Autoimmune Polyglandular Syndrome Research Articles

Polyneuropathy and Gastritis in Autoimmune Polyendocrine Syndrome Type 1 in a Young Adult: Uncommon Presentation of a Rare Disease

utoimmune Polyendocrine Syndrome type1 (APS-1), sometimes called, autoimmune polyglandular syndrome type 1, and autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED), is a rare recessive disorder with diverse features that occurs due to mutations in the autoimmune regulator (AIRE) gene inducing autoimmunity. This report summarizes the diagnosis of APS 1 in a 17-year-old young man presenting with vomiting, diarrhea, and limb weakness. Investigation reveals mixed features of endocrinopathies including hypoparathyroidism, hypothyroidism, adrenal insufficiency, and hypogonadism. Although autoimmune keratitis, hepatitis, pancreatitis, pneumonitis, and nephritis are common systemic affection of this condition, the reported case presents with severe sensory-motor polyneuropathy and pangastritis. He carries a single heterozygous copy of the missense variant (NM_000383.3 c.841G>A chr21:45709913 p.Ala281Thr) in exon 7 of the AIRE.

Autoimmune polyglandular syndrome type 2 in an 15-year-old boy

Autoimmune polyglandular syndrome type 2 in an 15-year-old boy

Association of Inherited Genotype and Severity of Clinical Presentation in Subjects with Verified Pas III Disorder.

Background:Polyglandular autoimmune syndrome type III (PAS III) is combination two most common autoimmune disease: Diabetes mellytus type 1 (DM1) and autoimmune thyroid disease (AITD).Objectives:The aims of the study were a) to define conection between polymorphism of CTLA-4 gene, rs 231775 with PAS III; b) to establish the conection of inherited genotype with severity of clinical features; and c) to estimate the rate of risk for severe clinical presentation among subgroups in study population.Methods:This research included 50 subjects with diagnosed PAS III syndrome, wich are on treatment in clinic for Nuclear medicine and andocrinology KCUS. As methods of research has used: hystory of disesase AND clinical examination. As material is used blood sample. From blood sample DNA was isolated withn Qiamp- DNA-mini kit, with accopanied protocol.Results:In our study, 50 patients with polyglandular autoimmune syndrome type III (PAS III) were examined, and in the study population had 26 female subjects and 24 male subjects. The average age of the participants was 31.64 years, and in the subgroups: group GWT (G-wild type) the average age was 30.20 years, group GM (G-mutated) 32.40 years and group GH (G-heterozygote) 30 , 60 years. Using the Chi-square test, the association between the polymorphism rs231775 and PAS-III was demonstrated, x2 (2.100) = 18.258, where p < 0.0001. Using the Chi-square test, the association between the rs231775 polymorphism and the severity of the clinical picture, x2 (2.50) = 8.531, where p< 0.0140 was proved. The CTLA-4 rs231775 genotypes were also assessed for disease severity.Conclusion:This study suggests that CTLA-4 expression plays a key role in balancing the immune system as well as the response against one’s own tissues, and thus in the regulation of autoimmune diseases.

Autoimmune encephalitis as a rare complication of autoimmune polyendocrine syndrome type 3

Autoimmune encephalitis as a rare complication of autoimmune polyendocrine syndrome type 3

Autoimmune polyglandular syndrome type 1 and eye damage

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.

Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model.

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro. We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo. These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.

Alterations in SLC4A2, SLC26A7 and SLC26A9 Drive Acid-Base Imbalance in Gastric Neuroendocrine Tumors and Uncover a Novel Mechanism for a Co-Occurring Polyautoimmune Scenario.

Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+ Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid–base imbalance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport together with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panel with 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total, 64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, proposing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients.

