Autoimmune Polyglandular Syndrome Research Articles

ODP273 Schmidt Syndrome Causing Multiorgan Failure

Abstract Introduction To our knowledge there has not been a case report published on the acute presentation of Schmidt syndrome (Polyglandular Autoimmune Syndrome Type 2) in which all three manifestations of type 1 diabetes mellitus (T1DM), primary adrenal insufficiency, and hypothyroidism were found and diagnosed at the same time. Case Description A 32-year-old male with suspected alcohol abuse presented to the hospital with nausea, vomiting, and weakness of two weeks duration after sustaining a fall. He was admitted for Diabetic Ketoacidosis (DKA) and shock requiring three pressors with unclear etiology. Labs were significant for severe hyponatremia of 113 mmol/L (136-145), elevated anion gap of 22, glucose 206 mg/dL (70-100), bicarbonate 11mmol/L (21-31), beta hydroxybutyrate 5.90 mmol/L (0. 0-0.42), and pH 7.22 (7.35-7.45) with Hemoglobin A1c 14.5% (<5.7). An insulin drip was instituted for DKA and the hyponatremia persisted. Cortisol was found to be suppressed at 3. 0 ug/dL (3.1-22.4) with significantly elevated ACTH 220.4 pg/mL (7.2-63.3) suggesting a new diagnosis of primary adrenal insufficiency. IV hydrocortisone 100 mg q8H was started on day 2 of hospitalization. Thyroid labs showed elevated TSH 10.10 uIU/mL (0.36-3.74) confirming hypothyroidism, prompting initiation of IV levothyroxine. His hospital course was complicated by cardiac arrest and acute respiratory failure requiring intubation. Cardiac work up was negative except for severe non-ischemic cardiomyopathy with significantly reduced ejection fraction of 20-25%. Bronchoscopy was performed and showed no evidence of obstructing pulmonary etiologies. SARS Coronavirus PCR was negative. He also had shock liver along with Disseminated intravascular coagulation (DIC). His kidney function worsened requiring continuous kidney replacement therapy (CRRT). Urine microscopy showed granular casts consistent with acute tubular necrosis. TPO antibodies, adrenal antibodies, GAD antibodies, and Zinc Transporter 8 antibodies all came back positive along with an undetectable C- peptide confirming the diagnosis of Hashimotos hypothyroidism, primary adrenal insufficiency, and T1DM respectively. He was eventually discharged on basal bolus insulin regimen, levothyroxine 75 mcg po daily, fludrocortisone 0. 05 mg po daily, and prednisone 5 mg po daily. The patient had multifactorial shock from an acute presentation of DKA, primary adrenal insufficiency, and hypothyroidism all presenting simultaneously. Conclusion This case illustrates the severe impact of having three endocrine organs affected all at once. The prevalence of Schmidt syndrome is very low at 1: 20,000 in the general population and can be associated with other non-endocrine autoimmune disorders. Prevalence of autoimmune thyroid disease is 70%, T1DM 50%, and Addison's disease is almost 100%. Due to the low prevalence, one needs a high clinical suspicion with the correct lab findings to diagnose this disease. Incorrect diagnoses or a late diagnosis can lead to life threatening consequences to the patient. The mainstay of treatment is hormone replacement, with corticosteroids given before thyroid replacement. Presentation: No date and time listed

PMON317 Rapid Progression of Adrenal insufficiency in Child with Autoimmune Polyendocrine Syndrome Type 1

