Autoimmune Polyendocrine Syndrome Type Research Articles

Un calciatore a cui tremano le gambe: un caso di ipoparatiroidismo

The paper presents the case of a 13-year-old athlete who experienced sudden tremors, limb pain, hand spasms and severe hypocalcemia (6 mg/dl). Tests revealed low parathyroid hormone (PTH), hyperphosphatemia and low vitamin D levels. The diagnosis of autoimmune hypoparathyroidism was made and treated with calcium and vitamin D. During hospitalization, Hashimoto’s thyroiditis and transient hyperthyroidism were also identified. Suspecting Autoimmune Polyendocrine Syndrome Type 1 (APS-1), AIRE mutations are being tested.

Bronchiectasis in a patient with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy: a case report

BackgroundThe rare monogenic syndrome Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) leads to multisystemic autoimmunity with possible lung involvement. Autoimmune pneumonitis is a rare manifestation, with bronchiectasis being the most frequent radiologic pattern, and may lead to fatal outcome. The Sardinian population in Italy has a high incidence of APECED, although no case of lung manifestation has been reported yet in this cohort. This is the case of a Sardinian APECED patient referred to a bronchiectasis clinic. Our aim is to raise awareness and screen these patients earlier for pulmonary involvement and to initiate multidisciplinary treatment for better outcome.Case presentationA 49-year-old female native of Sardinia from consanguineous parents was diagnosed with APECED in childhood and was referred to our bronchiectasis clinic in March 2023. In addition to typical APECED features, she reported recurrent respiratory infections since childhood, chronic purulent sputum and a hospitalization for pneumonia. She came to our attention with a recent isolation of P. aeruginosa on sputum culture and diffuse cylindrical and varicoid bronchiectasis on her first CT scan. She underwent aetiologic screening for bronchiectasis with no evidence of another cause of disease. Lung treatment was optimized according to bronchiectasis guidelines, and during follow-up the patient developed methicillin-resistant Staphylococcus aureus (MRSA) infection and M. intracellulare pulmonary disease. The patient was offered P. aeruginosa eradication treatment with intravenous antibiotics and initiation of antimycobacterial therapy.ConclusionThis is the first documented lung involvement case of APECED in a Sardinian patient, and the first patient reported to enter a bronchiectasis program. The patient was prescribed lung imaging late in time when bronchiectasis complications were already present. Our case report highlights the need for early pulmonary screening and multidisciplinary management in patients with APECED.

Uncovering ASO-Targetable Deep Intronic AIRE Variants: Insights and Therapeutic Implications.

High-throughput DNA sequencing has accelerated the discovery of disease-causing genetic variants, yet only in 10-40% of cases yield a genetic diagnosis. Increased implementation of genome sequencing has enabled a deeper exploration of the noncoding genome and recognition of noncoding variants as major contributors to disease. In a recent study, we identified a deep intronic variant in the AutoImmune REgulator (AIRE) gene (c.1504-818 G>A) as the cause of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a life-threatening monogenic autoimmune disorder most often caused by biallelic AIRE defects. This deep intronic variant disrupts normal splicing AIRE , causing pseudoexon inclusion and altered protein function. By developing an antisense oligonucleotide (ASO) targeting the pseudoexon sequence, we restored normal AIRE transcript in vitro, thereby revealing a potential genotype-specific candidate treatment. Our study illustrates key aspects of intronic variant detection, validation, and candidate ASO development. Herein, we briefly highlight the growing potential of ASO-based therapies for deep intronic variants, addressing the unmet need of personalized, genotype-specific therapies in diseases lacking curative options.

Where AIRE we now? Where AIRE we going?

The purpose of the review is to describe the most recent advancement in understanding of the pivotal role of autoimmune regulator (AIRE) gene expression in central and peripheral tolerance, and the implications of its impairment in the genetic and pathogenesis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) manifestations with insight into possible treatment options. AIRE gene expression has an important role of central and peripheral tolerance. Different AIRE gene mutations cause APECED, whereas polymorphisms and some variants may be implicated in development of other more frequently autoimmune diseases. Impaired negative T cell selection, reduction of T regulatory function, altered germinal center response, activated B cells and production of autoantibodies explain the development of autoimmunity in APECED. Recent data suggest that an excessive interferon-γ response may be the primer driver of the associated organ damage. Therefore, Janus kinase (JAK)-inhibitors may be promising therapies for treatment of broad spectrum of manifestations. AIRE has a pivotal role in immune tolerance. Disruption of this delicate equilibrium results in complex immune perturbation, ranging from severe autoimmunity, like APECED, to more common organ-specific disorders. Therefore, a deeper understanding of the correlation between AIRE function and clinical phenotype is warranted given the potential translational implication in clinical practice.

