Autoimmune Polyglandular Syndrome Type Research Articles

Особенности клинических проявлений и лечения синдрома Шмидта

Актуальность. Наиболее часто встречается аутоиммунный полигландулярный синдром 2-го типа. Представляет интерес развитие и течение синдрома Шмидта, что требует всесторонней диагностики ввиду сочетания нескольких аутоиммунных эндокринопатий и рациональной терапии. Цель: проанализировать особенности клинических проявлений и лечения аутоиммунного полигландулярного синдрома 2-го типа на конкретном примере. Материалы и методы. Для рассмотрения представлен наблюдаемый нами клинический случай синдрома Шмидта у пациентки 36 лет. Имели место первичная надпочечниковая недостаточность с аутоиммунным процессом к 21-гидроксилазе и наличие аутоиммунного тиреоидита с развитием гипотиреоза. Результаты. В клинических проявлениях заболевания доминировали синдромы гипотензии, общей и мышечной слабости, гиперпигментации, потери массы тела, диспептических расстройств, усугубившиеся в результате присоединения вирусной инфекции, на фоне отечного синдрома. Дополнительное обследование выявило значительное повышение адренокортикотропного гормона, ренина, гиперкалиемию, гиперхолестеринемию, повышение 17-гидроксипрогестерона, тиреотропного гормона, гипотироксинемию, повышение антител к 21-гидроксилазе и к тиреоидной пероксидазе при уменьшении объема щитовидной железы с наличием множественных линейных включений, повышением эхогенности. Анализ выявленных гормональных, метаболических и патоморфологических изменений позволил установить наличие в данном клиническом случае синдрома Шмидта. Проводимое лечение глюкокортикоидами сопровождалось побочными реакциями, что привело к неоднократной замене препаратов. Выбор был сделан в пользу кортефа, доза тщательно оттитрована под контролем кортизолурии. Назначение левотироксина сопровождалось достижением эутиреоза. Выводы. Манифестация синдрома Шмидта при одновременном проявлении первичной надпочечниковой недостаточности аутоиммунного генеза и аутоиммунного тиреоидита с развитием гипотиреоза отличалась взаимно отягощающим течением. Имелись значительные трудности в лечении данного полигландулярного синдрома, связанные с коррекцией гипокортицизма, вследствие плохой переносимости глюкокортикоидов, что требовало постоянного наблюдения, неоднократного контроля за состоянием гормонального и метаболического статусов.

Report of two siblings with APECED in Serbia: is there a founder effect of c.769C>T AIRE genotype?

BackgroundAutoimmune 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 presentationWe 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.ConclusionA 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.

Case Report: Dental Findings Can Aid in Early Diagnosis of APECED Syndrome.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1), is a rare genetic disorder caused most often by biallelic mutations in the AIRE gene. Classic clinical findings of the disease are chronic mucocutaneous candidiasis and autoimmunity that primarily targets endocrine tissues, such as hypoparathyroidism and adrenal insufficiency. Recently, however, it has been appreciated that enamel hypoplasia, together with intestinal malabsorption and a characteristic APECED rash, is a prominent early disease manifestation of APECED which can aid in the diagnosis of disease before other potentially life-threatening disease manifestations occur. To demonstrate this point, we present data from a cohort of APECED patients, approximately 70% of who present with enamel dysplasia at an early age. Importantly, early life presentation with enamel dysplasia was predictive of likelihood of development of a subsequent APECED diagnosis. Furthermore, we present a case of a patient with APECED and severe enamel defects and discuss the utility of medical-dental professional co-operation in the diagnosis and management of this complex disorder.

