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.

Gain-of-function STAT1 mutation and visceral leishmaniasis.

Gain-of-function mutations in the STAT1 gene have been initially associated with chronic mucocutaneous candidiasis. However, further research has shown that STAT1 GOF variants may increase susceptibility to infection by other intracellular pathogens. This report describes the first case of disseminated leishmaniasis associated with a STAT1 GOF mutation in a pediatric patient who did not have chronic mucocutaneous candidiasis. The patient was a four-year-old boy presenting with fever, severe asthenia, hepatosplenomegaly, pancytopenia, and liver failure. Bone marrow aspirate revealed hemophagocytosis and Leishmania parasites. Treatment consisted primarily of liposomal amphotericin B, as per the Hemophagocytic Lymphohistiocytosis 2004 protocol. After eight weeks of treatment, the patient did not improve and was submitted to diagnostic splenectomy. Activated macrophages and nodular spleen necrosis secondary to the visceral leishmaniasis were detected. Unfortunately, the patient died in the second week after splenectomy due to overwhelming systemic infection. DNA sequencing revealed a pathogenic (p. R274Q) GOF mutation in STAT1.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and esophageal rupture by candida infection: A case report and review.

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.

Chronic mucocutaneous candidiasis associated with paracoccidioidomycosis in a patient with mannose receptor deficiency: First case reported in the literature.

We describe the first report of a patient with chronic mucocutaneous candidiasis associated with disseminated and recurrent paracoccidioidomycosis. The investigation demonstrated that the patient had a mannose receptor deficiency, which would explain the patient's susceptibility to chronic infection by Candida spp. and systemic infection by paracoccidioidomycosis. Mannose receptors are responsible for an important link between macrophages and fungal cells during phagocytosis. Deficiency of this receptor could explain the susceptibility to both fungal species, suggesting the impediment of the phagocytosis of these fungi in our patient.

Bronchiectasis and Bronchiolectasis With Severe Herniating Pattern Associated With STAT1 Gain-of-Function Mutation: Detailed Clinicopathological Findings.

STAT1 gain-of-function (GOF) mutations are associated with a rare autosomal dominant immunodeficiency disorder with main clinical manifestations including chronic mucocutaneous candidiasis (CMC) and bronchiectasis. In addition, these patients show higher incidences of cerebral and extracerebral aneurysm, malignancies and various autoimmune conditions compared to the general population. Although previous publications have reported clinical findings in patients with STAT1 GOF mutation, they did not include histopathologic features. Herein, we describe the first case with detailed histologic findings in the lung of a 5-year-old patient with a de novo STAT1 GOF mutation, who presented with CMC and bronchiectasis. The biopsy showed severe bronchiolectasis with extensive airway dilatation and occasional disruptions. Peribronchiolar inflammation was not always present and evident mainly in areas of airway disruption; inflammation may have not been a main driver of the airway damage in this case. The airway dilatation often showed an interesting herniating pattern, possibly implying a connective tissue etiology. This case also demonstrates the diagnostic utility of whole exome sequencing as STAT1 GOF mutations are not detected by routine workup. The definitive diagnosis will lead to more specific treatments and increased surveillance for serious conditions, such as cerebral aneurysms and malignancies.

Chronic mucocutaneous candidiasis associated with paracoccidioidomycosis in a patient with mannose receptor deficiency: First case reported in the literature

Abstract We describe the first report of a patient with chronic mucocutaneous candidiasis associated with disseminated and recurrent paracoccidioidomycosis. The investigation demonstrated that the patient had a mannose receptor deficiency, which would explain the patient's susceptibility to chronic infection by Candida spp. and systemic infection by paracoccidioidomycosis. Mannose receptors are responsible for an important link between macrophages and fungal cells during phagocytosis. Deficiency of this receptor could explain the susceptibility to both fungal species, suggesting the impediment of the phagocytosis of these fungi in our patient.

Effect of CARD9 Deficiency on Neutrophil-Mediated Host Defense against Pulmonary Infection with Streptococcus pneumoniae.