ORAL FINDINGS AND CLINICAL BEHAVIOR IN PATIENT HAVING AUTOIMMUNE POLYENDOCRINOPATHY CANDIDIASIS ECTODERMAL DYSTROPHY (APECED)

Introduction: APECED (Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) is a rare autosomal recessive disease with significant impacts on oral health, including oral candidiasis and varying degrees of enamel hypoplasia. Objective: To present the oral findings of a girl with APECED and the minimally invasive approach taken in recovery and rehabilitation, taking into account the complexity of her medical condition. Material and methods: A case of a 16-year-old girl with APECED, who visited the dental clinic due to defects of the hard dental tissues and severe dentinal hyperesthesia, is described. There was an underbite with a reduced lower facial floor and enamel hypoplasia in the coronal and middle third of the anterior teeth and first molars. Results: Through direct composite restorations and a minimally invasive approach, a good healing, functional and aesthetic result was achieved.

Whitaker syndrome: A case report of autoimmune polyendocrine syndrome type 1 with dilated cardiomyopathy.

This case report highlights dilated cardiomyopathy as a cardiovascular complication in autoimmune polyendocrine syndrome type 1 (APS-1), emphasizing the need for early recognition and a multidisciplinary approach. Comprehensive care and regular follow-up are crucial in managing these atypical presentations to optimize patient outcomes. APS-1, also known as Whitaker syndrome, is characterized by a triad of mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. This rare autosomal recessive disorder results from mutations in the autoimmune regulator (AIRE) gene. Cardiovascular and pulmonary manifestations in APS-1 are infrequently reported in the literature. We present a case of a 28-year-old male who presented with shortness of breath and pedal edema. Physical examination revealed alopecia, absence of eyebrows, hyperpigmentation on joints, oral candidiasis, and nail dystrophy. Echocardiography demonstrated dilated cardiomyopathy (DCM) and pericardial effusion. Chest x-ray showed left-sided pleural effusion. Laboratory investigations revealed hypocalcemia, hyperphosphatemia, low parathyroid hormone (PTH), low cortisol, and high adrenocorticotropic hormone (ACTH) levels. The combination of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency confirmed the diagnosis of APS-1. To the best of our knowledge, this is the first Pakistani and second worldwide reported case of APS-1 presenting with such a combination of manifestations. Early recognition and multidisciplinary management are crucial for improving outcomes in these patients.

A deep intronic splice-altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendritic cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109-base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE-expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.

A case of panhypopituitarism due to a rathke's cleft cyst in a 32-year-old male with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

A case of panhypopituitarism due to a rathke's cleft cyst in a 32-year-old male with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

Complexity and multimorbidity in autoimmune polyendocrine syndrome type 2 - a case report

Complexity and multimorbidity in autoimmune polyendocrine syndrome type 2 - a case report

Decreased T-cell response against latentcytomegalovirus infection does not correlate with anti-IFN autoantibodies in patients with APECED.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inborn error of immunity affecting both multiple endocrine organs and susceptibility to candidiasis, each with an autoimmune basis. Recently, high titer neutralizing anti-type I interferon (IFN) autoantibodies have been linked with increased severity of SARS-CoV-2 and varicella zoster virus infections in APECED patients. Examining immunity against cytomegalovirus (CMV), we found a higher prevalence of anti-CMV IgG antibodies in patients with APECED (N = 19) than in 44 healthy controls (90% vs 64%, p = 0.04); the similar difference in their IgG levels did not achieve significance (95 ± 74 vs 64 ± 35 IU/mL, ns.). In contrast, the frequency of CMV-specific Tcells was lower (804 ± 718/million vs 1591 ± 972/million PBMC p = 0.03). We saw no correlations between levels of anti-CMV IgG and anti-IFN antibodies in APECED patients or in a separate cohort of patients with thymoma (n = 70), over 60% of whom also had anti-IFN antibodies. Our results suggest a dysregulated response to CMV in APECED patients and highlight immunodeficiency to viral infections as part of the disease spectrum.

Lymphocyte-Directed Immunomodulation Remits Thymoma-Associated Autoimmune Pneumonitis

BackgroundThymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described as an autoimmune manifestation associated with thymoma presenting with similar clinical, radiographic, histological, and autoantibody features as seen in patients with inherited AIRE deficiency who suffer from Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome.ObjectivesTo treat two patients with biopsy-proven thymoma-associated pneumonitis with lymphocyte-directed immunomodulation.MethodsTwo patients with thymoma were enrolled on IRB-approved protocols at the NIH Clinical Center. We performed history and physical examination; laboratory, radiographic, histologic and pulmonary function evaluations; and measurement of the lung-directed autoantibodies KCNRG and BPIFB1 prior to and at 1- and 6-months following initiation of lymphocyte-directed immunomodulation with azathioprine with or without rituximab.ResultsCombination T- and B-lymphocyte-directed immunomodulation resulted in improvement of clinical, functional, and radiographic parameters at 6-month follow-up evaluations in both patients with sustained remission up to 12–36 months following treatment initiation.ConclusionLymphocyte-directed immunomodulation remitted autoimmune pneumonitis in two patients with thymoma.

