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.

Nova mutação no gene STAT1 associada com candidíase mucocutânea crônica / New STAT1 gene mutation associated with chronic mucocutaneous candidiasis

Mutações no gene STAT1 (signal transducer and activator of transcription 1) têm sido identificadas como responsáveis pela maioria dos casos sindrômicos da candidíase mucocutânea crônica com herança autossômica dominante (AD). Nesse artigo, descrevemos uma menina de 7 anos que apresentou candidíase da mucosa oral e unhas, além de infecção disseminada da pele e couro cabeludo por Microspora gipseum. Recentemente, a paciente foi diagnosticada e tratada de meningite por Cryptococcus neoformans. Na família não existem outros casos de candidíase. A avaliação imunológica incluiu a detecção de subpopulações de linfócitos (CD3, CD4, CD8, CD20 e células NK), assim como a dosagem de IgG, IgA, IgM e IgE, subclasses de IgG e autoanticorpos. Excluindo-se discreta diminuição de CD3, CD4, CD8, NK e leve aumento de IgG1, os demais exames estiveram dentro da normalidade. O sequenciamento do exoma detectou uma rara mutação em heterozigose no exon 14 do domínio de ligação do DNA (DNA-binding domain) do gene STAT1, ocasionando um provável ganho de função (GOF) responsável pela doença (Gly384Asp). Essa variação foi também identificada pelo sequenciamento de Sanger, não estando reportada nos bancos de dados públicos e apresentando elevado potencial de dano (índice CADD=32). Será interessante contarmos com informações clínicas e estudos com outros pacientes para conhecermos mais essa mutação patológica. Além da apresentação do caso, discutiremos as formas de tratamento existentes.

STAT1 (signal transducer and activator of transcription 1) gene mutations have been identified as responsible for most syndromic cases of chronic mucocutaneous candidiasis with autosomal dominant (AD) inheritance. In this article, we described a 7-year-old girl who presented with candidiasis of the oral mucosa and nails, as well as disseminated infection of the skin and scalp caused by Microsporum gypseum. Recently, the patient was diagnosed and treated for Cryptococcus neoformans meningitis. There are no other cases of candidiasis in the family. The immunological evaluation consisted of detection of subpopulations of lymphocytes (CD3, CD4, CD8, CD20, and NK cells), as well as measurement of IgG, IgA, IgM, and IgE, IgG subclasses, and autoantibodies. Excluding a slight decrease in CD3, CD4, CD8, NK and a minimal increase in IgG1, the others were within normal limits. Exome sequencing detected a rare heterozygous variation in exon 14 of the DNA-binding domain of the STAT1 gene, causing a probable gain of function (GOF) responsible for the disease (Gly384Asp). This variation was also identified by Sanger sequencing, but it was not reported in public databases and had a high potential for damage (Combined Annotation-Dependent Depletion [CADD] score = 32). Having clinical information and conducting studies of other patients will be helpful to learn more about this pathological mutation. In addition to the presentation of the case, we will discuss the existing forms of treatment.

Progress in mechanisms and immunological treatment of chronic mucocutaneous candidiasis associat-ed with congenital IL-17 pathway deficiency / 中华微生物学和免疫学杂志

Chronic mucocutaneous candidiasis (CMC) is a rare, persistent and recurrent infection affecting skin, nails, and oral and genital mucosae. It is mainly caused by Candida albicans and hard to be cured with routine antifungal therapy. Usually, CMC is a primary immunodeficiency disease and can be di-vided into two categories. The most common one is CMC disease ( CMCD) , which defined as Candida infec-tion confined to the surface of the skin and mucous membranes and not complicated by systemic Candida al-bicans infection or other clinical symptoms. The other category is systemic CMC ( SCMC) complicated by in-fections caused by other pathogens, systemic invasive fungal infections, or other clinical symptoms apart from the symptoms of CMCD. It is currently believed that both CMCD and SCMC are related to immunodeficiency caused by gene mutations related to IL-17 signal pathway. The inhibited Th17 proliferation, decreased secre-tion of IL-17 or IL-22 cytokine, or increased IL-17 or IL-22 neutralizing antibody induced by the mutations promoted the susceptibility to Candida or other pathogens. In the treatment of CMC, in addition to the tradi-tional antifungal drugs such as azoles, polyenes and echinocandins, biological agents and target gene therapy offer potential new therapeutic strategies. This article reviewed the association between congenital immunode-ficiency in the IL-17 signaling pathway and CMC, and the possible immunological therapeutic approaches and new therapeutic targets.

