An uncommon presentation of autoimmune polyglandular syndrome type 1 (APS-1)-A case report.

Key Clinical Message: Autoimmune polyglandular syndrome type 1 (APS-1) is a rare disorder defined by the presence of at least two of the following conditions: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism, and Addison's syndrome. Despite the lack of CMC and autoimmune history, APS-1 can be diagnosed using genetic testing.We present the case of a 28-year-old female patient with a history of hypocalcemia due to hypoparathyroidism since the age of 2 years. She presented to the endocrine clinic with hypogonadism, primary amenorrhea, and primary ovarian insufficiency. Addison's disease was eventually diagnosed, despite a negative Synacthen test. The adrenal crisis required intravenous hydrocortisone therapy. No CMC was documented, and there was no family history of such conditions. The diagnosis of APS-1 was confirmed by genetic testing, revealing homozygous pathogenic variants of the autoimmune regulator gene. Management included oral calcium and calcitriol and oral hydrocortisone and fludrocortisone for Addison's disease. Hormonal induction of secondary sexual characteristics was initiated. The patient received combined oral estrogen and progesterone pills. This case highlights the critical significance of early recognition, thorough evaluation, and tailored treatment for patients with APS-1 to enhance their quality of life and mitigate potentially life-threatening complications. This underscores the importance of screening for associated minor autoimmune diseases as part of a holistic approach to care.

Novel homozygous mutations in AIRE leading to APS-1 and potential mechanisms based on bioinformatics analysis.

Background: Autoimmune Poly-endocrine Syndrome Type 1 (APS-1), also known as autoimmune poly-endocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a single-gene hereditary disorder usually characterized by chronic mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenocortical insufficiency. This syndrome is very rare in China. Methods: For our reported patient, we employed clinical and laboratory examinations along with genetic identification. For previously reported cases, we summarized findings based on meta-analysis principles. To investigate the AIRE gene's role in disease, we utilized bioinformatics analysis with existing databases and R language processing. Results: Nucleotide sequence analysis revealed two novel homozygous missense mutations (c.74C > G; c.1612C > T) in the patient's AIRE gene, confirming APS-1 diagnosis. The 3D structure of these mutation sites was described for the first time, showing that altered side chains could affect AIRE protein function. We analyzed 16 genetically diagnosed APS-1 Chinese patients, summarized the AIRE genetic spectrum, and found that exons 1, 2, 3, and 5 were most commonly affected. Hypoparathyroidism and adrenal insufficiency were the most common clinical manifestations (56%-93%), followed by hypothyroidism (31.25%), hypogonadism (12.5%), type 2 diabetes (6.25%), and type 1 diabetes (6.25%). Bioinformatics analysis indicated that AIRE mutations cause antigen presentation abnormalities in immune cells, leading to excessive endogenous and reduced exogenous antigen presentation. Conclusions: Our study summarized the clinical features of APS-1 caused by AIRE gene mutations and explored underlying mechanisms. For some patients, the prophylactic use of antimicrobial agents may be beneficial. These findings guide early genetic screening and inform potential research directions for treatment strategies.

Novel Insights into the Autoimmunity from the Genetic Approach of the Human Disease.

Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic inborn error of autoimmunity that is caused by damaging germline variants in the AIRE gene and clinically manifests with multiple autoimmune diseases in patients. Studies on the function of the AIRE gene, discovered in 1997, have contributed to fundamental aspects of human immunology as they have been important in understanding the basic mechanism of immune balance between self and non-self. This chapter looks back to the discovery of the AIRE gene, reviews its main properties, and discusses the key findings of its function in the thymus. However, more recent autoantibody profilings in APECED patients have highlighted a gap in our knowledge of the disease pathology and point to the need to revisit the current paradigm of AIRE function. The chapter reviews these new findings in APECED patients, which potentially trigger new thoughts on the mechanism of immune tolerance.

Analysis of the AIRE Gene Promoter in Patients Affected by Autoimmune Polyendocrine Syndromes.