Endocrine Petrified Ear: Associated Endocrine Conditions in Auricular Calcification/Ossification (A Sample-Focused Analysis).

Petrified ear (PE), an exceptional entity, stands for the calcification ± ossification of auricular cartilage (CAC/OAC); its pathogenic traits are still an open matter. Endocrine panel represents one of the most important; yet, no standard protocol of assessments is available. Our objective was to highlight most recent PE data and associated endocrine (versus non-endocrine) ailments in terms of presentation, imagery tools, hormonal assessments, biopsy, outcome, pathogenic features. This was a comprehensive review via PubMed search (January 2000-March 2024). A total of 75 PE subjects included: 46 case reports/series (N = 49) and two imagery-based retrospective studies (N = 26) with CAC/OAC prevalence of 7-23% (N = 251) amid routine head/temporal bone CT scans. Endocrine PE (EPE): N = 23, male/female ratio = 10.5; average age = 56.78, ranges: 22-79; non-EPE cohort: N = 26; male/female ratio = 1.88, mean age = 49.44; ranges: 18-75 (+a single pediatric case).The longest post-diagnosis follow-up was of 6-7 years. The diagnosis of PE and endocrine anomalies was synchronous or not (time gap of 10-20 years). A novel case in point (calcified EPE amid autoimmune poly-endocrine syndrome type 2 with a 10-year post-diagnosis documented follow-up) was introduced. We re-analyzed EPE and re-classified another five subjects as such. Hence, the final EPE cohort (N = 50) showed: adrenal insufficiency was the most frequent endocrine condition (36%) followed by hypopituitarism (22%) and hypothyroidism (18%); 39% of the patients with adrenal failure had Addison's disease; primary type represented 72% of all cases with hypothyroidism; an endocrine autoimmune (any type) component was diagnosed in 18%. We propose the term of "endocrine petrified ear" and a workflow algorithm to assess the potential hormonal/metabolic background in PE.

Neurological Diseases and Prevalence of Antineuronal Antibodies in Patients with Autoimmune Polyendocrine Syndrome Type 1 – A National Cohort Study

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare monogenic disease caused by mutations in the autoimmune regulator gene. Although the disease-associated autoantibodies mostly target endocrine organs, autoantibodies from patients with APS-1 bind also to rat brain structures. The patients often have GAD65-antibodies, that can cause autoimmune encephalitis. However, neurological manifestations of APS-1 have not been systematically explored. We conducted a retrospective chart review on 44 Finnish patients with APS-1 (median age 38 years, 61% females) and collected all their neurological diagnoses. To assess the prevalence of serum antineuronal antibodies in APS-1, serum samples of 24 patients (median age 36 years, 63% females) were analyzed using a fixed cell-based assay. Of the 44 APS-1 patients, 10 (23%) had also received a diagnosis of a neurological disease. Of these neurological comorbidities, migraine (n = 7; 16%), central nervous system infections (n = 3; 7%), and epilepsy (n = 2; 5%) were the most prevalent. Other diagnoses recorded for single patients were axonal sensorimotor polyneuropathy, essential tremor, idiopathic intracranial hypertension, ischemic stroke, and trigeminal neuralgia. Serum antineuronal antibodies were detected in 42% of patients tested (10/24, 50% females, median age 42 years), GAD65 antibodies being the most common finding. Antibodies against glycine and aquaporin 4 were found in low titers. In four patients, relatively high titers of GAD65 antibodies without coexisting type 1 diabetes were found, but none presented with GAD65-encephalitis. Our study suggests an association between APS-1 and neurological disorders, the mechanisms of which are to be further investigated.

A silent cause of shock: autoimmune polyglandular syndromes

Addison’s disease is a rare, autoimmune condition leading to the destruction of the adrenal gland. Autoimmune conditions are known to commonly co-occur. When Addison’s disease presents in the setting of autoimmune thyroid disease and/or type 1 diabetes, this condition is termed autoimmune polyendocrine syndrome type II, a rare endocrinopathy found in roughly 1.4-4.5 per 100,000 individuals. Here, we describe a clinical case presenting with hypotension refractory to fluid resuscitation and electrolyte derangements later diagnosed as autoimmune polyendocrine syndrome type II.