Unmasking of Neurosarcoidosis

Abstract Introduction: Central diabetes insipidus is a rare complication of neurosarcoidosis. In patients with concomitant adrenal insufficiency (AI), the symptoms of Diabetes Insipidus (DI) can be masked. Case: A 55-year-old female with past medical history of sarcoidosis presented to the hospital with hematemesis, nausea and dizziness. She has a past medical history of cardiac sarcoidosis that was revealed on a PET scan done before 10 years for which she was being treated with methotrexate and prednisone. She was off prednisone for a year prior to hospitalization. She underwent an upper endoscopy that showed diffusely erythematous gastric mucosa in the antrum. She was also hypotensive on admission, and she received packed red blood transfusions after which her sodium increased from 145mmol/L to 165mmol/L (Normal: 135-145mmol/L) in 48 hours. Further workup revealed persistent hypernatremia and urine osmolality was 75mOsm/kg H2O. (Normal: 50-1200mOsm/kg H2O). She was also hypoglycemic and hypotensive requiring multiple fluid boluses throughout her hospitalization. This prompted us to perform a random cortisol that came back at 2.1ug/dl (Normal: 3-23ug/dl) and 1.8ug/dl on two occasions. Cortisol Stimulation test was subsequently ordered, but was done only at 30 minutes, and Cortisol increased from 1.8ug/dl to 6.3ug/dl. Free thyroxine was 0.5 ng/dl (Normal: 0.9-1.8 ng/dl) and her TSH was 7.58uIU/ml (Normal: 0.55-4.78uIU/ml). MRI of the brain revealed extensive areas of extra-axial supra-sellar/infundibular nodular homogeneous intense enhancement that is most consistent with neuro-sarcoid. She was started on prednisone 40 mg daily, Desmopressin 0.05 mg twice daily, and levothyroxine as well. Her sodium level normalized and was 137mmol/L at discharge. She followed up later with outpatient Endocrinology and reported around 90lbs weight gain and no more episodes of nausea or vomiting or epistaxis or lightheadedness. Conclusion: The involvement of the hypothalamic-pituitary axis in sarcoidosis is extremely rare and attributes to < 1% of patients with a sellar mass. Small case series have shown that hypogonadism is the most common endocrine abnormality followed by DI. Our patient had a long-standing history of sarcoidosis with her pituitary dysfunction unmasked only on admission for other causes. She did not manifest any symptoms of DI or AI. There have been case reports where the symptoms of DI are masked due to underlying glucocorticoid deficiency. There have been theories that glucocorticoid deficiency impairs renal water excretion by both ADH (Anti-diuretic hormone) dependent and ADH independent pathways. Another notable feature in our case is that our patient presented with primary hypothyroidism. In fact, sarcoidosis has been commonly implicated in auto-immune polyglandular syndromes type 3, which can present with auto-immune thyroiditis more so in females.

Cepharanthine Blocks the Presentation of Thyroid & Islet Peptides in a Novel Humanized Autoimmune Polyglandular Syndrome Type 3 Variant (APS3v) Mouse Model

Introduction: There is a strong genetic association between autoimmune thyroiditis (AITD) and Type 1 diabetes (T1D), and the co-occurrence of AITD and T1D in the same individual is referred to as Autoimmune Polyglandular Syndrome type 3 variant (APS3v). We previously discovered a unique amino acid signature of the HLA-DR pocket (designated APS3v HLA-DR pocket) that predisposes to APS3v, and we found that both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides can bind to this flexible APS3v HLA-DR pocket. The goal of the present study is to identify small molecules that can block the presentation of these thyroid and islet peptides by the APS3v HLA-DR pocket as a potential therapeutic approach for APS3v. Methods: We screened a panel of small molecules using an in vitro screening assay we developed using Baculovirus-generated recombinant APS3v-DR. To validate “hit” compounds discovered by the in vitro assay in a mouse model we established a novel mouse model of APS3v. The APS3v mouse model was established by immunizing humanized NOD-DR3 mice with Tg.1571, TPO.758 and GAD.492 combined, together with adjuvant. We then validated hit small molecules for their effectiveness in blocking stimulation of T-cell responses in the APS3v mouse model. Results: Our screen identified 4 small molecules (S5, S9, S15, S53) that showed more than 50% inhibition in our in vitro assay. We were also able to establish a novel APS3v mouse model. Immunized mice showed an increase in cytokine production in response to all 3 thyroidal and islet peptides. The immunized mice also developed antibody responses against each peptide. When we tested the 4 “hit” compounds, only Cepharanthine (S53) which we previously identified as a small molecule blocking AITD immune responses, could block all 3 thyroidal/islet peptides in the APS3v mouse model. Treating with Cepharanthine prior to inducing APS3v in the mice also reduced T-cell proliferation in the immunized mice. Conclusions: We established a novel humanized APS3v mouse model by co-immunizing 3 thyroidal and islet peptides. We also identified Cepharanthine as a small molecule that can block thyroid and islet specific T-cell responses in this model. Cepharanthine can be further tested in APS3v patients carrying the specific APS3v-DR pocket as a potential therapeutic treatment.