Progress in mechanisms and immunological treatment of chronic mucocutaneous candidiasis associated with congenital IL-17 pathway deficiency / 中华微生物学和免疫学杂志

Chronic mucocutaneous candidiasis (CMC) is a rare, persistent and recurrent infection affecting skin, nails, and oral and genital mucosae. It is mainly caused by Candida albicans and hard to be cured with routine antifungal therapy. Usually, CMC is a primary immunodeficiency disease and can be divided into two categories. The most common one is CMC disease (CMCD), which defined as Candida infection confined to the surface of the skin and mucous membranes and not complicated by systemic Candida albicans infection or other clinical symptoms. The other category is systemic CMC (SCMC) complicated by infections caused by other pathogens, systemic invasive fungal infections, or other clinical symptoms apart from the symptoms of CMCD. It is currently believed that both CMCD and SCMC are related to immunodeficiency caused by gene mutations related to IL-17 signal pathway. The inhibited Th17 proliferation, decreased secretion of IL-17 or IL-22 cytokine, or increased IL-17 or IL-22 neutralizing antibody induced by the mutations promoted the susceptibility to Candida or other pathogens. In the treatment of CMC, in addition to the traditional antifungal drugs such as azoles, polyenes and echinocandins, biological agents and target gene therapy offer potential new therapeutic strategies. This article reviewed the association between congenital immunodeficiency in the IL-17 signaling pathway and CMC, and the possible immunological therapeutic approaches and new therapeutic targets.

Candidiasis mucocutánea crónica: una mirada al entendimiento genético / Chronic mucocutaneous candidiasis: a look at genetic understanding

RESUMEN La candidiasis mucocutánea crónica se caracteriza por infecciones recurrentes o persistentes en la piel, las uñas y las mucosas, producida por especies de Candida sp. Esta va a ser secundaria a cualquier alteración en la inmunidad antimicótica, en la cual no solo la producción de IL-17, sino cualquier defecto en la diferenciación de los linfocitos T hacia su perfil TH17, juegan un papel fundamental y van a desencadenar una susceptibilidad a esta infección, que dependiendo de la etiología genética, puede ser una manifestación sindrómica con otras características clínicas y endocrinológicas asociadas. Aquí revisamos de manera práctica, clara y concisa los defectos genéticos hasta ahora encontrados, implicados en la aparición de la candidiasis mucocutánea crónica.

SUMMARY Chronic mucocutaneous candidiasis is an infectious phenotype characterized by recurrent or persistent infections in the skin, nails and mucous membranes produced by Candida sp. This is secondary to any alteration in the antifungal immunity, in which not only the production of IL-17, but any defect in the differentiation of the T lymphocytes towards their TH17 profile, play a fundamental role and will unchain a susceptibility to this infection; that depending on the genetic etiology, can be a syndromic manifestation with other associated infectious and endocrinological clinical characteristics. Here, we review in a practical, clear and concise manner, the genetic defects so far found to be involved in the appearance of chronic mucocutaneous candidiasis.

Bronchiectasis and Recurrent Respiratory Infections with a De Novo STAT1 Gain-of-Function Variant: First Case in Korea

