scholarly journals Novel Pathogenic Variants of the AIRE Gene in Two Autoimmune Polyendocrine Syndrome Type I Cases with Atypical Presentation: Role of the NGS in Diagnostic Pathway and Review of the Literature

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 631
Author(s):  
Luigia Cinque ◽  
Cristina Angeletti ◽  
Alfredo Orrico ◽  
Stefano Castellana ◽  
Lucia Ferrito ◽  
...  
Keyword(s):  
Genetic Disorder ◽  
Molecular Defect ◽  
Type I ◽  
Atypical Presentation ◽  
Syndrome Type ◽  
Next Generation ◽  
Peripheral Tissues ◽  
Aire Gene ◽  
Pathogenic Variants ◽  
Autoimmune Polyendocrine Syndrome

Background. Autoimmune polyglandular syndrome type 1 (APS-1) with or without reversible metaphyseal dysplasia is a rare genetic disorder due to inactivating variants of the autoimmune regulator, AIRE, gene. Clinical variability of APS-1 relates to pleiotropy, and the general dysfunction of self-tolerance to organ-specific antigens and autoimmune reactions towards peripheral tissues caused by the underlying molecular defect. Thus, early recognition of the syndrome is often delayed, mostly in cases with atypical presentation, and the molecular confirm through the genetic analysis of the AIRE gene might be of great benefit. Methods. Our methods were to investigate, with a multigene panel next generation sequencing approach, two clinical cases, both presenting with idiopathic hypoparathyroidism, also comprising the AIRE gene; as well as to comment our findings as part of a more extensive review of literature data. Results. In the first clinical case, two compound heterozygote pathogenic variants of the AIRE gene were identified, thus indicating an autosomal recessive inheritance of the disease. In the second case, only one AIRE gene variant was found and an atypical dominant negative form of APS-1 suggested, later confirmed by further medical ascertainments. Conclusions. APS-1 might present with variable and sometimes monosymptomatic presentations and, if not recognized, might associate with severe complications. In this context, next generation diagnostics focused on a set of genes causative of partially overlapping disorders may allow early diagnosis.

scholarly journals Mutational analysis of the autoimmune regulator (AIRE) gene in sporadic autoimmune Addison's disease can reveal patients with unidentified autoimmune polyendocrine syndrome type I

2002 ◽  
pp. 519-522 ◽  
Author(s):  
AS Boe ◽  
PM Knappskog ◽  
AG Myhre ◽  
JI Sorheim ◽  
ES Husebye
Keyword(s):  
Mutational Analysis ◽  
Clinical Manifestations ◽  
Addison’S Disease ◽  
Addison's Disease ◽  
Common Mutation ◽  
Type I ◽  
Syndrome Type ◽  
Autoimmune Regulator ◽  
Aire Gene ◽  
Autoimmune Polyendocrine Syndrome

OBJECTIVE: To investigate whether patients with Addison's disease and polyendocrine syndromes have undiagnosed autoimmune polyendocrine syndrome type I (APS I). MATERIALS AND METHODS: Forty patients with clinical manifestations resembling APS I and with autoantibodies typical of this condition were screened for Norwegian autoimmune regulator (AIRE) gene mutations. RESULTS: A 30-year old man who had developed Addison' s disease at the age of 12, but had no other components of APS I, was homozygous for the 1094-1106 deletion mutation in exon 8 of the AIRE gene, the most common mutation found in Norway. CONCLUSIONS: APS I patients with milder and atypical phenotypes are difficult to diagnose on clinical grounds. Autoantibody analysis and mutational analysis of AIRE may therefore be helpful modalities for identifying these individuals.

scholarly journals The Transcription Factors SOX9 and SOX10 Are Vitiligo Autoantigens in Autoimmune Polyendocrine Syndrome Type I

2001 ◽  
Vol 276 (38) ◽  
pp. 35390-35395 ◽  
Author(s):  
Håkan Hedstrand ◽  
Olov Ekwall ◽  
Mats J. Olsson ◽  
Eva Landgren ◽  
E. Helen Kemp ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Type I ◽  
Syndrome Type ◽  
Autoimmune Polyendocrine Syndrome

scholarly journals Transcriptional Changes in Regulatory T Cells From Patients With Autoimmune Polyendocrine Syndrome Type 1 Suggest Functional Impairment of Lipid Metabolism and Gut Homing

2021 ◽  
Vol 12 ◽  
Author(s):  
Amund Holte Berger ◽  
Eirik Bratland ◽  
Thea Sjøgren ◽  
Marte Heimli ◽  
Torgeir Tyssedal ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Type I ◽  
Syndrome Type ◽  
Functional Studies ◽  
Autoimmune Polyendocrine Syndrome ◽  
Organ Specific ◽  
Hla Dqa1 ◽  
And Function ◽  
The Impact