A Case of Autoimmune Polyglandular Syndrome Type 3b Initially Presenting as Generalized Weakness in an Elderly Patient

Introduction: Autoimmune polyglandular syndrome (APS) is a multiorgan genetic autoimmune disease. APS-3B subtype is autoimmune thyroiditis with pernicious anemia. In this case, we will discuss an elderly female patient diagnosed with APS-3B. Case Presentation: A 69-year-old Caucasian female patient with a past medical history of autoimmune thyroiditis presented to the emergency department with a two-month history of generalized weakness and nausea. Associated symptoms included shortness of breath and diarrhea. Review of systems was otherwise unremarkable. Physical exam was positive for depigmented skin macules over the upper extremities. Lab results showed hemoglobin 8.2 [11.7 - 15.5 g/dL], MCV 121[80 - 100 fL], platelets 144,000 [150 - 450 X10E9/L], WBC 1.9 [4.0 - 11.0 X10E9/L], LDH 1153[100 - 235 U/L], TSH 0.28[0.49 - 4.67 uIU/mL], free T4 1.7 [0.61 - 1.60 ng/dL], direct Coombs test negative. Iron saturation 55%, vitamin B12 level <50 [180 - 914 pg/mL], folate >25[>5.8 ng/mL], total bilirubin 2.3 [0.3 - 1.2 mg/dL], haptoglobin <30 [32 - 228 mg/dL], AST 43 [0 - 41 U/L], reticulocyte 1.4%. Blood smear showed absolute neutropenia with flow cytometry unremarkable. Chest x-ray and urinalysis were negative. Immunofixation showed low IgM 44 [45 - 281 mg/dL], low IgG 619 [635 - 1,741 mg/dL]. Intrinsic factor antibodies (IF-Ab) were positive. Hematology reported that hemolytic anemia is less likely given Coombs test was negative. About 1.5% of Vitamin B12 deficiency present with a hemolytic picture due to ineffective erythropoiesis while Coombs test help to differentiate it from autoimmune hemolytic anemia. Diagnosis of pernicious anemia was made and the patient started on vitamin B12 injections. The combination of pernicious anemia, autoimmune thyroiditis, and vitiligo supported the diagnosis of autoimmune APS-3B. There was a normalization of vitamin B12 level and symptomatic improvement on a one-week follow-up. Discussion: The patient was diagnosed with autoimmune thyroiditis in 2014 with positive anti-TPO antibodies and elevated TSH; she required levothyroxine supplementation since diagnosis. Hypothyroidism causes macrocytic anemia, which may delay pernicious anemia diagnosis. APS-3B is associated with HLA-B8 and/or DR3 and DR5. Many studies reported that autoantibodies can be detected before developing symptoms of organ involvement. Thorough family history provides support for autoantibody testing to detect cases of APS-3B earlier. Active surveillance and early diagnosis will help minimize invasive testing such as bone marrow biopsy, so proper history taking is a key factor to early diagnose these conditions. Conclusion: APS-3B is a rare disorder. Diagnosis is difficult hypothyroidism causes macrocytic anemia. Early detection of APS-3B may help to prevent complications that increase the risk of mortality and morbidity, particularly in the elderly population.

