Chronic Mucocutaneous Candidiasis Due to STAT1 Gene Variant.

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.

Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib.

INTRODUCTION: The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity. METHODS: In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation. RESULTS: STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment. CONCLUSION: In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.

Progress in molecular diagnosis and treatment of chronic mucocutaneous candidiasis.

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.

Human STAT1 gain of function with chronic mucocutaneous candidiasis: A comprehensive review for strengthening the connection between bedside observations and laboratory research.

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.

Deep dermatophytosis caused by Trichophyton rubrum in an elderly patient with CARD9 deficiency: A case report and literature review.

Deep dermatophytosis is an invasive and sometimes life-threatening fungal infection mainly reported in immunocompromised patients. However, a caspase recruitment domain-containing protein 9 (CARD9) deficiency has recently been reported to cause deep dermatophytosis. Herein, we report the first Japanese case of deep dermatophytosis associated with CARD9 deficiency. An 80-year-old Japanese man with tinea corporis presented with subcutaneous nodules on his left sole. Histopathological findings revealed marked epithelioid cell granulomas with filamentous fungal structures in the deep dermis and subcutis, and the patient was diagnosed with deep dermatophytosis. Despite antifungal therapy, the subcutaneous nodule on his left sole gradually enlarged, his left calcaneal bone was invaded, and the patient finally underwent amputation of his left leg. Genetic analysis revealed a homozygous CARD9 c.586 A > G (p. Lys196Glu) variant, suggesting a CARD9 deficiency. Here, we discuss the clinical features of CARD9 deficiency-associated deep dermatophytosis with a case report and review of the literature.

Innate Error Immunities of the Th17 Immune Pathway Associated With Chronic Mucocutaneous Candidiasis: A Systematic Review.

BACKGROUND: Candida albicans is an opportunistic pathogenic yeast commensal in human mucosa. In individuals with compromised immune systems, it can present as chronic mucocutaneous candidiasis (CMC) or systemic infection. CMC often exists in the presence of other infectious phenotypes due to dysfunction of the Th17 immune response. OBJECTIVE: To examine innate error immunities (IEI) of the Th17 immune response associated with CMC. METHODS: MEDLINE PubMed, Embase, and Web of Science were searched for keywords and Medical Subject Headings (MeSH) related to the subject of interest. Nonapplicable and non-primary research methodologies were excluded. RESULTS: We identified 266 articles; 89 were removed for being a duplicate, 108 for irrelevance, and 51 for being a review. We examined 18 studies, 5 on murine models, and 13 human studies. CONCLUSION: Case reports in patients with CMC have identified a range of mutations in IL-17F, IL-17RA, IL-17RC, and ACT1. Mouse models confirm the role of IL-17A and IL-17F in disease susceptibility. J Drugs Dermatol. 2023;22(12):1197-1203. doi:10.36849/JDD.7579.

Isolated Chronic Mucocutaneous Candidiasis due to a Novel Duplication Variant of IL17RC.

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.

Novel STAT1 mutation in a paediatric case of chronic mucocutaneous candidiasis complicated by primary hypothyroidism: clinical presentation, genetic analysis and prognostic implications.

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.

Neutrophils in STAT1 Gain-Of-Function Have a Pro-inflammatory Signature Which Is Not Rescued by JAK Inhibition.

STAT1 gain-of-function (GOF) mutations cause an inborn error of immunity with diverse phenotype ranging from chronic mucocutaneous candidiasis (CMC) to various non-infectious manifestations, the most precarious of which are autoimmunity and vascular complications. The pathogenesis centers around Th17 failure but is far from being understood. We hypothesized that neutrophils, whose functions have not been explored in the context of STAT1 GOF CMC yet, might be involved in the associated immunodysregulatory and vascular pathology. In a cohort of ten patients, we demonstrate that STAT1 GOF human ex-vivo peripheral blood neutrophils are immature and highly activated; have strong propensity for degranulation, NETosis, and platelet-neutrophil aggregation; and display marked inflammatory bias. STAT1 GOF neutrophils exhibit increased basal STAT1 phosphorylation and expression of IFN stimulated genes, but contrary to other immune cells, STAT1 GOF neutrophils do not display hyperphosphorylation of STAT1 molecule upon stimulation with IFNs. The patient treatment with JAKinib ruxolitinib does not ameliorate the observed neutrophil aberrations. To our knowledge, this is the first work describing features of peripheral neutrophils in STAT1 GOF CMC. The presented data suggest that neutrophils may contribute to the immune pathophysiology of the STAT1 GOF CMC.

