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Autoimmune Polyendocrine Syndrome Type 1

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Autoimmune Polyendocrine Syndrome Type 1. Core disease mechanisms, molecul...

2026-04-22
Asta MONDO:0009411 Model: Asta Scientific Corpus Retrieval 20 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Autoimmune Polyendocrine Syndrome Type 1. Core disease mechanisms, molecul...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Autoimmune polyglandular syndrome type 1 and eye damage

  • Authors: L. Khamnueva, T. Iureva, L. S. Andreeva, E. Chugunova
  • Year: 2021
  • Venue: Acta Biomedica Scientifica
  • URL: https://www.semanticscholar.org/paper/9ff5215092b3849c233dcc2d4064ad4eaa96db73
  • DOI: 10.29413/abs.2021-6.6-1.3
  • Summary: This review presents the accumulated experimental and clinical data on the development of eye damage of autoimmune nature in APS type 1, as well as the laboratory and instrumental methods used for diagnosing the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.580) > Autoimmune polyendocrine syndrome type 1 (APS type 1) is a disease characterized by a variety of clinical manifestations resulting from the involvement of multiple endocrine and non-endocrine organs in the pathological process. APS type 1 is a rare genetically determined disease with autosomal recessive inheritance. Mutations in the autoimmune regulator gene (AIRE) lead to a disruption of the mechanism of normal antigen expression and the formation of abnormal clones of immune cells, and can cause autoimmune damage to organs. Within APS type 1, the most common disorders are primary adrenal insufficiency, hypoparathyroidism, and chronic candidiasis. Some understudied clinical manifestations of APS type 1 are autoimmune pathological processes in the eye: keratoconjunctivitis, dry eye syndrome, iridocyclitis, retinopathy, retinal detachment, and optic atrophy. This review presents the accumulated experimental and clinical data on the development of eye damage of autoimmune nature in APS type 1, as well as the laboratory and instrumental methods used for diagnosing the disease. Changes in the visual organs in combination with clinical manifestations of hypoparathyroidism, adrenal insufficiency and candidiasis should lead the clinical doctor to suspect the presence of APS type 1 and to examine the patient comprehensively. Timely genetic counselling will allow early identifi cation of the disease, timely prescription of appropriate treatment and prevention of severe complications.

[2] Diabetes and Atypical Autoimmune Polyglandular Syndrome Type 3: A Paediatric Case Report

  • Authors: I. Rutigliano, P. Maccarone, M. Sacco, D. Torres, S. Pedicelli
  • Year: 2020
  • Venue: Biomedical Journal of Scientific & Technical Research
  • URL: https://www.semanticscholar.org/paper/80dd20b7bc3b07e6545c07d3e5f2b6a243f945cf
  • DOI: 10.26717/bjstr.2020.29.004772
  • Summary: Type 1 Diabetes (T1DM) is an autoimmune disease and children affected by T1DM are at higher risk of other autoimmune diseases, including cancer and stroke.
  • Evidence snippets:
  • Snippet 1 (score: 0.543) > Type 1 Diabetes (T1DM) is an autoimmune, multifactorial, disease caused by beta cells destruction induced by immune response [1]. The pathophysiology of T1DM is still unclear but genetic predisposition is a landmark of this condition. HLA and non-HLA genes are involved in the risk of autoimmunity onset and many of these genes are shared by different autoimmune settings; thus, children affected by T1DM are at increased risk of other autoimmune comorbidities [2,3].In particular, T1DM could be part of autoimmune polyglandular syndrome cluster. > In 1980 Neufled and Blizzard proposed a classification of the autoimmune polyendocrine syndromes (APS) Table 1 [4]. These conditions are characterized by lack of self-tolerance and by induction of immune responses directed against self-structures with the coexistence, in the same patient, of more than one autoimmune disease [5]. The term polyendocrine is not completely appropriate, because several non-endocrine scenarios could be part of the clinical picture of these autoimmune syndromes [5,6]. > Here, we report the case of a girl affected by APS type 3 and the course of the different diseases' diagnosis in her young life. Treatment was started with methylprednisolone in bolus for three days at dosage of 10 mg/kg/die, followed by oral prednisone at 1 mg/kg/die for one month and then tapered in the following weeks. She had no good response with this first line therapy with persistent high proteinuria levels (703.57 mg/24 h). Second line therapy was started with cyclophosphamide at the dose of 2 mg/kg/die for three months, during corticosteroid tapering, with progressive reduction of proteinuria (402.5 mg/24 h, 242.1 mg/24 h).

[3] A novel compound heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrine syndrome type 1

  • Authors: Junghwan Suh, H. Choi, A. Kwon, H. Chae, Jin-Sung Lee et al.
  • Year: 2019
  • Venue: Annals of Pediatric Endocrinology & Metabolism
  • URL: https://www.semanticscholar.org/paper/538a1e71c9e24405c15b00133e08e9e2aa00b9b4
  • DOI: 10.6065/apem.2019.24.4.248
  • PMID: 31905445
  • PMCID: 6944864
  • Citations: 3
  • Summary: The case of a 10-year-old Korean girl with APS-1 due to a novel compound heterozygous mutation of the AIRE gene, where the main clinical manifestations were adrenal insufficiency and chronic mucocutaneous candidiasis is reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.539) > Autoimmune polyendocrine syndrome type 1 (APS-1), or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare, autosomal recessive autoimmune disease caused by a mutation of the autoimmune regulator (AIRE) gene. The main symptom triad in APS-1 comprises chronic mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. Various autoimmune diseases and ectodermal abnormalities are also commonly associated with the syndrome. The treatment of APS-1 includes hormone replacement and symptom control. It is important to monitor such patients for clinical manifestations of their disease through regular follow-up. We report the case of a 10-year-old Korean girl with APS-1 due to a novel compound heterozygous mutation of the AIRE gene. This patient's main clinical manifestations were adrenal insufficiency and chronic mucocutaneous candidiasis. The patient had a previously known pathogenic variant of c.1513delG (p.Ala505ProfsTer16), and a newly discovered variant of c.1360dupC (p.His454ProfsTer50).

