RESUMO
PURPOSE: Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients. METHODS: We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF. RESULTS: We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects. CONCLUSION: Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.
Assuntos
Candidíase Mucocutânea Crônica , Mutação com Ganho de Função , Imunofenotipagem , Pirazóis , Fator de Transcrição STAT1 , Humanos , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/terapia , Masculino , Feminino , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Azetidinas/uso terapêutico , Purinas/uso terapêutico , Criança , Adolescente , Taiwan , AdultoRESUMO
Autosomal recessive CARD9 deficiency can underly deep and superficial fungal diseases. We identified two Japanese patients, suffering from superficial and invasive Candida albicans diseases, carrying biallelic variants of CARD9. Both patients, in addition to another Japanese and two Korean patients who were previously reported, carried the c.820dup CARD9 variant, either in the homozygous (two patients) or heterozygous (three patients) state. The other CARD9 alleles were c.104G > A, c.1534C > T and c.1558del. The c.820dup CARD9 variant has thus been reported, in the homozygous or heterozygous state, in patients originating from China, Japan, or South Korea. The Japanese, Korean, and Chinese patients share a 10 Kb haplotype encompassing the c.820dup CARD9 variant. This variant thus originates from a common ancestor, estimated to have lived less than 4,000 years ago. While phaeohyphomycosis caused by Phialophora spp. was common in the Chinese patients, none of the five patients in our study displayed Phialophora spp.-induced disease. This difference between Chinese and our patients probably results from environmental factors. (161/250).
Assuntos
Proteínas Adaptadoras de Sinalização CARD , Efeito Fundador , Humanos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/deficiência , Masculino , Feminino , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/diagnóstico , Haplótipos , Mutação/genética , Ásia Oriental , Alelos , Candida albicans/genética , Adulto , Linhagem , Povo Asiático/genéticaRESUMO
This case report describes a man in his 40s who presented with a 5-month history of recurrent pruritic papular erythema with mild scaling on the face, left forearm, and groin.
Assuntos
Candidíase Mucocutânea Crônica , Fator de Transcrição STAT1 , Humanos , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/diagnóstico , Fator de Transcrição STAT1/genética , Masculino , FemininoRESUMO
Recent progress in the methods of genetic diagnosis of inborn errors of immunity has contributed to a better understanding of the pathogenesis of chronic mucocutaneous candidiasis (CMC) and potential therapeutic options. This review describes the latest advances in the understanding of the pathophysiology, diagnostic strategies, and management of chronic mucocutaneous candidiasis.
Assuntos
Antifúngicos , Candidíase Mucocutânea Crônica , Humanos , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/tratamento farmacológico , Candidíase Mucocutânea Crônica/genética , Antifúngicos/uso terapêuticoRESUMO
Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections with Candida of the skin, nails, and mucous membrane. It is a rare and severe disease resulting from autoimmune defects or immune dysregulations. Nonetheless, the diagnosis and treatment of CMC still pose significant challenges. Erroneous or delayed diagnoses remain prevalent, while the long-term utility of traditional antifungals often elicits adverse reactions and promotes the development of acquired resistance. Furthermore, disease relapse can occur during treatment with traditional antifungals. In this review, we delineate the advancements in molecular diagnostic and therapeutic approaches to CMC. Genetic and biomolecular analyses are increasingly employed as adjuncts to clinical manifestations and fungal examinations for accurate diagnosis. Simultaneously, a range of therapeutic interventions, including Janus kinase (JAK) inhibitors, hematopoietic stem cell transplantation (HSCT), cytokines therapy, novel antifungal agents, and histone deacetylase (HDAC) inhibitors, have been integrated into clinical practice. We aim to explore insights into early confirmation of CMC as well as novel therapeutic options for these patients.