Polyglandular Autoimmune Syndrome Type II in a Patient Presenting With Hypotension After Acute Illness

Introduction: Polyglandular Autoimmune Syndrome Type II (PAS-2) is a rare disorder characterized by two or more endocrine diseases (primary adrenal insufficiency, autoimmune thyroid disease, type 1 diabetes). Of these, the most common is autoimmune thyropathy, followed by Type 1 Diabetes (1). These endocrinopathies rarely have concurrent onset. This case reports a 22-year-old male, recently recovered from severe pneumonia, who presented to the Emergency Department in acute adrenal crisis and was diagnosed with PAS-2. Case: A 22-year-old male with past medical history of celiac disease presented with abdominal discomfort, nausea, vomiting, fatigue and dizziness for 1–2 weeks. Review of systems included a 20-pound weight loss over several months. Recent history included a hospitalization at another facility three weeks prior for pneumonia and septic shock requiring admission to the ICU and vasopressor treatment. He was not discharged on any medications. He was afebrile with heart rate of 105/min, blood pressure 78/48 mm Hg and BMI of 17.2. Physical exam revealed dry mucous membranes and mild diffuse abdominal tenderness. Skin was warm and dry without hyperpigmentation. Laboratory values included sodium 123 (135 - 146 mmol/L), potassium 6.8 (3.3 - 4.8 mmol/L), glucose 47 (70 - 100 mg/dL), TSH 37.67 (0.3 - 5.00 uIU/mL), and FT4 0.7 (0.7 - 1.7 ng/dL). He was started on fluids and intravenous hydrocortisone. Cortisol and ACTH levels drawn prior to the initiation of steroids resulted at 0.6 (6–20 mcg/dl) and 977 (9 - 46 pg/mL) respectively. Additional labs included: aldosterone < 1 ng/dL, 21 hydroxylase antibody positive, TPO antibody > 1000 (0 - 100 Units) and GAD-65 antibody > 47 IU/mL (<5 IU/mL). Levothyroxine was initiated after hydrocortisone. Blood glucose was elevated during hospitalization, peaking at 227 mg/dL. He was discharged on prednisone, fludrocortisone and levothyroxine. At 2 week follow up, he reported overall improvement in health and was pleased with a weight gain of 12 lbs. Blood glucose remained mildly elevated (123 - 143 mg/dL). Conclusion: The patient had pneumonia and septic shock septic at an outside hospital three weeks prior to presentation. There was no record of steroid administration or suspicion of adrenal insufficiency. We postulate that his severe illness contributed to significant depletion of his adrenal reserve, and therefore he presented to our facility a short time later in overt adrenal crisis. Adrenal crisis is unusual to be the first presentation of PAS-2. It is important to have a high index of suspicion for adrenal insufficiency and PAS-2 in patients presenting with severe illness or hypotension who have known autoimmune disorders. Reference: 1. Kahaly, G.J., Frommer, L. Polyglandular autoimmune syndromes. J Endocrinol Invest. 2018; 41: 91–98.

Autoimmune Addison's Disease as Part of the Autoimmune Polyglandular Syndrome Type 1: Historical Overview and Current Evidence.

The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene, located in the chromosomal region 21q22.3. The related protein, AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin and anchorage to multimolecular complexes involved in the initiation and post-initiation events of tissue-specific antigen-encoding gene transcription. Once synthesized, the self-antigens are presented to, and cause deletion of, the self-reactive thymocyte clones. The clinical diagnosis of APS1 is based on the classic triad idiopathic hypoparathyroidism (HPT)—chronic mucocutaneous candidiasis—autoimmune Addison's disease (AAD), though new criteria based on early non-endocrine manifestations have been proposed. HPT is in most cases the first endocrine component of the syndrome; however, APS1-associated AAD has received the most accurate biochemical, clinical, and immunological characterization. Here is a comprehensive review of the studies on APS1-associated AAD from initial case reports to the most recent scientific findings.

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

BackgroundPure 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 presentationA 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. treatmentConclusionAIRE is causally related to the development of LGLL and consequent PRCA, which may be due to some immunological mechanisms.

Neurotrophic keratitis in autoimmune polyglandular syndrome type 1: a case report

BackgroundAutoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive disease. In patients with APS-1, the most frequently reported ocular manifestations are keratoconjunctivitis with dry eye and retinal degeneration. However, to our knowledge, no research studies have reported the relationship between APS-1 and neurotrophic keratitis (NK). Possible explanations such as limbus cell deficiency being the primary cause of APS-1 keratopathy are not applicable to our unusual case of the patient with APS-1 presenting as ocular surface disease with NK. Our case findings suggest a new explanation for the observed corneal pathology and a potential treatment for these patients.Case presentationA 27-year-old woman was referred to our hospital because of intermittent blurred vision and recalcitrant ocular surface problems in both eyes for many years. She has a history of autoimmune polyglandular syndrome type 1 (APS-1), which includes hypothyroidism, hypoparathyroidism, hypoadrenalism, and hypogonadotropic hypogonadism. In vivo confocal microscopy clearly demonstrated significant degeneration of the sub-basal nerve plexus and stromal nerve bundles in her corneas bilaterally. She was diagnosed with severe NK and ocular surface disease caused by dry eye. Treatment included the application of therapeutic soft contact lenses and punctual occlusion; however, both treatments had a limited effect.ConclusionPatients with APS-1 may have ocular surface disease and severe damage to corneal nerves. Regular follow-up and treatment focusing on the regeneration of corneal nerves is particularly important in these patients.

Hypoparathyroidism as the single major component for decades of autoimmune polyglandular syndrome type 1.

SummaryAutoimmune polyglandular syndrome type 1 (APS-1) is a very rare autoimmune entity, accounting for about 400 cases reported worldwide. It is characterized by the presence of at least two of three cardinal components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism and Addison’s disease. It typically manifests in childhood with CMC and years later with hypoparathyroidism. A 50-year-old man was referred to the Endocrinology outpatient clinic due to irregular follow-up of primary hypoparathyroidism diagnosed at age 7. Previous analysis reported frequent fluctuations of calcium and phosphate levels and persistent hypercalciuria. He presented several comorbidities, including bilateral cataracts, other ocular disorders, transient alopecia and chronic gastritis. Due to weight loss, fatigue, gastrointestinal complaints and the findings at objective examination, Addison’s disease and CMC were investigated and confirmed. Antifungal therapy and hormonal replacement were started with evident clinical improvement. Regarding hypoparathyroidism, calcium-phosphate product decreased and other extraskeletal calcifications were diagnosed, such as nephrolithiasis and in basal ganglia. Further evaluation by genetic analysis revealed homozygosity for a frameshift mutation considered to be a pathogenic variant. It was reported only in two Asian siblings in compound heterozygosity. This case highlights the broad phenotypic spectrum of APS-1 and the significative intra-familial phenotype variability. A complete clinical history taking and high index of suspicion allowed the diagnosis of this rare entity. This case clarifies the need for regular long-term follow-up. In the specific case of hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex.Learning points:Autoimmune polyglandular syndrome type 1 (APS-1) is a deeply heterogeneous genetic entity with a broad spectrum of clinical manifestations and a significant intra-family phenotypic variability.Early diagnosis of APS-1 is challenging but clinically relevant, as endocrine and non-endocrine manifestations may occur during its natural history.APS-1 should be considered in cases of acquired hypoparathyroidism, and even more so with manifestations with early onset, family history and consanguinity.APS-1 diagnosis needs a high index of suspicion. Key information such as all the comorbidities and family aspects would never be valued in the absence of a complete clinical history taking.Especially in hypoparathyroidism and Addison’s disease in combination, the management of APS-1 can be complex and is not a matter of simply approaching individually each condition.Regular long-term monitoring of APS-1 is essential. Intercalary contact by phone calls benefits the control of the disease and the management of complications.

Autoimmune polyglandular syndrome type 3

Autoimmune polyglandular syndrome type 3 (APS type 3) is a combination of autoimmune thyroid damage in combination with one or more autoimmune endocrine or non-endocrine diseases. It is represented by three subtypes: APS 3A (graves ‘ Disease, or Hashimoto’s thyroiditis and type 1 diabetes mellitus), APS 3B (autoimmune thyroid disease and pernicious anemia), APS 3C (autoimmune thyroid disease and vitiligo, alopecia, and/or other organ-specific autoimmune diseases). Clinical observations of patients with type 3 APS are presented: characteristic clinical syndromes and clinical and laboratory characteristics of patients. These clinical examples demonstrate the importance of thorough examination, alertness and knowledge of endocrinologists about the possibility of developing polyglandular lesions of the endocrine system, the importance of timely prescribed treatment and interdisciplinary interaction of doctors.

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.

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.

Monocytic Cytokines in Autoimmune Polyglandular Syndrome Type 2 Are Modulated by VitaminD and HLA-DQ.