Autoimmune polyendocrine syndrome type I (APS-1) is a monogenic model disorder of organ-specific autoimmunity caused by mutations in the Autoimmune regulator (AIRE) gene. AIRE facilitates the expression of organ-specific transcripts in the thymus, which is essential for efficient removal of dangerous self-reacting T cells and for inducing regulatory T cells (Tregs). Although reduced numbers and function of Tregs have been reported in APS-I patients, the impact of AIRE deficiency on gene expression in these cells is unknown. Here, we report for the first time on global transcriptional patterns of isolated Tregs from APS-1 patients compared to healthy subjects. Overall, we found few differences between the groups, although deviant expression was observed for the genes TMEM39B, SKIDA1, TLN2, GPR15, FASN, BCAR1, HLA-DQA1, HLA-DQB1, HLA-DRA, GPSM3 and AKR1C3. Of significant interest, the consistent downregulation of GPR15 may indicate failure of Treg gut homing which could be of relevance for the gastrointestinal manifestations commonly seen in APS-1. Upregulated FASN expression in APS-1 Tregs points to increased metabolic activity suggesting a putative link to faulty Treg function. Functional studies are needed to determine the significance of these findings for the immunopathogenesis of APS-1 and for Treg immunobiology in general.

scholarly journals Autoimmune polyendocrine syndrome type I in Slovakia: relevance of screening patients with autoimmune Addison's disease

2008 ◽  
Vol 158 (5) ◽  
pp. 705-709 ◽  
Author(s):  
Ng'weina F. Magitta ◽  
Mikuláš Pura ◽  
Anette S Bøe Wolff ◽  
Peter Vanuga ◽  
Anthony Meager ◽  
...  
Keyword(s):  
Addison’S Disease ◽  
Monogenic Disease ◽  
Adrenal Crisis ◽  
Addison's Disease ◽  
Type I ◽  
Syndrome Type ◽  
Exon 2 ◽  
Clinical Criteria ◽  
Autoimmune Polyendocrine Syndrome ◽  
Major Mutation

BackgroundAutoimmune polyendocrine syndrome type I (APS I) is a monogenic disease affecting endocrine glands and other organs due to mutations of the autoimmune regulator (AIRE) gene. There is a wide variability in clinical phenotypes in patients with APS I, which makes the diagnosis a challenge.ObjectiveTo screen for APS I among Slovakian patients with sporadic Addison's disease and clinical features that raised the suspicion of APS I.MethodsAll 14 exons and exon–intron boundaries of the AIRE gene were sequenced. In addition, autoantibodies specific for Addison's disease and polyendocrine syndromes were assayed.ResultsUsing clinical criteria we identified four patients with APS I in three families. Two patients had a novel missense mutation in exon 2 (c.274C>T, p.R92W) and either the Finnish major mutation (c.769C>T) or the common 13 bp deletion (c.967–979del13bp). APS I was diagnosed in a brother of the latter after his death due to an adrenal crisis. A fourth patient had primary adrenal failure and hypoparathyroidism without AIRE mutations or APS-I specific autoantibodies.ConclusionsFour patients with APS I were found in a Slovakian cohort of Addison patients, although the lack of detectable AIRE mutations and APS I-specific autoantibodies raises uncertainty regarding the pathogenesis in one of the patients. This study demonstrates the merits of screening patients with phenotypic features or autoantibody findings that could indicate APS I, even in adult patients. It is necessary to identify APS I patients in order to provide appropriate treatment and follow-up of the various components of APS I.

scholarly journals Activating Autoantibodies against the Calcium-Sensing Receptor Detected in Two Patients with Autoimmune Polyendocrine Syndrome Type 1

2009 ◽  
Vol 94 (12) ◽  
pp. 4749-4756 ◽  
Author(s):  
E. Helen Kemp ◽  
Nikos G. Gavalas ◽  
Kai J. E. Krohn ◽  
Edward M. Brown ◽  
Philip F. Watson ◽  
...  
Keyword(s):  
Inositol Phosphate ◽  
Autosomal Recessive Disorder ◽  
Syndrome Type ◽  
Calcium Sensing Receptor ◽  
Autoimmune Reaction ◽  
Aire Gene ◽  
Calcium Sensing ◽  
Autoimmune Polyendocrine Syndrome ◽  
Activating Autoantibodies

