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Autoimmune polyendocrine syndrome type 1 (APECED) is a rare autosomal recessive disorder characterized by autoimmune multiorgan attack. The disease is caused by mutations in the autoimmune regulator gene (AIRE), resulting in defective AIRE protein, which is essential for selftolerance. Clinical manifestations are widely variable. Although the class...
Citations
... 3,4 AIRE can eliminate autoreactive T cells by controlling the expression of several tissue-specific antigens in medullary thymic epithelial cells and drive regulatory T cell production to maintain central immunological tolerance. 5,6 As a result, various autoimmune disorders arise at a young age. 7,8 Primary ovarian insufficiency (POI) affects approximately 60% of APS-1 women before the age of 30 years. ...
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.
... Further studies revealed that p.Val301Met alteration strongly reduced AIRE target gene activation in vivo generating clear differences in AIRE interactome compared to the wild-type protein [57]. The detected p.Thr441Met missense variant was suggested to be probably damaging by a previous functional study [22]. ...
Background
Premature ovarian insuffiency (POI) is one of the main cause behind infertility. The genetic analysis of POI should be part of the clinical diagnostics, as several genes have been implicated in the genetic background of it. The aim of our study was to analyse the genetic background of POI in a Hungarian cohort.
Methods
The age of onset was between 15 and 39 years. All patients had the 46,XX karyotype and they were prescreened for the most frequent POI associated FMR1 premutation. To identify genetic alterations next-generation sequencing (NGS) of 31 genes which were previously associated to POI were carried out in 48 unrelated patients from Hungary.
Results
Monogenic defect was identified in 16.7% (8 of 48) and a potential genetic risk factor was found in 29.2% (14 of 48) and susceptible oligogenic effect was described in 12.5% (6 of 48) of women with POI using the customized targeted panel sequencing. The genetic analysis identified 8 heterozygous damaging and 4 potentially damaging variants in POI-associated genes. Further 10 potential genetic risk factors were detected in seven genes, from which EIF2B and GALT were the most frequent. These variants were related to 15 genes: AIRE, ATM, DACH2, DAZL, EIF2B2, EIF2B4, FMR1, GALT, GDF9, HS6ST2, LHCGR, NOBOX, POLG, USP9X and XPNPEP2. In six cases, two or three coexisting damaging mutations and risk variants were identified.
Conclusions
POI is characterized by heterogenous phenotypic features with complex genetic background that contains increasing number of genes. Deleterious variants, which were detected in our cohort, related to gonadal development (oogenesis and folliculogenesis), meiosis and DNA repair, hormonal signaling, immune function, and metabolism which were previously associated with the POI phenotype. This is the first genetic epidemiology study targeting POI associated genes in Hungary. The frequency of variants in different POI associated genes were similar to the literature, except EIF2B and GALT. Both of these genes potential risk factor were detected which could influence the phenotype, although it is unlikely that they can be responsible for the development of the disease by themselves. Advances of sequencing technologies make it possible to aid diagnostics of POI Since individual patients show high phenotypic variance because of the complex network controlling human folliculogenesis. Comprehensive NGS screening by widening the scope to genes which were previously linked to infertility may facilitate more accurate, quicker and cheaper genetic diagnoses for POI. The investigation of patient’s genotype could support clinical decision-making process and pave the way for future clinical trials and therapies.
... CMC, except in Persian Jews, is the most common and the first presenting component, typically developing in infancy or early childhood (11). However, in a study of 23 Persian Jews (12), only four patients presented with CMC. The median age of onset for CMC was 3 years (range 0.0833 years). ...
Autoimmune polyendocrine syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic autosomal recessive autoimmune disease. It is caused by mutations in the autoimmune regulator (AIRE) gene. APS-1 is diagnosed clinically by the presence of two of the three major components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenocortical insufficiency. A 3.3-year-old girl was presented with a carpopedal spasm to the pediatric emergency clinic. She had a history of recurrent keratitis, and chronic candidiasis as urinary tract infections and oral thrashes. Hypoparathyroidism (HPT) was diagnosed based on low serum concentrations of calcium and parathyroid hormone and elevated serum concentrations of phosphate, and treatment with calcium and calcitriol supplementation was started. Genetic testing revealed homozygosity for nonsense c.769C>T (p.R257X) mutation in exon 6 in the AIRE gene which was reported previously. At the age of 5.6 years, she was presented with an adrenal crisis, and treatment with hydrocortisone and fludrocortisone was started. The reported case highlights that unexplained chronic keratitis in children may be the first and most severe component of this syndrome. The classic triad of APS-1 may also appear in the first decade of life.
