Case Report: Severe Hypocalcemic Episodes Due to Autoimmune Enteropathy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare monogenic disorder, associated with endocrine deficiencies and non-endocrine involvement. Gastrointestinal (GI) manifestations appear in approximately 25% of patients and are the presenting symptom in about 10% of them. Limited awareness among pediatricians of autoimmune enteropathy (AIE) caused by destruction of the gut endocrine cells in APECED patients delays diagnosis and appropriate therapy. We describe an 18-year-old female presenting at the age of 6.10 years with hypoparathyroidism, oral candidiasis and vitiligo. The clinical diagnosis of APECED was confirmed by sequencing the autoimmune regulator-encoding (AIRE) gene. Several characteristics of the disease-Hashimoto's thyroiditis, Addison's disease, diabetes mellitus type 1 and primary ovarian insufficiency-developed over the years. She had recurrent episodes of severe intractable hypocalcemia. Extensive GI investigations for possible malabsorption, including laboratory analyses, imaging and endoscopy with biopsies were unremarkable. Revision of the biopsies and chromogranin A (CgA) immunostaining demonstrated complete loss of enteroendocrine cells in the duodenum and small intestine, confirming the diagnosis of AIE. Management of hypocalcemia was challenging. Only intravenous calcitriol maintained calcium in the normal range. Between hypocalcemic episodes, the proband maintained normal calcium levels, suggesting a fluctuating disease course. Repeated intestinal biopsy revealed positive intestinal CgA immunostaining. The attribution of severe hypocalcemic episodes to AIE emphasizes the need for increased awareness of this unique presentation of APECED. The fluctuating disease course and repeated intestinal biopsy showing positive CgA immunostaining support a reversible effect of GI involvement. CgA immunostaining is indicated in patients with APECED for whom all other investigations have failed to reveal an explanation for the malabsorption.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Autoimmune Polyendocrine Syndrome Complicated by Pulmonary Hypertension.

A 24-years old female was admitted for acute renal failure, melanoderma, hyponatremia, and hyperkalemia. The clinical suspicion of Addison's disease was confirmed by laboratory test and the appropriate replacement therapy with corticosteroids and fludrocortisone was started. In the meantime primary hypothyroidism and diabetes mellitus type 1 were disclosed and treated, thus fulfilling a diagnosis of autoimmune polyendocrine syndrome type 2. Eighteen months later she was admitted for right-sided heart failure. The work-up allowed to diagnose pulmonary arterial hypertension. Here, we report the clinical course and discuss the putative link between these two rare diseases.

Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W). CONCLUSION: With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.

Pubertal development and premature ovarian insufficiency in patients with APECED.

OBJECTIVE: To determine the natural course of pubertal development, growth during puberty, and development of POI in females with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome type I. DESIGN: Longitudinal follow-up study. METHODS: A national cohort of females with APECED aged ≥12 years were followed during 1965-2018. Attainment of adult height was defined when patients' height increased less than 1 cm per year. Diagnosis of POI was based on delayed puberty or POI symptoms with amenorrhea, and/or FSH ≥40 IU/L. RESULTS: Altogether 40 women with APECED were followed up to the average age of 37.3 (range: 14.6-61.9) years; 16 females (40%) were ≥ 40 years. Pubertal development started spontaneously in 34 patients and 29 had spontaneous menarche. POI developed in 28 patients (70%) at the median age of 16.0 years (range: 11.3-36.5), and in 20 of them (71%) before attaining adult height. In 11 cases puberty was induced or completed by hormonal therapy. Patients with POI were significantly shorter at menarche, but adult heights did not differ from non-POI females. Patients with POI had more often primary adrenocortical insufficiency (93% vs 58%, P = 0.017) and ovarian antibodies (81% vs 30%, P=0.003) compared to those with normal ovarian function (n = 12). CONCLUSIONS: POI developed in the majority of patients with APECED, often before or shortly after menarche. Timely commencement of hormonal replacement therapy is important to ensure optimal pubertal development and growth. The possibility of fertility preservation before development of POI in APECED patients should be further studied.

Síndromes poliendocrinos autoinmunes que revelan mecanismos de tolerancia y autoinmunidad / Polyendocrine autoimmune syndromes reveal mechanisms of tolerance and autoimmunity

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[The Schmidt's Syndrome]. / Das Schmidt-Syndrom.

