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Abstract Background Hypoparathyroidism (HP) is a rare endocrine disease commonly caused by the removal or damage of parathyroid glands during surgery and resulting in transient (tHP) or chronic (cHP) disease. cHP is associated with multiple complications and comorbid conditions; however, the economic burden has not been well characterized. The objective of this study was to evaluate the healthcare resource utilization (HCRU) and costs associated with post-surgical cHP, using tHP as a reference. Methods This analysis of a US claims database included patients with both an insurance claim for HP and thyroid/neck surgery between October 2014 and December 2019. cHP was defined as an HP claim ≥ 6 months following surgery and tHP was defined as only one HP claim

Background Hypoparathyroidism (HP) is a rare endocrine disease commonly caused by the removal or damage of parathyroid glands during surgery and resulting in transient (tHP) or chronic (cHP) disease. cHP is associated with multiple complications and comorbid conditions; however, the economic burden has not been well characterized. The objective of this study was to evaluate the healthcare resource utilization (HCRU) and costs associated with postsurgical cHP, using tHP as a reference. Methods This analysis of a US claims database included patients with both an insurance claim for HP and thyroid/ neck surgery between October 2014 and December 2019. cHP was defined as an HP claim≥6 months following surgery and tHP was defined as only one HP claim<6 months following surgery. The cHP index date was the first HP diagnosis claim following their qualifying surgery claim, whereas the tHP index date was the last HP diagnosis claim following the qualifying surgery claim. Patients were continuously enrolled at least 1 year pre- and post-index. Patients’ demographic and clinical characteristics, all-cause HCRU, and costs were descriptively analyzed. Total allcause costs were calculated as the sum of payments for hospitalizations, emergency department, office/clinic visits, and pharmacy. Results A total of 1,406 cHP and 773 tHP patients met inclusion criteria. The average age (52.1 years cHP, 53.5 years tHP) and representation of females (83.2% cHP, 81.2% tHP) were similar for both groups. Neck dissection surgery was more prevalent in cHP patients (23.6%) than tHP patients (5.3%). During the 1–2 year follow-up period, cHP patients had a higher prevalence of inpatient admissions (17.4%), and emergency visits (26.0%) than the reference group -tHP patients (14.4% and 21.4% respectively). Among those with a hospitalization, the average number of hospitalizations was 1.5-fold higher for cHP patients. cHP patients also saw more specialists, including endocrinologists (28.7% cHP, 15.8% tHP), cardiologists (16.7% cHP, 9.7% tHP), and nephrologists (4.6% cHP, 3.3% tHP). Conclusion This study demonstrates the increased healthcare burden of cHP on the healthcare system in contrast to patients with tHP. Effective treatment options are needed to minimize the additional resources utilized by patients whose HP becomes chronic. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), or polyglandular autoimmune syndrome type 1 (PAS-1/APS-1), is a rare autosomal recessive disorder linked to mutations in the autoimmune regulator (AIRE) gene. This review provides a detailed analysis of cutaneous manifestations in APECED, focusing on chronic mucocutaneous candidiasis (CMC), alopecia areata (AA), and vitiligo. The classic triad of hypoparathyroidism, adrenal insufficiency, and CMC serves as a diagnostic cornerstone. However, the varied clinical spectrum of APECED, particularly its cutaneous presentations, poses a diagnostic challenge. CMC, often an early sign, varies in prevalence across populations, including Finnish (100%), Irish (100%), Saudi Arabian (80%), Italian (60–74.7%), North American (51–86%), and Croatian (57.1%) populations. Similarly, AA prevalence varies in different populations. Vitiligo also exhibits variable prevalence across regions. The review synthesizes the current knowledge arising from a narrative analysis of 14 significant human studies published in English up to October 2023. Moreover, this paper underscores the importance of early detection and monitoring, emphasizing cutaneous manifestations as key diagnostic indicators. Ongoing research and clinical vigilance are crucial for unraveling the complexities of this rare autoimmune syndrome and enhancing patient care. [ABSTRACT FROM AUTHOR]

