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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.

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OBJECTIVES: Over the past 3 years, coronavirus disease 2019 with its worldwide spread has profoundly marked public health, therefore anti-COVID-19 vaccinations have been developed to prevent the dissemination of the disease. To date, 71 cases of Graves' disease (GD) after vaccination against SARS-Cov-2 were described in the adult population. Our goal is to present the first case in the paediatric population. CASE PRESENTATION: We present the first case of a 16-year-old adolescent girl who developed GD 6-7 weeks after the second dose anti-COVID-19 mRNA vaccine. Therapy with methimazole and propranolol was started, achieving normal thyroid function and negativity of thyroid autoantibodies at the time of therapy discontinuation after 8 months. CONCLUSIONS: This case shows that the development of GD after COVID-19 mRNA vaccination can occur also in the adolescent population. Nevertheless, the small number of cases of GD described so far, after many millions of vaccinations, makes it impossible to determine whether this is simple a coincidence or a cause. Further epidemiological data on the incidence of GD in the vaccination period compared to the previous period will be able to clearly define this question.

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Introduction: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome is a rare monogenic disease determined by biallelic mutations in AIRE gene, which encodes a transcription factor essential for central immune tolerance. Classic diagnosis is determined by the presence of two of the main APECED clinical diseases: chronic mucocutaneous candidiasis, chronic hypoparathyroidism, and Addison's disease. Non-endocrine autoimmunity, involving the liver, intestine, eyes, and kidneys, is generally reported in a minority of European patients, while American APECED patients have a higher tendency of developing organ-specific non-endocrine manifestations early in life. This observation led to the revision of the diagnostic criteria to permit earlier diagnosis based on the appearance of one classic triad symptom or one non-classical manifestation at a young age in the presence of IFNωAbs or AIRE mutations (Ferre-Lionakis criteria). Patients and methods: We analyzed the clinical, genetic, and autoantibody (Ab) profiles in a series of 14 pediatric Italian APECED patients with gastrointestinal manifestations (seven male and seven female patients). Ten patients presented hepatitis (APECED-associated hepatitis (APAH)), while seven were affected by constipation, diarrhea, and malabsorption. Four patients had developed APAH before classic triad symptoms. Results: Based on the age of appearance of non-endocrine manifestations including APAH and gastro-enteropathy, the Ferre-Lionakis criteria would have allowed an expedited diagnosis in 11/14 patients. Abs to tryptophan hydroxylase (TPHAb) and hepatic aromatic l-amino acid decarboxylase (AADC) were significantly associated with APECED patients of the present series. Abs to cP4501A2 were detectable in the serum of 4/8 patients with APAH, and Abs to cP4502A6 were detectable in 3/8 patients. AADC Abs tested positive in 5/7 patients, which is indicative of gastrointestinal dysfunction in APECED and TPHAb in 5/7 patients with gastrointestinal dysfunction. IFNAb was significantly associated with the syndrome. Conclusion: Although Ferre-Lionakis expanded criteria applied to the American cohorts of APECED patients would require validation in independent large cohorts of European patients, the results of this study emphasize the importance to evaluate the presence and the age of appearance of APAH and autoimmune enteropathy even in European cohorts for an earlier APECED diagnosis. An earlier APECED diagnosis would also allow the prevention of episodes of life-threatening hypocalcemic seizures and adrenal crisis, which are the main manifestations of undiagnosed APECED.

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OBJECTIVE: COVID-19 is a potentially serious new infection firstly broken out in the North East Italy during Spring 2020. Patients with adrenal insufficiency (AI) have a known increased risk of infections, that could precipitate to adrenal crisis. Even COVID-19-related psycho-social impact could affect their health, requiring a dynamic adaptation of daily glucocorticoid (GC) therapy. The aim of this study was to evaluate the incidence of COVID-19 infection and self-reported outcomes in AI patients after the first pandemic waves. METHODS: Open-label, cross-sectional monocentric study on 84 (65 primary, 19 secondary) AI patients, resident in Veneto and followed-up in our out clinical of Endocrine Unit. All patients underwent serological investigation of anti-SARS-CoV2 IgG and purpose-built "ADDI-COVID" questionnaire by August 2020 and were recontacted to reevaluate COVID-19 infection occurrence in March-April 2021. RESULTS: All patients resulted negative to the serological test for anti-SARS-CoV2 IgG at the end of the first pandemic wave. After the third wave, COVID-19 infection occurred in 8 patients without need of hospitalization. Half patients felt an increased risk of COVID-19 infection, significantly associated with increased stress and GC stress-dose. Only one patient reported adrenal crisis stress-correlated. The majority of AI workers changed working habits, significantly reducing COVID-19-related stress. CONCLUSION: AI patients did not show an increased incidence of COVID-19, but the perception of increased COVID-19 infection risk significantly impacts their psychological well-being, working habits and GC daily doses. Therapeutic patient education is crucial especially for AI workers to prevent and treat situations that could lead to an adrenal crisis.