Autoimmune polyglandular syndromes (APS) are classified into four main categories, APS1-APS4. APS1 is caused by AIRE gene loss of function mutations, while the genetic background of the other APS remains to be clarified. Here, we investigated the potential association between AIRE gene promoter Single Nucleotide Polymorphisms (SNPs) and susceptibility to APS. We sequenced the AIRE gene promoter of 74 APS patients, also analyzing their clinical and autoantibody profile, and we further conducted molecular modeling studies on the identified SNPs. Overall, we found 6 SNPs (-230Y, -655R, -261M, -380S, -191M, -402S) of the AIRE promoter in patients' DNA. Interestingly, folding free energy calculations highlighted that all identified SNPs, except for -261M, modify the stability of the nucleic acid structure. A rather similar percentage of APS3 and APS4 patients had polymorphisms in the AIRE promoter. Conversely, there was no association between APS2 and AIRE promoter polymorphisms. Further AIRE promoter SNPs were found in 4 out of 5 patients with APS1 clinical diagnosis that did not harbor AIRE loss of function mutations. We hypothesize that AIRE promoter polymorphisms could contribute to APS predisposition, although this should be validated through genetic screening in larger patient cohorts and in vitro and in vivo functional studies.

Thymus as Incontrovertible Target of Future Immune Modulatory Therapeutics.

Thymus plays a crucial role in cellular immunity by acting as a warehouse for proliferating and differentiating lymphocytes. Thymic stromal cells educate T-cells to differentiate self from non-self antigens while nurse cells and thymoproteasome play a major role in the maturation and differentiation of T-cells. The thymic conditions dictate T-cells to cope with the risk of cancer development. A study was designed to demonstrate potential mechanisms behind the failure to eliminate tumors and impaired immune surveillance as well as the impact of delay in thymus regression on cancer and autoimmune disorders. Scientific literature from Pubmed; Scopus; WOS; JSTOR; National Library of Medicine Bethesda, Maryland; The New York Academy of Medicine; Library of Speech Rehabilitation, NY; St. Thomas' Hospital Library; The Wills Library of Guys Hospital; Repository of Kings College London; and Oxford Academic repository was explored for pathological, physiological, immunological and toxicological studies of thymus. Studies have shown that systemic chemotherapy may lead to micro inflammatory environment within thymus where conventionally and dynamically metastasized dormant cells seek refuge. The malfunctioning of the thymus and defective T and Treg cells, bypassing negative selection, contributes to autoimmune disorders, while AIRE and Fezf2 play significant roles in thymic epithelial cell solidity. Different vitamins, TCM, and live cell therapy are effective therapeutics. Vitamin A, C, D, and E, selenium and zinc, cinobufagin and dietary polysaccharides, and glandular extracts and live cell injections have strong potential to restore immune system function and thymus health. Moreover, the relationship between different ages/stages of thymus and their corresponding T-cell mediated anti-tumor immune response needs further exploration.

Identification of AIRE pathogenic variants ends diagnostic odyssey for Saudi child with infantile-onset keratoconjunctivitis as an early sign of autoimmune polyglandular syndrome type1; a case report.

PURPOSE: Chronic keratoconjunctivitis is a rare presentation of autoimmune polyglandular syndrome type 1 (APS-1) during the first year of life. Herein, We report a case of a 10-month-old baby girl with chronic bilateral keratoconjunctivitis, corneal scarring and neovascularization that was treated initially with topical immunosuppressants. METHODS: Detailed ophthalmological assessment followed by molecular testing using whole exome sequencing. RESULTS: In addition to the severe chronic bilateral keratoconjunctivitis, corneal scarring and neovascularization, patient weight was found to be low than 10th percentile. Further genetic testing revealed autoimmune regulator (AIRE) gene variant that was only reported once in the literature confirming the diagnosis of APS-1. Further workup detected hypoparathyroidism that was treated with calcium supplementation. CONCLUSION: Our case represents the importance of multidisciplinary services and highlights the role of genetic testing in diagnosing such syndromic cases. We reviewed previous reports and found that available treatment for ocular involvement is usually nonsatisfactory; however, early detection and referral by ophthalmologists could result in treating previously undetected endocrine disorders that can be life threatening if left untreated.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy-Associated Hepatitis.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inborn error of immunity, resulting from variation in the autoimmune regulator gene (AIRE). Pathogenic variants in the AIRE gene result in autoimmunity typically involving endocrine organs with nonendocrine organs less commonly affected. Hepatitis associated with APECED has emerged as a potentially fatal complication with higher reported prevalence in the Americas. We describe a case of a 3-year-old boy presenting with hepatitis from APECED without classical clinical diagnostic criteria. This case highlights the importance of APECED in the evaluation of hepatitis given response to immunomodulator treatment and risk of fulminate liver failure.

Leber congenital amaurosis as the initial and essential manifestation in a Chinese patient with autoimmune polyglandular syndrome Type 1.

