplenomegaly, recurrent severe opportunistic infections, eosinophilia, and failure to thrive in the early neonatal period.70 The findings are reminiscent of graft-versus-host disease (GVHD), although histology is not consistent with GVHD and there is no evidence of maternal engraftment of lymphocytes.71

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Although the initial cutaneous presentation of Omenn syndrome is most commonly described as erythroderma, it may present with a neonatal eczematous rash. Infants with classic SCID mutations may develop GVHD secondary to engraftment of transplacentally derived maternal T cells, or of T cells derived from transfusion of nonirradiated blood products. The GVHD that develops in these patients with SCID appears identical to the clinical picture of Omenn syndrome, including the cutaneous findings of erythroderma and alopecia.72,73

Comel-Netherton syndrome Comel-Netherton syndrome is a rare autosomal recessive disorder caused by mutations in the serine protease inhibitor of Kazal type 5 gene (SPINK5).74 The protein product, a serine protease inhibitor, is expressed on epithelial and mucosal surfaces. The initial skin abnormality in infants is described as generalized exfoliative erythroderma.75,76 Some affected infants are born with a tight, clear sheath covering their skin called a collodion membrane. Eventually, infants will develop a triad of ichthyosiform erythroderma, trichorrhexis invaginata (“bamboo hair”), and atopic disease, potentially including a superimposed atopic dermatitis rash. Infants are at high risk of life-threatening complications due to severe erythroderma. Because of the degradation of the epidermal barrier, many proinflammatory cytokines are increased including thymic stromal lymphopoietin, inducing a TH2 differentiation, which can predispose to the development of atopic manifestations.77 Therefore, older children with Comel-Netherton syndrome manifest a wide range of atopic diseases including asthma, atopic dermatitis, and allergic rhinitis with markedly elevated serum IgE levels and eosinophils. Angioedema and anaphylaxis to foods have also been reported.78 Children with Comel-Netherton syndrome may also show short stature, growth hormone deficiency, mild development delay, recurrent infections, and pancreatic insufficiency.79,80 There is no targeted therapy at present for Comel-Netherton syndrome, although kallikrein inhibitors may alleviate symptoms in animal models.81 Gene therapy using a lentiviral vector encoding SPINK5 is also being studied.82 EVALUATION FOR PRIMARY IMMUNODEFICIENCY IN CASES OF ATOPIC DERMATITIS Most often, severe atopic dermatitis is seen in patients without any underlying primary immune deficiency. Awareness of associations between skin findings and immunodeficiency diseases may lead to early detection and treatment of serious or lifethreatening immunologic defects in patients with PIDD presenting as eczema. Thorough medical history, family history, and physical examination may lead the clinician to suspect and investigate specific primary immune deficiencies. Genetic testing is required for most of the PIDDs with eczema, though protein detection by flow cytometry is available for WAS and DOCK8 deficiency. A clinical challenge remains to differentiate patients early in the course of HIES versus children with eczema and atopy. A scoring system was proposed in 1999 to identify patients with hyper-IgE syndromes.83 This was developed before the genetic causes of AD-HIES and AR-HIES were known. The initial scoring cutoff of 15 in this system has subsequently been shown to not be specific for HIES, with many patients with simple eczema and atopy reaching this score. However, it has since been

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shown that a score 40 along with low TH17 cell enumeration is sensitive for STAT3 dominant negative mutation.84 However, this scoring system may also pick up patients with DOCK8 deficiency in the group with score 40. A new “DOCK8 score” has been described to differentiate patients with DOCK8 deficiency versus STAT3 dominant negative mutation.85