Autoimmune polyglandular syndrome type I. Features of clinical manifestations, difficulties in diagnosis and methods of correction

Autoimmune polyglandular syndrome (APG) type I is an orphan disease with autosomal recessive inheritance caused by mutations in the autoimmune regulator gene (AIRE); the disease onset typically occurs in childhood. The disease is characterized by a wide variety of clinical manifestations with a certain stage in the manifestation of individual symptoms. The rare occurrence of this pathology determines its late diagnosis, which can lead to the decompensated life-threatening conditions and an unfavorable outcome. Widely informing pediatric specialists will contribute to the development of a diagnostic algorithm for timely verifying the disease from the moment its first clinical manifestations appear, and will improve the quality and life expectancy of the patients.

Calculation of Similarity Between 26 Autoimmune Diseases Based on Three Measurements Including Network, Function, and Semantics.

Autoimmune diseases (ADs) are a broad range of diseases in which the immune response to self-antigens causes damage or disorder of tissues, and the genetic susceptibility is regarded as the key etiology of ADs. Accumulating evidence has suggested that there are certain commonalities among different ADs. However, the theoretical research about similarity between ADs is still limited. In this work, we first computed the genetic similarity between 26 ADs based on three measurements: network similarity (NetSim), functional similarity (FunSim), and semantic similarity (SemSim), and systematically identified three significant pairs of similar ADs: rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), myasthenia gravis (MG) and autoimmune thyroiditis (AIT), and autoimmune polyendocrinopathies (AP) and uveomeningoencephalitic syndrome (Vogt-Koyanagi-Harada syndrome, VKH). Then we investigated the gene ontology terms and pathways enriched by the three significant AD pairs through functional analysis. By the cluster analysis on the similarity matrix of 26 ADs, we embedded the three significant AD pairs in three different disease clusters respectively, and the ADs of each disease cluster might have high genetic similarity. We also detected the risk genes in common among the ADs which belonged to the same disease cluster. Overall, our findings will provide significant insight in the commonalities of different ADs in genetics, and contribute to the discovery of novel biomarkers and the development of new therapeutic methods for ADs.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

Thyroid Disorders.

Thyroid Disorders.

Differential diagnosis of idiopathic hypoparathyroidism: a case series

Idiopathic hypoparathyroidism is a rare endocrine disease diagnosed when all possible causes of hypoparathyroidism are excluded. Data on the prevalence of idiopathic hypoparathyroidism is limited, there are several local studies in some countries. The variety and non-specificity of the hypoparathyroidism symptoms, similarity to other diseases (eg. epilepsy), causes the misdiagnosis and delay in pathogenetic therapy. Idiopathic hypoparathyroidism is rare. Therefore, the absence of neck surgery in the anamnesis practically excludes hypoparathyroidism from the diagnostic search. Moreover, it is necessary to rule out all known causes of decreased PTH hypoparathyroidism to determine the form of non-surgical hypoparathyroidism. We present a case series of idiopathic hypoparathyroidism, which demonstrates the difficulty in diagnosis, and the clinical features of the disease. The article covers also the problem of modern diagnostic approaches including the determination of the interferon-omega for patients with suspected autoimmune polyglandular syndrome type 1 as the most common cause of nonsurgical hypoparathyroidism.

Autoimmune Polyglandular syndrome presenting with multiple Endocrinopathies

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications.

During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity.

Clinical profile, etiology, and diagnostic challenges of primary adrenal insufficiency in Sudanese children: 14-years' experience from a resource limited setting.