... Diagnosis is based on biochemical measurements, and patients present with numbness around the mouth, hands, or feet, seizures, low blood pressure, and coarse or brittle hair. 14,15 Periodic measurement of calcium and intact parathyroid hormone levels should be conducted to prevent unsuspected acute hypocalcemic seizures and/or tetany. 16 Addison's disease or adrenal insufficiency usually presents by the age of 12 years, and patients present with fatigue, weight loss, hypotension, abdominal pain, and increased pigmentation of the oral mucosa and skin. ...
... 12 Other autoimmune disorders reported in the literature include autoimmune hepatitis, alopecia, keratoconjunctivitis, and rheumatologic, bony, muscular, renal, and hematologic impairments. 15 A more detailed list is given in Table 1. ...
Aim:
To report a unique case of Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a young boy and discuss the oral health impact and management of the disease.
Background:
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autoimmune disorder with various clinical manifestations. Biallelic mutations in the autoimmune regulator (AIRE) gene lead to impairment of central immune tolerance and a targeted attack on various endocrine and non-endocrine organs. Patients classically suffer from a triad of disorders, including chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenocortical failure (Addison's disease).
Results:
In recent times, it has been observed that oral manifestations of the disorder, such as enamel hypoplasia, appear early and frequently. Affected individuals require a comprehensive preventive and minimally invasive approach for oral health along with follow-up throughout their lifespan to manage potentially life-threatening disease manifestations.
Conclusion:
Prompt recognition by a pediatric dentist can facilitate an earlier diagnosis and allow for screening, preventive and therapeutic services.
Clinical significance:
To deliver oral health care in an effective and comprehensive manner, clinicians should be able to recognize, diagnose and manage the signs and symptoms of the disease.
How to cite this article:
Tyagi R, Kalra N, Khatri A, et al. A Rare Case of Autoimmune Polyendocrinopathy-candidiasis-ectodermal Dystrophy Syndrome: Dental Perspective on Diagnosis and Management. Int J Clin Pediatr Dent 2023;16(1):139-146.
... Autoimmune polyendocrine syndrome type 1 (APS-1), also known as autoimmune polyglandular syndrome type 1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, is a rare and peculiar autosomal recessive inherited disease that typically debuts in childhood (2-5 years of age) and gives rise to endocrine and nonendocrine manifestations [1,2]. Type 1 APS includes chronic candidiasis of the skin and mucous membranes, adrenal insufficiency, and hypoparathyroidism. ...
... The endocrine disorders involving APS-1 usually include gonadal insufficiency, type1 diabetes, and autoimmune thyroiditis. In addition, APS-1 is often accompanied by vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, intestinal dysfunction, nephritis, and hepatitis [2][3][4]. ...
... Such mutations 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. In most cases, diagnosis of APS type 1 syndrome is delayed by several years in relation to the time of manifestation of the first components, which determines the need to clarify the clinical criteria of the disease and diagnostic approaches [2]. ...
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.
... 11 The management of this condition is usually carried out with polyenes, imidazoles, triazoles agents, used separately or in combination. 12 Another aspect that may contribute to a greater propensity for persistent candidosis in this group of patients is dysbiosis in the oral ecosystem. Bruserud et al. ...
... 14 Since mucocutaneous candidosis has an early appearance in APS-1, a critical point in the treatment of these lesions lies in the fact that many patients need to use topical and systemic antifungals for long periods throughout their lives, which can result in microbial resistance. 12 Currently, the recommendation for the use of azole antifungals is not to exceed two to three treatments per year. 16 It is important to emphasize that there are currently no clinical trials that provide evidence of a standard protocol for the treatment of oral candidiasis in APS-1 patients. ...