Assuntos
Candidíase Mucocutânea Crônica , Humanos , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/terapia , Antifúngicos/uso terapêutico , Doença Crônica , Candida , MucosaRESUMO
Germline human heterozygous STAT1 gain-of-function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF. Among this broad range of complications, it has been determined that invasive infections, aneurysms, and malignancies are poor prognostic factors for STAT1 GOF. The effectiveness of JAK inhibitors as a therapeutic option has been established, although further investigation of their long-term utility and side effects is needed. In contrast to the advancements in treatment options, the precise molecular mechanism underlying STAT1 GOF remains undetermined. Two primary hypotheses for this mechanism involve impaired STAT1 dephosphorylation and increased STAT1 protein levels, both of which are still controversial. A precise understanding of the molecular mechanism is essential for not only advancing diagnostics but also developing therapeutic interventions. Here, we provide a comprehensive review of STAT1 GOF with the aim of establishing a stronger connection between bedside observations and laboratory research.
Assuntos
Aneurisma , Candidíase Mucocutânea Crônica , Humanos , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/terapia , Mutação com Ganho de Função , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , PesquisaRESUMO
This case report presents a young girl in her early childhood diagnosed with chronic mucocutaneous candidiasis (CMC) and primary hypothyroidism. Genetic analysis revealed a novel de novo mutation in the STAT1 gene (exon 11, c.972C>G, p.Cys324Trp), adding to the existing literature on STAT1 mutations, which account for approximately 53% of CMC cases. The identified mutation is predicted to have a more severe pathogenic impact based on PolyPhen-2 scoring. Our findings emphasise the importance of comprehensive genetic testing in CMC diagnosis and suggest that the specific mutation site may correlate with disease prognosis. The case underscores the need for vigilant monitoring and targeted therapeutic interventions, given the potential for poorer outcomes.
Assuntos
Candidíase Mucocutânea Crônica , Hipotireoidismo , Feminino , Humanos , Pré-Escolar , Criança , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/complicações , Prognóstico , Mutação , Fator de Transcrição STAT1/genética , Testes Genéticos , Hipotireoidismo/complicações , Hipotireoidismo/genéticaRESUMO
PURPOSE: Inborn errors of the IL-17A/F-responsive pathway lead to chronic mucocutaneous candidiasis (CMC) as a predominant clinical phenotype, without other significant clinical manifestations apart from mucocutaneous staphylococcal diseases. Among inborn errors affecting IL-17-dependent immunity, autosomal recessive (AR) IL-17RC deficiency is a rare disease with only three kindreds described to date. The lack of an in vitro functional evaluation system of IL17RC variants renders its diagnosis difficult. We sought to characterize a 7-year-old Japanese girl with CMC carrying a novel homozygous duplication variant of IL17RC and establish a simple in vitro system to evaluate the impact of this variant. METHODS: Flow cytometry, qPCR, RNA-sequencing, and immunoblotting were conducted, and an IL17RC-knockout cell line was established for functional evaluation. RESULTS: The patient presented with oral and mucocutaneous candidiasis without staphylococcal diseases since the age of 3 months. Genetic analysis showed that the novel duplication variant (Chr3: 9,971,476-9,971,606 dup (+131bp)) involving exon 13 of IL17RC results in a premature stop codon (p.D457Afs*16 or p.D457Afs*17). Our functional evaluation system revealed this duplication to be loss-of-function and enabled discrimination between loss-of-function and neutral IL17RC variants. The lack of response to IL-17A by the patient's SV40-immortalized fibroblasts was restored by introducing WT-IL17RC, suggesting that the genotype identified is responsible for her clinical phenotype. CONCLUSIONS: The clinical and cellular phenotype of the current case of AR IL-17RC deficiency supports a previous report on this rare disorder. Our newly established evaluation system will be useful for the diagnosis of AR IL-17RC deficiency, providing accurate validation of unknown IL17RC variants.
Assuntos
Candidíase Mucocutânea Crônica , Candidíase , Feminino , Humanos , Lactente , Criança , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/genética , Interleucina-17/genética , Candidíase/genética , Fibroblastos/metabolismo , Sequência de BasesRESUMO
PURPOSE: The aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors. METHODS: Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans. RESULTS: Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-É£ and CXCL10 were downregulated. CONCLUSIONS: The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.