CHRONIC MUCOCUTANEOUS CANDIDIASIS IN PIDDs Host defense against Candida and dermatophytes involves both the innate and cellular immune pathways. These fungi encounter the human host’s innate immune response as a first-line combatant to infection. Fungal pathogen-associated molecular patterns are recognized by pattern recognition receptors (PRRs) on phagocytes including TLRs and C-type lectin receptors. TLR2 and TLR4 recognize O-linked mannan on the fungal cell wall, leading to the activation of adaptor protein MyD88 and downstream activation of nuclear factor-kB (NF-kB). An example of C-type lectin receptor is Dectin-1, which recognizes b-glucans in the fungal cell wall and also leads to the activation of NF-kB through adaptor protein caspase recruitment domain 9 (CARD9). The downstream effect of NF-kB activation in phagocytes is transcription of proinflammatory cytokines that bind to the receptors of TH17 cells. Defects along these described pathways lead to primary immune deficiencies that are associated with chronic mucocutaneous candidiasis (Figure 1).86,87 It has long been recognized that PIDDs with major defects in cellular immunity, including SCID, complete DGS, and acquired immunodeficiency syndrome, may present with mucocutaneous candidal infections as one of many infectious susceptibilities. This is due to the lack of TH17 cells, whereas the presence of other opportunistic infections is due to the absence of other T-cell subsets. In contrast, patients with a phenotype of primary chronic mucocutaneous candidiasis (CMCC), with few other major infectious susceptibilities, have been identified in having one of several genetic defects leading to isolated TH17 impairment, including STAT1 GOF mutation, IL-17F or IL-17RA/RC mutations, ACT1 mutation, and retinoic aciderelated orphan receptor C (RORC) mutation. Complex syndromes with mucocutaneous candidiasis as a main infectious feature include autoimmune polyendocrinopathy, candidiasis, and ectodermal dysplasia (APECED) and autosomal dominant hyper-IgE syndrome. Table I summarized genetic defects with CMCC as a major feature. STAT1 GOF mutations The most common genetic mutation identified in patients with a CMCC phenotype is an autosomal dominant, GOF STAT1 mutation. STAT1 is a transcription factor important to TH1 cell development. It plays a pivotal role in cellular response to interferons and is central to many pathways involving hormones, interleukins, and growth factors.88 STAT1 GOF mutations have been found in either the coiled-coil domain or the DNA-binding domain of STAT1. These mutations result in prolonged phosphorylation of the STAT1 protein, leading to prolonged transcription factor activity in response to IFN-a/b, IFN-g, and IL-27, which suppress TH17 cell development, as well as in response to IL-6 and IL-21, which normally activate the STAT3 transcription factor rather than STAT1.89-92

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GOF mutations in STAT1 result in a phenotype of mucocutaneous candidiasis and invasive fungal infections including coccidioidomycosis and histoplasmosis. In addition, patients are at increased susceptibility to bacterial sinopulmonary, mycobacterial, and herpesvirus family infections.93-95 Autoimmunity is a common finding in STAT1 GOF, with autoimmune thyroid disease being reported in 44% of 1 large patient cohort.96 Other autoimmune conditions reported include autoimmune cytopenias, autoimmune hepatitis, vitiligo, and alopecia.89,96 Malignancy as well as aortic and cerebral aneurysms has also been reported.89,97,98

Dectin-1 deficiency Dectin-1 is a PRR expressed on phagocytes that is able to bind to b-glucans on fungal cell walls. Dectin-1-mediated signaling promotes secretion of IL-2 and IL-23, which induces a tightly regulated TH17 differentiation and response.99,100 Homozygous mutations in CLEC7A (DECTIN1) resulting in Dectin-1 deficiency were reported in a single family in 2009.101 Three affected siblings homozygous for a Y238X polymorphism developed recurrent vulvovaginal candidiasis and onychomycosis, but were not predisposed to invasive candida infections. However, because the Y238X polymorphism is actually quite common in several populations and healthy homozygotes exist, the significance of Dectin-1 defects as a cause of CMCC is unclear.102,103 It has been suggested that this polymorphism of CLEC7A may confer the risk of CMCC in the presence of other modifying factors, rather than represent a monogenic cause of CMCC on its own.103 CARD9 deficiency CARD9 is an adaptor protein in the signaling pathway downstream of the Dectin-1 and Dectin-2 PRRs. Autosomal recessive mutations that result in CARD9 deficiency lead to defects in TH17 differentiation and impaired neutrophil killing of fungi.104 Production of IL-6 and IL-1b in response to Candida albicans requires CARD9. In contrast to Dectin-1 polymorphisms, patients with CARD9 deficiency appear susceptible to invasive fungal infection, particularly candidal meningitis,105,106 in addition to mucocutaneous candidiasis. These patients also develop deep dermatophytosis, in which dermatophytes may initially infect the epidermis and nails, but then invade the dermis and disseminate into underlying tissues including bone, lymph nodes, and brain.106 Although CARD9-deficient mice have been shown to be susceptible to Mycobacterium tuberculosis and Listeria monocytogenes,107,108 these infections have not been seen in patients with CARD9 deficiency to date. Gene mutations in IL-17RA, IL-17RC, IL-17F, and ACT1 associated with CMCC Autosomal recessive mutations in the IL-17RA, IL-17RC, and ACT1 genes and autosomal dominant mutations in the IL-17F gene have also been found to cause the TH17 dysfunction underlying CMCC in small numbers of patients.109,110 These mutations have been described to disrupt IL-17 signaling, including downstream activation of pathways such as NF-kB. IL17RA and IL-17F mutations were actually the first 2 genetic causes of CMCC disease identified, but all of the above defects have remained rare causes of CMCC overall.109 The phenotype of these defects is much more limited than that of STAT1 GOF. IL-17F and IL-17RC mutations have