Bronchiectasis is a chronic disease characterized by airway infection and inflammation, leading to permanent dilation of the bronchi. Evaluation of underlying etiology is important in managing young bronchiectasis patients with recurrent infections caused by unusual pathogens. The signal transducer and activator of transcription 1 (STAT1) protein plays a key role in STAT signaling and immune system regulation. Heterozygotes for gain-of-function (GOF) alleles of the STAT1 gene usually display autosomal dominant chronic mucocutaneous candidiasis (CMC) and a wide range of clinical features, such as bronchiectasis. Here, we report on a patient with CMC and bronchiectasis with various types of infections who carried a pathogenic variant of the STAT1 gene. The 24-year-old female presented with recurrent respiratory bacterial and nontuberculous mycobacterial infections complicated by severe bronchiectasis and CMC. Whole-exome sequencing revealed a c.800C>T (p.Ala267Val) heterozygous mutation in the STAT1 gene. Further analysis by Sanger sequencing of STAT1 from the patient and her parents revealed the patient had a de novo occurrence of the variant. This is the first report of a Korean patient with a GOF pathogenic variant in STAT1. Physicians should be aware of the existence of this variant as a genetic factor associated with CMC and bronchiectasis complicated by recurrent infection.

Gain-of-function signal transducer and activator of transcription 1 deficiency / 中华实用儿科临床杂志

Chronic mucocutaneous candidiasis (CMC) is characterized by persistent or recurrent disease of the nails,skin,oral,or genital mucosae caused by candida albicans.CMC usually can occur in patients with T cell deficiencies,autosomal dominant hyper-immunoglobulin E(IgE) syndrome,interleukin(IL)-12p40 and IL-12 receptor β1 (IL-12Rβ1) deficiency,caspase recruiment domain 9 deficiency and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.CMC pathogenesis apparently involves the impairment of IL-17A,IL-17F and IL-22 immunity.Autosomal recessive IL-17RA deficiency and dominant-negative IL-17F deficiency are etiologies of pure isolated CMC (CMCD).Nearly half of patients with CMC had gain-of-function signal transducer and activator of transcription 1 mutations.These patients also had bacterial and virus infections,autoimmunity and inflammatory diseases,which show broad clinical heterogenity.

A case of chronic mucocutaneous candidiasis caused by STAT1 gain-of-function mutation and literature review / 中华实用儿科临床杂志

Objective To summarize the clinical characteristics,diagnosis and treatment of chronic mucocutaneous candidiasis(CMC).Methods The case diagnosed as CMC in the Department of Nephrology and Immunology of Shenzhen Children's Hospital in February 24,2014 was analyzed in terms of symptoms,signs,laboratory findings,gene tests and treatment process,and related literature was reviewed.Results The patient was a 14-year-old boy.The patient started to develop recurrent oral candida infection shortly after birth,then candida infection of skins and nails,which could be alleviated by antifungal agents,but easily relapsed.Since 4 years ago,autoimmune reactions such as autoimmune anemia,thrombocytopenia,leucopenia,proteinuria,and hypothyroidism had successively appeared,and cytopenia began to palliate after administering Glucocorticoid and Cyclosporin,but easily relapsed when the dosage was reduced.The genetic test showed the case was of signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation.During the hospitalization,hemophagocytic syndrome (HPS) and stagnation of hematopoietic function successively occurred.The cytopenia did not improve and the patient suffered severe infection in spite of washing red blood cells 13 times and blood palate 3 times via infusion,together with high dosage of Dexamethasone and Cyclosporine.The peripheral blood cells and bone marrow gradually returned to normal after being treated by human granulocyte colony-stimulating factor combined with Dexamethasone and Cyclosporin.Retrieving the database in PubMed database,824 articles were found which were about CMC,and 39 of them were about the STAT1 gain-of-function mutation,including 120 cases.But there was only 1 domestic case in 2012,who was a three-year-old child,manifesting recurrent fungal infection of the skin.Conclusions STAT1 gain-of-function acquired mutation is one of the reasons that can lead to CMC.Autoimmune reactions prominently represented by cytopenia occur in a few patients with CMC.It should be alert on those who are with CMC and simultaneously with autoimmtne reaction of blood system.And gene tests facilitate the early diagnosis.