Streptococcus pneumoniae is a major causative bacterium of community-acquired pneumonia. Dendritic cell-associated C-type lectin-2 (dectin-2), one of the C-type lectin receptors (CLRs), was previously reported to play a pivotal role in host defense against pneumococcal infection through regulating phagocytosis by neutrophils while not being involved in neutrophil accumulation. In the present study, to elucidate the possible contribution of other CLRs to neutrophil accumulation, we examined the role of caspase recruitment domain-containing protein 9 (CARD9), a common adaptor molecule for signal transduction triggered by CLRs, in neutrophilic inflammatory response against pneumococcal infection. Wild-type (WT), CARD9 knockout (KO), and dectin-2 KO mice were infected intratracheally with pneumococcus, and the infected lungs were histopathologically analyzed to assess neutrophil accumulation at 24 h postinfection. Bronchoalveolar lavage fluids (BALFs) were collected at the same time point to count the neutrophils and assess the production of inflammatory cytokines and chemokines. Neutrophil accumulation was significantly decreased in CARD9 KO mice, but not in dectin-2 KO mice. Tumor necrosis factor alpha (TNF-α), keratinocyte-derived chemokine (KC), and macrophage inflammatory protein-2 (MIP-2) production in BALFs were also attenuated in CARD9 KO mice, but not in dectin-2 KO mice. Production of TNF-α and KC by alveolar macrophages stimulated with pneumococcal culture supernatants was significantly attenuated in CARD9 KO mice, but not in dectin-2 KO mice, compared to that in each group's respective control mice. In addition, pneumococcus-infected CARD9 KO mice showed larger bacterial burdens in the lungs than did WT mice. These data indicate that CARD9 is required for neutrophil migration after pneumococcal infection, as well as inflammatory cytokine and chemokine production by alveolar macrophages, and suggest that a CLR distinct from dectin-2 may be involved in this response.

Complete clinical remission of invasive Candida infection with CARD9 deficiency after G-CSF treatment.

Caspase-associated recruitment domain-containing protein 9 (CARD9) deficiency is an autosomal-recessive primary immunodeficiency characterized by susceptibility to recurrent Candida infections, and its diagnosis and treatment is challenging. The present study aims to investigate the genetic characteristic and treatment strategy of a Chinese pediatric patient with CARD9 deficiency. In the present study, whole-exome sequencing (WES) was performed to screen the causal variants in a Chinese pediatric patient who exhibited an invasive Candida infection in the abdominal cavity and central nervous system. After the disease-causing gene being confirmed, the patient was treated with a combination of G-CSF and antifungal agents. DNA sequencing revealed a homozygous insertion mutation (c.819-820insG) in exon 6 of the CARD9 gene, which led to downstream amino acids conversion on codon 274 (p.D274fsX60). Th17 cell populations and cytokine levels showed decreased levels. The treatment regimen successfully resolved the patient's symptoms, and he remained symptom-free after more than 1 year of follow-up. This study described an invasive Candida infection in a pediatric patient and WES identified an insertion variant of the CARD9 gene. A combination of G-CSF and antifungal agents was highly effective in treating the invasive fungal infection accompanied by CARD9-induced immunodeficiency.

[Chronic mucocutaneous candidiasis with STAT1 gain-of-function mutation associated with herpes virus and mycobacterial infections]. / Candidose cutanéo-muqueuse chronique avec mutation gain-de-fonction du gène STAT1 associée à des infections herpétiques et à mycobactérie.

INTRODUCTION: Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to chronic or recurrent infections with yeasts of the genus Candida affecting the skin, nails and mucous membranes. We describe a Moroccan patient presenting CMC with heterozygous STAT1 gain-of-function (GOF) mutation. PATIENTS AND METHODS: A 5-year-old boy with no consanguinity presented recurrent episodes of oral thrush, chronic nail candidiasis and herpetic gingivostomatitis from the age of 8 months. He also had mycobacterial adenitis secondary to BCG vaccination and atypical rosacea. Genetic analysis revealed GOF mutation of the STAT1 gene. DISCUSSION: CMC was diagnosed in our patient despite poor clinical features. Sequencing of the genome revealed STAT1GOF mutation. This mutation affects production of IL-17, an important cytokine in mucocutaneous defense against Candida. The association with mycobacterial adenitis is rare and continues to be poorly understood. The presence of atypical rosacea in this setting is suggestive of this entity. Antifungal therapy and prevention of complications are necessary to reduce the morbidity and mortality associated with this condition. CONCLUSION: CMC due to STAT1GOF mutation is characterized by a broad clinical spectrum and should be considered in all cases of chronic or recurrent fungal infection, whether or not associated with other infections.