Abstract Background Autoimmune Polyendocrine Syndrome type 1 (APS-1) is an autosomal recessive rare disease resulting from mutations in the autoimmune regulator gene (AIRE) on chromosome 21q22.3. APS-1 was first described as a syndrome in 1946 as a triad of mucocutaneous candidiasis, primary hypoparathyroidism, and adrenal insufficiency. With an AIRE gene mutation, the immune system will have a T-regulatory cell defect, which leads to a loss of immune tolerance. This will increase the risk of autoimmune disease in the body's organs such as the pancreas, thyroid, adrenal gland, liver, intestine, skin, and parathyroid gland. Clinical case A 6-year-old male was admitted to the pediatric floor for new-onset seizures and tetany. Initial laboratory assessment was concerning for severe hypocalcemia associated with low parathyroid hormone (PTH) and hyponatremia. Blood workup showed: low serum sodium 130 mmol/L (136-144), potassium 4.1 mmol/L(3.4-4.7), carbon dioxide 16 mmol/L; ionized calcium 0.67 mmol/L (1.19-1.41), phosphorus 7.4mg/dL (4.0-7.0), PTH 9.0pg/mL (12.0-88.0). Calcium replacement and calcitriol were initiated with a resolution of symptoms. Further investigations were done for the adrenal gland given his low sodium level. He underwent an ACTH stimulation test that he passed, with a cortisol baseline of 39mcg/dl with a peak of 48mcg/dl. ACTH level was high at 120pg/mL (5-27), and a repeat in 4 weeks was normal at 11pg/ml. His renin activity was elevated at 71ng/ml/hr (1.5-3.5). Renin activity was repeated and was elevated again at 34ng/ml/hr, prompting adrenal antibody testing, which revealed an elevated titer 1: 10 (<1: 10). Due to concern for APS-1, genetic testing was obtained and revealed a pathological variant of AIRE of c.892G>A and c.967_979del consistent with APS-1. He was started on 0.1mg Florinef and was later followed routinely at an outpatient endocrinology clinic. Fifteen months after diagnosis, he had a repeat ACTH stimulation test, and his baseline cortisol was 9.1mcg/dl with a peak at 60 minutes of 9.6mcg/dl (<18). ACTH level was elevated at 425pg/ml at this time. He was started on hydrocortisone replacement. Of note, investigation of siblings revealed a 10-month-old sister with abnormal AIRE mutation and a 17-month-old sister with unexplained death. Conclusion APS-1 can affect multiple organs, and cases can significantly vary in age and the number of affected organs at presentation. The patient presented with atypical presentation as he had hypocalcemia and hypoparathyroidism as an initial abnormality. Typically, adrenal insufficiency appears in the second decade of life but, the patient has it at the time of diagnosis, and it rapidly progresses. Family history plays an essential role in investigating autoimmune disease and warrants further assessment for autoimmune markers. While typically a disease that progresses insidiously into adulthood, cases like ours demonstrate rapid autoimmune disease progression. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Growth alterations in rare forms of primary adrenal insufficiency: a neglected issue in paediatric endocrinology.

Primary adrenal insufficiency (PAI) is an endocrine disorder characterized by direct adrenal failure, with consequent glucocorticoid, and eventually mineralocorticoid, deficiency. In children, the main cause of PAI is congenital adrenal hyperplasia (CAH), due to a loss of function of adrenal steroidogenic enzymes, but also rarer forms, including autoimmune polyglandular syndrome, adrenoleucodistrophy, adrenal hypoplasia congenita, familial glucocorticoid deficiency, and Allgrove's Syndrome, may be observed. In PAI children, growth alterations represent a major issue, as both inadequate and excessive glucocorticoid replacement treatment may lead to reduced growth rate and adult height impairment. However, growth abnormalities are poorly studied in rare forms of paediatric PAI, and specific studies on growth rate in these children are currently lacking. In the present review, the currently available evidence on growth alterations in children with rare PAI forms will be summarized, with a major focus on comorbidities with a potential impact on patients' growth rate.

Umbilical Cord-Derived Mesenchymal Stem Cells for the Treatment of Infertility Due to Premature Ovarian Failure.