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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.

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OBJECTIVES: The reported prevalence of TSH-receptor (TSHR) autoantibodies (TRAb) in patients with chronic thyroiditis (CT) range from 0 to 48%. The objective was to study the prevalence of TRAb in patients with CT and hypothyroidism and to correlate it with gender, age, thyroid dimensions, TSH levels, and autoimmune diseases. METHODS: The study comprised 245 patients with CT and hypothyroidism (median age 42 years, 193 females, 52 males) and 123 Italian healthy subjects matched for sex and age as controls. TRAb were tested with ELISA using a >2.5 IU/L cut off for positivity. TSHR blocking (TBAb) and TSHR stimulating autoantibodies (TSAb) were measured in 12 TRAb-positive patients using bioassays with Chinese hamster ovary (CHO) cells expressing wild-type or R255D-mutated TSHR. RESULTS: TRAb positivity was found in 32/245 (13.1%) patients and significantly correlated (p<0.05) with TSH levels. TRAb positivity was significantly higher in males vs. females (p=0.034), in females 16-45 years of age vs. >45 years of age (p<0.05) and in patients with reduced vs. normal/increased thyroid dimensions (p<0.05). Linear regression analysis showed a correlation between TRAb concentrations with age (p<0.05) and TRAb concentrations with TSH (p<0.01). In bioassay with TSHR-R255D all 12 patients tested were TBAb-positive while 33% were also TSAb-positive suggesting the presence of a mixture of TRAbs with different biological activities in some patients. CONCLUSIONS: TRAb have been found in patients with CT and hypothyroidism. A mixture of TBAb and TSAb was found in some patients and this may contribute to the pathogenesis of thyroid dysfunction during the course of the disease.

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CONTEXT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; also known as autoimmune polyendocrine syndrome type 1) has a severe, unpredictable course. Autoimmunity and disease components may affect fertility and predispose to maternal and fetal complications, but pregnancy outcomes remain unknown. OBJECTIVE: To assess fetal and maternal outcomes and course of clinical APECED manifestations during pregnancy in women with APECED. DESIGN AND SETTING: A multicenter registry-based study including 5 national patient cohorts. PATIENTS: 321 females with APECED. MAIN OUTCOME MEASURE: Number of pregnancies, miscarriages, and deliveries. RESULTS: Forty-three patients had altogether 83 pregnancies at median age of 27 years (range, 17-39). Sixty (72%) pregnancies led to a delivery, including 2 stillbirths (2.4%) and 5 (6.0%) preterm livebirths. Miscarriages, induced abortions, and ectopic pregnancies were observed in 14 (17%), 8 (10%), and 1 (1.2%) pregnancies, respectively. Ovum donation resulted in 5 (6.0%) pregnancies. High maternal age, premature ovarian insufficiency, primary adrenal insufficiency, or hypoparathyroidism did not associate with miscarriages. Women with livebirth had, on average, 4 APECED manifestations (range 0-10); 78% had hypoparathyroidism, and 36% had primary adrenal insufficiency. APECED manifestations remained mostly stable during pregnancy, but in 1 case, development of primary adrenal insufficiency led to adrenal crisis and stillbirth. Birth weights were normal in >80% and apart from 1 neonatal death of a preterm baby, no serious perinatal complications occurred. CONCLUSIONS: Outcome of pregnancy in women with APECED was generally favorable. However, APECED warrants careful maternal multidisciplinary follow-up from preconceptual care until puerperium.

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Vaccines represent one of the most effective measures of public health medicine, saving countless lives and preventing lifelong disabilities. Vaccines are extremely safe, however, no vaccine is completely free from risks and adverse events can occur following vaccination. An adverse event following immunization (AEFI) may be a true adverse reaction caused by the vaccine or an event that temporally occurred after immunization but is not caused by it. Among the adverse reactions to vaccines, one of the most feared is the triggering of autoimmune diseases, which are a heterogeneous group of disorders characterized by dysregulation of the immune system. Currently, no mechanisms have been demonstrated that could explain the correlation between vaccination and the development of autoimmune diseases. Furthermore, epidemiological studies do not support the hypothesis that vaccines cause systemic autoimmune diseases. The only confirmed associations, although very rare, are those between the flu vaccine and Guillain-Barré syndrome, especially with old vaccine preparations, and measles-mumps-rubella (MMR) vaccine and thrombocytopenia. Due to the SARS-CoV2 pandemic, new types of vaccines have been developed and are now available. Close vaccine safety-surveillance is currently underway for these new vaccines.

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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.