Prototheca zopfii Colitis in Inherited CARD9 Deficiency.

Human protothecosis is a rare microalgae infection, and its dissemination typically occurs in immunocompromised individuals, but no specific immune defect has been reported. Here, we describe an 8-year-old daughter of a consanguineous union with abdominal pain and bloody diarrhea for 3 months who was found to have pancolitis with numerous microalgae identified as Prototheca zopfii. In the absence of a known immunodeficiency, exome sequencing was performed, which uncovered a novel recessive frameshift mutation in CARD9 (p.V261fs). This report highlights that CARD9 deficiency should be investigated in patients with unexplained systemic/visceral protothecosis and suggests a new mechanistic insight into anti-Prototheca immunity.

Chronic mucocutaneous candidiasis: what can we conclude about IL-17 antagonism?

PURPOSE: IL-17 antagonists are effective for psoriasis in clinical trials, but long-term safety is not fully characterized. Since chronic mucocutaneous candidiasis (CMC) is caused by defects in the IL-17 pathway, CMC risk data have been touted as providing reassurance about the safety of IL-17 antagonism. METHODS: We performed a literature review to identify patients with CMC and compared the prevalence of cancer in these patients to the reported 5-year prevalence. RESULTS: There was a higher prevalence of oropharyngeal (2.5% vs. 0.028%; p < .0001) and esophageal cancer (1.9% vs. 0.013%; p < .0001) in patients with CMC. There were no reports of cancer in 31 patients with CMC caused by an isolated IL-17 deficiency (IL-17F, IL-17RA, IL17RC); however, a study would need over 1000 patients to detect even a 10-fold increase in the most common malignancy of CMC patients. CONCLUSIONS: There is evidence that some forms of CMC are associated with an increase in cancer. While CMC is heterogeneous, our findings suggest that we cannot use CMC data to reassure patients on the long-term safety of IL-17 antagonists beyond the safety results from clinical trials, and perhaps caution should be taken with the development of candidiasis in patients taking these medications.

[Cancer and mycoses and literature review]. / Cancer et mycoses et revue de la littérature.

Various infectious agents are classical risk factors for cancer including bacteria, viruses and parasites. There is less evidence concerning the implication of fungal infection in carcinogenesis. The role of chronic Candida infection in the development of squamous cell carcinoma has been suspected for years. Candida sp are more prevalent in potentially malignant disorder and cancer of the oral mucosa. Other epidemiological evidence of a link between Candida infection and cancer is what is observed in patients with Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED). Oral and oesophagal carcinoma are frequent in these patients with chronic mucocutaneous candidiasis. Production of nitrosamine and metabolism of procarcinogen are mecanisms in which Candida sp may be involved in oral cancer development. In chromomycosis and lobomycosis chronic lesions may have a risk of malignant transformation. A diagnosis of paracoccidioidomycosis appears to increase the risk of lung cancer.

Gain-of-function STAT1 mutations are associated with intracranial aneurysms.

Chronic mucocutaneous candidiasis, characterized by persistent or recurrent fungal infections, represents the clinical hallmark in gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) mutation carriers. Several cases of intracranial aneurysms have been reported in patients with GOF STAT1 mutation but the paucity of reported cases likely suggested this association still as serendipity. In order to endorse this association, we link the development of intracranial aneurysms with STAT1 GOF mutation by presenting the two different cases of a patient and her mother, and demonstrate upregulated phosphorylated STAT4 and IL-12 receptor ß1 upon stimulation in patient's blood cells. We also detected increased transforming growth factor (TGF)-ß type 2 receptor expression, particularly in CD14+ cells, and a slightly higher phosphorylation rate of SMAD3. In addition, the mother of the patient developed disseminated bacille Calmette-Guérin disease after vaccination, speculating that GOF STAT1 mutations may confer a predisposition to weakly virulent mycobacteria.