Females belonging to the reproductive age group may face challenges regarding infertility or miscarriage due to conditions such as premature ovarian failure (POF). It is the conditionthat happens when a female's ovaries stop working before she is 40. The majority of the causes of POF cases are idiopathic. Other reasons includegenetic disorders (Turner's syndrome, bone morphogenetic protein 15 (BMP15) mutation, galactosemia, mutation of forkhead box protein L2 (FOXL2), growth differentiation factor-9 (GDF9), mutation of luteinizing hormone (LH) and follicle-stimulating hormonereceptors (FSHR), etc.), enzymatic mutation such as aromatase, autoimmune disorders (Addison's disease, vitiligo, systemic lupus erythematosus, myasthenia gravis, autoimmune thyroiditis, autoimmune polyglandular syndrome, etc.), vaccination, and environmental factors (cigarette smoking, toxins, and infections). Manyattempts have been made to treat POF by various methods. Some of the methods of treatment include hormone replacement therapy (HRT), melatonin therapy, dehydroepiandrosterone (DHEA) therapy, and stem cell therapy. Stem cell therapy has proven to be the most efficient form for treating POF as compared to all other options. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) are the best among the other sources of mesenchymal stem cells (MSCs) for the treatment of POF as they have a painless extraction procedure. They have a tremendous capacity for self-repair and regeneration, which helps them in restoring degenerated ovaries. This review includes informationon the causes of POF, its efficacious therapeutic approaches, and the impact of transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) as an option for the therapy of POF. Numerous studies conducted on stem cell therapy provethat it is an effective approach for the treatment of sterility.

Screening patients with autoimmune endocrine disorders for cytokine autoantibodies reveals monogenic immune deficiencies

BackgroundAutoantibodies against type I interferons (IFN) alpha (α) and omega (ω), and interleukins (IL) 17 and 22 are a hallmark of autoimmune polyendocrine syndrome type 1 (APS-1), caused by mutations in the autoimmune regulator (AIRE) gene. Such antibodies are also seen in a number of monogenic immunodeficiencies. ObjectivesTo determine whether screening for cytokine autoantibodies (anti–IFN–ω and anti-IL22) can be used to identify patients with monogenic immune disorders. MethodsA novel ELISA assay was employed to measure IL22 autoantibodies in 675 patients with autoimmune primary adrenal insufficiency (PAI) and a radio immune assay (RIA) was used to measure autoantibodies against IFN-ω in 1778 patients with a variety of endocrine diseases, mostly of autoimmune aetiology. Positive cases were sequenced for all coding exons of the AIRE gene. If no AIRE mutations were found, we applied next generation sequencing (NGS) to search for mutations in immune related genes. ResultsWe identified 29 patients with autoantibodies against IFN-ω and/or IL22. Of these, four new APS-1 cases with disease-causing variants in AIRE were found. In addition, we identified two patients with pathogenic heterozygous variants in CTLA4 and NFKB2, respectively. Nine rare variants in other immune genes were identified in six patients, although further studies are needed to determine their disease-causing potential. ConclusionScreening of cytokine autoantibodies can efficiently identify patients with previously unknown monogenic and possible oligogenic causes of autoimmune and immune deficiency diseases. This information is crucial for providing personalised treatment and follow-up of patients and their relatives.

Ocular Sarcoidosis and Autoimmune Polyglandular Syndrome Type 2: A Case Report

ABSTRACT Purpose to describe a clinical case of ocular sarcoidosis in a patient with Autoimmune Polyglandular Syndrome Type 2 (APS-2). Methods an 86-year-old female diagnosed with APS-2 was referred to our uveitis department with rapid visual loss in her left eye during a 3-month period. Her best-corrected visual acuity (BCVA) was counting fingers in her left eye (OS) and 20/40 in her right eye (OD). Slit-lamp biomicroscopy was unremarkable OD but revealed granulomatous keratic precipitates OS. Fundoscopy revealed bilateral optic disc oedema and +2 and 4+ vitritis (SUN classification) in her OD and OS, respectively. Results the patient underwent chest X-Ray which revealed bilateral hilar lymphadenopathy and fibrosis. On high-resolution computed tomography of the lungs, ground-glass opacities were visible, and a diagnosis of ocular sarcoidosis was presumed. After exclusion of infectious diseases, the patient was treated with methotrexate and oral corticosteroids and there was substantial improvement of the optic nerve oedema and vitritis. At the most recent visit, 2 years later, OS BCVA was 20/50. Conclusion There may be an association between ocular sarcoidosis and APS or other autoimmune disorders.