Aims:
Autoimmune polyglandular syndrome type I (APS-I) is a rare condition of autosomal recessive and monogenic inheritance, which is characterized clinically by at least two signs of the classic triad: mucocutaneous candidosis, hypoparathyroidism, and Addison's disease. This study aims to report the oral manifestations of APS-I in a 42-year-old woman, who attended the Special Care Dentistry Center.
Methods and results:
The patient presented with hypoparathyroidism, diabetes mellitus, and autoimmune hepatitis. Chronic hyperplastic candidosis (CHC) was the main oral manifestation and it was diagnosed based on clinical and cytologic characteristics. Microstomia, angular cheilitis, xerostomia, enamel hypoplasia, and microdontia were also present.
Conclusions:
CHC was treated with topical nystatin and oral fluconazole, resulting in a significant improvement of the lesions.
... (11) Hypoparathyroidism (13) Addison's disease (14) Pernicious anemia (10) Malabsorption (11) Alopecia (13) [17] a, c 13. F/20 15 not available Adrenal insufficiency (15) Hypoparathyroidism (15) Graves' disease (15) Vitiligo (15) POF (15) Alopecia universalis (18) Vogt-Koyanagi-Harada syndrome (20) [18] a APECED patients for which sufficient information is retrospectively available to support a clinical diagnosis also based on the presence of Ferre/Lionakis criteria (i.e., presence of one symptom of the classic triad and one symptom of the adjunct triad of urticarial eruption, intestinal dysfunction and enamel hypoplasia). Epidemiological investigations conducted on different populations demonstrate that CMC is usually the first manifestation of APECED, often before 5 years of age [19,23]. The frequency of CMC ranges between 17 and 100% in APECED patients in different series, with the lowest incidence in Iranian Jews [23]. ...
... Epidemiological investigations conducted on different populations demonstrate that CMC is usually the first manifestation of APECED, often before 5 years of age [19,23]. The frequency of CMC ranges between 17 and 100% in APECED patients in different series, with the lowest incidence in Iranian Jews [23]. CH is the second most common manifestation in order of appearance (rev in [3,8,11,19,23]) whilst AAD is usually the third manifestation, occurring in 22-95% of the patients (rev in [8,11]). ...
... The frequency of CMC ranges between 17 and 100% in APECED patients in different series, with the lowest incidence in Iranian Jews [23]. CH is the second most common manifestation in order of appearance (rev in [3,8,11,19,23]) whilst AAD is usually the third manifestation, occurring in 22-95% of the patients (rev in [8,11]). Concurrently, APECED patients suffer additional endocrine and non-endocrine autoimmune conditions [2,3]. ...
Background
Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome Type 1 is a rare autosomal recessive syndrome. The disorder is caused by mutations in the AIRE (AutoImmune Regulator) gene. According to the classic criteria, clinical diagnosis requires the presence of at least two of three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Furthermore, patients are often affected by other endocrine or non-endocrine associated autoimmune conditions. The enrichment of the non-classical triad seems to occur differently in different cohorts. Screenings of the population revealed that homozygous AIRE mutations c.769C > T, c.415C > T and c.254A > G have a founder effect in Finnish, Sardinian and Iranian Jew populations respectively.
Case presentation
We report here the clinical and genetic characteristics of two new Serbian APECED siblings, one male and one female, actual age of 27 and 24 respectively, born from non-consanguineous parents. Addison’s disease was diagnosed in the male at the age of 3.5 and hypoparathyroidism at the age of 4. The female developed hypoparathyroidism at 4 years of age. She presented diffuse alopecia, madarosis, onychomycosis, teeth enamel dysplasia. She further developed Addison’s disease at the age of 11 and Hashimoto’s thyroiditis at the age of 13.5. She had menarche at the age of 14 but developed autoimmune oophoritis and premature ovarian failure at the age of 16. A treatment with hydrocortisone, fludrocortisone and alfacalcidiol was established for both siblings; L-T4 (levo-thyroxine) for thyroid dysfunction and levonorgestrel and etinilestradiol for POF were also administered to the female.