HISTORY AND CLINICAL FINDINGS: We report the case within a 22-year-old patient, initially seen because of fatigue, weight loss and discoloration of the skin. A Hashimoto-Thyroditis had been diagnosed a few months prior to the clinical presentation. DIAGNOSTICS: Blood samples showed a hyponatremia and hyperkalemia. Addison's disease was diagnosed by management of cortisol, ACTH and adrenal antibodies. In combination with the previously diagnosed Autoimmune thyreoiditis the criteria for a Schmidt's Syndrome were fulfilled. TREATMENT AND CLINICAL COURSE: We initiated the substitution of Hydrocortisone (20 mg/d) and Fludrocortisone (0.1 mg/d) in combination with an increased levothyroxin-dosage (100 µg/d). The patient's condition improved over the course of a few days. CONCLUSION: The presented case underlines the importance of focused examinations and diagnostics when dealing with a patient with unspecific symptoms and a pre-existing autoimmune disease. This also applies to patients with a positive family history for autoimmune disorders.

Autoimmune Enteropathy: An Updated Review with Special Focus on Stem Cell Transplant Therapy.

Autoimmune enteropathy (AIE) is a complex disease affecting both children and adults. Although associated with significant morbidity and mortality, the pathophysiology of the disease and its treatment have not been well characterized. This study aims to review the medical literature available on this rare but clinically significant ailment, to help establish a better understanding of its pathophysiology and enumerate the available diagnostic and treatment modalities. A literature search was conducted on PubMed using key terms related to autoimmune enteropathy and intractable diarrhea, with no restrictions on the date of publication or language. We found a total of 98 reports of AIE published in the form of case reports and case series. The evidence reviewed suggests that AIE is a multifaceted disorder that requires a high index of suspicion in the appropriate clinical setting to be able to make an early diagnosis. Current evidence supports the use of supportive care to correct nutritional and metabolic deficiencies, and immunosuppressives and immunomodulators as directed therapies. Hematopoietic stem cell transplant is an aggressive, but successful curative modality for patients with AIE as part of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Cumulative clinical experience with management of AIE has allowed improved outcomes in transplanted and non-transplanted AIE patients even though morbidity and mortality with are still high in patients with this condition. More research is needed to further define the role of new therapies for AIE, and a central registry with participation of multiple institutions might help share and standardize care of patients with this rare but serious condition.

The heterogeneity of autoimmune polyendocrine syndrome type 1: Clinical features, new mutations and cytokine autoantibodies in a Brazilian cohort from tertiary care centers.

Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by multiorgan autoimmunity. We aim at characterizing a multi-center Brazilian cohort of APS1 patients by clinical evaluation, searching mutation in the AIRE gene, measuring serum autoantibodies, and investigating correlations between findings. We recruited patients based on the clinical criteria and tested them for AIRE mutations, antibodies against interferon type I and interleukins 17A, 17F and 22. We identified 12 unrelated families (13 patients) with typical signs of APS1 in the proband, and the screening of relatives recognized an asymptomatic child. Candidiasis was present in all cases, and 19 other manifestations were observed. All patients carried one of 10 different mutations in AIRE, being 3 new ones, and were positive for anti-interferon type I serum antibody. Anti-interleukin-17A levels inversely correlated with the number of manifestations in each patient. This negative correlation may suggest a protective effect of anti-interleukin-17A with a potential therapeutic application.

Unexplained cyanosis caused by hepatopulmonary syndrome in a girl with APECED syndrome.

Autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED) is a rare but devastating primary immunodeficiency disease caused by loss-of-function mutations in autoimmune regulator (AIRE) gene on chromosome 21q22.3. The clinical spectrum of the disease is characterized by a wide heterogeneity because of autoimmune reactions toward different endocrine and non-endocrine organs. Here, we report a 17-year-old Turkish girl diagnosed with APECED at 9 years in whom a novel homozygote mutation in AIRE gene p.R15H (c.44G>A) was found. In the clinical course of the patient, chronic liver disease due to autoimmune hepatitis has evolved resulting in hepatopulmonary syndrome (HPS) which has not been reported before in patients with APECED.

Topical tacrolimus solution in autoimmune polyglandular syndrome-1-associated keratitis.