Inborn errors of immunity and related microbiome.

Inborn errors of immunity (IEI) are characterized by diverse clinical manifestations that are dominated by atypical, recurrent, chronic, or severe infectious or non-infectious features, including autoimmunity, lymphoproliferative disease, granulomas, and/or malignancy, which contribute substantially to morbidity and mortality. Some data suggest a correlation between clinical manifestations of IEI and altered gut microbiota. Many IEI display microbial dysbiosis resulting from the proliferation of pro-inflammatory bacteria or a decrease in anti-inflammatory bacteria with variations in the composition and function of numerous microbiota. Dysbiosis is considered more established, mainly within common variable immunodeficiency, selective immunoglobulin A deficiency, severe combined immunodeficiency diseases, Wiskott–Aldrich syndrome, Hyper-IgE syndrome, autoimmune polyendocrinopathy–candidiasis–ectodermal-dystrophy (APECED), immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, IL-10 receptor deficiency, chronic granulomatous disease, and Kostmann disease. For certain IEIs, the specific predominance of gastrointestinal, respiratory, and cutaneous involvement, which is frequently associated with dysbiosis, justifies the interest for microbiome identification. With the better understanding of the relationship between gut microbiota, host immunity, and infectious diseases, the integration of microbiota modulation as a therapeutic approach or a preventive measure of infection becomes increasingly relevant. Thus, a promising strategy is to develop optimized prebiotics, probiotics, postbiotics, and fecal microbial transplantation to rebalance the intestinal microbiota and thereby attenuate the disease activity of many IEIs.

New Approach to Addison Disease: Oral Manifestations Due to Endocrine Dysfunction and Comorbidity Burden.

This review highlights oral anomalies with major clinical impact in Addison disease (AD), including dental health and dermatologic features, through a dual perspective: pigmentation issues and AD comorbidities with oral manifestations. Affecting 92% of AD patients, cutaneomucosal hyperpigmentation is synchronous with or precedes general manifestations by up to a decade, underlying melanocytic infiltration of the basal epidermal layer; melanophages in the superficial dermis; and, rarely, acanthosis, perivascular lymphocytic infiltrate, and hyperkeratosis. Intraoral pigmentation might be the only sign of AD; thus, early recognition is mandatory, and biopsy is helpful in selected cases. The buccal area is the most affected location; other sites are palatine arches, lips, gums, and tongue. Pigmented oral lesions are patchy or diffuse; mostly asymptomatic; and occasionally accompanied by pain, itchiness, and burn-like lesions. Pigmented lingual patches are isolated or multiple, located on dorsal and lateral areas; fungiform pigmented papillae are also reported in AD individuals. Dermoscopy examination is particularly indicated for fungal etiology; yet, it is not routinely performed. AD’s comorbidity burden includes the cluster of autoimmune polyglandular syndrome (APS) type 1 underlying AIRE gene malfunction. Chronic cutaneomucosal candidiasis (CMC), including oral CMC, represents the first sign of APS1 in 70–80% of cases, displaying autoantibodies against interleukin (IL)-17A, IL-17F ± IL-22, and probably a high mucosal concentration of interferon (IFN)-γ. CMC is prone to systemic candidiasis, representing a procarcinogenic status due to Th17 cell anomalies. In APS1, the first cause of mortality is infections (24%), followed by oral and esophageal cancers (15%). Autoimmune hypoparathyroidism (HyP) is the earliest endocrine element in APS1; a combination of CMC by the age of 5 years and dental enamel hypoplasia (the most frequent dental complication of pediatric HyP) by the age of 15 is an indication for HyP assessment. Children with HyP might experience short dental roots, enamel opacities, hypodontia, and eruption dysfunctions. Copresence of APS-related type 1 diabetes mellitus (DM) enhances the risk of CMC, as well as periodontal disease (PD). Anemia-related mucosal pallor is related to DM, hypothyroidism, hypogonadism, corresponding gastroenterological diseases (Crohn’s disease also presents oral ulceration (OU), mucogingivitis, and a 2–3 times higher risk of PD; Biermer anemia might cause hyperpigmentation by itself), and rheumatologic diseases (lupus induces OU, honeycomb plaques, keratotic plaques, angular cheilitis, buccal petechial lesions, and PD). In more than half of the patients, associated vitiligo involves depigmentation of oral mucosa at different levels (palatal, gingival, alveolar, buccal mucosa, and lips). Celiac disease may manifest xerostomia, dry lips, OU, sialadenitis, recurrent aphthous stomatitis and dental enamel defects in children, a higher prevalence of caries and dentin sensitivity, and gingival bleeding. Oral pigmented lesions might provide a useful index of suspicion for AD in apparently healthy individuals, and thus an adrenocorticotropic hormone (ACTH) stimulation is useful. The spectrum of autoimmune AD comorbidities massively complicates the overall picture of oral manifestations.