Genetic screening revealed a homozygous c.769C > T (R257X (p.Arg257X)) AIRE mutation. We additionally reviewed the literature on 11 previously published Serbian patients and evaluated the frequency of their main diseases in comparison to Finnish, Sardinian, Turkish, Indian and North/South American cohorts.
Conclusion
A founder effect was discovered for the R257X genotype detected in the DNA of 10 homozygous and 2 heterozygous patients. Of note, all Serbian APECED patients were affected by adrenal insufficiency and 10 out of 13 patients presented CMC.
... have HOAC in human medicine, there are fewer reports of these cases in veterinary medicine (Cryer, 2008;Neufeld, 1981;Weiler, 2012). ...
Background
Autoimmune polyendocrine syndrome, also called polyglandular autoimmune syndrome, is a rare immune‐mediated disorder that involves various endocrine glands.
Purpose
To report autoimmune polyendocrine syndrome in a dog.
Methods
A 9‐year‐old spayed female miniature poodle diagnosed with insulin‐dependent diabetes mellitus emergently visited our clinic for anorexia, severe depression, and vomiting. Hyponatremia, hypochloridemia, and recurrent hypoglycaemia were found. Hypoadrenocorticism was diagnosed based on consistent clinical signs and repeated adrenocorticotropic hormone stimulation tests.
Results
After injecting deoxycorticosterone pivalate and increasing the oral prednisolone dose, the patient's systemic condition improved.
Conclusions
To the best of our knowledge, this is the first case report of hypoadrenocorticism concurrent with diabetes mellitus in a dog. Furthermore, we would like to present the probability of an immune‐mediated disorder with multiple organs involved, like type IV autoimmune polyendocrine syndrome in humans.
... Although APS/MAS-1 is a clear example of autoimmune monogenic disease, a clear genotype-phenotype correlation is lacking. In some cases, individuals with the same mutation (even siblings) have presented with different clinical manifestations and experienced a different course of the disease (Weiler et al. 2012). A recently reported Italian family disclosed an extremely variable clinical picture despite the same AIRE gene mutation. ...
... A lower prevalence of CMC and AD was found among the Iranian Jewish patients with the Y85C mutation. Alopecia was more common in individuals with the 967-979del13 deletion, and autoimmune thyroiditis was usually found in individuals carrying the G228W mutation (Weiler et al. 2012). It seems evident that the allelic heterogeneity of the AIRE gene provides insufficient insight on the different phenotypes. ...
... Many cohort studies were published in the past, including more than 500 patients with APS/MAS-1 (Betterle et al. 2016;Guo et al. 2018). The prevalence of CMC in these cohorts varied from 17% to 100% and the lowest was among Iranian Jews (Weiler et al. 2012). In most cases, CMC is the first of the main components of APS/MAS-1 to appear, often before 5 years of age (Perheentupa 2006;Weiler et al. 2012). ...
... AIRE gene plays an essential role in central tolerance. Mutations in the AIRE gene prevent the elimination of self-reactive T cells at central level and induce a Treg defect at peripheral levels [4,18,19]. This leads to the development of multiple autoimmune diseases at a young age [4,20,21]. ...
... As (%) 17 n/a n/a 11 n/a n/a n/a 19 n/a n/a n/a 5 n/a n/a n/a 16 n/a 2 5 n/a [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] Diabetology (SIEDP), the Association of Medical Endocrinologists (AME) and the Italian Association of Patients with Addison's disease (AIPAd), all the APS-1 patients who were diagnosed and followed up in different specialist endocrine centers in Italy have been recruited, their sera and/or DNA samples were collected and the first Italian national register of patients with APS-1 has been created. ...
... For example, in the Norwegian population some gene deletions were associated with the onset of APS-1 later in life and a milder phenotype while some genotypes which lead to formation of truncated proteins appeared to be associated with CMC and AD [20]. In contrast, some patients carrying the same mutation (even siblings) presented different clinical manifestations and experienced different courses of the disease [18,87]. Among our Italian patients, there were some direct genotype-phenotype associations for R139X, R257X, W78R, T16M and R203X. ...
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.
