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.

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.

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.

Malignant Transformation and Treatment Recommendations of Chronic Hyperplastic Candidiasis-A Six-year Retrospective Cohort Study.

BACKGROUND: Oral chronic hyperplastic candidiasis (CHC) is the most uncommon type of oral candidiasis with diverse manifestations. Up to date the diagnosis, long-term management and prognosis of this oral potentially malignant disorder remain obscure. OBJECTIVES: The aim of this study was to provide the recommendations guiding the diagnostic procedure, clinical management and prognosis assessment of CHC. METHODS: A retrospective cohort study was performed during January 2015 to April 2021 involving patients with a definite diagnosis of CHC in the Department of Oral Medicine of Peking University School and Hospital of Stomatology. Demographic features, clinical and histopathological features, treatment protocols and follow-ups including malignancy transformation were analysed. RESULTS: Fourty eight CHC patients were collected and reviewed, with a male-to-female ratio of 2.69:1. The average age at diagnosis was 54.92 ± 9.79 (36-80) years old. Clinically, the multiform oral lesions were diverse and frequently presented as white plaque and erythematous lesions. As a result, the initial diagnostic accordance rate was only 54.17%, and the most common presumptive initial diagnoses were oral lichen planus (22.92%), oral leukoplakia (20.83%) and traumatic lesion (2.08%). Histopathologically, ten (20.83%) patients had varying degrees of epithelial dysplasia, and two (4.17%) patients had malignant transformation with a mean transformation time of 6.5 ± 6.36 months. Among the 28 patients who underwent fungal culture, 24 patients were exclusively infected by Candida albicans, with two patients each mixed infected by C glabrata and C tropicalis, respectively. Notably, treatment with fluconazole had the lower recurrence rate compared with topical nystatin. CONCLUSIONS: The diagnosis and management of CHC remain a challenge due to its polymorphic clinical presentations, chronic progression and potential of malignant transformation.

Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy.

Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1-dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.

Successful Allogenic Stem Cell Transplantation in Patients with Inherited CARD9 Deficiency.

Autosomal recessive (AR) CARD9 (caspase recruitment domain-containing protein 9) deficiency underlies invasive infections by fungi of the ascomycete phylum in previously healthy individuals at almost any age. Although CARD9 is expressed mostly by myeloid cells, the cellular basis of fungal infections in patients with inherited CARD9 deficiency is unclear. Therapy for fungal infections is challenging, with at least 20% premature mortality. We report two unrelated patients from Brazil and Morocco with AR CARD9 deficiency, both successfully treated with hematopoietic stem cell transplantation (HSCT). From childhood onward, the patients had invasive dermatophytic disease, which persisted or recurred despite multiple courses of antifungal treatment. Sanger sequencing identified homozygous missense CARD9 variants at the same residue, c.302G>T (p.R101L) in the Brazilian patient and c.301C>T (p.R101C) in the Moroccan patient. At the ages of 25 and 44 years, respectively, they received a HSCT. The first patient received a HLA-matched HSCT from his CARD9-mutated heterozygous sister. There was 100% donor chimerism at D + 100. The other patient received a T cell-depleted haploidentical HSCT from his CARD9-mutated heterozygous brother. A second HSCT from the same donor was performed due to severe amegakaryocytic thrombocytopenia despite achieving full donor chimerism (100%). At last follow-up, more than 3 years after HSCT, both patients have achieved complete clinical remission and stopped antifungal therapy. HSCT might be a life-saving therapeutic option in patients with AR CARD9 deficiency. This observation strongly suggests that the pathogenesis of fungal infections in these patients is largely due to the disruption of leukocyte-mediated CARD9 immunity.

Treatment options for chronic mucocutaneous candidiasis.

Autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) is a rare and severe primary immunodeficiency that is characterized by mucocutaneous fungal infection, autoimmunity, cerebral aneurysms, and oropharyngeal and esophageal cancer. Recently, it was discovered that STAT1 mutations are responsible for AD-CMC. These mutations lead to the inability of STAT1 to be dephosphorylated, resulting in hyperphosphorylation, increased binding to the DNA, and gain of function (GOF) effects on STAT1 signaling. Furthermore, a characteristic feature of AD-CMC patients is deficiency in the T-helper 17 (Th17) responses, which is believed to be the immunological cause of the mucocutaneous fungal infection. No targeted treatment other than lifelong antifungal prophylaxis exists for AD-CMC. However, the discovery of the genetic and immunological defects makes it now possible to explore new treatment strategies. This review will discuss immunomodulatory treatment options that can be explored in patients with STAT1 GOF mutations.