[4] Search for Genetic Predictors of Adult Autoimmune Polyendocrine Syndrome in Monozygotic Twins

  • Authors: Marina Yukina, A. Larina, E. Vasilyev, E. Troshina, D. A. Dimitrova
  • Year: 2021
  • Venue: Clinical Medicine Insights. Endocrinology and Diabetes
  • URL: https://www.semanticscholar.org/paper/88aaac9d3e7d26c1779aef9f543110ac853421c5
  • DOI: 10.1177/11795514211009796
  • PMID: 33953634
  • PMCID: 8058797
  • Citations: 3
  • Summary: The article presents the case of isolated Addison’s disease and APS type 2 in monozygotic twins with a revealed compound heterozygosity in the candidate gene VTCN1.
  • Evidence snippets:
  • Snippet 1 (score: 0.536) > Autoimmune polyendocrine syndromes (APS) are a heterogeneous group of diseases characterized by the presence of autoimmune dysfunction of 2 or more endocrine glands and other non-endocrine organs. The components of the syndrome can manifest throughout life: in childhood—APS type 1 (the juvenile type) and in adulthood—APS type 2, 3, and 4 (the adult types). Adult types of APS are more common in clinical practice. It is a polygenic disease associated with abnormalities in genes encoding key regulatory proteins of the major histocompatibility complex (MHC). The search of for candidate genes responsible for mutations in adult APS is continuing. Genetic predisposition is insufficient for the manifestation of the APS of adults, since the penetrance of the disease, even among monozygotic twins, does not approach 100% (30–70%). The article presents the case of isolated Addison’s disease and APS type 2 in monozygotic twins with a revealed compound heterozygosity in the candidate gene VTCN1.

[5] Autoimmune polyendocrine syndrome type 2 in children: a case report and literature review

  • Authors: Yahong Liu, Fei Wang, Lijuan Zhang, Hongxia Zhang, Yanfang Zhu
  • Year: 2025
  • Venue: BMC Pediatrics
  • URL: https://www.semanticscholar.org/paper/7b92a470911f0a47c2814ef7ebdee3c459a2fb76
  • DOI: 10.1186/s12887-025-05697-3
  • PMID: 40316945
  • PMCID: 12046904
  • Citations: 3
  • Summary: This case of a 3-year-old girl diagnosed with autoimmune polyendocrine syndrome type 2 represents the youngest reported patient of APS-2 at the time of diagnosis, as well as the shortest documented interval between the onset of autoimmune disorders affecting distinct endocrine glands.
  • Evidence snippets:
  • Snippet 1 (score: 0.531) > Autoimmune polyendocrine syndrome (APS) is a clinical disorder characterized by the loss of immune tolerance, leading to dysfunction in multiple endocrine glands. According to the latest disease classification, APS is categorized into three main subtypes: APS-1, APS-2, and IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. APS-2 is defined by the presence of at least two autoimmune endocrine disorders, such as type 1 diabetes mellitus, autoimmune thyroiditis, or Addison’s disease. APS-2 typically manifests later than APS-1, with onset most commonly occurring in early adulthood. However, pediatric cases involving a combination of autoimmune thyroid disease, type 1 diabetes mellitus, and myasthenia gravis, are extremely rare. This article reported the case of a 3-year-old girl diagnosed with autoimmune polyendocrine syndrome type 2 (APS-2). The patient initially presented with hyperthyroidism and exophthalmos and was subsequently diagnosed with type 1 diabetes mellitus and myasthenia gravis. To our knowledge, this case represents the youngest reported patient of APS-2 at the time of diagnosis, as well as the shortest documented interval between the onset of autoimmune disorders affecting distinct endocrine glands. Through a retrospective analysis, we comprehensively reviewed the phenotypic characteristics of APS-2 and explored its potential immune mechanisms. This article aims to provide clinicians with a valuable reference case to enhance early recognition and facilitate the implementation of targeted prevention and treatment strategies.

[6] Immune Checkpoint Blockade Anti–PD-L1 as a Trigger for Autoimmune Polyendocrine Syndrome