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been shown to present with only isolated chronic mucocutaneous candidiasis, without other infectious risks. Patients with IL-17RA and ACT1 mutations show an additional predisposition to superficial staphylococcal infections, including dermatitis and blepharitis.109,111 The differences have been suggested to lie in the fact that IL-17RC and IL-17F mutations leave IL17E function intact, whereas IL-17RA and ACT1 mutations impact IL-17E function as well as IL-17A and IL-17F.110

Autoimmune polyendocrinopathy, candidiasis, and ectodermal dysplasia APECED is a monogenic disease caused by mutations in the autoimmune regulator (AIRE) gene. Its inheritance is typically autosomal recessive, but dominant negative mutations have been described as well. This condition was first described in 1929, when an association between hypoparathyroidism and chronic candidiasis was observed.113 The triad of CMCC, hypoparathyroidism, and adrenal insufficiency was reported first in 1946, with clinical diagnosis of classic APECED requiring 2 of these 3 findings.99,114 However, additional autoimmune manifestations in the skin and other organs are common and some of these may present before 2 manifestations of the classic triad for APECED have developed. Therefore, expanded diagnostic criteria have been proposed, adding an “adjunct triad” of urticarial eruption, intestinal dysfunction, and enamel hypoplasia. The presence of any 2 of the 6 features of the classic and adjunct triad should prompt diagnostic testing for APECED, including genetic testing and evaluation for IFN-u autoantibodies.115 In 1997, AIRE mutation was identified as the cause of APECED.116,117 AIRE is found in medullary thymic epithelial cells that fulfill an important role in self-antigen presentation to developing thymocytes and is required for deletion of autoreactive T cells. Dysfunctional or absent AIRE allows survival of these autoreactive T cells.118,119 The presence of various autoantibodies is hallmark to APECED, leading to the various clinical findings seen in the syndrome, including hypergonadotropic hypogonadism, type I diabetes, autoimmune thyroid diseases, and pituitary defects, along with features in the classic triad.120 More than 100 APECED-associated mutations have been reported in the AIRE gene. However, 2 mutations are found in the majority of patients.121 The cause of CMCC in APECED was unclear until in 2010 it was demonstrated to be caused by neutralizing autoantibodies against TH17 cytokines (IL-22, IL-17F, and IL-17A).122-124 Chronic Candida infection in early childhood is often the first sign of APECED. Early candidiasis often presents as persistent oral thrush. Oral infection can spread to the esophagus, causing an increased risk of squamous cell carcinoma.125 The nails are often affected, with the fingernails more commonly affected than toenails, likely due to spreading of infection from the mouth in infancy.126 Autoimmune hypoparathyroidism and adrenal failure (Addison’s disease) follow later in the disease course. The ectodermal manifestations associated with APECED include vitiligo, alopecia, keratoconjunctivitis, dental enamel hypoplasia, nail dystrophy, and tympanic membrane calcification.115,127

RORC mutation RORgt is the key transcription factor for the development of TH17 cells. Patients with RORgt deficiency, caused by autosomal recessive mutations in RORC, have been identified as a cause of chronic mucocutaneous candidiasis.112 In addition to the lack of IL-17A/F-producing cells, these patients surprisingly have diminished IFN-g production in response to mycobacteria, with associated impairments in gd-T cells, as well as absent NKT cells and mucosal associated invariant T cells. The poor IFN-g response leads to susceptibility to disseminated mycobacterial infection (bacille Calmette-Guérin infection in all patients described to date) in addition to CMCC.