Avalia ao da susceptibilidade a antifungicos de diferentes espécies de leveduras candida isoladas de mucosa bucal e pele / Evaluation of antifungal susceptibility of different species of candida yeast isolated from buccal mucosa and skin

A variabilidade das diferentes especies de Candida sp, juntamente com as distintas respostas as formas de tratamento, desenvolveram a necessidade da utiliza tao de diferentes metodos diagn6sticos e esquemas terapeuticos. Entre as leveduras deste grupo, a Candida albicans e urn dos pat6genos mais comuns envolvidos nas candidiases mucocutaneas e da orofaringe, porem as especies nao albicans tern aumentado em numero e em importancia devido ao acrescimo do perfil de resistencia aos antifUngicos. A resistencia da Candida albicans e das especies nao albicans ao fluconazole outros derivados az61icos e descrito na literatura com freqOencia, o que torna importante a realiza tao de testes de susceptibilidade. Neste contexte esta pesquisa tern como objetivo determinar o perfil de susceptibilidade das leveduras Candida em diferentes sftios anatomicos. As leveduras isoladas da mucosa bucal e de pele foram semeadas em CHROMagar Candida, incubadas por 48 horas, a 35°C sendo posteriormente identificadas e avaliado in vitro o perfil de susceptibilidade utilizando o metodo da macrodilui tao. Entre as 25 amostras analisadas, verificou-se urn perfil de resistencia maior ao fluconazol em compara tao ao cetoconazol, sendo que 44% dos isolados de boca e 50% de pele mostraram-se resistentes ao fluconazol.

The variability of the different species of Candida sp, together with the distinct responses to treatment, elicited the need of using different diagnostic methods and therapeutic programs. Among the yeast of this group, Candida albicans is one of the most common pathogens involved in muco-cutaneous and oropharingeal candidiases, but the non-albicans species have increased in number and importance due to antifungal resistance. The resistance of Candida albicans and the non-albicans species to fluconazole and other azolic derivatives is frequently reported, which makes susceptibility tests important. Within this scope, this research has the purpose of determining the susceptibility profile of Candida yeast from different anatomical sites. The yeast cells isolated from buccal mucosa and skin were seeded in CHROMagar Candida, incubated for 48 hours at 35°C; later, they were identified and the susceptibility profile was assessed in vitro using themacrodilution method. Of the 25 samples analyzed, a higher profile of resistance to fluconazole compared to ketoconazole was noticed, where 44% ofthe buccal and 50% ofthe skin isolates were resistant to fluconazole.

Candidiasis mucocutánea crónica. Informe de un caso / Chronic mucocutaneous candidiasis. Case report

La candidiasis mucocutánea crónica (CMC) es una inmunodeficienciaprimaria que se caracteriza por infecciones candidiásicaspersistentes o recurrentes en piel, uñas o membranas mucosas. La CMC puede asociarse con endocrinopatías, comohipoparatiroidismo, enfermedad de Addison, hipotiroidismo, diabetes mellitus de tipo 1 o hipogonadismo; otras patologías asociadas son enfermedades autoinmunitarias, como gastritis autoinmunitarias y hepatitis autoinmunitaria. Se presentauna paciente con CMC con déficit específico de linfocitos T ycélulas NK, sin otra enfermedad asociada.

Chronic mucocutaneous candidiasis and oesophageal cancer.

Chronic mucocutaneous candidiasis (CMC) is often accompanied by endocrine or inflammatory disorders. The association of CMC with squamous cell carcinoma of the oral cavity or oesophagus have been described in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). We describe three cases of CMC and oesophageal cancer without the APECED syndrome. The first case refers to a 41-year-old man with Candida paronychia and oral infection and selective IgA deficiency since childhood, who later developed an oesophageal cancer. The second case is a 30-year-old man who presented CMC features at the age of 2 together with selective IgA deficiency. Later on he was diagnosed with an oesophageal squamous cell carcinoma. His mother, the third case reported, had oral thrush since childhood and at the age of 29 she presented with an oesophageal squamous cell carcinoma. The three patients reported died due to oesophageal cancer. This is the first case report describing the development of oesophageal cancer in patients with CMC without the APECED syndrome. Patients with CMC need close follow-up with good oral hygiene and aggressive treatment of oral and oesophageal candidiasis. Routine endoscopic screening for patients with CMC that develop symptoms of oesophageal candidiasis and for patients with CMC with a family history of oesophageal cancer is suggested. Avoidance of additional risk factors for oral and oesophageal cancer like cigarette smoking and excessive alcohol consumption are also warranted.

Candidíase extragenital / Extragenital candidiasis

As vulvovaginites constituem-se um dos diagnósticos mais frequêntes na prática diária em ginecologia. Os ginecologistas enfrentam o problema da candidíase genital näo complicada com algum sucesso, entretanto, conhecem pouco da doença, quando esta assume formas extragenitais ou recorrentes, tendo sérias dificuldades no manuseio das pacientes. Breve resumo do diagnóstico e tratamento da infecçäo extragenital nas seguintes formas de candidíase: oral, cutânea, mucocutânea crônica, esofágica, gastrointestinal, urinária, do sistema nervoso central, respiratório, cardíaca, ocular, entre outras

Successful allogeneic bone marrow transplantation in severe chronic mucocutaneous candidiasis syndrome.

We report the successful HLA-identical sibling bone marrow transplantation (BMT) of a 12-year-old boy with chronic mucocutaneous candidiasis (CMC) syndrome who also had Coomb's positive haemolytic anaemia and recurrent bronchopneumonia with resulting bronchiectasis. Conditioning was with busulfan and cyclophosphamide. Engraftment was slow but complete. Selective red cell haemopoietic failure was encountered soon after transplantation but resolved spontaneously. The patient remains alive 3 years after transplantation and now has normal immune, haemopoeitic and pulmonary functions. No manifestation of CMC has been evident since transplantation.

Chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis is a complex disorder in which patients have chronic and recurrent Candida albicans infections of the skin, nails, and mucous membranes. There are several subgroups of patients with chronic mucocutaneous candidiasis, and these can be identified by associated disorders such as autoimmune diseases, endocrinopathies, thymoma, and interstitial keratitis, as well as the distribution and severity of the Candida infections. Several other disorders may coexist in patients with chronic mucocutaneous candidiasis. These include other infectious diseases, endocrinopathies, dental enamel dysplasia, vitiligo, and alopecia totalis. Successful treatment programs should include antifungal drugs and manipulations that correct the immunologic abnormalities that predispose the patient to Candida infections.

Candidiasis mucocutánea crónica: reporte de un caso / Chronic mucocutaneous candidiasis: report of a case

Se presenta un caso de candidiasis mucocutánea crónica de tipo crónico, de inicio a los 8 meses, manifestado por lesiones orales en placa en la totalidad de la mucosa oral y nasal, con afección de lechos ungueales. El paciente recibió diversos tratamientos por 10 años, sin mejoría. Se estableció el diagnóstico por cuadro clínico, exámenes de laboratorio que incluyeron prueba cutánea a Cándida y PPD, roseta T y B, MIF a Cándida, frotis directo de lesiones, inmunoglobulinas, migración al azar y transformación blastoide a mitógeno yCándida. Recibió tratamiento con ketoconazol don dosis inicial de 100 mg diarios, que fue incrementada a 200 mg cada 24 horas, hasta concluir un periodo de 2 años. Posteriormente, continuó con 100 mg cada tercer día por 1 año más, simultáneo al tratamiento anterior se instituyó estimulo antigénico con Cándida. Con el tratamiento mencionado curso asintomático. Se hacen comentarios en relación al posible efecto del Ketaconazol como inmunopotenciador a través de correlación de la inmunodeficiencia secundaria al estímulo antigénico crónico

Chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis can be defined as a group of syndromes that have as a common feature infections of the skin, nails and mucous membranes with Candida albicans. A variety of disorders including endocrine dysfunctions, alopecia, vitiligo, malabsorption syndromes, neoplasms and other infections may also occur in patients with chronic mucocutaneous candidiasis, but these vary considerably from patient to patient. In most patients with chronic mucocutaneous candidiasis, there are abnormalities of cell-mediated immunity. These may be limited to antigens of Candida albicans, but in some patients they are more extensive and involve the T-lymphocyte-mediated responses to all antigens. These immunologic defects are the factors that predispose patients to infections with opportunistic organisms such as Candida spp. Fungal infections in patients with chronic mucocutaneous candidiasis usually respond to treatment with conventional antifungal agents, but often relapse shortly after treatment is stopped unless the defects in the cell-mediated immune system have been corrected.

Reconstitution of T-cell deficiency by thymic hormone or thymus transplantation therapy.

Correction of T-cell defects by either thymic hormone treatment or thymus transplantation has proven to be more difficult clinically than historically anticipated. Because the precise action of thymic hormones is unknown and because these hormones act upon post-thymic cells, therapeutic attempts may fail owing to lack of sufficient substrate population. Results of thymic transplantation suggest that this procedure may be best utilized for the treatment of mild T-cell defects, rather than as complete replacement treatment for severe deficiency. Future clinical trials of thymic transplantation or thymic hormone appear justified in narrowly circumscribed and well-characterized conditions.

Severe aplastic anemia associated with chronic mucocutaneous candidiasis. Immunologic and hematologic reconstitution after allogeneic bone marrow transplantation.

Chronic mucocutaneous candidiasis (CMC) is typically associated with the inability of T lymphocytes to proliferate and produce lymphokines in response to Candida antigen. A 7-year-old girl with CMC developed severe aplastic anemia and, after conditioning with cyclophosphamide, 200 mg/kg, underwent bone marrow transplantation from her HLA-identical sister. Engraftment was prompt and complete. The patient is surviving more than 3 years after transplantation with normal donor-derived hemopoiesis and immune function. Manifestations of CMC have resolved completely and she has not received antifungal therapy for more than 2 years.

[Chronic mucocutaneous candida mycosis (CMCC) caused by a T-cell defect]. / Chronische mukokutane Candida-Mykose (CMCC) infolge eines T-Zelldefektes.

It is reported on a 42-year-old book-keeper with the granulomatous variant of the chronic mucocutaneous candidiasis which could be followed up for 28 years. The intensive systemic treatment with nystatin, 5-fluorocytosin and miconazol combined with the subcutaneous injection of transfer-factor and the local application of ointments containing nystatin and clotrimazol did not only lead to the complete clearing of the lesions (4 years without any relapse), but also to the normalization of the T-lymphocyte count and the reconstitution of the formerly negative delayed type skin reactivity to candidin.