  • Authors: G. Lanzolla, A. Coppelli, M. Cosottini, S. Del Prato, C. Marcocci et al.
  • Year: 2019
  • Venue: Journal of the Endocrine Society
  • URL: https://www.semanticscholar.org/paper/a6e6815222fa063ff276df837668b4eedbcb83dd
  • DOI: 10.1210/js.2018-00366
  • PMID: 30746508
  • PMCID: 6364624
  • Citations: 51
  • Influential citations: 1
  • Summary: A link exists between HLA haplotypes, gene variants involved in immune checkpoint molecule expression, and increased susceptibility to autoimmune endocrinopathies, and additional studies are needed to identify susceptible patients and adapt therapy to each patient.
  • Evidence snippets:
  • Snippet 1 (score: 0.524) > Abstract Context The programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway is a key regulator in T-cell activation and tolerance, limiting effector T-cell function in peripheral tissues. Atezolizumab, an anti–PD-L1 monoclonal antibody, is approved for treatment of some types of advanced cancer. Its main treatment-related adverse events are immune related, such as thyroid dysfunction and hypophysitis. Autoimmune endocrinopathy can occur as isolated manifestations; only a few cases of autoimmune polyendocrine syndromes have been reported thus far. Case We report a case of polyendocrine syndrome type 2, characterized by Addison disease (AD), type 1 diabetes mellitus (T1DM), accompanied by hypophysitis, in a patient treated with atezolizumab. Testing was positive for 21-hydroxylase and pituitary antibodies and negative for islet cells antibodies. HLA typing revealed DRB104 and DQB103 haplotypes, which are associated with increased susceptibility to T1DM and AD. Conclusion The type and severity of immune-related adverse events in polyendocrine syndrome type 2 are different and depend on the monoclonal antibody used. Although the numerous molecular mechanisms inducing autoimmune endocrine diseases are still unclear, a link exists between HLA haplotypes, gene variants involved in immune checkpoint molecule expression, and increased susceptibility to autoimmune endocrinopathies. Additional studies are needed to identify susceptible patients and adapt therapy to each patient.

[7] Identifying a Common Autoimmune Gene Core as a Tool for Verifying Biological Significance and Applicability of Polygenic Risk Scores

  • Authors: Victoria S Shchekina, Nikita Aleksandrovich Batashkov, A. Maznina, J. Krupinova, V. Bogdanov et al.
  • Year: 2026
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/cf658a97de9166afe9055c8c9251b46847759973
  • DOI: 10.3390/ijms27010543
  • PMID: 41516417
  • PMCID: 12786532
  • Summary: Clustering of PRS based on used genes showed that clusters of ADs remained consistent across all chosen PRS sizes, concluding that PRS size does not have an impact on biological relevance.
  • Evidence snippets:
  • Snippet 1 (score: 0.523) > Autoimmune diseases (ADs) are conditions resulting from an abnormal response of the adaptive immune system in which it mistakenly targets healthy, functional tissues of the organism as if they were foreign [1]. Over 100 types of autoimmune diseases have been identified [2]. Monogenic autoimmune diseases, such as Autoimmune polyendocrine syndrome type 1 and IPEX syndrome, result from pathogenic mutations in single genes (AIRE and FOXP3, respectively) that disrupt the function of the corresponding proteins [3]. Polygenic autoimmune diseases have several common features that are caused by a complex interplay of genetic and environmental factors [4]. These diseases arise from variations in multiple genes, often involving immune-related genes, such as the HLA region, and their onset can be influenced by multiple factors, such as gender (can be triggered during pregnancy or due to a disbalance of sex hormones) [2] and environmental triggers (infections, toxins, stress, and diet). Infections often act as triggers for autoinflammatory processes in genetically susceptible individuals through various mechanisms, such as activation of innate immune responses, molecular mimicry, and T-cell activation [5]. Despite these associations, the exact mechanisms of polygenic AD development are still unclear. Common pathophysiological mechanisms include dysregulation of the immune system, chronic inflammation, and epigenetic changes influenced by external factors. Clinically, these diseases often present with overlapping symptoms such as fatigue, joint pain, or organ-specific inflammation and progress in episodes, typically being challenging to diagnose and treat [6]. > An overlap of two or more autoimmune diseases commonly manifests in a single patient [7]. Type 1 diabetes (T1D) is commonly associated with autoimmune thyroid diseases, such as Addison's disease, celiac disease, Hashimoto's thyroiditis, and Graves' disease. Other ADs may also be associated with each other, particularly Sjögren's syndrome with systemic lupus erythematosus and systemic sclerosis [8]. These conditions co-occur in 17-30% of cases.

[8] Clinical case of demyelynating polyneuropathy of patient with autoimmune polyendocrine syndrome

  • Authors: Y. Solovyova, N. Nekrasova, A.V. Stromylo, L. V. Tykhonova
  • Year: 2024
  • Venue: Psychiatry Neurology and Medical Psychology
  • URL: https://www.semanticscholar.org/paper/90ea19335f73af7d28018ea87f743a15ab5e16ea
  • DOI: 10.26565/2312-5675-2024-25-10
  • Summary: The clinical case of autoimmune polyendocrine syndrome described in this article is very representative because of the presence of combination of immune system dysfunction and the impact of glucose toxicity phenomenon on NS.
  • Evidence snippets:
  • Snippet 1 (score: 0.517) > Background. The function of a nervous system (NS) has a strong correlation with a somatic state of each individual. Therefore, somatoneurology as a new branch of medicine appeared. Nowadays due to pathophysiological researches we possess the knowledge of mechanisms on NS damage at the background of diseases of endocrine, cardiovascular, digestive, respiratory and other systems. Nevertheless, practically all these processes are difficult to be separated in each case of illness because of the complexity of their simultaneous interaction and polymorphism of clinical symptoms. Autoimmune diseases are worth special attention due to their chameleon-like way of progressing when different organ systems get involved with new exacerbations. Moreover, the pathogenesis of NS damage at the background of autoimmunisation is not only connected with the response of nervous tissue on inflammation and demyelination, but it’s also a result of multiorgan disfunction – a consequence of their autoimmune disruption. According to the mentioned fact the clinical case of autoimmune polyendocrine syndrome described in this article is very representative because of the presence of combination of immune system dysfunction (what is a potential trigger of demyelination) and the impact of glucose toxicity phenomenon on NS (a symptom of diabetes mellitus caused by autoimmune pancreatitis). To sum up with, studying somatoneurological features of autoimmune diseases is a relevant topic for practitioners at the «century of autoimmune diseases». > Purpose – to describe the clinical case of polyneuropathy at the background of autoimmune polyendocrine syndrome. > Materials and Methods. The results of objective examination and data of instrumental and laboratory tests protocols made at «Kharkiv Regional Clinical Hospital» were used. > Results. Polyneuropathic type of nervous system damage was verified due to electroneuromyographic examination and the scale «Neuropathy Impairment Score of Lower Limbs» (NIS-LL). The efficiency of combined therapy with «Nerviplex», «Dialipon» and «Gabapentin» was demonstrated in this case. > Conclusions. Autoimmune diseases can lead to nervous tissue damage due to different pathophysiological mechanisms, including the direct impact on it with the processes of inflammation and