Hyper-IgE syndromes and CMCC Susceptibility to mucocutaneous candidiasis, along with Aspergillus, Cryptococcus, and S. aureus infections, is seen in patients with AD-HIES due to autosomal dominant STAT3 lossof-function mutation. In 1 series, 85% of patients with AD-HIES due to STAT3 mutation exhibited CMCC.29 STAT3 is critical for RORgt induction in response to IL-6 and IL-23, leading to differentiation of TH17 lineage cells. Therefore, patients with STAT3 deficiency have decreased TH17 cells and resultant mucocutaneous candidiasis. Mucocutaneous candidiasis has been observed somewhat less often in the diseases underlying autosomal recessive hyper-IgE syndrome, DOCK8 deficiency, and PGM3 deficiency. In a series of 64 patients with DOCK8 deficiency, 64% had

FIGURE 1. Components of Candida albicans (mannans and b-glucan) are recognized by pattern recognition receptors such as Toll-like receptors (TLRs), Dectin-1 and Dectin-2, present on antigen presenting cells (APCs) and phagocytes. Dectin-1 and Dectin-2 signaling is transduced through caspase recruitment domain 9 (CARD9). This leads to transcription of proinflammatory cytokines IL-1b, IL-6, and IL-23. Cytokine-receptor interactions with IL-1R and IL-23R activate T cells via STAT3 and RORgt transcription factors to differentiate into TH17 lymphocytes. These cells produce IL-17 and IL-22 cytokines, which interact with receptors on various cell types, including neutrophils. Activation of T cells via STAT1 transcription factor alternatively impairs the differentiation of TH17 lymphocytes and promotes TH1 cell differentiation. Defects in molecules associated with chronic mucocutaneous candidiasis are labeled in red.

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TABLE I. Genetic mutations with chronic mucocutaneous candidiasis as a major feature Gene

Inheritance

AIRE

AD or AR

STAT3 (LOF)

STAT1 (GOF)

AD

AD

Infectious susceptibilities in addition to CMCC

Immunologic defect causing CMCC

Development of anti-IL-17A, IL-17F, and IL-22 neutralizing autoantibodies

Staphylococcal skin and lung infections Aspergillus lung infections

Compromised development of TH17 cells

Coccidioidomycosis

Compromised development of TH17 cells

Histoplasmosis Herpes simplex virus

IL-17F IL-17RA IL-17RC ACT1 CARD9

AD AR AR AR AR

CLEC7A/DECTIN1

AR

RORC

AR

Staphylococcal skin infections Staphylococcal skin infections Candida meningoencephalitis

Noninfectious complications

Hypoparathyroidism

Adrenal insufficiency Other autoimmune disorders Hypothyroidism Diabetes Gonadal dysfunction Alopecia areata Pernicious anemia Eczema Pneumatoceles Hyperextensible joints Osteoporosis and bone fractures Scoliosis Retention of primary teeth Cerebral and coronary aneurysms Autoimmunity Thyroid disease Cytopenias Hepatitis Vitiligo Alopecia Cerebral and aortic aneurysms

Impaired IL-17 signaling Impaired IL-17 signaling Impaired IL-17 signaling Impaired IL-17 signaling Impaired signaling downstream of Dectin-1 and Dectin-2 pattern recognition receptors

Deep dermatophytosis

Disseminated mycobacterial infection

Absent Dectin-1 pattern recognition receptor Absent TH17 cells

AD, Autosomal dominant; AR, autosomal recessive; CMCC, chronic mucocutaneous candidiasis.

mucocutaneous candidiasis,85 whereas 53% of another series of 136 DOCK8 patients reported CMCC.128 DOCK8 deficiency is typically characterized as a combined immune deficiency (CID), as it has effects on the function of T cells, B cells, and NK cells, and is associated with susceptibility to a relatively diverse group of pathogens.129 Impaired TH17 cell differentiation, with skewing instead towards TH2 cells, has been demonstrated in patients with DOCK8 deficiency,130 accounting for both predisposition to candidal infections and the presence of atopic disease. PGM3 deficiency has been reported in a small number of patients to date, with a phenotype of CID/hyper-IgE syndrome in some,44,45 versus SCID in others.43 One series of 9 patients described mucocutaneous candidiasis in two-thirds of cases,44 whereas another series of 8 patients reported no evidence of CMCC.45