A novel AIRE mutation leads to autoimmune polyendocrine syndrome type-1.

Autoimmune polyendocrine syndrome type-1 (APS-1) is a rare inherited monogenic autoimmune disease characterized by the presence of at least two of three following major clinical features: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. Mutations in autoimmune regulator (AIRE) gene have been found to contribute to APS-1. In the present study, we reported a 36-years-old male APS-1 patient who presented with hypoparathyroidism and Addison’s disease. The proband underwent complete clinical examinations and mutation screening was performed by Sanger sequencing on AIRE gene. A novel homozygous mutation in exon 9 of the AIRE gene (c.1024C>T) was identified. Based on sequencing findings, HEK293T cell-based assays were conducted to analyze the subcellular localization and mutant transcript processing. Our results revealed that p.Q342X mutant localized in nuclear speckles and exerted a dominant-negative effect on wildtype AIRE function. We reported the c.1024C>T mutation of AIRE gene for the first time, which enriched the AIRE mutation database and contributed to further understanding of APS-1.

Autoimmune polyglandular syndrome type 1 in siblings: assembling the jigsaw puzzle

Autoimmune polyglandular syndrome type 1 in siblings: assembling the jigsaw puzzle

SYSTEMIC AND ORAL MANIFESTATIONS OF AUTOIMMUNE POLYGLANDULAR SYNDROME TYPE 1

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare condition of autosomal recessive and monogenic inheritance, which is characterized clinically by at least 2 signs of the classic triad: mucocutaneous candidiasis, hypoparathyroidism, and Addison's disease. The aim of this study is to report the systemic and oral manifestations of APS-1 in a 42-year-old woman. Among other systemic characteristics, the patient had hypoparathyroidism, type I diabetes mellitus, and autoimmune hepatitis. Chronic hyperplastic candidiasis (CHC) was the main oral manifestation present, and this was diagnosed clinically and through exfoliative cytology. In addition, microstomy, angular cheilitis, xerostomia, enamel hypoplasia, and microdontia were present. The initial treatment plan included the management of CHC with local and systemic antifungals, which resulted in significant improvement of the lesions. Unfortunately, the patient died from complications of APS-1 and was unable to finalize the proposed treatment plan.

Adrenal crisis prompted by SARS-CoV-2 infection in a patient with autoimmune polyglandular syndrome type 1 (APS type 1).