PURPOSE: Autoimmune polyglandular syndrome Type 1 (APS-1) is a rare autosomal recessive disorder caused by defects in the autoimmune regulator (AIRE) gene. Patients are generally diagnosed at ages between five and fifteen years when they exhibit three or more manifestations, most typically mucocutaneous candidiasis, autoimmune Addison's disease, and hypoparathyroidism. Our study aims to report the first case of a Chinese APS-1 patient, presented with LCA as the initial and essential clinical feature of this rare syndrome. METHODS: Detailed medical and family history were recorded for the patient. Also, the comprehensive ophthalmological examinations were conducted. Whole exome sequencing (WES) was applied to screen pathogenic variants. Sanger sequencing validation and segregation analysis were further performed for confirmation. RESULTS: A 3-year-old boy with severely impaired vision and initially referred as LCA. However, with a detailed history review, oral candidiasis, dental enamel hypoplasia, and nail candida infection were revealed. Moreover, genetic analysis revealed the homozygous c.769C>T (p.R257X) in AIRE gene (NM_000383.3) as the causative variant. CONCLUSION: We presented one case diagnosed with APS-1 based on clinical characteristics and genetic analysis. Our study demonstrated that LCA could serve as a warning sign for APS-1 and a potential trigger of early screening, which might prevent life-threatening complications.

Left Ventricular Systolic Dysfunction Related to Adrenal Insufficiency in a Case due to Autoimmune Polyendocrine Syndrome Type 1 with a Novel Variant.

Introduction: Primary adrenal insufficiency associated with cardiomyopathy has been rarely reported in children. We report a case of left ventricular (LV) systolic dysfunction related to adrenal insufficiency with autoimmune polyendocrine syndrome type 1 (APS1). Case Presentation: A 7-year-old girl presented with a loss of consciousness. She had hyperpigmentation over joints and enamel hypoplasia. Laboratory tests showed hypoglycemia, hyponatremia, hypocalcemia, and hyperphosphatemia. Endocrine evaluations revealed low serum parathyroid hormone, low cortisol, and high ACTH. Echocardiography showed moderate to severe mitral regurgitation and LV systolic dysfunction. Serum pro-brain natriuretic peptide (pro-BNP) level was high (2,348 pg/mL). Adrenal insufficiency, hypoparathyroidism, and enamel dysplasia suggested APS1. A novel homozygous variant in the AIRE gene, NM_000383, p.Cys322Arg (c.964T>C) confirmed the diagnosis. Calcium, calcitriol, and hydrocortisone treatments were started. Serum pro-BNP level returned to normal, and LV systolic function improved. Conclusion: Here, we present a case of adrenal insufficiency and hypoparathyroidism associated with LV systolic dysfunction whose cardiac findings improved completely with hydrocortisone and calcitriol treatments. Our case is the second reported case of APS1 presenting with LV dysfunction.

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

Autoimmune diseases are a heterogeneous group of disorders of the immune system. They can cluster in the same individual, revealing various preferential associations for polyendocrine autoimmune syndromes. Clinical observation, together with advances in genetics and the understanding of pathophysiological processes, has further highlighted that autoimmunity can be associated with immunodeficiency; autoimmunity may even be the first primary immunodeficiency manifestation. Analysis of susceptibility genes for the development of these complex phenotypes is a fundamental issue. In this manuscript, we revised the clinical and immunologic features and the presence of AIRE gene variations in a cohort of 48 patients affected by high polyautoimmunity complexity, i.e., APECED-like conditions, also including patients affected by primary immunodeficiency. Our results evidenced a significant association of the S278R polymorphism of the AIRE gene with APECED-like conditions, including both patients affected by autoimmunity and immunodeficiency and patients with polyautoimmunity compared to healthy controls. A trend of association was also observed with the IVS9+6 G>A polymorphism. The results of this genetic analysis emphasize the need to look for additional genetic determinants playing in concert with AIRE polymorphisms. This will help to improve the diagnostic workup and ensure a precision medicine approach to targeted therapies in APECED-like patients.

Autoimmune polyendocrine syndrome type 1: Clinical manifestations, pathogenetic features, and management approach.

