Variable Presentations of Gain of Function STAT1 Mutations within a Single Institution with Features Beyond Chronic Mucocutaneous Candidiasis

Bina, Sheila M.; Yoon, Jenni; Leiding, Jennifer W.

doi:10.1016/j.jaci.2014.12.1541

Cited by 3 publications

(2 citation statements)

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“…P2 and P4 were also treated for suspected pulmonary tuberculosis and tuberculous meningitis, respectively, without microbiological confirmation. None of the other clinical manifestations previously reported in patients with GOF STAT1 mutations, such as autoimmune endocrinopathy, aneurysms, or mucosal carcinomas, were detected (16,17,23,37,51). Detailed phenotyping of lymphocyte subsets was performed for patients from kindreds D, E, and H and revealed no abnormality (Fig.…”

Section: Resultsmentioning

confidence: 94%

“…In patients with STAT1 GOF mutations, CMC results, at least partly, from impairment of the development and/or survival of IL-17A/F-producing T cells, the underlying mechanisms of which remain unknown (28,52). Patients with these mutations, who had long been known to be prone to thyroid autoimmunity, were recently found to display other infectious and autoimmune phenotypes (16,17,23,37,51). Another genetic etiology of syndromic CMCD has recently been described, with AR retinoic acid-related orphan receptors γ (ROR-γ/γT) deficiency in three kindreds with CMC and severe mycobacterial disease (53).…”

Section: Significancementioning

confidence: 99%

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Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

150

127

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Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensalCandidaspecies. The first genetic etiology of isolated CMC—autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency—was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity toCandidaandStaphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

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Section: Resultsmentioning

confidence: 94%

Section: Significancementioning

confidence: 99%

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Lévy

Okada

Béziat

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

150

127

View full text Add to dashboard Cite

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Chronic mucocutaneous candidiasis, a case study and literature review

Khosravi

Mansouri

Saffarian

et al. 2018

Journal de Mycologie Médicale

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Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Toubiana

Okada

Hiller

et al. 2016

Blood

473

649

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Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-GuÃ©rin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis

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Variable Presentations of Gain of Function STAT1 Mutations within a Single Institution with Features Beyond Chronic Mucocutaneous Candidiasis

Cited by 3 publications

References 0 publications

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Chronic mucocutaneous candidiasis, a case study and literature review

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

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