ContextAutoimmune polyglandular syndrome (APS-2: autoimmune Addison’s disease or type 1 diabetes) is conferred by predisposing HLA molecules, vitamin D deficiency, and heritable susceptibility. Organ destruction is accompanied by cytokine alterations. We addressed the monocytic cytokines of two distinct APS-2 cohorts, effects of vitamin D and HLA DQ risk.MethodsAPS-2 patients (n = 30) and healthy controls (n = 30) were genotyped for HLA DQA1/DQB1 and their CD14+ monocytes stimulated with IL1β and/or 1,25(OH)2D3 for 24 h. Immune regulatory molecules (IL-6, IL-10, IL-23A, IL-15, CCL-2, PD-L1), vitamin D pathway gene transcripts (CYP24A1, CYP27B1, VDR), and CD14 were analyzed by enzyme-linked immunosorbent assay and RTqPCR.ResultsPro-inflammatory CCL-2 was higher in APS-2 patients than in controls (p = 0.001), whereas IL-6 showed a trend – (p = 0.1). In vitro treatment with 1,25(OH)2D3 reduced proinflammatory cytokines (IL-6, CCL-2, IL-23A, IL-15) whereas anti-inflammatory cytokines (IL-10 and PD-L1) rose both in APS-type 1 diabetes and APS-Addison´s disease. Patients with adrenal autoimmunity showed a stronger response to vitamin D. Expression of IL-23A and vitamin D pathway genes VDR and CYP27B1 varied by HLA genotype and was lower in healthy individuals with high-risk HLA (p = 0.0025; p = 0.04), while healthy controls with low-risk HLA showed a stronger IL-10 and CD14 expression (p = 0.01; p = 0.03).Conclusion1,25(OH)2D3 regulates the monocytic response in APS-2 disorders type 1 diabetes or Addison´s disease. The monocytic cytokine profile of individuals carrying HLA high-risk alleles is proinflammatory, enhances polyglandular autoimmunity and can be targeted by vitamin D.

Primary Adrenal Insufficiency in Childhood: Data From a Large Nationwide Cohort.

Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children. To describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI. Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected. The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was -0.70 ± 1.20 standard deviation score. We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.

Levothyroxine and insulin requirement in autoimmune polyglandular type 3 syndrome: a real-life study

PurposeTo evaluate factors influencing the insulin and levothyroxine requirement in patients with autoimmune polyglandular syndrome type 3 (APS-3) vs. patients with type 1 diabetes mellitus (T1DM) and autoimmune hypothyroidism (AH) alone, respectively.MethodsFifty patients with APS-3, 60 patients with T1DM and 40 patients with AH were included. Anthropometric, clinical and biochemical parameters were evaluated in all patients. Insulin requirement was calculated in patients with APS-3 and T1DM, while levothyroxine requirement was calculated in APS-3 and AH.ResultsPatients with APS-3 showed higher age (p = 0.001), age of onset of diabetes (p = 0.006) and TSH (p = 0.004) and lower total insulin as U/day (p < 0.001) and U/Kg (p = 0.001), long-acting insulin as U/day (p = 0.030) and U/kg (p = 0.038) and irisin (p = 0.002) compared to T1DM. Patients with APS-3 had higher waist circumference (p = 0.008), duration of thyroid disease (p = 0.020), levothyroxine total daily dose (p = 0.025) and mcg/kg (p = 0.006), triglycerides (p = 0.007) and VAI (p = 0.010) and lower age of onset of thyroid disease (p = 0.007) than AH.At multivariate analysis, levothyroxine treatment and VAI were associated with insulin and levothyroxine requirement in APS-3, respectively. VAI was independently associated with insulin requirement in T1DM. Circulating irisin levels were independently associated with levothyroxine requirement in AH.ConclusionPatients with APS-3 show lower insulin requirement and higher levothyroxine requirement than T1DM and AH alone, respectively. Levothyroxine treatment and VAI affect insulin and levothyroxine requirement, respectively, in APS-3. In T1DM, adipose tissue dysfunction, indirectly expressed by high VAI, is associated with an increased insulin requirement, while circulating irisin levels influence the levothyroxine requirement in AH.