Objective: Data are inconclusive regarding pregnancy complications associated with maternal chronic hypoparathyroidism. Therefore, we aimed to compare pregnancy, delivery and neonatal outcomes in patients affected by chronic hypoparathyroidism to those without chronic hypoparathyroidism. Design: A retrospective population‐based study utilising data from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (HCUP‐NIS) database over 11 years from 2004 to 2014 inclusively. Multivariate logistic regression was used to control for confounders. Patients: Patients with chronic hypoparathyroidism compared with those without. Measurements: Obstetric and neonatal outcomes. Results: We identified 204 pregnancies in mothers with chronic hypoparathyroidism and 9,096,584 pregnancies without chronic hypoparathyroidism. After adjusting for age, insurance plan type, obesity, chronic hypertension, thyroid disease, pregestational diabetes mellitus, and previous caesarean section, patients in the hypoparathyroidism group, compared with those without hypoparathyroidism, were found to have an increased rate of preterm birth (<37 weeks) (19.1% vs. 7.2%, aOR: 2.49, 95% confidence interval [CI]: 1.74–3.54, p < 0.0001, respectively); and blood transfusions (4.9% vs. 1.0%, aOR: 4.07, 95% CI: 2.15–7.73, p < ‐0.0001). Neonates to mothers with chronic hypoparathyroidism had a higher rate of congenital anomalies (4.4% vs. 0.4%, aOR: 6.50, 95% CI: 3.31–12.75, p < 0.0001), with comparable rates of small‐for‐gestational‐age neonates and intrauterine foetal death. Conclusion: This is the largest study of chronic hypoparathyroidism in pregnancy to date. We found significant increases in the rates of preterm birth, blood transfusions and congenital anomalies in chronic hypoparathyroidism. Our findings highlight the importance of identifying chronic hypoparathyroidism as a risk factor for pregnancy and neonatal complications, although it remains unknown if maintaining calcium in the target range will mitigate these risks. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism (hypoPT) is a relatively rare endocrine disease, mainly due to thyroid surgery. The classical supplementation with calcium and active vitamin D may represent a challenge to the clinician.

Abstract Background The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. Methods An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. Results As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. Conclusions At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. Trial registration EUPAS16927, NCT01922440

Background: The PARADIGHM registry of adult and pediatric patients with chronic hypoparathyroidism evaluates the long-term safety and effectiveness of treatment with recombinant human parathyroid hormone, rhPTH(1-84), and describes the clinical disease course under conditions of routine clinical practice. In this first report, we detail the registry protocol and describe the baseline characteristics of two adult patient cohorts from an interim database analysis. One cohort after study entry were prescribed rhPTH(1-84), and the other cohort received conventional therapy of calcium and active vitamin D. Methods: An observational study of patients with chronic hypoparathyroidism in North America and Europe, collecting data for ≥10 years per patient. Main outcome measures were baseline patient demographics, clinical characteristics, medications, and disease outcome variables of symptoms, biochemical parameters, and health assessments. Baseline is the enrollment assessment for all variables except biochemical measurements in patients treated with rhPTH(1-84); those measurements were the most recent value before the first rhPTH(1-84) dose. Exclusion criteria applied to the analysis of specified outcomes included pediatric patients, patients who initiated rhPTH(1-84) prior to enrollment, and those who received rhPTH(1-34). Clinically implausible biochemical outlier data were excluded. Results: As of 30 June 2019, data of 737 patients were analyzed from 64 centers; 587 (80%) were women, mean ± SD age 49.1±16.45 years. At enrollment, symptoms reported for patients later prescribed rhPTH(1-84) (n=60) and those who received conventional therapy (n=571), respectively, included fatigue (51.7%, 40.1%), paresthesia (51.7%, 29.6%), muscle twitching (48.3%, 21.9%), and muscle cramping (41.7%, 33.8%). Mean serum total calcium, serum phosphate, creatinine, and estimated glomerular filtration rate were similar between cohorts. Health-related quality of life (HRQoL) 36-item Short Form Health Survey questionnaire scores for those later prescribed rhPTH(1-84) were generally lower than those for patients in the conventional therapy cohort. Conclusions: At enrollment, based on symptoms and HRQoL, a greater percentage of patients subsequently prescribed rhPTH(1-84) appeared to have an increased burden of disease than those who received conventional therapy despite having normal biochemistry measurements. PARADIGHM will provide valuable real-world insights on the clinical course of hypoparathyroidism in patients treated with rhPTH(1-84) or conventional therapy in routine clinical practice. Trial registration: EUPAS16927, NCT01922440 [ABSTRACT FROM AUTHOR]