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Adrenal hemorrhage following direct oral anticoagulant (DOAC) therapy: two case reports and literature review

BackgroundAdrenal hemorrhage (AH) is a rare condition that can result in a life-threatening medical emergency. This medical condition could be caused by several underlying factors, one of which is the use of anticoagulants. As far as we are aware, direct oral anticoagulant (DOAC) agents are a rare but possible cause of AH.Case presentationHerein, we described two cases of AH due to DOACs. The first case was a 35-year-old Iranian woman with a past medical history of Hashimoto thyroiditis who was being treated with apixaban due to the previous thrombosis. Her first symptoms of AH (November 2021) were strangely similar to symptoms of autoimmune Addison disease (AAD) which led to a confirmed diagnosis of autoimmune polyendocrine syndrome type 2 (APS-2). An abdominal MRI revealed an oval shape well-encapsulated cystic mass with a diameter of 20 × 14 mm with a thick and low signal intensity rim in the left adrenal gland, highly suggestive of sub-acute left-sided AH. Our second case was an 89-year-old Iranian woman who had been admitted to the hospital (August 2021) with low blood pressure and disorientation. At the beginning of her admission, the evaluation showed hyponatremia, and further evaluations confirmed adrenal insufficiency (AI). The patient reported rivaroxaban usage for deep vein thrombosis prophylaxis after femur fixation surgery. Her abdominal CT scans showed bilateral adrenal masses highly suggestive of AH. Her follow-up examination showed persistent AI after three months.ConclusionGiven the history of our cases, physicians should be aware of AH in patients receiving DOACs, particularly in elderly patients who are at high risk of bleeding. It is also worth noting that AH can occur in any patient with any medical history and history of DOAC use, which is why patients must be closely monitored.

Blue scales on an “iced” scalp

Although the diagnosis of actinic keratosis (AK) is mainly clinical, dermoscopy is a highly useful and accurate diagnostic technique. The dermoscopic features of AK include the strawberry pattern with white areas, keratotic, follicular openings, a pseudonetwork, and rosettes [1]. An 82-year-old male with a personal history of type 3 autoimmune polyglandular syndrome and hypertension was referred to the dermatology department due to the presence of scaly lesions located on the scalp and forehead. A physical examination revealed asymptomatic, keratotic lesions on the forehead and in the occipital region (Fig. 1a). The patient denied the application of any product except toning shampoo for white hair. Interestingly, the lesions had a blue, superficial scale, although they clinically resembled AK. Dermoscopy evidenced an erythematous background with multiple, arctic-blue, keratotic plugs (Fig. 1b). Moreover, a superficial excision of one of the lesions was performed, evidencing solar elastosis and a chronic dermal infiltrate, as well as basal keratinocytes with loss of polarity, presenting with irregular nuclei (Fig. 2). Thus, the clinical and pathological correlation confirmed the diagnosis of AK. The lesions were treated with cryotherapy leading to their resolution. Figure 1: (a) Clinical presentation of the cutaneous lesions: numerous bluish-gray, scaly lesions in the occipital area; the patient confirmed using toning shampoo for white hair containing Acid Violet 43. (b) Dermoscopy of one of the lesions: an erythematous background, as well as numerous arctic-blue, keratotic plugs; the blue scale compatible with the iceberg sign present in AK neglecta. Figure 2: Solar elastosis and a chronic dermal infiltrate, as well as basal keratinocytes with loss of polarity presenting with irregular nuclei; findings compatible with the clinical suspicion of AK; no basophilic amorphous material present in the stratum corneum (H&E, 20×). Blue AK has been termed AK neglecta while the dermoscopic blue coloration the iceberg sign [2,3]. The latter is described to be caused both by sunscreens containing titanium dioxide [3] or shampoos containing Acid Violet (present in the shampoo that the patient used) [2]. Moreover, this exogenous pigmentation may easily be removed with alcohol [3]. Histologically, a basophilic amorphous material on the stratum corneum is described to be present [2]. A lack of this finding in our case might have been explained due to the 10% formol used to preserve the biopsy, eliminating the pigment. Recognizing this presentation is essential due to the widespread use of toning shampoos and sunscreens among the elder population.