S1929 A Case Series of Eosinophilic Esophagitis Associated With Primary Adrenal Insufficiency

INTRODUCTION: Eosinophilic esophagitis (EoE) is associated with the development of secondary adrenal insufficiency in patients treated with topical corticosteroids; however, the association with primary adrenal insufficiency is not reported in the literature. In this study, our aim was to review patients with primary adrenal insufficiency and a diagnosis of EoE and describe their disease characteristics and treatments. CASE DESCRIPTION/METHODS: We reviewed cases at Mayo Clinic Florida with the diagnosis of both EoE and primary adrenal insufficiency. Information gathered included sex, age at diagnosis, symptoms, white blood cell and eosinophil count, endoscopic and histological findings, EoE endoscopic reference score, and treatment including medical and procedural therapies.Three cases were identified and reviewed in the electronic medical record. The average age at diagnosis was 25.3 years, and two patients were female. Patients B and C were siblings with primary adrenal insufficiency associated with polyglandular autoimmune syndrome type 1, an inherited autoimmune disorder with multi-system effects including primary adrenal insufficiency and chronic mucocutaneous candidiasis. Both exhibited evidence of esophageal candidiasis. All patients presented with dysphagia and globus sensation, and one had peripheral eosinophilia (patient B). Despite esophageal symptoms, one patient had normal endoscopic findings with characteristic findings of eosinophils on histology. The other two patients had characteristic mucosal changes of EoE including ringed and small-caliber esophagus with areas of stenosis. Their endoscopic reference scores were 3 and 5. All patients were treated with omeprazole 40 mg twice daily, one patient with inhaled fluticasone 220 mcg twice daily, and one with oral budesonide 3mg twice daily. One patient underwent dilation of an esophageal stricture. DISCUSSION: Primary adrenal insufficiency has been associated with peripheral eosinophilia, seen in one of our study patients. Two patients were siblings with an inherited autoimmune disorder. All patients had characteristic symptoms of eosinophilic esophagitis and evidence of eosinophilia on histology, and responded to treatment with a proton pump inhibitor or topical steroid. For patients with primary adrenal insufficiency, young age, and symptoms of dysphagia, eosinophilic esophagitis should be considered as an etiology of symptoms. Further studies are needed to determine the pathogenesis and implications of this association.Figure 1.: Patient characteristics.

Follicle-stimulating hormone receptor autoantibody associated primary ovarian insufficiency successfully treated with corticosteroids: a case report

ObjectiveTo report a case of successful controlled ovarian stimulation (COH) for oocyte cryopreservation in a patient with autoimmune primary ovarian insufficiency (POI) and polyglandular autoimmune syndrome (PGAS) type 2.DesignCase report.SettingPrivate in vitro fertilization clinic.Patient(s)25-Year-old woman, G0, with autoimmune POI and PGAS type 2.Intervention(s)Diagnosis of autoimmune interference with FSH signaling, with subsequent high-dose corticosteroid immune suppression and successful oocyte cryopreservation.Main Outcomes Measure(s)Successful stimulation with exogenous gonadotropins, oocyte retrieval, and cryopreservation.Result(s)Retrieval and cryopreservation of 36 metaphase-II (MII) oocytes.Conclusion(s)Scrutiny of POI cases will facilitate identification of a subset of patients in whom immune suppression with short-term, high-dose corticosteroids may enable successful COH.

A Review of Autoimmune Enteropathy and Its Associated Syndromes.

Autoimmune enteropathy is an extremely rare condition characterized by an abnormal intestinal immune response which typically manifests within the first 6months of life as severe, intractable diarrhea that does not respond to dietary modification. Affected individuals frequently present with other signs of autoimmunity. The diagnosis is made based on a characteristic combination of clinical symptoms, laboratory studies, and histological features on small bowel biopsy. Autoimmune enteropathy is associated with a number of other conditions and syndromes, most notably immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome and autoimmune polyglandular syndrome type 1 (APS-1). Diagnosis and treatment is challenging, and further research is needed to better understand the pathogenesis, disease progression, and long-term outcomes of these conditions.

Autoimmune polyglandular syndrome (APS) type 2 associated with chronic kidney disease

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)