[9] A Rare Case of Refractory Epilepsy Associated With Brain Calcifications and Mucocutaneous Candidiasis

  • Authors: P. Dubey, P. Rao, P. Naphade
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/08b2b56a78dcc35d8ca029a07e86084ba52cd5b3
  • DOI: 10.7759/cureus.83507
  • PMID: 40470404
  • PMCID: 12135895
  • Summary: A 23-year-old female with a history of abnormal body movement associated with posturing and transient loss of consciousness, along with a history of recurrent oral ulceration, itchy patches over intertriginous areas, and pigmentation of skin is presented.
  • Evidence snippets:
  • Snippet 1 (score: 0.512) > Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare and complex primary immunodeficiency disorder. The classic clinical triad of APS-1 includes chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency [1,2]. While the overall prevalence of APS-1 is estimated at 10 cases per million people, certain populations, such as Iranian Jews and Finns, exhibit higher rates [3,4,5]. Clinically, APS-1 presents with significant variability and is characterized by autoimmune dysfunction affecting both endocrine organs (including the parathyroids, adrenal glands, thyroid, gonads, and pituitary) as well as non-endocrine tissues (such as the skin, hair, liver, kidneys, lungs, eyes, and intestines [6,7]. > Autoimmune polyglandular syndrome type 1 arises from a failure in central immune tolerance, which leads to the development of autoimmunity. Since the identification of the AIRE gene, significant progress has been made in unraveling the underlying mechanisms of this condition. AIRE is predominantly expressed in medullary thymic epithelial cells and encodes a DNA-binding protein known as the autoimmune regulator. This protein plays a crucial role in promoting the expression of a wide range of tissue-specific antigens within the thymus. By exposing developing T cells to these antigens, the immune system is able to eliminate potentially self-reactive cells through negative selection. When AIRE is defective or absent, this screening process is impaired, allowing autoreactive T cells to bypass deletion and enter the peripheral circulation, where they can contribute to autoimmune disease [8].

[10] Limbal stem cell deficiency secondary to vitrectomy in the context of an autoimmune polyendocrine syndrome type

  • Authors: Francesc March de Ribot, Anna March de Ribot, J. Núñez Pérez, Joshua M. Huang, Jordan J. Huang et al.
  • Year: 2025
  • Venue: American Journal of Ophthalmology Case Reports
  • URL: https://www.semanticscholar.org/paper/75838aa2866020fd0dd5b65c8f63d07d9d37848b
  • DOI: 10.1016/j.ajoc.2025.102421
  • PMID: 40978286
  • PMCID: 12446495
  • Summary: It is proposed that surgical trauma near the limbus and damage to the corneal sub‐basal nerve plexus during vitrectomy may result in the development of limbal stem cell deficiency in a predisposed eye, as postulated in this patient with an APS.
  • Evidence snippets:
  • Snippet 1 (score: 0.511) > Autoimmune polyendocrine syndromes (APS) are a group of rare diseases characterized by immune activity against more than one endocrine organ. However, non-endocrine organs can be affected due to the loss of immunologic tolerance. APS can be differentiated as polyendocrine syndrome type 1 (APS-1), monogenic and aggressive, and polyendocrine syndrome type 2 (APS-2), polygenic and appearing later in life with more benign forms. APS may present across a broad age spectrum, from infancy to advanced age, with considerable heterogeneity in clinical manifestations and frequency. This variability is influenced by both genetic predisposition and environmental factors, often observed even among individuals within the same family. The pathogenesis is typically insidious, characterized by the presence of circulating autoantibodies and progressive lymphocytic infiltration of target tissues, which may culminate in organ dysfunction and eventual failure. 1,2 PS-1 is a rare autosomal recessive disease caused by autoimmune regulator gene (AIRE) mutations with T-cell-mediated loss of immune tolerance, presenting in some cases with autoantibodies targeting proteins with key functions in the affected endocrine organs. It is characterized by a minimum of two of three main components during infancy: chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). The two most common ocular manifestation of APS-1 include keratoconjunctivitis with dry eye and retinal degeneration. 3,4 Findings within the keratopathy phenotype may vary greatly, and are typically bilateral, ranging from a mild superficial keratitis, to epithelial ulcerations, stromal opacities, and/or severe stromal scarring. One potential complication of this may be the development of a limbal stem cell deficiency. 3,4 In contrast, the retinopathy phenotype is primarily characterized by changes to the retinal pigment epithelium (RPE).

