VKH with APECED in a Two-Year-Old Child: A Rare Concomitant Diagnosis in an Unprecedented Age.

PURPOSE: To present a case of Vogt Koyanagi Harada (VKH) associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) in a two-year-old. CASE PRESENTATION: A two-year-old type 1 diabetic with hypothyroidism presented with impaired fixation. Ocular examination revealed right vitritis, choroiditis, a hyperemic disc, and an area of exudative detachment. At the same time, there was no fundus view in the left eye, and ultrasonographic assessment revealed vitritis and a thickened choroid. Patient developed sunset glow fundus with alopecia, poliosis and vitiligo and a diagnosis of complete VKH with APECED was made. CONCLUSION: APECED is a rare endocrine disorder and has been reported to be associated with VKH twice. Likewise, VKH is commonly present in much older patients; this is the first time ever to be diagnosed in a two-year-old child.

Autoimmune Polyglandular Syndrome Type 3 Complicated with IgG4-related Disease.

A 52-year-old Japanese woman developed type 1 diabetes mellitus (type 1 DM) at 41 years old. She became complicated with Hashimoto's disease and showed swelling of both submandibular glands, which was diagnosed as IgG4-related disease (IgG4-RD). This is a rare case of a Japanese patient with autoimmune polyglandular syndrome type 3A (APS-3A) coexisting with autoimmune thyroid disease (AITD) and type 1 DM complicated by IgG4-RD. Bilateral submandibular gland resection was successfully performed without steroid therapy. We discuss the possibility that the immunological pathogenic mechanisms of APS-3A and IgG4-RD are related.

A case report of anti-GAD65 antibody-positive autoimmune encephalitis in children associated with autoimmune polyendocrine syndrome type-II and literature review.

Background: Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme for the synthesis of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Antibodies against glutamic acid decarboxylase (GAD) are associated with various neurologic conditions described in patients, including stiff person syndrome, cerebellar ataxia, refractory epilepsy, and limbic and extra limbic encephalitis. While there are few case reports and research on anti-GAD65 antibody-associated encephalitis in adults, such cases are extremely rare in pediatric cases. Methods: For the first time, we report a case of anti-GAD65-positive autoimmune encephalitis associated with autoimmune polyendocrine syndrome (APS) type II. We reviewed previously published pediatric cases of anti-GAD65 autoimmune encephalitis to discuss their clinical features, laboratory tests, imaging findings, EEG patterns, and prognosis. Case presentation: An 8-year-old, male child presented to the outpatient department after experiencing generalized convulsions for twenty days. The child was admitted for epilepsy and had received oral sodium valproate (500 mg/day) in another center, where investigations such as USG abdomen and MRI brain revealed no abnormalities, however, had abnormal EEG with diffuse mixed activity in the left anterior middle prefrontal temporal region. On the follow-up day, a repeat blood test showed a very low serum drug concentration of sodium valproate hence the dose was increased to 750 mg/day. Then, the child experienced adverse effects including increased sleep, thirst, and poor appetite, prompting the parents to discontinue the medication. A repeat MRI showed increased signals on FLAIR sequences in the right hippocampus hence admitted for further management. The child's past history included a diagnosis of hypothyroidism at the age of 4, and receiving levothyroxine 75 mcg once daily. His parents are healthy with no history of any similar neurological, autoimmune, or genetic diseases, but his uncle had a history of epilepsy. At presentation, he had uncontrolled blood glucose levels with elevated HbA1c levels. Additionally, the serum and CSF autoantibodies were positive against the anti-GAD65 antibody with the titer of 1:100 and 1:32 respectively. The patient was managed with a mixed type of insulin regimen and received first-line immunotherapy (intravenous immunoglobulin, IVIG) for five consecutive days, followed by oral prednisone and sodium valproate as an antiepileptic drug. Upon achieving a favorable clinical outcome, the patient was discharged with oral medications. Results: Among the 15 pediatric patients reported in this literature, nine presented with limbic encephalitis (LE), three with extralimbic encephalitis (ELE), and three with a combination of limbic and extralimbic encephalitis. Most of these cases exhibited T2-W FLAIR hyperintensities primarily localized to the temporal lobes in the early phase, progressing to hippocampal sclerosis/atrophy in the later phase on MRI. EEG commonly showed slow or spike waves on frontotemporal lobes with epileptic discharges. Prognostic factors varied among patients, with some experiencing persistent refractory seizures, type-1 diabetes mellitus (T1DM), persistent memory impairment, persistent disability requiring full assistance, and, in severe cases, death. Conclusion: Our findings suggest that anti-GAD65 antibody-positive autoimmune encephalitis patients may concurrently present with other APS. Our unique case presented with multiple endocrine syndromes and represents the first reported occurrence in children. Early diagnosis and timely initiation of immunotherapy are crucial for improving clinical symptoms and reducing the likelihood of relapses or permanent disabilities. Therefore, emphasis should be placed on prompt diagnosis and appropriate treatment implementation to achieve better patient outcomes.