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OBJECTIVE: While vitamin D regulates immune cells, little is known about it in autoimmune Addison's disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes. DESIGN: Cross-sectional study. METHODS: A total of 1028 patients with AAD from Germany (n = 239), Italy (n = 328), Norway (n = 378), UK (n = 44) and Poland (n = 39) and 679 controls from Germany (n = 301) and Norway (n = 378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP). RESULTS: Vitamin D deficiency (25(OH)D3 10-20 ng/mL) was highly prevalent in AAD patients (34-57%), 5-22% were severely deficient (<10 ng/mL), 28-38% insufficient (20-30 ng/mL) and only 7-14% sufficient (>30 ng/mL). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (P = 0.03/0.003 and P = 1 × 10-5/< 1 × 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/mL), AAD patients remained largely deficient (18.0 to 21.2 ng/mL) and synthesize less 1,25(OH)2D3. CONCLUSION: Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.

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Adrenal insufficiency (AI) is a life-threatening disorder, with increased morbidity and mortality, especially in case of an acute illness that can increase the requirement of cortisol. A novel infectious disease, termed Coronavirus Disease 2019 (COVID-19), appeared in 2020. Therefore, AI patients are experiencing a novel challenge: the risk of infection. In our experience, a prompt contact to the Endocrine center (with a telemedicine consultation) and a full awareness of diseases (cortisol deficiency, COVID-19 and the self-management of an adrenal crisis) are important to motivate patients. Vaccine is an effective treatment to prevent hospitalization and aggressive course of COVID-19. Some patients manifest challenges due to inequitable access and vaccine hesitancy, resulting in a delay in the acceptance of vaccines despite the availability of vaccination services. Therefore, an effort of all physicians must be conducted in order to advise patients with AI. In this short review, we try to answer some frequently asked questions regarding the management of patients with AI.

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CONTEXT: Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children. OBJECTIVE: To describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI. PATIENTS AND METHODS: Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected. RESULTS: 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. CONCLUSIONS: We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.

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Autoimmune Addison's disease (AAD) is a rare condition occurring either in isolation or associated with other autoimmune diseases as part of an autoimmune polyglandular syndrome (APS) type 1, 2 or 4. Multiple endocrine neoplasia (MEN) type 1, 2 or 4 is a hereditary autosomal dominant cancer syndrome. Medullary thyroid carcinoma and pheochromocytoma are neoplasms common to MEN-2a and MEN-2b. We describe a unique, complex case of a man resulted affected by both APS-2 and MEN-2a. The patient developed Hashimoto's thyroiditis, diabetes mellitus type 1 and AAD, despite testing negative for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OHAb). Moreover, he had also a family history for MEN-2a and he first developed medullay thyroid cancer, then bilateral pheochromocytoma on the adrenal substrate of an AAD. On adrenal histology we found complete bilateral cortical atrophy in the presence of a lymphocytic infiltration and fibrosis, confirming an ACA and 21-OHAb-negative AAD. This datum is the first documented in a living individual and confirms that the absence of autoantibodies is not incompatible with an autoimmune disease and confirms that AAD is a cell-mediated autoimmune disease limited to the adrenal cortex and sparing medullary. In the light of a literature review concerning the association between APS and MEN, this is the first proven case to be reported in humans. Finally, our findings suggest that adrenal medullary tumor can develop even on an adrenal gland with cortical atrophy due to autoimmune adrenalitis.

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BACKGROUND: Adrenal cortex autoantibodies (ACAs) and/or 21-hydroxylase (21OHAb) are markers of autoimmune Addison's disease (AAD) and progression to overt AAD. The reported cumulative risk of developing AAD varies from 0 to 90% in different studies. AIM: To assess the predictive value of different parameters in the progression toward AAD in patients with ACA and/or 21OHAb-positive patients with autoimmune polyendocrine syndromes (APS). MATERIALS AND METHODS: Twenty-nine patients with APS-1 and 114 patients with APS-2 or APS-4 were followed up for a median of 10 years (range 6 months to 33 years) and were assessed using ACTH test. The risk of AAD was estimated according to age, gender, stage of adrenal dysfunction, associated diseases and antibody titer. Univariate and multivariate Cox proportional hazard models were used for statistical analysis. RESULTS: The cumulative risk (CR) of developing AAD was higher in APS-1 patients (94.2%) than in patients with APS-2/APS-4 (38.7%). The CR was high in both male and female APS-1 patients, while in patients with APS-2/APS-4 it was high only in males. Stage 1 (increased plasma renin) for patients with APS-1 and Stage 2 (no response of cortisol to ACTH test) for patients with APS-2/APS-4 were established as the points of no return in the progression to AAD. Adjusted hazard ratio analyses by multivariate Cox model for AAD showed that gender, diseases and adrenal function were independent risk factors for developing clinical AAD. The risk of developing clinical AAD appears to subside after 19 years of follow-up. CONCLUSIONS: A model for estimating the probability to survive free of AAD has been developed and should be a useful tool in designing appropriate follow-up intervals and future therapeutic strategies.

