[Oral diseases in auto-immune polyendocrine syndrome type 1]. / Polyendocrinopathies auto-immunes de type 1 et pathologies buccales.

Auto-immune polyendocrine syndrome type 1 (APS1) also called Auto-immune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED) is a rare monogenic childhood-onset auto-immune disease. This autosomal recessive disorder is caused by mutations in the auto-immune regulator (AIRE) gene, and leads to autoimmunity targeting peripheral tissues. There is a wide variability in clinical phenotypes in patients with APSI, with auto-immune endocrine and non-endocrine disorders, and chronic mucocutaneous candidiasis. These patients suffer from oral diseases such as dental enamel hypoplasia and candidiasis. Both are frequently described, and in recent series, enamel hypoplasia and candidiasis are even the most frequent components of APS1 together with hypoparathyroidism. Both often occur during childhood (before 5 years old for canrdidiasis, and before 15 years old for enamel hypoplasia). Oral candidiasis is recurrent all life long, could become resistant to azole antifungal after years of treatment, and be carcinogenic, leading to severe oral squamous cell carcinoma. Oral components of APS1 should be diagnosed and rigorously treated. Dental enamel hypoplasia and/or recurrent oral candidiasis in association with auto-immune diseases in a young child should prompt APS1 diagnosis.

[On the forensic relevance of orphan diseases]. / Zur forensischen Relevanz seltener Erkrankungen.

A 40-year-old woman died shortly after complaining of non-specific symptoms after a pharmacist had accidentally given her the wrong medication. The woman's partner was not familiar with her medical history and the medical file had to be obtained from the family doctor. Autopsy findings and histological examination confirmed the clinically diagnosed autoimmune polyglandular syndrome without a tangible cause of death. Poisoning could not be demonstrated and no relation between the dosage error and death could be established. Laboratory tests revealed diabetic coma with ketoacidosis as the cause of death, which was probably caused by a prolonged lack of insulin administration. In addition to the clarification of legal issues, the complete post-mortem examination of orphan diseases is also relevant for achieving a better understanding of differential diagnostic aspects and complex pathophysiological contexts. Moreover, the genetic background often underlying such diseases should be a reason to inform the family of the deceased about the autopsy results. Only then can secondary preventive measures be taken in time.

COEXISTENCE OF ADDISON'S DISEASE AND PERNICIOUS ANEMIA: IS THE NEW CLASSIFICATION OF AUTOIMMUNE POLYGLANDULAR SYNDROME APPROPRIATE?

A case of autoimmune polyglandular syndrome (APS) is presented. A 45-year-old man was admitted due to fatigue, malaise and inappetence. He had a history of primary hypothyroidism and was on levothyroxine substitution therapy. One year before, he was diagnosed with normocytic anemia and vitamin B12 deficiency, which was treated with vitamin B12 substitution therapy. Physical examination revealed hypotension and marked hyperpigmentation. Laboratory testing showed hyponatremia, hyperkaliemia and severe normocytic anemia. Endocrinological evaluation disclosed low morning cortisol and increased adrenocorticotropic hormone levels. Hence, the diagnosis of Addison's disease was established. Additional laboratory workup showed positive parietal cell antibodies. However, his vitamin B12 levels were increased due to vitamin B12 supplementation therapy, which was initiated earlier. Gastroscopy and histopathology of gastric mucosa confirmed atrophic gastritis. Based on prior low serum vitamin B12 levels, positive parietal cell antibodies and atrophic gastritis, the patient was diagnosed with pernicious anemia. Hydrocortisone supplementation therapy was administered and titrated according to urinary-free cortisol levels. Electrolyte disbalance and red blood cell count were normalized. This case report demonstrates rather unique features of pernicious anemia in a patient with Addison's disease. It also highlights the link between type II and type III APS. Not only do they share the same etiological factors, but also overlap in pathophysiological and clinical characteristics. This case report favors older classification of APS, which consolidates all endocrine and other organ-specific autoimmune diseases into one category. This is important since it might help avoid pitfalls in the diagnosis and treatment of patients with APS.

HLA class II haplotypes differentiate between the adult autoimmune polyglandular syndrome types II and III.