Primary adrenal insufficiency (PAI) in children is an uncommon condition. Congenital adrenal hyperplasia (CAH) is the commonest cause followed by autoimmune disorders. Diagnosis and management are challenging especially in resource-limited settings. Studies from Africa are scanty and here we describe for the first time the clinical presentation, possible etiologies, and challenges in diagnosis and management of PAI in a large cohort of Sudanese children. This was a descriptive hospital-based study where all patients diagnosed with PAI between 2006 and 2020 were reviewed. The diagnosis was based on clinical presentation, low morning cortisol±high adrenocorticotropic hormone (ACTH), or inadequate response of cortisol to synacthen stimulation. Challenges faced in diagnosis and management were identified. From 422 PAI suspected patients, 309 (73.2%) had CAH, and 33 (7.8%) had PAI-like symptoms and were not furtherly discussed. Eighty patients (19%) had fulfilled the study criteria: 29 had Allgrove syndrome, nine auto-immune polyendocrinopathy syndrome, seven adrenoleukodystrophy, and one had an adrenal hemorrhage. Hyperpigmentation was the cardinal feature in 75 (93.8%) while the adrenal crisis was not uncommon. Lack of diagnostic facilities has obscured the etiology in 34 (42.5%) patients. PAI is not uncommon in Sudanese children where genetic causes outweigh the autoimmune ones. Many cases were missed due to nonspecific presentation, lack of awareness, and difficult access to tertiary health care facilities. In addition to the clinical findings, early morning cortisol±ACTH levels can be used in diagnosis where facilities are limited particularly synacthen stimulation test.

IMPENDING PERICARDIAL TAMPONADE AS THE INITIAL PRESENTATION OF AUTOIMMUNE POLYGLANDULAR SYNDROME 3B

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Autoimmune polyglandular syndromes (APS) are rare polyendocrinopathies characterized by loss of immune tolerance to self-antigens leading to autoimmune destruction of endocrine glands and other tissues. APS is classified into APS types 1, 2, 3 and 4. APS Type 3 is recognized by absence of adrenal insufficiency. APS type 3b (APS3b) specifically comprises of the association of autoimmune thyroid disease with pernicious anemia. CASE PRESENTATION: A 66-year-old female with history of pernicious anemia presented to the emergency department with shortness of breath and lethargy which started on day of arrival. She was diagnosed with pernicious anemia 2 years ago and was receiving intramuscular cyanocobalamin injections. In the emergency department, she was found to be hypoxic with oxygen saturation of 90%. Her physical exam was notable for muffled heart sounds. Her labs on admission were: Hb 11.8 g/dl, HCT 35.8 %, WBC 6.3 K/ul, PLT 166 K/ul, Glucose 106 mg/dl, Sodium 143 mmol/l, BUN 13 mg/dl, Creatinine 1.13 mg/dl, pro-BNP 171 pg/ml, TSH 44.6 UIU/ml, Free T4 0.2 ng/dl, Free T3 0.5 pg/ml and positive thyroid peroxidase antibody >1300 u/ml. Serial troponins were unremarkable. Chest x-ray showed an enlarged cardiac silhouette concerning for pericardial effusion. EKG showed normal sinus rhythm with low voltage QRS complexes. 2D Echo showed a large circumferential pericardial effusion with end diastolic RV collapse suggestive of impending pericardial tamponade. LV ejection fraction was 60%. Pericardiocentesis drained 1700 cc of fluid with relief of patient's symptoms. This was followed by placement of pericardial drain. Her pericardial effusion was attributed to her new diagnosis of hypothyroidism. She was started on low dose levothyroxine given her age above 60 with plan for slowly increasing her dose with close outpatient follow up. DISCUSSION: Pernicious anemia is the most common association with thyroid autoimmune disease in APS type 3 seen in 39% of cases. APS3 is more commonly seen in females. The diagnosis of this condition requires the presence of multiple autoimmune diseases in the same individual, diagnosed in any order and at any age. CONCLUSIONS: A high index of suspicion is required whenever one autoimmune disease is diagnosed to prevent morbidity and mortality from other associated conditions. Here, we describe a patient with known history of pernicious anemia presenting with impending tamponade who was subsequently diagnosed with Hashimoto's thyroiditis. The constellation of these findings represent APS Type 3b. REFERENCE #1: Betterle, Corrado et al. "A rare combination of type 3 autoimmune polyendocrine syndrome (APS-3) or multiple autoimmune syndrome (MAS-3)." Auto- immunity highlights vol. 5,1 27-31. 11 Feb. 2014, doi:10.1007/s13317-013-0055-6 REFERENCE #2: Lahner E, Centanni M, Agnello G, et al. Occurrence and risk factors for autoimmune thyroid disease in patients with atrophic body gastritis. Am J Med. 2008;121(2):136-141. doi:10.1016/j.amjmed.2007.09.025 DISCLOSURES: No relevant relationships by Sana Fatima, source=Web Response No relevant relationships by Shumail Syed, source=Web Response