[11] The “polyglandular crisis” behind recurrent hyponatremia: misdiagnosis of a case of autoimmune polyglandular syndrome type 2 and clinical lessons learned

  • Authors: Manli Yan, Hai Wu, Jingyu Deng, Yiting Wang, Haoyue Huang et al.
  • Year: 2026
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/963c27fccb4171b455854864bb733e0b5e3efe0c
  • DOI: 10.3389/fimmu.2026.1744295
  • PMID: 41659856
  • PMCID: 12872557
  • Summary: The case of APS type 2 (APS-2) in an adult female, characterized predominantly by emaciation, fatigue, palpitations, and notably, refractory hyponatremia is reported, highlighting the importance of dynamic monitoring of multiple glandular functions, enhancing clinicians’ recognition of this syndrome, and multidisciplinary collaboration to improve patient outcomes and reduce delays caused by misdiagnosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.503) > Autoimmune polyendocrine syndrome (APS) (1) is a group of clinical syndromes caused by genetic dysfunction of the immune system, which can manifest as simultaneous or sequential dysfunction of multiple endocrine or non-endocrine glands (2). > Based on pathogenesis and clinical characteristics, APS can be classified into type 1 (APS-1), type 2 (APS-2), and IPEX syndrome (3). APS-1 is more common in children and is mainly caused by mutations in the AIRE gene (4), which lead to immune tolerance defects and abnormal clonal proliferation of immune cells. The classic triad of APS-1 includes chronic mucocutaneous candidiasis, primary adrenocortical insufficiency, and hypoparathyroidism (4,5). APS-2 occurs more frequently in adults (6) and is usually associated with certain HLA haplotypes, such as HLA-DR3 and HLA-DR4 (6). Its typical manifestations (7) include autoimmune adrenal insufficiency, autoimmune thyroid disease, and type 1 diabetes mellitus, and it may also be accompanied by various other autoimmune disorders. > The clinical manifestations of APS are highly complex and heterogeneous (8), with significant individual differences in the types of glands affected, the extent of glandular dysfunction, and the specific symptoms presented. Early-stage APS often lacks distinctive features, making misdiagnosis or missed diagnosis common and potentially leading to delays in treatment and increased healthcare costs. Here, we report a case of APS-2 admitted to Guangdong Provincial Hospital of Traditional Chinese Medicine in March 2022, in which emaciation, fatigue, and palpitations were the initial presentations, with refractory hyponatremia as a prominent feature. By reviewing the patient's repeated misdiagnoses and treatment course and analyzing relevant literature, this article aims to enhance clinical awareness of the syndrome's diversity and the importance of early recognition, thereby promoting standardized diagnosis and management.

[12] Cutaneous vasculitis in patients with autoimmune polyendocrine syndrome type 1: report of a case and brief review of the literature

  • Authors: N. Improda, D. Capalbo, E. Cirillo, Manuela Cerbone, A. Esposito et al.
  • Year: 2014
  • Venue: BMC Pediatrics
  • URL: https://www.semanticscholar.org/paper/e1f9ed511cf6e0334026ccd67b22ed4c00b21676
  • DOI: 10.1186/1471-2431-14-272
  • PMID: 25361846
  • PMCID: 4286916
  • Citations: 15
  • Summary: This case suggests that cutaneous vasculitis may represent a first sign of autoimmune polyendocrine syndrome type 1 and children presenting with unexplained vasculitic skin rash should be followed-up in order to early identify APS 1.
  • Evidence snippets:
  • Snippet 1 (score: 0.501) > Autoimmune polyendocrine syndrome type 1 (APS 1), also known as autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED), is a rare autosomal recessive disease caused by pathogenic variants in the autoimmune regulator (AIRE) gene. AIRE encodes for the homonymous protein, AIRE, which acts as a regulator of the process of gene transcription and is involved in the mechanisms of deletional central (and presumably peripheral) tolerance. AIRE deficiency leads to the escape and extra-thymic spreading of autoreactive T-cell clones: this creates the basis for the onset of the autoimmune attack against several tissue-specific self-antigens [1]. > The clinical diagnosis of APS 1 is defined by the presence of at least two components of the classic triad, which is given by chronic mucocutaneous candidiasis (CMC), chronic idiopathic hypoparathyroidism (HPT) and Addison disease (AD). The disease generally begins in childhood and CMC is the first component appearing by five years of age, followed by HPT and then by AD. Other endocrine and non-endocrine components, such as hypergonadotropic hypogonadism, hypothyroidism, type 1 diabetes, gastrointestinal dysfunction, autoimmune hepatitis, asplenia and various ectodermal abnormalities (interstitial keratitis, alopecia, vitiligo, nail dystrophy and dental enamel hypoplasia), may occur with a different prevalence [2][3][4][5]. In addition to ectodermal features, which are quite common features of the disease, APS 1 patients may experience other types of skin alterations. Indeed, in a restricted number of cases a maculopapular, or morbilliform, or urticaria-like skin rash, eventually accompanied by fever, splenomegaly and arthralgia, has been reported [2,3,[6][7][8][9][10][11][12][13][14][15][16