PURPOSE: To evaluate the efficacy of topical tacrloimus eye drops in the treatment of keratitis associated with autoimmune polyglandular syndrome (APS)-1. METHODS: This is a retrospective review of 10 patients with APS-1. The patients were treated with topical tacrolimus 0.01% solution at The Eye Center, between 1 March 2012 and 30 April 2016. The outcome measures included improvement in visual acuity, photophobia and keratitis following treatment. Clinical assessment was carried out before, during and on the last visit following initiation of therapy. RESULTS: A total of 10 patients were included. There were five male and five female patients. The mean age was 11 years with age range of 3-42 years. The mean duration of treatment with topical tacrolimus was 26 months (range 8-46 months). There was improvement of photophobia in 7 out of 10 patients following therapy with topical tacrolimus. In three patients, the photophobia was persistent. There was no clinically detectable improvement in the severity of keratitis in all patients. The mean best corrected visual acuity was 0.1 before and following therapy. CONCLUSION: Topical tacrolimus is effective in reducing the photophobia in patients with APS-1-associated keratitis, but showed no effects on the severity of keratitis.

Autoimmune encephalitis mimicking sporadic Creutzfeldt-Jakob disease: A retrospective study.

Autoimmune encephalitis associated with anti-voltage-gated potassium channel antibodies are most likely to be misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Our goal was to delineate patients who were initially suspected to have CJD but were later found to have AE. We performed a retrospective clinical review of cases of individuals and made a comparison between groups of patients diagnosed with sCJD and AE. Patients who had rapidly progressing dementia and focal neurological impairment, such as aphasia, gait disturbance, visual disturbance, and depression, at onset were diagnosed with sCJD, whereas epilepsy, hyponatremia and dysautonomia were strong hints for AE. Fluoroscope-positron emission tomography (PET) of patients with AE revealed variable metabolism and normative and long-term immunosuppression were less likely to relapse.

APECED syndrome in childhood: clinical spectrum is enlarging.

Autoimmune polyendocrinopathy-candidiasis-ectodermal-distrophy (APECED) is a rare autosomal recessive disease, which is mainly characterized by the association of many autoimmune diseases, with a classic triad including chronic mucocutaneous candidiasis, hypoparathyroidism and adrenocortical failure. Its clinical spectrum has significantly enlarged in the last years and other non-classic components have been recently described. Aim of this review was to alert pediatricians to these novel clinical aspects of this syndrome, that have been recently included among the autoimmune APECED manifestations: a) chronic lung disease, that may evolve to cor pulmonale and terminal respiratory failure; b) chronic inflammatory demyelinating polineuropathy, with progressive muscular weakness of both arms and legs and sensory loss; c) gastrointestinal dysfunction, with recurrent diarrhea, malabsorption and steatorrhea or chronic constipation. For each of these novel components of APECED, specific autoantibodies against either lung autoantigens or peripheral nerves or tryptophan hydroxylase have been just recently identified.

Seasonal variation of haemoglobin A1c in a Portuguese adult population

Objective Haemoglobin A1c (Hb A1c) is routinely used for monitoring glycemic control in patients with diabetes. Hb A1c seasonal fluctuations can be directly related to different biological, geographical and cultural influences. Our purpose was to evaluate seasonal variation of Hb A1c in a hospital-based adult population over a period of 5 years.Materials and methods We analyzed retrospectively monthly Hb A1c mean values (DCCT, %) based on all the assays performed to adult patients at a tertiary care university Portuguese hospital between 2008-2012.Results We obtained 62,384 Hb A1c valid measurements, with a peak level found in January-February (7.1%), a trough in August-October (6.8%) and an average peak-to-trough amplitude value of 0.3%. This trend was observed in both genders and age subgroups evaluated.Conclusions There is a Hb A1c circannual seasonal pattern with peak levels occurring in winter months in this Portuguese population. This finding should be recognized in daily clinical practice to warrant better clinical and epidemiological interpretation of Hb A1c values. Arch Endocrinol Metab. 2015;59(3):231-5.

Induction of thyroid remission using rituximab in a patient with type 3 autoimmune polyglandular syndrome including Graves' disease and type 1 diabetes mellitus: a case report.