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive hereditary pathology that develops with endocrine and non-endocrine manifestations in childhood. The classic triad of APS-1 includes chronic candidiasis of the skin and mucous membranes, adrenal insufficiency, and hypoparathyroidism. APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis. The prevalence rate is highest in genetically isolated populations (up to 1:6500-1:9000). APS-1 occurs because of mutations in the autoimmune regulator (AIRE) gene, leading to a disrupted mechanism of normal antigen expression, the formation of abnormal clones of immune cells, and autoimmune damage to various organs. Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1 and the choice of methods for its treatment. Timely genetic counseling makes it possible to identify the disease early, prescribe appropriate treatment and prevent serious complications. This paper analyzes scientific information characterizing clinical manifestations of autoimmune polyendocrine syndrome type 1 in association with its pathogenetic features, epidemiology, and current management.

The absence of the autoimmune regulator gene (AIRE) impairs the three-dimensional structure of medullary thymic epithelial cell spheroids.

BACKGROUND: Besides controlling the expression of peripheral tissue antigens, the autoimmune regulator (AIRE) gene also regulates the expression of adhesion genes in medullary thymic epithelial cells (mTECs), an essential process for mTEC-thymocyte interaction for triggering the negative selection in the thymus. For these processes to occur, it is necessary that the medulla compartment forms an adequate three-dimensional (3D) architecture, preserving the thymic medulla. Previous studies have shown that AIRE knockout (KO) mice have a small and disorganized thymic medulla; however, whether AIRE influences the mTEC-mTEC interaction in the maintenance of the 3D structure has been little explored. Considering that AIRE controls cell adhesion genes, we hypothesized that this gene affects 3D mTEC-mTEC interaction. To test this, we constructed an in vitro model system for mTEC spheroid formation, in which cells adhere to each other, establishing a 3D structure. RESULTS: The comparisons between AIRE wild type (AIREWT) and AIRE KO (AIRE-/-) 3D mTEC spheroid formation showed that the absence of AIRE: i) disorganizes the 3D structure of mTEC spheroids, ii) increases the proportion of cells at the G0/G1 phase of the cell cycle, iii) increases the rate of mTEC apoptosis, iv) decreases the strength of mTEC-mTEC adhesion, v) promotes a differential regulation of mTEC classical surface markers, and vi) modulates genes encoding adhesion and other molecules. CONCLUSIONS: Overall, the results show that AIRE influences the 3D structuring of mTECs when these cells begin the spheroid formation through controlling cell adhesion genes.

Autoimmune regulator act in synergism with thymocyte adhesion in the control of lncRNAs in medullary thymic epithelial cells.

The autoimmune regulator (Aire) gene in medullary thymic epithelial cells (mTECs) encodes the AIRE protein, which interacts with its partners within the nucleus. This "Aire complex" induces stalled RNA Pol II on chromatin to proceed with transcription elongation of a large set of messenger RNAs and microRNAs. Considering that RNA Pol II also transcribes long noncoding RNAs (lncRNAs), we hypothesized that Aire might be implicated in the upstream control of this RNA species. To test this, we employed a loss-of-function approach in which Aire knockout mTECs were compared to Aire wild-type mTECs for lncRNA transcriptional profiling both in vitro and in vivo model systems. RNA sequencing enables the differential expression profiling of lncRNAs when these cells adhere in vitro to thymocytes or do not adhere to them as a way to test the effect of cell adhesion. Sets of lncRNAs that are unique and that are shared in vitro and in vivo were identified. Among these, we found the Aire-dependent lncRNAs as for example, Platr28, Ifi30, Morrbid, Malat1, and Xist. This finding represents the first evidence that Aire mediates the transcription of lncRNAs in mTECs. Microarray hybridizations enabled us to observe that temporal thymocyte adhesion modulates the expression levels of such lncRNAs as Morrbid, Xist, and Fbxl12o after 36 h of adhesion. This finding shows the existence of a synergistic mechanism involving a link between thymocyte adhesion, Aire, and lncRNAs in mTECs that might be important for immune self-representation.

Characterization of the clinical and genetic spectrum of autoimmune polyendocrine syndrome type 1 in Chinese case series.