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Autoimmune forms of hypoglycemia are a rare cause of low blood sugar levels among Caucasians, and often go misdiagnosed, exposing patients to lengthy series of pointless, potentially harmful and expensive tests. There are two types of autoimmune hypoglycemia. One is insulin autoimmune syndrome (IAS), which is characterized by hyperinsulinemic hypoglycemia, elevated insulin autoantibody (IAA) titers, no prior exposure to exogenous insulin, and no of pathological abnormalities of the pancreatic islets. This condition is also known as "Hirata's disease". The other is type B insulin resistance syndrome (TBIRS), a rare autoimmune disorder resulting in a broad array of abnormalities in glucose homeostasis-from hypoglycemia to extremely insulin-resistant hyperglycemia-caused by the presence of insulin receptor autoantibodies (IRAbs). This review focuses on these two syndromes, describing their epidemiology, possible genetic background, clinical presentation, pathophysiology, diagnosis and treatment.

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Autoimmune-poly-endocrinopathy-candidiasis-ectodermal-dystrophy syndrome (APECED) is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the following disorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CHP), and Addison's disease. APECED develops at high incidence in Finns, Sardinians, and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes. In this manuscript, we report the clinical, endocrinological, and molecular features of a 16-year-old female patient from Pakistan living in Italy and presenting the major APECED clinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarian failure, chronic bronchopneumopathy, vitiligo, Hashimoto's thyroiditis emerged as associated diseases. In our patient, AIRE gene screening revealed the novel c.396G>C (p.Arg132Ser; p.R132S) mutation in homozygosity thus confirming APECED diagnosis. This is the first reported mutation within the nuclear localization signal (NLS) that is associated with APECED. The NLS mutation affects the nuclear import of classical transcription factors through nuclear pore by recognition of nuclear import receptors, the importin α molecules. By displaying crystal structures of the peptide containing the KRK basic residue cluster bound to α importins, we show that p.R132S replacement in 131-KRK-133 does not reproduce these interactions. Thus, we propose that the novel mutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein. The present case report is added to a limited series of Pakistani APECED patients who we reviewed from the scientific literature, mostly diagnosed on clinical findings.

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APECED is a rare monogenic recessive disorder caused by mutations in the AIRE gene. In this manuscript, we report a male Turkish patient with APECED syndrome who presented with chronic mucocutaneous candidiasis associated with other autoimmune manifestations developed over the years. The presence of the homozygous R257X mutation of the AIRE gene confirmed the diagnosis of APECED syndrome. We further performed literature review in 23 published Turkish APECED patients and noted that Finnish major mutation R257X is common in Turks. In particular, we assessed retrospectively how often the Ferre/Lionakis criteria would have resulted in earlier diagnosis in Finns, Sardinians and Turks in respect to the classic criteria. Since an earlier diagnosis could have been possible in 18.8% of Turkish, in 23.8% of Sardinian and 38.55% of Finnish patients we reviewed from literature, Ferre/Lionakis criteria could indeed allow in future earlier initiation of immunomodulatory treatments, if found effective in future studies.

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Angiotensin II type-1 receptor autoantibodies (AT1RAb) have been involved in the genesis of primary aldosteronism (PA), both in aldosterone-producing adenoma (APA) and in idiopathic hyperaldosteronism (IHA). In this study, we evaluated the titer of AT1RAb in 44 PA patients (15 with APA and 29 with IHA) compared with 18 normotensive healthy controls who were matched for gender and age. In 17 PA patients (6 APA and 11 IHA) the titer was evaluated under mineralocorticoid receptor (MR) antagonist treatment. We found that PA patients had a significantly higher titer of AT1RAb compared with controls (median values 33 [IQR 15.6] IU/mL vs 17.5 [IQR 10.8] IU/mL, respectively; P < 0.0001). No significant difference of the AT1RAb titer was reported among PA patients, subdivided according to the subtypes and the concomitant MR antagonist therapy. No significant correlation was detected between age, gender, BMI, blood pressure values, baseline aldosterone, ARR, and the AT1RAb titer of all patients enrolled. Our data confirm an increased titer of AT1RAb in both subtypes of PA, independently from the concomitant use of MR antagonists and clinical/biochemical characteristics of PA patients. The small sample of patients and the relatively short time of treatment could have influenced these results. Moreover, the ELISA assay fails to evaluate the bioactivity of AT1RAb. Further studies should evaluate if the subtype, the clinical/biochemical recovery of PA, or both, influence the pathogenetic role of AT1RAb. The possible autoimmune pathogenesis and reversal effect with AT1R blocker treatment in PA patients with AT1RAb positivity is intriguing and requires further study.

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Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.

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