[13] Biomarkers of Mercury Exposure in the Amazon

  • Authors: Nathália Santos Serrão de Castro, M. Lima
  • Year: 2014
  • Venue: BioMed Research International
  • URL: https://www.semanticscholar.org/paper/c206729d43837c1a94bb84c81183aef7d37bc250
  • DOI: 10.1155/2014/867069
  • PMID: 24895619
  • PMCID: 4020561
  • Citations: 10
  • Summary: The general aspects involved with each biomarker that was studied in the Amazon region are introduced in order to contextualize the reader and add information about the Amazonian life style and health that may be considered for future studies.
  • Evidence snippets:
  • Snippet 1 (score: 0.492) > Autoimmune diseases (AID) comprise a class of clinical outcomes associated with an imbalance of the discrimination between self and nonself. The biological mechanisms associated with AID are poorly comprehended, but some general events can unleash the disease, such as pathogenic mechanisms, inflammation response, autophagy, and diet [29][30][31]. > Genetic predisposition can contribute to the susceptibility to developing an AID. The hereditary studies and the discoveries of the molecular basis of AID have evolved and some researchers have already associated some genetic factors, such as the autoimmune polyendocrine syndrome type 1 (APS-1) and multiple sclerosis (MS), to disease development. The development of APS1, formerly autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is attributed to the loss of function mutation and dysregulation of the AIRE gene [32][33][34]. This gene codifies an autoimmune regulator protein (AIRE), which is a transcriptional factor that controls the expression of selfantigens in the thymus [35]. Different from APS1, multiple genes have been linked with the development of MS [36]. Among them, polymorphisms in the Human Leukocyte Antigen (HLA) class II genes have been extensively investigated [37][38][39]. Exposure to sunlight coupled with the intake of vitamin D has emerged as a factor to be involved with the development of MS and the advances in neuroepigenetic studies provide new clues about the plasticity and phenotype of the disease [40][41][42][43]. In spite of the progress of immunogenetics, no single gene has been identified as the main cause of the development of an AID. It is believed that AID is a conjunction of multiple genes working simultaneously to produce autoreactivity. Moreover, environmental triggers may play an important role in AID and, in conjunction with the genetic background, may determine the disease phenotype.

[14] In Search for the Missing Link in APECED-like Conditions: Analysis of the AIRE Gene in a Series of 48 Patients

  • Authors: A. Fierabracci, E. Belcastro, Elena Carbone, Olivia Pagliarosi, A. Palma et al.
  • Year: 2022
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/a2740213a93d9a1254bc7f589e0b82654b97d3e5
  • DOI: 10.3390/jcm11113242
  • PMID: 35683627
  • PMCID: 9181695
  • Citations: 5
  • Summary: The results of this genetic analysis emphasize the need to look for additional genetic determinants playing in concert with AIRE polymorphisms, which will help to improve the diagnostic workup and ensure a precision medicine approach to targeted therapies in APECED-like patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.488) > Autoimmune diseases are a heterogeneous group of disorders of the immune system.Environmental factors, family history and/or genetic susceptibility underlie their etiopathogenesis [1].These disorders are due to a loss of tolerance to self-proteins or autoantigens that can be organ specific or systemic [2].Organ-specific autoimmune diseases are due to target cell destruction determined by autoreactive T lymphocytes and can cluster in the same individual revealing various preferential associations; this is the case of polyendocrine autoimmune syndrome Type I (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome (APECED)), Type II and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome [3].Indeed, although phenotypically different and confirmed by different diagnostic procedures, autoimmune disorders can share similar immune and genetic defects, a phenomenon called 'autoimmune tautology' [2], i.e., the cooccurrence of polyautoimmunity or multiple autoimmune syndrome (MAS) and familiarity for autoimmunity [4]. > Clinical observation has further highlighted that autoimmunity can even share some common characteristics and mechanisms with other conditions that initially were considered independent polar opposites.Indeed, this was suggested by the high prevalence of autoimmune manifestations in primary immunodeficiencies (PID) and the observation that autoimmunity may even be the first manifestation [5]. > Identifying susceptibility genes for these complex phenotypes and unraveling their putative effects in their etiopathogenesis is a relevant issue.Further increased awareness and use of genetic screening of confirmatory functional studies, together with immunological markers, can lead to a precision medicine workup for early specific diagnosis in highly vulnerable patient categories [6]. > Both purely autoimmune conditions and PIDs can exhibit defects in central and peripheral tolerance influenced by mutations in genes that regulate immunological tolerance [5].

[15] A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1

  • Authors: B. Oftedal, A. Berger, Øyvind Bruserud, Yael Goldfarb, André Sulen et al.
  • Year: 2023
  • Venue: The Journal of Clinical Investigation
  • URL: https://www.semanticscholar.org/paper/58c03a4375e8b65a44eba1fe42dd4879e37565bb
  • DOI: 10.1172/JCI169704
  • PMID: 37909333
  • PMCID: 10617782
  • Citations: 6
  • Influential citations: 1
  • Summary: The data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.
  • Evidence snippets:
  • Snippet 1 (score: 0.484) > Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7–/–) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7–/– mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X–/– mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.