BACKGROUND: Genetics of the adult autoimmune polyglandular syndrome (APS) is poorly understood. AIM: The aim of this study was to gain further insight into the genetics of the adult APS types. SITE: The study was conducted at a university referral center. METHODS: The human leukocyte antigen (HLA) class II alleles, haplotypes, and genotypes were determined in a large cohort of patients with APS, autoimmune thyroid disease (AITD), and type 1 diabetes and in healthy controls by the consistent application of high-resolution typing at a four-digit level. RESULTS: Comparison of the allele and haplotype frequencies significantly discriminated patients with APS vs AITD and controls. The HLA class II alleles DRB1*03:01 *04:01, DQA1*03:01, *05:01, DQB1*02:01, and *03:02 were observed more frequently (P<.001) in APS than in AITD and controls, whereas the alleles DRB1*15:01, DQB1*03:01, and *06:02 were underrepresented in APS vs AITD (Pc<.001) and controls (Pc<.01), respectively. The DRB1*03:01-DQA1*05:01-DQB1*02:01 (DR3-DQ2) and DRB1*04:01-DQA1*03:01:DQB1*03:02 (DRB1*04:01-DQ8) haplotypes were overrepresented in APS (Pc<.001). Combination of both haplotypes to a genotype was highly prevalent in APS vs AITD and controls (Pc<.001). Dividing the APS collective into those with Addison's disease (APS type II) and those without Addison's disease but including type 1 diabetes and AITD (APS type III) demonstrated DR3-DQ2/DRB1*04:01-DQ8 as a susceptibility genotype in APS III (Pc<.001), whereas the DR3-DQ2/DRB1*04:04-DQ8 genotype correlated with APS II (Pc<.001). The haplotypes DRB1*11:01-DQA1*05:05-DQB1*03:01 and DRB1*15:01-DQA1*01:02-DQB1*06:02 are protective in APS III but not in type II (Pc<.01). CONCLUSIONS: HLA class II haplotypes differentiate between the adult APS types II and III. Susceptible haplotypes favor the development of polyglandular autoimmunity in patients with AITD.

Polyendocrine syndrome type 3C in a family from Pakistan.

In type 3 polyendocrine syndrome (PAS3), autoimmune thyroiditis occurs with other organ-specific autoimmune disease, but not with autoimmune adrenalitis. In this report we described a family from Pakistan in which mother and three daughters were affected by a PAS3. We studied a family from Pakistan: Father MMu age 44, mother KN aged 44, three daughters MM age 20, MH age 16 and MA age 14 and a son MU age 18. These subjects were tested for thyroids function, metabolic function, adrenal function, autoimmune disease. In this family the four females were shown hypothyroidism with presence of anti thyroid autoantibodies (AA) and high TSH serum concentration in association with the presence of anti transglutaminase AA. Moreover KN, MM and MH were positive for anti nuclear AA (granular pattern) and for antibodies against Saccaromyces cerevisiae. MM was positive for AA against nuclear extractable antigens (SSA and SSB) too. No diabetes or pernicious anemia were observed. Adrenal and Pituitary function were normal. PAS 3C is an uncommon disease. In this family from Pakistan we observed a PAS3C in the four female members: mother and three daughters while father and son were unaffected.

Polyglandular autoimmune syndrome type II.

The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders. There exist a juvenile (PAS I) and an adult type (PAS II). The nature of PAS has been based on the presence of lymphocyte infiltration in the affected gland, organ-specific antibodies in the serum, cellular immune defects and an association with the human leucocyte antigen (HLA) DR/DQ genes or immune response genes. Autoantibodies to the various endocrine and non-endocrine tissues not only offer a diagnostic clue to the autoimmune nature of diseases but also can be used to identify asymptomatic individuals who are at risk of developing other component diseases of the syndrome. Although target tissues or glands differ, several common threads link the diseases of PAS. A defect resides in one of the genes of the HLA locus which, in concert with other gene(s), results in susceptibility. Genetic susceptibility is necessary but not sufficient to produce the disorder. This is illustrated by the lack of 100% concordance of disease in identical twins. Genetic testing may identify patients with PAS I, but not those with PAS II. For PAS II, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T-lymphocyte antigen (CTLA-4) gene, and the protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes on chromosomes 6, 2, and 1, respectively. When the genetic defects and environmental influences of organ-specific autoimmunity are better understood, it may be possible to devise specific replacement or corrective therapies. Given the similar features of many of the organ-specific autoimmune disorders, it is likely that if immunotherapeutic modalities are successful in one disease, they may be of benefit in related disorders.