Assuntos
Candidíase Mucocutânea Crônica , Inibidores de Janus Quinases , Humanos , Mutação com Ganho de Função , Inibidores de Janus Quinases/uso terapêutico , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/tratamento farmacológico , Candidíase Mucocutânea Crônica/genética , Biomarcadores , Fator de Transcrição STAT1/metabolismoRESUMO
We probably describe the first report of esophageal rupture in a patient with autoimmune polyendocrinopathy - candidiasis - ectodermal dystrophy (APECED, OMIM # 240300), who had candida esophagitis as the main feature for decades. Strong evidence shows that this rupture may have been caused directly and indirectly by chronic candidiasis. In this way, we demonstrate how severe and harmful the persistent esophageal candidiasis can cause in the esophagus, especially in immunodeficient patients.
Assuntos
Candidíase Mucocutânea Crônica , Candidíase , Poliendocrinopatias Autoimunes , Candidíase/complicações , Candidíase/diagnóstico , Candidíase Mucocutânea Crônica/complicações , Candidíase Mucocutânea Crônica/diagnóstico , Humanos , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/diagnósticoRESUMO
Összefoglaló. A krónikus mucocutan candidiasis genetikailag heterogén betegségcsoport, amelyre a bor, a körmök és a nyálkahártyák Candida okozta tartós vagy visszatéro, nem invazív fertozése jellemzo. A Candida-fertozések iránti fokozott fogékonyság oka a Th17-sejtes immunitás defektusa, amelynek hátterében különbözo gének mutációja állhat. A betegség izolált formájában, amelyet más néven krónikus mucocutan candidiasis betegségnek is nevezünk, a mucocutan candidiasis a betegség egyetlen vagy elsodleges tünete. Ezzel szemben a betegség ún. szindrómás formáira a nem invazív Candida-fertozések mellett autoimmun betegség társulása is jellemzo, amely a leggyakrabban az endokrin rendszert érinti. A diagnózis megerosítésében fontos a genetikai vizsgálat, amely az érintett családokban lehetoséget teremt praenatalis genetikai vizsgálatok végzésére is. A szerzok bemutatják a krónikus mucocutan candidiasis fobb típusait, klinikumát, és elemzik a diagnosztikus, illetve terápiás lehetoségeket. A szerzok összefoglalják továbbá a betegség molekuláris genetikai hátterét és a patomechanizmus jelenleg ismert folyamatait. Orv Hetil. 2022; 163(5): 171-180. Summary. Chronic mucocutaneous candidiasis is a genetically heterogeneous group of disorders, which are characterised by chronic or recurrent non-invasive skin, nail and mucous membrane infections caused by Candida. The increased susceptibility to Candida infections is due to a Th17-cell mediated immune defect with different gene mutations in the background. The isolated form of the disorder, referred to as chronic mucocutaneous candidiasis, presents primarily or only with mucocutaneous candidiasis. In contrast, the syndromic form of the disorder is characterised, besides the non-invasive Candida infections, by autoimmune disorders, which most commonly affect the endocrine system. Genetic tests are important in confirming the diagnosis, which in affected families would provide the opportunity for prenatal genetic testing. The authors present the main types of chronic mucocutaneous candidiasis, exploring the clinical aspects, diagnostic methods, and available therapies. Furthermore, the authors conclude the molecular genetic background and the currently known pathomechanism of the disorder. Orv Hetil 2022; 163(5): 171-180.
Assuntos
Candidíase Mucocutânea Crônica , Candidíase , Neoplasias , Candidíase/diagnóstico , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/genética , Humanos , PeleAssuntos
Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/patologia , Úlcera Cutânea/microbiologia , Tinha/diagnóstico por imagem , Tinha/patologia , Tronco/microbiologia , Adulto , Antifúngicos/uso terapêutico , Candidíase Mucocutânea Crônica/tratamento farmacológico , Humanos , Masculino , Úlcera Cutânea/patologia , Úlcera Cutânea/terapia , Tronco/patologiaRESUMO
Chronic mucocutaneous candidiasis (CMC) is a disorder of recurrent or persistent chronic noninvasive symptomatic infections of the skin, nails and mucous membranes. This disorder is primarily caused by Candida albicans. Many factors, including primary immunodeficiencies, can make a host more susceptible to CMC. Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations are the most common genetic etiologies of CMC. We describe a case of CMC with disseminated Talaromyces marneffei infection caused by a new pathogenic Y287N mutation at amino acid 287 in the coiled-coiled domain of STAT1, which was identified using whole-exome sequencing. Position 287 might be a hot spot for missense mutations because several amino acid substitutions were found there. Flow cytometry suggested that the Y287N mutation might reduce the expression of IL-17 of Th17 cells in peripheral blood mononuclear cells stimulated by phorbol myristate acetate and ionomycin. The STAT1 Y287N GOF mutation may be the direct cause of recurrent cutaneous and mucosal candidiasis, including the T. marneffei infection in this patient.