Chronic Mucocutaneous Candidiasis Misdiagnosed as Lichen Planus / 대한의진균학회지

Chronic mucocutaneous candidiasis is a rare syndrome characterized by persistent and refractory infection of the skin, nail and mucosal tissue by yeasts of the genus Candida. A 70-year-old woman presented with the following skin lesions: ill-defined annular shaped whitish macules on the upper and lower lips accompanying dryness, pain and burning sensation, and yellowish discoloration with onycholysis of the right 4th finger nail. The upper lip lesion showed histopathologic feature of band-like infiltration of lymphocytes in the upper dermis, consistent with lichen planus. But, systemic glucocorticoid was not effective in treating erosive lip lesions. KOH examination and fungal culture of specimens from the upper lip showed hyphal elements and growth of Candida albicans, respectively. Antifungal agent was administered. After the oral medication, skin lesions were improved but there was repeated recurrence. We report a case of chronic mucocutaneous candidiasis misdiagnosed as lichen planus.

Avaliação funcional de fagócitos em imunodeficiências com manifestações cutâneas / Functional phagocyte evaluation in immunodeficiencies with cutaneous manifestations

A pele e as mucosas constituem as primeiras barreiras na defesa contra infecções e os macrófagos são componentes essenciais do sistema imune inato, importante neste aspecto. O envolvimento destas células pode ser verificado em grande percentual das imunodeficiências primárias. Desta forma, a avaliação da função fagocitária é de extrema relevância para o reconhecimento dos distúrbios imunológicos que acometem a pele. O objetivo do presente estudo foi avaliar a metodologia laboratorial para a detecção de defeitos funcionais dos fagócitos. Para isto foram estabelecidos os seguintes testes laboratoriais: Nitro Blue Tetrazolium (NBT), Dihidrorodamina (DHR), quimiotaxia, fagocitose e a aderência de S. aureus e C. albicans por citometria de fluxo (CF), além de morte intracelular de S. aureus e C. albicans (CF). Para verificar a integridade do sistema complemento realizou-se ensaios hemolíticos para as vias clássica e alternativa (CH50 e AP50). A metodologia proposta foi aplicada em indivíduos normais para a padronização dos testes. O burst oxidativo avaliado pelo teste da dihidrorodamina (DHR) foi aplicado em 101 indivíduos saudáveis e em paralelo, 50 indivíduos sadios para o teste do NBT. Os mesmos testes foram realizados em pacientes com Candidíase mucocutânea crônica (CMC) (n=9 ), Candidíase persistente (n=5), Suspeita de distúrbios de fagócitos (SDF) (n=14), Doença Granulomatosa Crônica (DGC)(n= 7) e portadores de DGC (n=5)...

Skin and mucosa are part of the first barriers in the defense against infections, and the macrophages are essential components of the innate immune system, important when related to this aspect. The involvement of these cells can be seen in a large percentage of the primary immunodeficiencies. Therefore, the assessment of the phagocitary function is extremely important for the recognition of immunological disorders which affect the skin. The present study focus on the evaluation of the laboratorial methodology for the detection of functional defects of phagocytes. For this the following laboratorial tests were established: Nitro Blue Tetrazolium (NBT), chemotaxis, phagocytosis and adherence of S. aureus and C. albicans through flow cytometry (FC), besides the intracellular death of S. aureus and C. albicans (FC). To assess the integrity of the complement system hemolytic assays were performed for the classic and alternative pathways (CH50 and AP50). The proposed methodology was applied to normal individuals for the standardization of the assays. The oxidative burst evaluated through the dihydrorodamine essay (DHR) was applied to 101 healthy individuals and in parallel, 50 healthy individuals for the NBT assay. The same assays were performed on patients with Chronic mucocutaneous candidiasis (CMC)(n=9), persistent candidiasis (n=5), Phagocytes disorders suspicious (PDS) (n=14), Chronicle granulomatous disease (CGD)(n=7) and CGD carriers (n=5). Chemotaxis was standardized using 34 controls for neutrophils stimulated by lipopolisacharydes from e. coli (LPS) and 5 by C. albicans...