[16] Late-Onset Isolated Corticotrope Deficiency in a Woman with Down Syndrome

  • Authors: I. Oueslati, M. Ben Jemaa, M. Yazidi, F. Chaker, M. Chihaoui
  • Year: 2021
  • Venue: Case Reports in Endocrinology
  • URL: https://www.semanticscholar.org/paper/9c47406f6240fdab53843aade23bbf658ae8608a
  • DOI: 10.1155/2021/5562831
  • PMID: 34007493
  • PMCID: 8100382
  • Citations: 1
  • Summary: A case of an isolated corticotrope deficiency diagnosed at the age of 33 years in a woman with Down syndrome, which may be induced by autoimmune mechanism in similar to other disorders of patients with Down syndrome is reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.482) > 's disease are the commonest. ese patients are also more predisposed to develop early-onset type 1 diabetes, Addison disease, celiac disease, alopecia areata, chronic autoimmune hepatitis, and primary sclerosing cholangitis [12]. According to many authors, these patients share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients suffering from autoimmune polyendocrine syndrome type 1 [13]. > is syndrome results from inactivating mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21. e AIRE acts as a transcriptional regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens [14]. Its mutations are associated with a huge spectrum of phenotypes. Two major forms were identified. e classical autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APCED) is an autosomal recessive disease defined by the presence of at least two of the major components including chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and autoimmune Addison's disease [15]. e nonclassical form is caused by dominant heterozygous mutations mainly in the first plant homeodomain (PHD1) zinc finger of AIRE and is characterized by late-onset, milder phenotype, and reduced penetrance [15]. e pituitary involvement in autoimmune polyendocrine syndrome type 1 is a rare condition. Growth hormone deficiency, central diabetes insipidus, gonadotropin deficiency, and ACTH deficiency were reported. > In patients with Down syndrome, Skogberg et al. demonstrated that the AIRE gene is overexpressed, which may alter thymic selection processes and affect the susceptibility for autoimmune diseases [13]. On the contrary, other authors reported that the level of AIRE expression in the thymus of patients with Down syndrome is reduced [16,17]. > Corticotrope cells are often the first to be affected in lymphocytic hypophysitis, and adult isolated corticotrope

[17] A Functional Alternative Splicing Mutation in AIRE Gene Causes Autoimmune Polyendocrine Syndrome Type 1

  • Authors: Junyu Zhang, Hongbin Liu, Zhiyuan Liu, Y. Liao, Luo Guo et al.
  • Year: 2013
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/de936b913b09761caa8187b66af5eaf247d4615e
  • DOI: 10.1371/journal.pone.0053981
  • PMID: 23342054
  • PMCID: 3540864
  • Citations: 30
  • Influential citations: 1
  • Summary: This study represents the first functional characterization of the alternatively spliced AIRE mutation that may explain the pathogenetic role in APS-1 and potentially compromised the recognition of the splice donor of intron 3.
  • Evidence snippets:
  • Snippet 1 (score: 0.475) > Autoimmune polyendocrine syndrome type 1 (APS-1, OMIM 240300), formerly known as Autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy (APECED), is a rare but devastating primary immunodeficiency disorder, which usually manifests during childhood and adolescence [1,2]. Clinical diagnosis for APS-1 typically requires the presence of at least two of the three hallmark conditions: chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease [2]. Mutations in autoimmune regulator (AIRE) gene have been linked to APS-1 [3,4]. The AIRE gene encodes a 57 kDa transcription regulator of 545 amino acids involved in regulating autoimmunity by promoting the ectopic expression and presentation of tissuerestricted antigens during T-cell development in the thymus [5]. AIRE protein contains several distinct domains, such as a potential bipartite nuclear localization signals (NLS) consisting of amino acids 110-114 and 131-133, four interspersed LXXLL motifs, two plant homeodomain (PHD) fingers, caspase-recruitment domain (CARD), and SAND (named after Sp100, AIRE-1, NucP41/75, DEAF-1) domain [3,4,6,7]. Consistent with these features, the AIRE protein is localized predominantly in the nucleus, where it potentially modulates the transcription of a variety of genes by interacting with specific DNA sequences and/or acting through epigenetic mechanisms [5,6,8]. > Patients with APS-1 also routinely exhibit additional autoimmune diseases, including type 1 diabetes mellitus, hypothyroidism, vitiligo, alopecia, autoimmune hepatitis, pernicious anemia, and asplenism [9]. The range of these secondary disorders is broad and variable, affected siblings carrying the same mutations can develop divergent spectrums of autoimmune disorders [10].

[18] On type 1 diabetes mellitus pathogenesis

  • Authors: S. Paschou, N. Papadopoulou-Marketou, G. Chrousos, C. Kanaka-Gantenbein
  • Year: 2017
  • Venue: Endocrine Connections
  • URL: https://www.semanticscholar.org/paper/b5152d55833c335afe30a8dc8204f1418cbf33e8
  • DOI: 10.1530/EC-17-0347
  • PMID: 29191919
  • PMCID: 5776665
  • Citations: 198
  • Influential citations: 6
  • Summary: Genetic, environmental and immunologic factors that destroy β cells of the endocrine pancreas and lead to insulin deficiency are presented, which reflects the large percentage of β cells that need to be destroyed before overt diabetes become evident.
  • Evidence snippets:
  • Snippet 1 (score: 0.467) > Presentation of autoantigens in both the thymus and the periphery to negatively select and delete T lymphocytes that are highly reactive (central and peripheral immune tolerance, respectively) is a very important regulatory mechanism of autoimmunity. The AIRE protein (autoimmune regulator) is mainly expressed in the epithelial and dendritic cells of the thymus marrow. It is a transcription factor which controls the expression of many specific autopeptides (8). Patients with mutations in the AIRE gene, located on the long arm of the chromosome 21 (21q22.3), exhibit autoimmune polyendocrine syndrome 1 (APS 1), also known as APECED syndrome, which is the acronym of its main clinical manifestations, polyendocrine autoimmunity (Addison's disease, hypoparathyroidism, T1DM), candidiasis and ectodermal dystrophy (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy -APECED). The presence of T1DM in patients with AIRE mutations (less frequent of course than in APS 2) demonstrates that the expression and presentation of relevant autoantigens (insulin, GAD, IA-2) in the thymus are under the surveillance of this transcription factor (21,22).