Oral candidiasis.

Oral candidiasis (OC) is a common fungal disease encountered in dermatology, most commonly caused by an overgrowth of Candida albicans in the mouth. Although thrush is a well-recognized presentation of OC, it behooves clinicians to be aware of the many other presentations of this disease and how to accurately diagnose and manage these cases. The clinical presentations of OC can be broadly classified as white or erythematous candidiasis, with various subtypes in each category. The treatments include appropriate oral hygiene, topical agents, and systemic medications. This review focuses on the various clinical presentations of OC and treatment options.

Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation.

Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3(+)-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNÉ£ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/É£-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms.

Clinical heterogeneity of dominant chronic mucocutaneous candidiasis disease: presenting as treatment-resistant candidiasis and chronic lung disease.

In gain-of-function STAT1 mutations, chronic mucocutaneous candidiasis disease (CMCD) represents the phenotypic manifestation of a complex immunodeficiency characterized by clinical and immunological heterogeneity. We aimed to study clinical manifestations, long-term complications, molecular basis, and immune profile of patients with dominant CMCD. We identified nine patients with heterozygous mutations in STAT1, including novel amino acid substitutions (L283M, L351F, L400V). High risk of azole-resistance was observed, particularly when intermittent regimens of antifungal treatment or use of suboptimal dosage occurs. We report a case of Cryptococcosis and various bacterial and viral infections. Risk of developing bronchiectasis in early childhood or gradually evolving to chronic lung disease in adolescent or adult ages emerges. Lymphopenia is variable, likely progressing by adulthood. We conclude that continuous antifungal prophylaxis associated to drug monitoring might prevent resistance to treatment; prompt diagnosis and therapy of lung disease might control long-term progression; careful monitoring of lymphopenia-related infections might improve prognosis.

IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation.

BACKGROUND: Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. OBJECTIVE: We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. METHODS: We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. RESULTS: As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1ß and TNF-α, which is consistent with the persistent systemic inflammation. CONCLUSIONS: This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.

IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations.

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αß T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

Síndrome poliglandular autoinmune tipo 1 y mutación C322fsX372 / Type i polyglandular autoimmune syndrome associated with C322fsx372 mutation

Los síndromes poliglandulares autoinmunes son raras endocrinopatías en las que coexisten alteraciones de las glándulas endocrinas, basadas en mecanismos autoinmunes con otras enfermedades no endocrinas. En el tipo 1, las manifestaciones características son la candidiasis mucocutánea crónica, el hipoparatiroidismo y la insuficiencia suprarrenal. Presentamos a una paciente que presenta la secuencia clínica típica, junto con otras alteraciones, realizando estudio genético del gen autoimmune regulator (AIRE), detectándose una mutación en homocigosis, C322fsX372. La herencia es autonómica recesiva, asociada a mutaciones en el gen AIRE, el cual codifica una protei′na que interviene en procesos de autoinmunidad e inmunodeficiencia. Para el diagnóstico, se requieren al menos 2 de las 3 manifestaciones clínicas principales, aunque en el estudio de familiares de pacientes afectados solo se requiere una de ellas. Estos síndromes deben ser diagnosticados en etapas tempranas, dada su alta morbimortalidad. Es necesario tratar cada una de las alteraciones, con el objetivo de preservar la calidad de vida

Polyglandular autoimmune syndromes are rare diseases based on autoimmune mechanisms in which endocrine and non-endocrine disorders coexist. In type 1 the characteristic manifestations are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. A case is presented of a patient with typical clinical sequence, along with other changes, and in whom a mutation in homozygosis, C322fsX372, was detected after performing a molecular analysis of autoimmunity regulator gene (AIRE). Polyglandular autoimmune syndromes are rare diseases based on autoimmune mechanisms in which endocrine and non-endocrine disorders coexist. In type 1 the characteristic manifestations are chronic mucocutaneous candidiasis, hypoparathyroidism and adrenal insufficiency. A case is presented of a patient with typical clinical sequence, along with other changes, and in whom a mutation in homozygosis, C322fsX372, was detected after performing a molecular analysis of autoimmunity regulator gene (AIRE)