[Associations of autoimmune disorders in endocrine diseases]. / Autoimmun endokrin kórképek társulásai.

Increasing data are known for dialogue between neuroendocrine and immune systems recently. Results of molecular genetic studies provided evidences for common languages of these systems by various signals including neurotransmitters, hormones, cytokines. It is proved the immune system is able to produce neurotransmitters and hormones and endocrine organs can even result in cytokines. This new integrative approach allows to investigate the physiologic events and diseases as interactions between the psycho-neuro-endocrine-immune systems. The autoimmune polyendocrine syndromes constitute a heterogeneous group of disorders characterized by loss of immune tolerance to self-antigens. In spite of distinct clinical pictures, molecular genetic studies revealed a common molecular mechanism in the associations of organ-specific diseases. Autoimmune polyendocrine syndrome-1 is characterized by associations at least two out of three cardinal signs: Addison's disease, autoimmune hypoparathyroidism and mucocutaneous candidiasis. This is a rare autosomal recessive syndrome induced by mutations in autoimmune regulator gene. Autoimmune polyendocrine syndrome-2 occurs more frequently and defined as the coexistence of Addison's disease, autoimmune thyroid disease and/or type-1 diabetes mellitus. Autoimmune polyendocrine syndrome-3 is characterized by association of autoimmune thyroid disease and type-1 diabetes mellitus. The HLA and other genes proved to be important in associations of the syndrome-2 and 3 in contrast to autoimmune polyendocrine syndrome-1. Identification of predisposing genetic helps to understand the common mechanisms and provide possibility for early therapy and prevention as well.

Neurologic consequences of autoimmune polyglandular syndrome type 1.

BACKGROUND: Autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive disorder that is chiefly characterized by polyendocrinopathy, chronic mucocutaneous candidiasis, and ectodermal dystrophy. The neurologic complications of this disorder have not been well characterized. METHOD: The authors report a patient with a previously undescribed autoimmune cerebellar degeneration occurring in association with APS-1 and review the literature regarding the neurologic complications of this disorder. RESULTS: This 24-year-old woman with APS-1 presented with gait ataxia associated with band-like hyperintense signal abnormalities of both cerebellar hemispheres and a unique antibody to cerebellar Purkinje cells and brainstem neurons. At age 9, she had C. Miller Fisher syndrome, from which she had fully recovered. CONCLUSIONS: Autoimmune neurologic disease may develop with autoimmune polyglandular syndrome type 1. Neurologic disease may also result from the associated endocrinopathies (hypoparathyroidism, hypothyroidism, diabetes mellitus), vitamin deficiency (vitamins B12 and E), and celiac sprue.

[Autoimmune polyglandular syndromes]. / Autoimmunologiczne zespoly wielogruczolowe.

Autoimmune polyglandular syndromes are conditions characterised by the association of two or more organ-specific disorders. On the basis of the clinical picture, they are divided into four different types. Type 1 is a monogenic autoimmune syndrome, which is caused by defect in AIRE gene located on chromosome 21. Its major components include mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. Type 2 is defined as the combination of autoimmune adrenal insufficiency with autoimmune thyroid disease and/or type 1 diabetes mellitus. Type 3 is composed of autoimmune thyroid diseases associated with other autoimmune conditions with the exception of Addison's disease. The remaining autoimmune combinations not included in the previous groups belong to type 4. Proper care of individuals with autoimmune polyendocrine syndromes requires knowledge of the problems that may arise, and the best approaches to detect and care for the manifestations of these incurable, but manageable, diseases. The objective of this paper is to review the aetiology, clinical manifestations, diagnosis and treatment of autoimmune polyglandular syndromes with a special emphasis on the most recent literature.

Genetic dissection of autoimmune polyendocrine syndrome type 2: common origin of a spectrum of phenotypes.