Evaluation and treatment of CMCC The diagnosis of CMCC should be considered in patients with chronic or recurrent candidal or dermatophytic infections of the nails, skin, and mucous membranes as their major or exclusive infectious presentation. It is important to consider whether any other infectious or noninfectious complications are present that may point towards a specific genetic cause of CMCC. The 2015 Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency recommends quantitative and functional evaluation of NK cells and assessment of lymphocyte stimulation to Candida in the evaluation of suspected CMCC.131 Decreased TH17 cell enumeration is found in certain causes of CMCC, including STAT3, CARD9, and STAT1 GOF, but TH17 cells are at normal levels with mutations in IL17RA and

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IL17F.13,92,105,131 Abnormally prolonged STAT1 phosphorylation assays support the diagnosis of STAT1 GOF. Genetic testing is typically required to confirm a specific diagnosis in cases of CMCC. The treatment of isolated CMCC has traditionally focused on acute treatment and prophylaxis of candidal infections. Fluconazole is typically considered a first-line agent, followed by other azole antifungals. Resistance to at least 1 azole antifungal is common in patients with CMCC.132 Echinocandins and amphotericin B can be considered for patients with severe, treatment-refractory disease. Antifungal drugs have had modest success in treating dermatophyte infections. For superficial fungal infections, terbinafine or posaconazole has been recommended.133 Granulocyte-macrophage-colony stimulating factor (GMCSF) and granulocyte-colony stimulating factor have been proposed as second-line therapies for severe and invasive fungal infections. These products have been proposed as ways of augmenting TH17 cell differentiation,134,135 and GM-CSF increases Dectin-1 expression.136 However, results of these products in patients with severe CMCC have been variable.132,135 Management of patients with STAT1 GOF mutation has been challenging. Traditional immunosuppression to control autoimmunity further increases the risk of infections. HSCT has been attempted in cases of STAT1 GOF mutation with severe symptoms. However, the nature of STAT1 GOF mutations amplifies the risk for uncontrolled infections and graft-versushost disease after HSCT, resulting in the risk of secondary graft failure and mortality.137-139 Recently, novel biologic therapy with ruxolitinib, a JAK1 and JAK2 inhibitor, has shown promise in the treatment of STAT1 disease. The initial report of ruxolitinib use in CMCC described complete resolution of alopecia areata and oral candidiasis in a patient with STAT1 GOF, with return of the oral candidiasis 2 weeks after discontinuation of ruxolitinib.140 A second case experienced significant improvement, but not resolution, of ulcerative mucositis due to C. albicans with the use of ruxolitinib.141 A third case showed significant effects of ruxolitinib, with control of autoimmune cytopenias, cured mucocutaneous candidiasis and diarrhea, and improvement of pulmonary function.88 After these 3 cases of success with ruxolitinib, there was a report of ruxolitinib treatment failure in 2 further patients with STAT1 GOF mutation.142 A case series of jakinib use in 11 patients with STAT1 GOF (along with several patients with STAT3 GOF mutations) across multiple different institutions is in press and reports improvement in 10 of 11 patients with STAT1 GOF, with the case of treatment failure occurring in a patient with disseminated coccidioidomycosis that was active at the time ruxolitinib was initiated.143 The authors infer that initiation of jakinibs late in the course of disease may be too late to control severe manifestations, and they recommend consideration of jakinib therapy in STAT1 GOF or STAT3 GOF when immune dysregulation, organ-specific autoimmunity, chronic autoimmune cytopenias, lymphoproliferation, refractory CMCC, or recurrent severe infections are present. Histone deacetylase (HDAC) inhibitors have also been proposed as potential treatment for CMCC in STAT1 GOF mutations. The altered gene transcription of STAT1 and STAT3 seen in STAT1 GOF mutation has been demonstrated to be modified by inhibition of HDAC1 and HDAC2.91 The use of selective HDAC inhibitors, Entinostat and RGFP966, has been associated with decreased STAT1 phosphorylation in in vitro

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studies of peripheral blood mononuclear cells from patients with STAT1 GOF.144

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