BACKGROUND: Autoimmune polyendocrine syndrome type 1 (APS1) is a hereditary disease caused by mutations in the AIRE gene with both endocrine and non-endocrine organ involvement. The existing data from China are limited, and this study aims to describe the phenotypes and genetic characterization in Chinese APS1 patients. In this single-center, retrospective, observational study, comprehensive endocrine and extra-endocrine manifestations were collected, and genetic analysis in AIRE was conducted in patients with APS1 between the years of 1984 and 2018 at Peking Union Medical College Hospital. RESULTS: In total, 13 patients from 12 unrelated families were enrolled, seven of whom were female, with hypoparathyroidism, chronic mucocutaneous candidiasis, and Addison's disease being the most frequently observed manifestations. Up to 84.7% presented with two or three of the above-mentioned manifestations, and nearly 4.9 ± 1.8 components presented in patients aged 21.2 ± 7.9 years old. Several less common phenotypes, such as myeloproliferative disease, pure red cell aplasia, renal tubular acidosis, asplenia, autoimmune hepatitis, and ankylosing spondylitis, were also observed in patients. Altogether, seven different AIRE mutations were found in six patients, four of which (K161fs, G208V, A246fs, and L308F) had not been previously reported in patients with APS1. CONCLUSION: We have provided a comprehensive profile of Chinese patients with APS1, with less commonly observed features being observed in addition to more regularly seen manifestations. Additionally, different AIRE mutations that were observed have expanded the genetic spectrum, which will help with future understanding of the molecular pathogenesis of APS1.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy in Two Siblings: Same Mutations but Very Different Phenotypes.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype-phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated.

Acquired pure red cell aplasia and T cell large granular lymphocytic leukaemia in patients with autoimmune polyglandular syndrome type 1.

BACKGROUND: Pure red cell aplasia (PRCA) and large granular lymphocytic leukaemia (LGLL) are very rare complications of autoimmune polyendocrine syndrome type 1 (APS1). Here, we report a case of APS1 with PRCA and LGLL. Previous cases were reviewed, and possible mechanisms are discussed. CASE PRESENTATION: A 31-year-old female presented with anaemia and was diagnosed with PRCA in our centre. She also had hypoparathyroidism for 24 years, premature ovarian failure for 10 years, osteoporosis for 5 years, recurrent pneumonia with bronchiectasis for 4 years and chronic diarrhoea for 1 year. Boosted whole-exome analysis showed AIRE heterozygous mutations, confirming the diagnosis as APS1. LGLL was diagnosed during follow-up. The PRCA responded well to glucocorticoid. treatment CONCLUSION: AIRE is causally related to the development of LGLL and consequent PRCA, which may be due to some immunological mechanisms.

Novel mutation in AIRE gene with autoimmune polyendocrine syndrome type 1.

PURPOSE: Autoimmune polyendocrine type 1 (APS-1) is a complex inherited autosomal recessive disorder. Classically, it appears within the first decade of life followed by adrenocortical insufficiency, mucocutaneous candidiasis, Addison's disease, and hypoparathyroidism. The clinical phenotype of APS-1 varies depending upon mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. METHODS: In this study, we performed Sanger sequencing ofAIRE in Iranian patients to identify different variants and probable new mutations corresponding to a clinical diagnosis of APS-1. RESULTS: After analyzing 14AIRE exons, we detected a novel insertion mutation in exon 2 in a patient who presented with severe APS-1, Lys50AsnfsX168. Furthermore, the known mutations in AIRE, including Arg139X, Arg257X, and Leu323SerfsX51, were detected in enrolled patients. DISCUSSION: According to our results, sequencing analysis ofAIRE provides a useful screening method to diagnose patients with incomplete or unusual clinical presentations of APS-1.

Autoimmune Polyglandular Syndrome Type 1: a case report.

BACKGROUND: Mutations of the autoimmune regulator gene (AIRE), located on chromosome 21q22.3, are recognized as the cause of a rare monogenic organ-specific autoimmune disorder called autoimmune polyglandular syndrome type 1 (APS-1). Three major components of this syndrome include chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenocortical failure. CASE PRESENTATION: We report a 19-year-old girl, who was born in an Iranian Muslim family with a clinical diagnosis of APS-1. To identify the causative mutation, a direct sequencing of the entire AIRE gene sequence was performed by Sanger sequencing method. Three distinct variants were discovered, including c.1095 + 2 T > A, c.1197 T > C (rs1800521) and c.1578 T > C (rs1133779), in intron 9, exons 10 and 14 of the AIRE gene, respectively. CONCLUSIONS: To the best of our knowledge, this is the first report of an Iranian Muslim APS-1 patient with combination of these variations. In addition, the effect of c.1095 + 2 T > A mutation on AIRE mRNA expression was reported for the first time. This study expands the diversity of variants that could cause APS-1. More genetic studies are required to determine the exact frequency of these variants and their diagnostic significance.

Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1.

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.