[19] Autoimmunity and Genetic Syndromes: A Focus on Down Syndrome

  • Authors: M. Ferrari, S. Stagi
  • Year: 2021
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/0796d39809e74381c0923aa4a4afa3b875e9cd84
  • DOI: 10.3390/genes12020268
  • PMID: 33668420
  • PMCID: 7918365
  • Citations: 30
  • Influential citations: 3
  • Summary: This short review aims to report the current literature regarding the genetic, immune, and environmental factors that have been proposed as the possible underlying mechanism of autoimmunity in individuals with DS, with the intent to provide insight for a comprehensive understanding of these diseases in genetic syndromes.
  • Evidence snippets:
  • Snippet 1 (score: 0.466) > Autoimmunity commonly features many well-known genetic conditions, such as Turner syndrome (TS), Trisomy 21 or Down syndrome (DS), and 22q11.2 deletion syndrome (22q11.2DS) [1]. The susceptibility toward this disorder has been recently investigated for many other genetic syndromes, such as Kabuki, Noonan, and Klinefelter [2][3][4][5]. In these patients, virtually all autoimmune disorders have been described, in particular thyroid disorders and celiac disease, in addition to alopecia, vitiligo, type 1 diabetes, juvenile idiopathic arthritis, and systemic lupus erythematosus (SLE). Several mechanisms have been attributed to the etiology of autoimmunity, including genetic or acquired defects of immune regulatory pathways, impaired apoptosis, and molecular mimicry to viral or bacterial antigens [5]. Although the exact mechanisms underlying autoimmune diseases are still elusive, it appears as though a pathogenic inflammatory response by self-antigen-specific T cells is frequently involved [1]. Given the common association between autoimmunity and chromosomal aberrations, many efforts have been made with the intent of identifying possible underlying mechanisms and perhaps also provide insights for a better understanding of other clinical aspects related to genetic syndromes. Among the many genetic alterations, DS was one of the first to be studied in relation to autoimmunity. In fact, as early as 1969, an association between DS (at the time defined as Mongolism) and autoimmune thyroiditis was observed [6]. Since that time, much progress has been made in defining Genes 2021, 12, 268 2 of 10 the main features of this syndrome and associated autoimmune complications; however, many questions still need to be answered. In this short review, we aim to report the current literature regarding mechanisms underlying autoimmunity and its main clinical outcomes, providing, where possible, recommendations for early identification, follow up, and monitoring of these disorders in DS.

[20] Autoimmune hepatitis in genetic syndromes: A literature review

  • Authors: A. Capra, E. Chiara, S. Briuglia
  • Year: 2021
  • Venue: World Journal of Hepatology
  • URL: https://www.semanticscholar.org/paper/60dffb45c6a2cec3b2a3f11536ce56f91689de36
  • DOI: 10.4254/wjh.v13.i10.1328
  • PMID: 34786169
  • PMCID: 8568577
  • Citations: 6
  • Summary: It is suggested that when a patient presents a clinical picture of cryptogenic chronic hepatitis, that is unexplained, it is useful to explore differential diagnosis of AIH associated with genetic syndrome, that could be useful for pathogenetic hypothesis and clinical approach to genetic syndrome.
  • Evidence snippets:
  • Snippet 1 (score: 0.464) > Autoimmune polyendocrinopathy syndromes: The term APS refers to a group of rare endocrine diseases characterized by autoimmune activity against more than one endocrine organ, with possible additional involvement of non-endocrine organs. > Autoimmunity is typically directed against different target antigens in different tissues. The two more common autoimmune polyendocrine syndromes, APS type 1 and type 2, have a strong genetic background and have Addison's disease as a major feature. The group furthermore includes APS type 3 and type 4. > The APS type 1 is a rare recessive autosomal disease, also named APECED syndrome (OMIM 240300), and related to AIRE gene mutations. Because of a founder effect, APECED is particularly prevalent in Finland (1:25000) but is observed worldwide with variable prevalence [15]. Diagnosis is classically based on presence of at least two out of three "majors" criterions of Whitaker's triad (chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism and adrenal insufficiency or Addison disease). AIRE gene (21q22.3), coding for the AIRE transcription factor, is involved in immune tolerance mechanisms and contributes to the negative selection of autoreactive T lymphocytes in the thymus, lymph nodes and spleen. AIH and hepatitis as an APECED component may be distinguished on the basis of a different autoantibody profile. The anti-LM antibodies are specific of AIH, which develops in individuals with APECED. > The major target autoantigen of anti-LM antibodies has been documented as the CYP1A2 [8,12,14]. In the considered period, we have found four papers reporting in all six patients with APECED syndrome and AIH, that is non-endocrine complication [7,[16][17][18]. > The girl described by Huibregtse et al [7] had homozygous 967-979del13bp mutation. Meloni et al [17] described a longitudinal cohort study in which AIH was seen in 27% of their APS1 Sardinian patients.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.