Introduction: In patients with chronic hypoparathyroidism disordered calcium homeostasis has been associated with risk of cardiovascular diseases, including cardiomyopathy, congestive heart failure, and arrhythmia; however, larger-scale studies are needed to examine these risks. This study evaluated the risk of cardiovascular conditions among patients with chronic hypoparathyroidism. Methods: Adults with and without chronic hypoparathyroidism were selected from a medical insurance claims database in the USA from January 2007 to June 2017, and were followed for up to 5 years. Associations between chronic hypoparathyroidism and incident atrial fibrillation (AF), tachyarrhythmia, myocardial infarction (MI), coronary artery disease (CAD), heart failure (HF), stroke, cerebrovascular disease, peripheral vascular disease (PVD), and a combined cardiovascular endpoint of cerebrovascular disease, CAD, HF, and PVD were compared between cohorts using Kaplan–Meier analyses and unadjusted and adjusted Cox proportional hazards models. Results: In 8097 patients with chronic hypoparathyroidism compared with 40,485 patients without, respectively, mean ± SD ages were 58.6 ± 16.3 and 47.3 ± 18.0 years, 76.2% and 54.4% were female, and 19.4% and 9.5% had the combination of cardiovascular findings at baseline. In adjusted analyses, patients with chronic hypoparathyroidism had significantly higher risk (adjusted hazard ratio and 95% confidence interval) of incident AF (1.72; 1.51–1.97), tachyarrhythmia (1.68; 1.32–2.14), MI (1.18; 1.01–1.38), CAD (1.39; 1.26–1.54), HF (1.64; 1.46–1.84), stroke (1.45; 1.31–1.62), cerebrovascular disease (1.48; 1.34–1.62), PVD (1.66; 1.51–1.81), and combined cardiovascular endpoint (1.63; 1.52–1.75), all P < 0.001 except P = 0.036 for MI, compared with patients without chronic hypoparathyroidism. Conclusions: This large retrospective cohort study showed that chronic hypoparathyroidism was associated with increased risk of incident cardiovascular conditions and arrhythmias. Results should be evaluated in light of limitations inherent to claims database analyses. Further studies are warranted to investigate reasons for these risks and to develop strategies for reducing cardiovascular conditions in patients with chronic hypoparathyroidism. [ABSTRACT FROM AUTHOR]

Introduction: Chronic hypoparathyroidism, treated with conventional therapy of oral calcium supplements and active vitamin D, may increase the risk of kidney complications. This study examined risks of development and progression of chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR) decline in patients with chronic hypoparathyroidism.Methods: A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017 included patients with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism followed for up to 5 years. Main outcome measures were (1) development of CKD, defined as new diagnosis of CKD stage 3 and higher or ≥ 2 eGFR measurements < 60 ml/min/1.73 m2 ≥ 3 months apart, (2) progression of CKD, defined as increase in baseline CKD stage, (3) progression to end-stage kidney disease (ESKD), and (4) eGFR decline ≥ 30% from baseline. Time-to-event analyses included Kaplan-Meier analyses with log-rank tests, and both unadjusted and adjusted Cox proportional hazards models were used to compare outcomes between cohorts.Results: The study included 8097 adults with and 40,485 without chronic hypoparathyroidism. In Kaplan-Meier analyses, patients with chronic hypoparathyroidism had higher risk of developing CKD and CKD progression and higher rates of eGFR decline (all P < 0.001). In multivariable Cox models adjusted for baseline characteristics, hazard ratios (95% confidence intervals [CIs]) were 2.91 (2.61-3.25) for developing CKD, 1.58 (1.23-2.01) for CKD stage progression, 2.14 (1.51-3.04) for progression to ESKD, and 2.56 (1.62-4.03) for eGFR decline (all P < 0.001) among patients with chronic hypoparathyroidism compared with those without hypoparathyroidism.Conclusion: Patients with chronic hypoparathyroidism have increased risk of development and progression of CKD and eGFR decline compared with those without hypoparathyroidism. Further studies are warranted to understand underlying mechanisms for the associations between chronic hypoparathyroidism and kidney disease. [ABSTRACT FROM AUTHOR]

