Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome

Kisand, Kai; Peterson, Pärt

doi:10.1111/j.1749-6632.2011.06308.x

Cited by 87 publications

(69 citation statements)

References 142 publications

(228 reference statements)

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“…In addition to CMC, APS-1 patients usually present hypoparathyroidism, adrenal insufficiency, and, occasionally, thyroiditis, autoimmune enteropathy, vitiligo, alopecia, diabetes, and hepatitis. 3,76 Although the corresponding patients share autoimmune phenotypes, LOF AIRE and GOF STAT1 mutations have not been mechanistically connected yet. The enhanced autoimmunity of patients with STAT1 GOF mutations is likely to result from stronger IFN-a/b signaling, as some of these autoimmune features are observed in patients treated with recombinant IFN-a (eg, thyroiditis) and in patients with type I interferonopathies (eg, SLE).…”

Section: Discussionmentioning

confidence: 99%

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

Toubiana

Okada

Hiller

et al. 2016

Blood

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489

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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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Section: Discussionmentioning

confidence: 99%

“…3 By contrast, since the late 1960s, patients have been reported who display an apparently inherited form of isolated CMC and no distinctive associated clinical or immunological phenotype (CMC disease, CMCD).…”

Section: Introductionmentioning

confidence: 99%

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

Toubiana

Okada

Hiller

et al. 2016

Blood

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489

649

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“…A utoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome type 1, is a rare, recessively inherited disease caused by mutations in the autoimmune regulator (AIRE) gene (1,2). AIRE is expressed in medullary thymic epithelial cells (1,2), where it promotes the expression of tissue-restricted Ags.…”

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confidence: 99%

“…AIRE is expressed in medullary thymic epithelial cells (1,2), where it promotes the expression of tissue-restricted Ags. In the periphery AIRE is expressed at a lower level in lymphoid tissues and dendritic cells (3)(4)(5).…”

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confidence: 99%

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Hetemäki

Jarva

Kluger

et al. 2016

The Journal of Immunology

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Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the AIRE gene. Although mainly an endocrine disease, a substantial fraction of patients have gastrointestinal manifestations. In this study, we have examined the role of anticommensal responses and their regulation. APECED patients had increased levels of Abs against Saccharomyces cerevisiae (p < 0.0001) and against several species of commensal gut bacteria, but not against species predominantly associated with other locations. The anticommensal Ab levels did not correlate with gastrointestinal autoantibodies, neutralizing anti–IL-17 or –IL-22 Abs, or gastrointestinal symptoms, although scarcity of the available clinical data suggests that further study is required. However, the anti–S. cerevisiae Ab levels showed a significant inverse correlation with FOXP3 expression levels in regulatory T cells (Treg), previously shown to be dysfunctional in APECED. The correlation was strongest in the activated CD45RO+ population (ρ = −0.706; p < 0.01). APECED patients also had decreased numbers of FOXP3+ cells in gut biopsies. These results show that APECED patients develop early and sustained responses to gut microbial Ags in a pattern reminiscent of Crohn’s disease. This abnormal immune recognition of gut commensals is linked to a systemic Treg defect, which is also reflected as a local decrease of gut-associated Treg. To our knowledge, these data are the first to show dysregulated responses to non-self commensal Ags in APECED and indicate that AIRE contributes to the regulation of gut homeostasis, at least indirectly. The data also raise the possibility of persistent microbial stimulation as a contributing factor in the pathogenesis of APECED.

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“…What is striking about the autoimmunity in APECED is its predilection to cause sequential dysfunction of endocrine glands, such that an individual may suffer from insulin-dependent diabetes, hypothyroidism and hypogonadism in addition to the hypoparathyroidism and adrenal insufficiency that herald this disorder. What is also striking is the relentless progression of disease that may burden an individual life [1,2]. Particularly disheartening in this illness may be the occurrence of alopecia.…”

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confidence: 99%

Hydroxychloroquine Reverses Alopecia in Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED): A Case Report

Seton¹

2013

J Clin Cell Immunol

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Background: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare, autosomal recessive disease characterized by the onset of mucocutaneous candidiasis in childhood, followed by hypoparathyroidism, and in a subset of patients, alopecia and other endocrinopathies and autoimmune diseases. There is no known treatment to mitigate the course of the disease. Goal:To describe the outcomes in a woman with APECED who presented later in her life with Sjogren's disease and alopecia totalis, and was treated with hydroxychloroquine (HCQ). HCQ was in addition to treatment regimens for mucocutaneous candidiasis with esophageal stricture, hypoparathyroidism, insulin-dependent diabetes, hypothyroidism, B12 deficiency, and autoimmune hepatitis. Methods:Office visits, laboratory studies, including genetic characterization of her disease; and review of available medical records. ManuscriptAutoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare, autosomal recessive disease classically characterized by the onset of mucocutaneous candidiasis in childhood, followed by hypoparathyroidism, and in a subset of patients, adrenal insufficiency. Dental complications such as enamel hypoplasia are well recognized, and other autoimmune diseases frequently mark the lives of these patients including alopecia, pernicious anemia, malabsorption syndromes, autoimmune hepatitis and keratoconjunctivitis. What is striking about the autoimmunity in APECED is its predilection to cause sequential dysfunction of endocrine glands, such that an individual may suffer from insulin-dependent diabetes, hypothyroidism and hypogonadism in addition to the hypoparathyroidism and adrenal insufficiency that herald this disorder. What is also striking is the relentless progression of disease that may burden an individual life [1,2]. Particularly disheartening in this illness may be the occurrence of alopecia.This case study reports the reversal of alopecia in a woman with APECED using hydroxychloroquine (HCQ), and describes the impact HCQ has in diminishing some other features of this disease. Started on HCQ in late 2007, she had gradual re-growth of her hair, easing of the sicca symptoms in her mouth, and improvement in other parameters of APECED. This is the first report of HCQ being used in this disorder, and of its efficacy. Case ReportE.L. is a 58-year-old white female, born in Boston in 1955 to parents with no evidence of consanguinity, or clear Finnish or European ancestry. One of 5 children, E.L shares this genetic imprint with two other siblings, although their manifestations are remarkably different and neither sibling has alopecia. E.L. remembers the onset of oral candidiasis in primary or middle school. Dental abnormalities (presumed incongruities in the enamel) are mentioned later in her records, when it is reported that she presented with tetany age 14 years (1970), and was diagnosed with hypoparathyroidism at that time. Her older brother had been identified with hypocalcemia (calcium 5.2 mg/ dL)...

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Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome

Cited by 87 publications

References 142 publications

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

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

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

Hydroxychloroquine Reverses Alopecia in Autoimmune Polyendocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED): A Case Report

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