Autoimmune polyglandular syndrome type 1

Type 1 autoimmune polyglandular syndrome (APS1) is a rare disease, with an unknown prevalence in the Russian population. Due to the low awareness of doctors, it takes more time to make the accurate diagnosis and provide correct medical care. This article describes classical features of APS1 and a clinical case of a patient, who did not have one of the most common first manifestation of the disease - mucocutaneous candidiasis. Hypocalcemia was detected much later than the first clinical manifestations in the form of generalized seizures occurred. Patient also suffers from tapetoretinal abiotrophy, he completely lost vision in childhood which made it difficult for the doctor and patient to interact in the treatment of the disease.

Extrathymic expression of Aire controls the induction of effective TH17 cell-mediated immune response to Candida albicans.

Patients with loss of function in the gene encoding the master regulator of central tolerance AIRE suffer from a devastating disorder called autoimmune polyendocrine syndrome type 1 (APS-1), characterized by a spectrum of autoimmune diseases and severe mucocutaneous candidiasis. Although the key mechanisms underlying the development of autoimmunity in patients with APS-1 are well established, the underlying cause of the increased susceptibility to Candida albicans infection remains less understood. Here, we show that Aire+MHCII+ type 3 innate lymphoid cells (ILC3s) could sense, internalize and present C. albicans and had a critical role in the induction of Candida-specific T helper 17 (TH17) cell clones. Extrathymic Rorc-Cre-mediated deletion of Aire resulted in impaired generation of Candida-specific TH17 cells and subsequent overgrowth of C. albicans in the mucosal tissues. Collectively, our observations identify a previously unrecognized regulatory mechanism for effective defense responses against fungal infections.

Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.

Spectrum of germline AIRE mutations causing APS-1 and familial hypoparathyroidism.

ObjectiveThe autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disorder characterised by immune dysregulation and autoimmune endocrine gland destruction. APS-1 is caused by biallelic mutations affecting the autoimmune regulator (AIRE) gene on chromosome 21q22.3, which facilitates immunological self-tolerance. The objective was to investigate >300 probands with suspected APS-1 or isolated hypoparathyroidism for AIRE abnormalities.MethodsProbands were assessed by DNA sequence analysis. Novel variants were characterised using 3D modelling of the AIRE protein. Restriction enzyme and microsatellite analysis were used to investigate for uniparental isodisomy.ResultsBiallelic AIRE mutations were identified in 35 probands with APS-1 and 5 probands with isolated hypoparathyroidism. These included a novel homozygous p.(His14Pro) mutation, predicted to disrupt the N-terminal caspase activation recruitment domain of the AIRE protein. Furthermore, an apparently homozygous AIRE mutation, p.Leu323fs, was identified in an APS-1 proband, who is the child of non-consanguineous asymptomatic parents. Microsatellite analysis revealed that the proband inherited two copies of the paternal mutant AIRE allele due to uniparental isodisomy. Hypoparathyroidism was the most common endocrine manifestation in AIRE mutation-positive probands and >45% of those harbouring AIRE mutations had at least two diseases out of the triad of candidiasis, hypoparathyroidism, and hypoadrenalism. In contrast, type 1 diabetes and hypothyroidism occurred more frequently in AIRE mutation-negative probands with suspected APS-1. Around 30% of AIRE mutation-negative probands with isolated hypoparathyroidism harboured mutations in other hypoparathyroid genes.ConclusionsThis study of a large cohort referred for AIRE mutational analysis expands the spectrum of genetic abnormalities causing APS-1.

Polyglandular autoimmune syndrome in the elderly: a case report

Polyglandular autoimmune syndrome in the elderly: a case report

Autoimmune polyglandular syndrome Type 2 presenting with autoimmune thyroid disease, diabetes mellitus Type 1 and addison's disease

Autoimmune polyglandular syndrome Type 2 presenting with autoimmune thyroid disease, diabetes mellitus Type 1 and addison's disease