Rituximab (RTX) is a monoclonal antibody that targets the B-cell-specific CD20 antigen. Recent reports indicate that RTX is effective against type 1 diabetes mellitus (T1DM) and hematologic as well as autoimmune diseases. Other studies have indicated that RTX therapy leads to the remission of recurrent or active Graves' disease (GD). However, the efficacy of RTX in Japanese patients with autoimmune polyglandular syndrome (APS) has not been reported to date. Herein, we report the case of a patient with GD and T1DM with sustained endogenous insulin secretion capacity. To protect pancreatic ß cells, we administered RTX at a dose of 500 mg (approximately 300 mg/m2) on 2 occasions 1 week apart. After treatment, no adverse effects were observed, and thyroid stimulating hormone receptor antibody (TRAb) was no longer detectable 4 months after RTX administration. In addition, the reduction in TRAb level improved thyroid function. Notably, the treatment induced remission over a period of 1 year after the diagnosis of GD.

IgG4 antibodies in autoimmune polyglandular disease and IgG4-related endocrinopathies: pathophysiology and clinical characteristics.

PURPOSE OF REVIEW: This review discusses the IgG4-related disease spectrum (IgG4-RD), the autoimmune polyglandular syndromes (APS), the association of IgG4 with APS, and possible pathobiology. RECENT FINDINGS: IgG4-RD is a multiorgan autoimmune disorder characterized by fibrous inflammation, IgG4-positive plasma cell infiltration in affected tissues, and elevated serum concentrations of IgG4. IgG4-RD can affect any organ and has a heterogeneous presentation. Consensus criteria for diagnosis in specific organs have been established. The recognition and diagnosis of IgG4-RD are crucial because the disease responds favorably to immunosuppression (e.g., glucocorticoids, rituximab). The precise mechanisms leading to disease are unknown, but IgG4 antibodies may undergo a half antibody exchange, which renders them incapable of activating the complement pathway. SUMMARY: Despite significant advances in disease recognition and treatment strategies, the disorder remains poorly understood. The precise role of IgG4, whether it is protective or pathogenic, is still being debated.

Kidney involvement in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in a Finnish cohort.

BACKGROUND: Autoimmune tubulo-interstitial nephritis (TIN) is a rare complication of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Previous data on TIN and other renal or urologic manifestations of APECED are sparse. METHODS: We performed a retrospective study on the urinary and renal tract diseases in a cohort of 30 Finnish patients with APECED (mean age 40 years), with special emphasis on the clinical presentation and the immunologic characteristics of TIN. Clinical and laboratory findings, specific anticytokine and kidney-specific antibodies were analysed. RESULTS: Five of the 30 (17%) patients had moderate-to-severe renal failure, including 3 (10%) with TIN, leading to either transplantation, haemodialysis or immunosuppressive treatment. No other cause other than APECED was found for the TIN. All three patients with TIN had circulating antibodies against the distal part of the nephron, as did 30% of all cohort cases. Two had nephrocalcinosis, and two had renal tubular acidosis type 1. Immunosuppressive therapy with mycophenolate mofetil or rituximab in one pediatric case did not revert the TIN, however. CONCLUSIONS: Renal failure should raise concern for TIN in APECED. It discloses some specific features: no uveitis, no glycosuria and inconstant urinalysis anomalies. Regular renal monitoring for any APECED patient should be performed. Circulating antibodies against the distal part of the nephron are frequent and present in all TIN patients, but their pathologic significance is not yet known. Future studies will be needed to understand the triggers leading to overt clinical disease in these patients.

Autoimmune polyglandular syndrome presenting with jaundice and thrombocytopenia.

OBJECTIVE: To report an uncommon presentation of a rare case of autoimmune polyglandular syndrome type IIIb in an elderly woman. CLINICAL PRESENTATION AND INTERVENTION: A 62-year-old woman presented with anaemic symptoms and jaundice. Blood tests showed macrocytic anaemia due to vitamin B12 deficiency with Coombs negative haemolysis. A thyroid function test was consistent with hypothyroidism. Autoimmune antibody assays were positive for anti-parietal cell, anti-intrinsic factor and anti-thyroid peroxidase antibodies. A final diagnosis of autoimmune thyroiditis with pernicious anaemia, which constituted autoimmune polyglandular syndrome type IIIb, was made and the patient was treated with L-thyroxine, vitamin B12 injection and a blood transfusion. She was discharged uneventfully after a week of hospitalization. CONCLUSION: This case showed that the presence of one autoimmune endocrine disease should prompt clinicians to look for other coexisting autoimmune diseases which may be asymptomatic despite positive autoantibodies.