Assuntos
Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/microbiologia , Coinfecção , Mutação com Ganho de Função , Micoses/diagnóstico , Micoses/etiologia , Fator de Transcrição STAT1/genética , Talaromyces , Alelos , Biomarcadores , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/tratamento farmacológico , Análise Mutacional de DNA , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Humanos , Hospedeiro Imunocomprometido , Micoses/tratamento farmacológico , Avaliação de SintomasRESUMO
BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.
Assuntos
Doença de Addison , Candidíase Mucocutânea Crônica , Hipoparatireoidismo , Interferon Tipo I/imunologia , Poliendocrinopatias Autoimunes , Fatores de Transcrição/genética , Doença de Addison/diagnóstico , Doença de Addison/etiologia , Adulto , Autoanticorpos/sangue , Candidíase Mucocutânea Crônica/diagnóstico , Candidíase Mucocutânea Crônica/etiologia , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Hipoparatireoidismo/etiologia , Itália/epidemiologia , Masculino , Mortalidade , Mutação , Poliendocrinopatias Autoimunes/diagnóstico , Poliendocrinopatias Autoimunes/genética , Poliendocrinopatias Autoimunes/mortalidade , Poliendocrinopatias Autoimunes/fisiopatologia , Prevalência , Proteína AIRERESUMO
We report this rare case of cerebral phaeohyphomycosis in a previously healthy Chinese boy, who was found to have caspase recruitment domain family member 9 (CARD9) deficiency. Initial radiological features suggested a neoplastic cerebral lesion, while histopathological examination supplemented by internal transcribed sequencing (ITS) of cerebral tissue confirmed the diagnosis of phaeohyphomycosis. He was treated with intravenous (IV) liposomal amphotericin B and voriconazole, guided by plasma and cerebrospinal fluid (CSF) level monitoring at drug initiation. At the 1 year follow-up, the patient demonstrated near complete neurological and radiological recovery.
Assuntos
Candidíase Mucocutânea Crônica/diagnóstico , Feoifomicose Cerebral/diagnóstico , Administração Intravenosa , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Proteínas Adaptadoras de Sinalização CARD/genética , Candidíase Mucocutânea Crônica/tratamento farmacológico , Feoifomicose Cerebral/tratamento farmacológico , Feoifomicose Cerebral/microbiologia , Feoifomicose Cerebral/cirurgia , Criança , China , Humanos , Masculino , Mutação de Sentido Incorreto , Radiografia/métodos , Resultado do Tratamento , Voriconazol/administração & dosagemRESUMO
Chronic mucocutaneous candidiasis (CMC) is characterized by a chronic or recurrent non-invasive infection, mainly due to Candida albicans, in skin, nails, and mucous membranes, associated in some cases with autoimmune manifestations. The key immune defect is a disruption of the action of cytokine IL-17, whose most common genetic etiology is STAT1 gene gain-of-function (GOF) mutations. The initial appropriate treatment for fungal infections is with azoles. However, the frequent occurrence of drug resistance is the main limitation. Therefore, identification of the underlying inborn error if immunity in CMC may allow to widen therapeutic options aimed at restoring immunological function. Type I and II Janus kinase-inhibitors have been shown to control CMC in cases associated with STAT1 GOF. In this review, we delve into the pathogenesis of CMC and the underlying immune mechanisms. We describe the reported genetic defects in which CMC is the main manifestation. Diagnostic and therapeutic approaches for these patients are also offered.