Oral candidiasis and seborrheic dermatitis in an 8-year-old female with a heterozygous variant of the IL-17RC gene.

An 8-year-old female with chronic oral candidiasis and severe seborrheic dermatitis was found to have a heterozygous mutation (p.R14X c.40 C>T) of the IL-17RC gene, which was predicted to possibly represent a new pathogenic variant via truncation or nonsense-mediated mRNA decay. Given previously reported IL-17RC-related disorders are autosomal recessive, we would expect an affected individual to have two mutated alleles whereas our patient was heterozygous. Given the overlapping clinical picture, this variant could be responsible for altered immunity against both Candida and Malassezia species. This is the first report to our knowledge of chronic oral candidiasis and severe seborrheic dermatitis in a patient with a heterozygous variant (p.R14X c.40 C>T) for the IL-17RC gene.

The Th17/IL-17 Axis and Host Defense Against Fungal Infections.

Chronic mucocutaneous candidiasis (CMC) was recognized as a primary immunodeficiency in the early 1970s. However, for almost 40 years, its genetic etiology remained unknown. The progressive molecular and cellular description of inborn errors of immunity (IEI) with syndromic CMC pointed toward a possible role of IL-17-mediated immunity in protecting against fungal infection and CMC. Since 2011, novel IEI affecting either the response to or production of IL-17A and/or IL-17F (IL-17A/F) in patients with isolated or syndromic CMC provided formal proof of the pivotal role of the IL-17 axis in mucocutaneous immunity to Candida spp, and, to a lesser extent, to Staphylococcus aureus in humans. In contrast, IL-17-mediated immunity seems largely redundant against other common microbes in humans. In this review, we outline the current knowledge of IEI associated with impaired IL-17A/F-mediated immunity, highlighting our current understanding of the role of IL-17A/F in human immunity.

Case report: Myocarditis in congenital STAT1 gain-of function.

Autosomal dominant Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations result in an inborn error of immunity characterized by chronic mucocutaneous candidiasis, recurrent viral and bacterial infections, and diverse autoimmune manifestations. Current treatment consists of chronic antifungal therapy, antibiotics for concomitant infections, and immunosuppressive therapy in case of autoimmune diseases. More recently, treatment with Janus kinases 1 and 2 (JAK1/2) inhibitors have shown promising yet variable results. We describe a STAT1 GOF patient with an incidental finding of elevated cardiac troponins, leading to a diagnosis of a longstanding, slowly progressive idiopathic myocarditis, attributed to STAT1 GOF. Treatment with a JAK-inhibitor (baricitinib) mitigated cardiac inflammation on MRI but was unable to alter fibrosis, possibly due to the diagnostic and therapeutic delay, which finally led to fatal arrhythmia. Our case illustrates that myocarditis could be part of the heterogeneous disease spectrum of STAT1 GOF. Given the insidious presentation in our case, a low threshold for cardiac evaluation in STAT1 GOF patients seems warranted.

A family with interleukin-17 receptor A deficiency: a case report and review of the literature.

BACKGROUND: Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosa with Candida species, mainly Candida albicans. In a single patient, the first genetic etiology of isolated CMC autosomal recessive interleukin-17 receptor A (IL-17RA) deficiency was reported in 2011. CASE: We report four patients with CMC who displayed autosomal recessive IL-17RA deficiency. The patients were from the same family, and their ages were 11, 13, 36, and 37 years. They all had their first CMC episode by six months of age. All patients manifested staphylococcal skin disease. We documented high IgG levels in the patients. In addition, we found the coexistence of hiatal hernia, hyperthyroidism, and asthma in our patients. CONCLUSIONS: Recent studies have provided new information on the heredity, clinical course, and prognosis of IL-17RA deficiency. However, further studies are needed to reveal the full picture of this congenital disorder.