Addison's disease presented as a persistent hyperkaliemia in a patient with diabetic ketosis and autoimmune polyendocrine syndrome type 2 (APS-2). a case report and review of literature

Addison's disease presented as a persistent hyperkaliemia in a patient with diabetic ketosis and autoimmune polyendocrine syndrome type 2 (APS-2). a case report and review of literature

Update on autoimmune polyendocrine syndrome type-1 in Norway: Using longitudinal immune cell composition incorporated with clinical features

Update on autoimmune polyendocrine syndrome type-1 in Norway: Using longitudinal immune cell composition incorporated with clinical features

Exploring Chronic Hypocalcemia: Insights into Autoimmune Polyglandular Syndrome Type 1-A Case Study and Literature Review.

Hypocalcemia is a common occurrence in pediatric patients, attributed to various causes and presenting with diverse clinical manifestations. A prompt evaluation is necessary to determine its underlying cause, whether it presents acutely or chronically, and to tailor treatment based on its severity. Among the potential causes of chronic hypocalcemia, primary hypoparathyroidism stands out. The case of a seven-year-old male patient with hypocalcemia reported in this article serves as an illustration, wherein targeted next-generation sequencing revealed a homozygous p.R257X mutation in the AIRE gene, indicative of autoimmune polyendocrine syndrome type 1 (APS-1). It poses challenges due to its multisystemic nature and involvement of specific autoantibodies, often leading to underdiagnosis, owing to its rarity, varied manifestations, and incomplete penetrance. A comprehensive review of the APS-1 literature was conducted to provide insights into the clinical manifestations, genetic spectrum, potential immunological mechanisms, and current medical strategies. Additionally, the recognition of AIRE gene mutations is crucial for facilitating genetic diagnosis, prognosis, and potential treatment strategies for APS-1. The management of such cases involves individualized approaches to treatment, regular monitoring, medication adjustments, and the early identification of associated conditions.

Lessons from prospective longitudinal follow-up of a French APECED cohort.

APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.

Progressive Impairment of Prepubertal Growth in Children With APECED.

Subjects with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) have subnormal adult height. There are several potential APECED-related risk factors for suboptimal height attainment during childhood. To determine the growth patterns in children with APECED. Retrospective longitudinal study. The Finnish national APECED cohort. 59 children with APECED. Length/height and weight z-scores from birth to the end of prepuberty. Collectively, 59 children [30 (51%) girls] were included. Their median birth weight z-score (-0.60) was below the population average; 12 (20%) patients were born small for gestational age. Height attainment progressively declined from birth until the end of prepuberty (z-score -1.95), whereas weight-for-height z-score did not (+0.26). Of the 59 patients, 38 (64%) had all height z-scores below 0 during prepuberty, and seven (12%) had z-scores below -2.0. Age at the end of prepuberty, number of APECED manifestations, duration of glucocorticoid treatment, and growth hormone deficiency correlated negatively with height z-score at the end of prepuberty (p < 0.0001; p = 0.041; p = 0.013; p = 0.034, respectively). Children with APECED had a progressive growth impairment from birth through prepuberty. Multiple predisposing risk factors were recognized, including disease severity and growth hormone deficiency. Timely interventions are needed to ensure optimal height attainment and new treatment options need to be developed.

Interleukin (IL)-23, IL-31, and IL-33 Play a Role in the Course of Autoimmune Endocrine Diseases.

Interleukins (IL)-23, 31, and 33 are involved in the regulation of T helper 17 (Th17)/regulatory T (Treg) cells balance. The role of IL-23, 31 and 33 in non-endocrine autoimmune diseases has been confirmed. Data on the involvement of these cytokines in endocrine autoimmune diseases are limited. This study aimed to determine the involvement of cytokines regulating the T helper 17 (Th17)/regulatory T (Treg) cells axis in the course of autoimmune endocrine diseases. A total number of 80 participants were divided into 4 groups: the autoimmune polyendocrine syndrome (APS) group consisting of APS type 2 (APS-2) and type 3 (APS-3) subgroups, the Hashimoto's thyroiditis (HT) group, the Graves' disease (GD) group and the control (C) group. Fifteen cytokines related to Th17 and Treg lymphocytes were determined in the serum of all participants. Higher levels of IL-23 and IL-31 were found in the APS, GD, and HT groups compared to the C group. Higher levels of IL-23 and IL-31 were also observed in the APS-2 group, in contrast to the APS-3 group. Correlation analysis of variables in the groups showed a statistically significant correlation between the cytokines IL-23, IL-31, and IL-33 in the APS and APS-2 groups, but no correlation in the APS-3 and C groups. IL-23 and IL-31 are independent factors in the course of HT, GD, and APS-2, in contrast to APS-3. The positive correlation between IL-23 and IL-31, IL-23 and IL-33, and between IL-31 and IL-33 in the APS, APS-2 groups, but the lack of correlation in the APS-3 and C groups may further suggest the involvement of these cytokines in the course of Addison's disease.