Context: Autoimmune polyendocrine syndrome type 1 (APS1) is an autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Hypoparathyroidism occurs in 80% of patients with APS1 and has been suggested to result from an autoimmune reaction against the calcium-sensing receptor (CaSR) in parathyroid cells. Anti-CaSR binding antibodies have previously been detected in patients with APS1. Objective: The aim of this study was to determine whether anti-CaSR antibodies present in APS1 patients could modulate the response of the CaSR to stimulation by Ca2+. Results: The results indicated that two of the 14 APS1 patients included in the study had anti-CaSR antibodies that stimulated the receptor. These antibodies were detected by their ability to increase both Ca2+-dependent extracellular signal-regulated kinase phosphorylation and inositol phosphate accumulation in human embryonic kidney 293 cells expressing the CaSR. Conclusion: An important implication of the present results is that although the majority of APS1 patients do not have CaSR-stimulating antibodies, there may be a small but substantial minority of patients in whom the hypoparathyroid state is the result of functional suppression of the parathyroid glands rather than their irreversible destruction.

scholarly journals Genetic analyses of the NF1 gene in Turkish neurofibromatosis type I patients and definition of three novel variants

2017 ◽  
Vol 20 (1) ◽  
pp. 13-20 ◽  
Author(s):  
SD Ulusal ◽  
H Gürkan ◽  
E Atlı ◽  
SA Özal ◽  
M Çiftdemir ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Diagnosis ◽  
Neurofibromatosis Type ◽  
Type I ◽  
Neurofibromatosis Type I ◽  
Next Generation ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Nf1 Gene ◽  
Generation Sequencing

Abstract Neurofibromatosis Type I (NF1) is a multi systemic autosomal dominant neurocutaneous disorder predisposing patients to have benign and/or malignant lesions predominantly of the skin, nervous system and bone. Loss of function mutations or deletions of the NF1 gene is responsible for NF1 disease. Involvement of various pathogenic variants, the size of the gene and presence of pseudogenes makes it difficult to analyze. We aimed to report the results of 2 years of multiplex ligation-dependent probe amplification (MLPA) and next generation sequencing (NGS) for genetic diagnosis of NF1 applied at our genetic diagnosis center. The MLPA, semiconductor sequencing and Sanger sequencing were performed in genomic DNA samples from 24 unrelated patients and their affected family members referred to our center suspected of having NF1. In total, three novel and 12 known pathogenic variants and a whole gene deletion were determined. We suggest that next generation sequencing is a practical tool for genetic analysis of NF1. Deletion/duplication analysis with MLPA may also be helpful for patients clinically diagnosed to carry NF1 but do not have a detectable mutation in NGS.

Psoriasis vulgaris and autoimmune polyendocrine syndrome type I: a case report

2014 ◽  
Vol 27 (7-8) ◽  
Author(s):  
Atilla Cayir ◽  
Ragıp Ismail Engin ◽  
Mehmet Ibrahim Turan ◽  
Erdal Pala
Keyword(s):  
Case Report ◽  
Psoriasis Vulgaris ◽  
Type I ◽  
Syndrome Type ◽  
Autoimmune Polyendocrine Syndrome

scholarly journals Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I

2010 ◽  
Vol 207 (2) ◽  
pp. 291-297 ◽  
Author(s):  
Anne Puel ◽  
Rainer Döffinger ◽  
Angels Natividad ◽  
Maya Chrabieh ◽  
Gabriela Barcenas-Morales ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Chronic Mucocutaneous Candidiasis ◽  
Type I ◽  
Syndrome Type ◽  
Mucocutaneous Candidiasis ◽  
Autoimmune Polyendocrine Syndrome ◽  
Clinical Syndromes ◽  
Macrophage Colony ◽  
Factor Α

Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs against cytokines previously shown to cause other well-defined clinical syndromes in other patients (IL-6, interferon [IFN]-γ, or granulocyte/macrophage colony-stimulating factor) or against other cytokines (IL-1β, IL-10, IL-12, IL-18, IL-21, IL-23, IL-26, IFN-β, tumor necrosis factor [α], or transforming growth factor β). These findings suggest that auto-Abs against IL-17A, IL-17F, and IL-22 may cause CMC in patients with APS-I.

scholarly journals Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

2021 ◽  
Vol 218 (7) ◽  
Author(s):  
Paul Bastard ◽  
Elizaveta Orlova ◽  
Leila Sozaeva ◽  
Romain Lévy ◽  
Alyssa James ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Type I Interferons ◽  
Type I ◽  
Syndrome Type ◽  
Loss Of Function ◽  
Type I Ifns ◽  
Autoimmune Polyendocrine Syndrome ◽  
Life Threatening ◽  
Very High

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

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