Autoimmune diseases constitute a heterogeneous group of disorders characterized by the loss of immune tolerance to self-antigens. Despite their distinct clinical picture, there is growing evidence that common molecular mechanisms may contribute to the whole spectrum of autoimmune diseases. This theory is strongly supported by the existence of the autoimmune polyendocrine syndromes (APS). Thus, the clinical diagnosis of APS1 is made in an individual who presents with at least two out of three cardinal symptoms, namely autoimmune Addison's disease, autoimmune hypoparathyroidism, and mucocutaneous candidiasis. APS1 is a rare autosomal recessive syndrome caused by mutations in the autoimmune regulator (AIRE) gene. APS2, which occurs at a much higher frequency, is classically defined as the coexistence of autoimmune Addison's disease, autoimmune thyroid disease, and/or type 1 diabetes. In contrast to APS1, the precise modes of inheritance and the genetic causes underlying APS2 remain unknown. Identification of genetic factors predisposing to this syndrome may contribute to our understanding of common mechanisms involved in autoimmunity.

[Pluriglandular autoimmune syndrome. Systematic review]. / Síndrome pluriglandular autoinmune. Revisión.

There are a lot of autoimmune syndromes with glandular disfunction which are associated to another diseases. Sometimes, these processes are associated to similar cases in the same family. Autoimmune polyglandular syndromes are characterized by the coexistence of two or more endocrine insufficiencies due to an autoimmune mechanism: the activity of autoantibodies or T activated lymphocytes against organs or endocrine glands. In this report, they have been described the main autoimmune syndromes, the diagnostic methods and the mechanisms which take a role in their origin.

Síndrome autoinmune poliglandular tipo II: reporte de un caso y revisión de la literatura / Autoinmune polyglandular syndrome type II: a case report and review of literature

El síndrome autoinmune poliglandular (SAP) corresponde a una infrecuente entidad clínica que se reconoce por el compromiso de dos o más glándulas endocrinas basados en mecanismos autoinmunes, siendo posible además la afectación de órganos no endocrinos por esta misma causa. Debido a esto último el término síndrome autoinmune "poliendocrino", antes utilizado frecuentemente, ya no es completamente aceptado para referirse a esta patología. Actualmente existen dos grupos clásicos (SAP tipo I y tipo II) los cuales se clasifican de acuerdo a la edad de presentación de la enfermedad, combinaciones características de órganos comprometidos y patrón hereditario, entre otros. Además se describen otros dos grupos de menor importancia clínica llamados SAP tipo III y IV. A continuación se presenta un caso clínico pediátrico de SAP tipo II diagnosticado en el Hospital Herminda Martín de Chillán y una revisión actualizada de la literatura correspondiente.

Clasificación de las inmunodeficiencias primarias, unas entidades múltiples y diversas / No disponible

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Immunophenotypic characterisation of peripheral blood lymphocytes in autoimmune polyglandular syndrome type 1: clinical study and review of the literature.

Autoimmune endocrinopathies are characterised by an increased number of peripheral blood lymphocytes (PBL) expressing activation/ memory markers on their surface. The aim of this study was to determine whether a similar finding could be detected in a group of 11 paediatric and young adult patients suffering from autoimmune polyglandular syndrome type 1 (APS1), also called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), as very few data have previously been reported in this field. The control group was made up of 11 sex- and age-matched healthy subjects. Fifteen lymphocyte subsets were compared, in terms of percentage and absolute number, and statistical analysis was performed by the Mann-Whitney test. Measurement of T (CD3+), B (CD19+), natural killer (NK, CD3-CD16/56+), CD4+ and CD8+ T lymphocytes showed that patients with APS1 had a higher percentage and absolute count of T lymphocytes: this was entirely due to the statistically larger CD3+CD4+ fraction. Patients with APS1 also had slightly fewer B and NK lymphocytes, but the difference was negligible. Comparison of CD4+ subpopulations bearing activation and naive/memory antigens (marked by CD69, CD25, anti-HLA-DR, CD45RA and CD45RO) showed that patients with APS1 had generally larger percentages and absolute counts of these subsets: however, only the percentage and absolute size of the CD4+CD25+ subset (p = 0.0354 and p = 0.0151, respectively), and the absolute number of the CD4+ anti-HLA-DR+ and CD4+ CD45RO+ subsets (p = 0.0193 and p = 0.0209, respectively) were significantly higher. Interestingly, patients with APS1 also had significantly fewer CD8+CD11b+ and CD3-CD8+ cells. In conclusion, PBL distribution in APS1 resembles that of other autoimmune diseases. Further studies are needed to confirm and possibly extend these data.