Introduction: Chronic hypoparathyroidism managed with conventional treatment, comprising oral administration of calcium and active vitamin D, has been associated with renal complications, including nephrolithiasis and nephrocalcinosis. Further larger-scale studies are needed to examine these risks. This study evaluated the risk of nephrolithiasis and nephrocalcinosis in patients with chronic hypoparathyroidism.Methods: A retrospective cohort study using a managed care claims database in the United States from January 2007 to June 2017. Included patients were those with chronic hypoparathyroidism (excluding those receiving parathyroid hormone) and randomly selected patients without hypoparathyroidism over a maximum of 5-year follow-up. The main outcome measures were nephrolithiasis, identified by diagnosis codes or procedure codes for removing kidney stones, and nephrocalcinosis, identified by diagnosis codes.Results: The nephrolithiasis analyses included 8097 adult patients with hypoparathyroidism and 40,485 adult patients without hypoparathyroidism. After excluding patients with a diagnosis of nephrocalcinosis at baseline, nephrocalcinosis analyses included 8051 patients with hypoparathyroidism and 40,466 patients without hypoparathyroidism. During 5 years of follow-up, patients with chronic hypoparathyroidism had significantly increased risk of nephrolithiasis and nephrocalcinosis in Kaplan-Meier analysis compared with patients without hypoparathyroidism (both P < 0.001). In the adjusted analyses, chronic hypoparathyroidism was associated with higher risks of nephrolithiasis (hazard ratio [HR], 1.81; 95% confidence interval [CI] 1.60-2.04) and nephrocalcinosis (HR, 6.94; 95% CI 4.41-10.92). A sensitivity analysis restricted to patients with at least one kidney imaging examination showed that 2.6% of patients (n = 59) with hypoparathyroidism and 0.5% of patients (n = 20) without hypoparathyroidism (ratio, 5.5; P < 0.001) developed nephrocalcinosis.Conclusions: This large retrospective cohort study showed a statistically significant and clinically meaningful increased risk of nephrolithiasis and nephrocalcinosis in patients who have chronic hypoparathyroidism compared with those who do not have chronic hypoparathyroidism. [ABSTRACT FROM AUTHOR]

Context: Chronic hypoparathyroidism (HypoPT) is conventionally managed with oral calcium and active vitamin D. Recombinant human parathyroid hormone (1-84) (rhPTH[1-84]) is a therapy targeting the pathophysiology of HypoPT by replacing parathyroid hormone.Objective: To compare changes in the estimated glomerular filtration rate (eGFR) in patients with chronic HypoPT receiving or not receiving rhPTH(1-84) during a 5-year period.Design/setting: A retrospective analysis of patients with chronic HypoPT treated with or without rhPTH(1-84).Patients: Sixty-nine patients with chronic HypoPT from 4 open-label, long-term trials (NCT00732615, NCT01268098, NCT01297309, and NCT02910466) composed the rhPTH(1-84) cohort and 53 patients with chronic HypoPT not receiving rhPTH(1-84) from the Geisinger Healthcare Database (01/2004-06/2016) composed the historical control cohort.Interventions: The rhPTH(1-84) cohort (N = 69) received rhPTH(1-84) therapy; the historical control cohort (N = 53) did not receive rhPTH(1-84).Main Outcome Measures: Changes in eGFR from baseline during a 5-year follow-up were examined in multivariate regression analyses.Results: At baseline, demographic characteristics and eGFR were similar between cohorts, though the proportions with diabetes and cardiac disorders were lower in the rhPTH(1-84) cohort. At the end of follow-up, mean eGFR increased by 2.8 mL/min/1.73 m2 in the rhPTH(1-84) cohort, while mean eGFR fell by 8.0 mL/min/1.73 m2 in the control cohort. In the adjusted model, the difference in the annual eGFR change between the rhPTH(1-84) cohort and the control cohort was 1.7 mL/min/1.73 m2 per year (P = 0.009).Conclusions: Estimated glomerular filtration rate was preserved for over 5 years among patients with chronic HypoPT receiving rhPTH(1-84) treatment, contrasting with an eGFR decline among those not receiving rhPTH(1-84). [ABSTRACT FROM AUTHOR]

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.