181 Characterization of APS1 patient-derived induced pluripotent stem cells for potential therapeutic gene correction

Autoimmune polyglandular syndrome type 1 (APS1) is a severe and incurable autoimmune disease caused by mutations in the AIRE gene. Without functional AIRE immune tolerance is impaired as self-reactive T cells escape from negative selection and a variety of autoantibodies develop. Recently AIRE has also been found to have novel functions in stem cells and to actively participate in pluripotency. We have pioneered a pilot study to assess the potential of patient-derived, gene- corrected induced pluripotent stem cells (iPSCs) for use as cell therapy in APS1.

Candidiasis in patients with APS-1: low IL-17, high IFN-γ, or both?

Chronic mucocutaneous candidiasis (CMC) is one of the earliest and most frequent clinical manifestations of autosomal recessive autoimmune polyendocrine syndrome type 1 (APS-1), a monogenic inborn error of immunity caused by deleterious variants of the autoimmune regulator (AIRE) gene. APS-1 patients suffer from various autoimmune diseases, due to the defective thymic deletion of autoreactive T cells, and the development of a large range of autoantibodies (auto-Abs) against various tissue antigens, and some cytokines. The mechanisms underlying CMC remained elusive for many years, until the description in 2010 of high serum titers of neutralizing auto-Abs against IL-17A, IL-17F, and/or IL-22, which are present in almost all APS-1 patients. Excessively high mucosal concentrations of IFN-γ were recently proposed as an alternative mechanism for CMC in APS-1.

Intracranial Calcifications in Autoimmune Polyendocrine Ectodermal Dystrophy Syndrome (APECED): About A Case Report

Autoimmune polyendocrinopathy ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS I), is an uncommon, but debilitating autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE), It is characterized by a broad and diverse clinical spectrum which can lead to severe metabolic alterations and eventually life-threatening events. Hypoparathyroidism is one of the major criteria for clinical diagnosis, in addition to chronic mucocutaneous candidiasis and autoimmune adrenal insufficiency. This component is responsible for the forming of brain calcifications which tend to have a characteristic predilection for the basal ganglia. In this article, we report an additional case to the literature and provide a literature review of the expanding radiological spectrum of this syndrome

Autoimmune hepatitis as the first manifestation of autoimmune polyendocrine syndrome type 1 in a 5-year-old girl

Autoimmune hepatitis is a chronic inflammatory liver disease of unknown etiology; the prevalence of juvenile autoimmune hepatitis is unknown. Autoimmune hepatitis occurs in 10–20% of patients with type 1 autoimmune polyendocrine syndrome, a rare (orphan) disease, which is characterized by a clinical triad in 70–100% of cases: chronic mucocutaneous candidiasis, hypopara thy roidismand adrenal insufficiency, as well as more 25 possible autoimmune endocrine and non-endocrine manifestations.Thisstudy describes a case of a 5-year-old girl with autoimmune hepatitis as the first clinical manifestation of the disease. The symptoms of chronic mucocutaneous candidiasis enabled us to suggest and genetically confirm the diagnosis of autoimmune poly endocrine syndrome type 1 before the lesions of endocrine organs. The girl had nonsense mutations R257 * and p.Q94* of the AIRE gene in a compound heterozygous state. Later, there appeared another autoimmune disorder – common vitiligo.Timelydiagnosisoftype1autoimmunepolyendocrinesyndromeinachildwiththefirstnon-endocrine autoimmune manifestation, initiation of therapy and further medical management made it possible to preventseve recomplications and improve the patient’s quality of life.