A Case of Chronic Mucocutaneous Candidiasis Occurring in a Patient with Scrofuloderma-like BCGitis / 대한의진균학회지

Chronic mucocutaneous candidiasis (CMC) consists of several clinical syndrome characterized by chronic, treatment-resistant, superficial candidal infections of skin, nails and oropharynx. The patients with CMC usually have other manifestations including non-candidal infections, endocrinopathies and autoimmune diseases. These findings suggest that patients with CMC have multiple or complex abnormalities in their immune systems, especially of cell mediated immunity. The scrofuloderma or scrofuloderma-like BCGitis is used to describe the skin reaction and enlargement of regional lymph node with suppuration. In contrast to chronic mucocutaneous candidiasis, BCGitis does not suggest underlying host immune defect in most cases. In our knowledge, there is no report about scrofuloderma-like BCGitis and chronic mucocutaneous candidiasis occurring in the same patient. Herein, we report a case of chronic mucocutaneous candidiasis associated with scrofuloderma-like BCGitis.

Familial Chronic Mucocutaneous Candidiasis / 대한의진균학회지

Chronic mucocutaneous candidiasis (CMCC) is a complex group of disorder characterized by chronic and recurrent candida infections of the skin, nail and oropharynx. The classification of CMCC varies but is commonly based on the clinical feature, existence of an endocrinopathy, and the pattern of inheritance, which can be either autosomal dominant or recessive. We herein report a rare case of familial CMCC. A family of a 42-year-old woman and her 17- and 12-year-old daughters commonly presented with a recurrent whitish plaque in the oral cavity for several years, and the mother and her 9-year-old son also had presented with dystrophic nails. They had no evidence of concomitant immunodeficiency or endocrinopathy. Candida albicans was commonly isolated from the oral lesion of the mother and two daughters. They were successfully managed with intermittent oral antifungal treatment.

Chronic Mucocutaneous Candidiasis in Korea / 대한의진균학회지

Chronic mucocutaneous candidiasis (CMCC) is a general term used to denote a complex group of disorders characterized by a recurrent and persistent infection of the skin, mucous membranes and nails with organism of the genus candida, most frequently Candida albicans. It is often associated with an endocrinopathy and cell mediated immunopathy. CMCC is not a single disease entity, but rather a final common pathway for multiple predisposing abnormalities of the immune system that ranges from severe, life-threatening immunodeficiency syndromes to subtle deficiencies, especially of cell mediated immunity. Conditions that have been associated with CMCC include; candida esophagitis or laryngitis, endocrinopathies (usually hypoparathyroidism, hypadrenalism, hypothyroidism), circulating autoimmune antibodies, diabetes mellitus, vitiligo with antibodies to melanocytes, iron deficiency, chronic active hepatitis, pernicious anemia, malabsorption, alopecia totalis, dental enamel dysplasia, keratoconjunctivitis, pulmonary fibrosis, KED syndrome (keratitis, ichthyosis, and deafness), and recurrent pyogenic, viral or other fungal infections. When CMCC first appaears in adulthood, it is often associated with a thymoma. There is virtually no propensity for disseminated, visceral candidiasis. A suitable clinical classification of the major subtypes of CMCC was described by Lehner and Wells et al into six groups. Kirkpatrick et al found the mean age of onset of CMCC to be 3 years and both boys and girls are affected equally. We review CMCC and 5 reported CMCC cases in the dermatologic literatures in Korea.

A Case of Chronic Mucocutaneous Candidiasis

A 6-year-old male patient had been suffering from angular cheilitis and paronychia with fragmentation and dystrophic change of the finger nails. Laboratory findings showed low serum iron level and anemia. Immunologic studies revealed defects in cell mediated immunity. KOH examination and culture of specimens from the lesions showed hyphal elements and growth of Candida albicans respectively. Concomitantly itraconazole and iron sulfate were administered. Four months after treatment he was free of any clinical evidence of the disease.

A case of chronic mucocutaneous candidiasis associated with hypoparathyroidism / 대한피부과학회지

Chronic mucocutaneous randidiasis is a clinical syndrome characte ized by chronic and reccurent superficial candidal infection of the skin, mucous membranes, and nails. This syndrome is frequently associated with immune deficiency or endocrinopathy, especially hypopar; thyroidism. We report a case of chrcinic mucocutaneous candidiasis associated with hypoparathyroidism in a 8- year-old girl.