Hypoparathyroidism, a disorder characterized by hypocalcemia ensuing from inadequate parathyroid hormone secretion, is a rather rare disorder caused by multiple etiologies. When not caused by inadvertent damage or removal of the parathyroids during neck surgery, it is usually genetically determined. Epidemiological figures of this disease are still scarce and mainly limited to countries where non-anonymous databases are available and to surgical case series. Both the surgical and non-surgical forms pose diagnostic challenges. For surgical hypoparathyroidism, transient forms have to be ruled out even in the long term, in order to avoid unnecessary chronic replacement therapy with calcium and calcitriol. Regarding non-surgical hypoparathyroidism, once referred to as idiopathic, a systematic clinically and genetically-driven approach to define the precise diagnosis have to be pursued. In the case of syndromic hypoparathyroidism, patients have to be screened for associated abnormalities. Autoimmune, non-genetic hypoparathyroidism is still a diagnosis of exclusion, since no specific autoantibodies are specific for this condition. [ABSTRACT FROM AUTHOR]

Epidemiological data on prevalence and incidence of chronic hypoparathyroidism are still scarce. This study aimed to establish prevalence of chronic hypoparathyroidism and incidence of surgical hypoparathyroidism using the analysis of electronic anonymous public health care database. Data referred to a 5-year period (2009-2013, Region of Tuscany, Italy, as a sample representative of the whole Mediterranean/European population, estimated mean population: 3,750,000 inhabitants) were retrieved by the analysis of pharmaceutical distribution dataset, containing data related to drugs reimbursed by public health system, hospital discharge and procedures codes, and ICD9 exemption codes for chronic diseases. The application of a specific algorithm was applied to indirectly identify people with chronic hypoparathyroidism as assuming chronic therapy with active vitamin D metabolites (AVDM). The number of people taking AVDM for a period equal to or longer than 6 months till the end of the study period, with ICD9 exemption code for hypoparathyroidism, and with a disease-related discharge code were identified. Within this restricted group, patients with chronic kidney disease and osteoporosis were excluded. The indirect estimate of chronic hypoparathyroidism in a European Mediterranean subpopulation by means of the analysis of chronic therapy with AVDM was 27/100,000 inhabitants (female:male ratio = 2.2:1), with a mean age of 63.5 ± 16.7 years. The risk of developing hypoparathyroidism after neck surgery was 1.5%. While the epidemiological approaches based on disease code and hospital discharge code greatly underestimates the prevalence of hypoparathyroidism, the indirect estimate of this disease through the analysis of prescriptions of AVDM in a European region is in line with the results of studies performed in other regions of the world. [ABSTRACT FROM AUTHOR]

Abstract: Hypoparathyroidism (HP) is clinically characterized by the presence of hypocalcemia, usually associated with specific signs and symptoms that depend on how severe and chronic the disease becomes. HP is usually caused by surgical removal of all four parathyroids, while other forms are rarer. Autoimmune HP can occur as an isolated disease or as part of an autoimmune polyendocrine syndrome. Here we review what is known about parathyroid gland autoimmunity, focusing on recently-proposed parathyroid autoantibody markers, and particularly those directed against NACHT leucine-rich-repeat protein 5 and calcium-sensing receptor. We also describe the clinical characteristics of HP and design a diagnostic algorithm for autoimmune HP. [Copyright &y& Elsevier]

Hypoparathyridism and pseudohypoparathyroidism are the common causes of pathological calcification in the brain. Though in 0.3- 1.5 % cases it can be physiological, we describe a case of pathological basal ganglia calcification due to hypoparathyroidsm. A 39 years old diabetic lady who presented with neuropsychiatric problems and seizures and finally diagnosed as a primary hypoparathyroidism with symptoms related to metastatic calcification in the brain. This case emphasizes the importance of thinking about the whole spectrum of the disease even though the biochemical markers are stable on treatment. [ABSTRACT FROM AUTHOR]

Autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasisectodermal dystrophy syndrome, is a very rare disorder of childhood. It is mainly characterised by the presence of at least two of the following: chronic mucocutaneous candidiasis, chronic hypoparathyroidism and autoimmune Addison's disease. We report on the case of a 12-year-old Ugandan female patient who presented with features that were most consistent with APS-1 (chronic mucocutaneous candidiasis and hypoparathyroidism). Significant clinical improvement was noted following oral antifungal therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]