Autoimmune amelogenesis imperfecta in patients with APS-1 and coeliac disease.

Ameloblasts are specialized epithelial cells in the jaw that have an indispensable role in tooth enamel formation-amelogenesis1. Amelogenesis depends on multiple ameloblast-derived proteins that function as a scaffold for hydroxyapatite crystals. The loss of function of ameloblast-derived proteins results in a group of rare congenital disorders called amelogenesis imperfecta2. Defects in enamel formation are also found in patients with autoimmune polyglandular syndrome type-1 (APS-1), caused by AIRE deficiency3,4, and in patients diagnosed with coeliac disease5-7. However, the underlying mechanisms remain unclear. Here we show that the vast majority of patients with APS-1 and coeliac disease develop autoantibodies (mostly of the IgA isotype) against ameloblast-specific proteins, the expression of which is induced by AIRE in the thymus. This in turn results in a breakdown of central tolerance, and subsequent generation of corresponding autoantibodies that interfere with enamel formation. However, in coeliac disease, the generation of such autoantibodies seems to be driven by a breakdown of peripheral tolerance to intestinal antigens that are also expressed in enamel tissue. Both conditions are examples of a previously unidentified type of IgA-dependent autoimmune disorder that we collectively name autoimmune amelogenesis imperfecta.

A 20-year study of autoimmune polyendocrine syndrome type II and III in Taiwan.

Purpose: Autoimmune polyendocrine syndrome (APS) is a rare immune-endocrinopathy characterized by the failure of at least two endocrine organs. Clinical characteristics have mainly been described in the Western population. This study comprehensively analyzed the demographic and clinical manifestations of APS II and APS III in Taiwan. Methods: Patients aged ≥20 years with a diagnosis of APS II or APS III in ten hospitals between 2001 and 2021 were enrolled. The clinical and serological characteristics of the patients were retrospectively reviewed. Results: Among the 187 enrolled patients (45 men and 142 women); only seven (3.7%) had APS II, while the others had APS III. Fifty-five patients developed hyperthyroidism and 44 patients developed hypothyroidism. Men were diagnosed with APS at a younger age than women (16.8 vs 27.8 years old, P = 0.007). Most patients were initially diagnosed with type 1 diabetes mellitus. There was a positive correlation between age at diagnosis and the likelihood of developing thyroid dysfunction. For every year older patients were diagnosed with APS III, the risk of developing hyperthyroidism increased by 3.6% (P = 0.002), and the risk of developing hypothyroidism increased by 3.7% (P = 0.035). Positive anti-parietal cell antibodies (APCA) were associated with a higher risk of anemia in patients with APS III (P < 0.001). Conclusion: This study provides the most comprehensive analysis of APS II and APS III in Asia. The percentage of patients with APS II was significantly lower than in the Western population. A second autoimmune endocrinopathy may develop several years after the first one. APCA examination is valuable when evaluating anemia in patients with APS.

Leber congenital amaurosis as the initial and essential manifestation in a Chinese patient with autoimmune polyglandular syndrome Type 1.

PURPOSE: Autoimmune polyglandular syndrome Type 1 (APS-1) is a rare autosomal recessive disorder caused by defects in the autoimmune regulator (AIRE) gene. Patients are generally diagnosed at ages between five and fifteen years when they exhibit three or more manifestations, most typically mucocutaneous candidiasis, autoimmune Addison's disease, and hypoparathyroidism. Our study aims to report the first case of a Chinese APS-1 patient, presented with LCA as the initial and essential clinical feature of this rare syndrome. METHODS: Detailed medical and family history were recorded for the patient. Also, the comprehensive ophthalmological examinations were conducted. Whole exome sequencing (WES) was applied to screen pathogenic variants. Sanger sequencing validation and segregation analysis were further performed for confirmation. RESULTS: A 3-year-old boy with severely impaired vision and initially referred as LCA. However, with a detailed history review, oral candidiasis, dental enamel hypoplasia, and nail candida infection were revealed. Moreover, genetic analysis revealed the homozygous c.769C>T (p.R257X) in AIRE gene (NM_000383.3) as the causative variant. CONCLUSION: We presented one case diagnosed with APS-1 based on clinical characteristics and genetic analysis. Our study demonstrated that LCA could serve as a warning sign for APS-1 and a potential trigger of early screening, which might prevent life-threatening complications.

Alopecia areata and occurrence of vitiligo and hypothyroidism in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inherited disorder of immunity which leads to increased risk for mucocutaneous candidiasis and multiorgan autoimmune disease. While alopecia areata (AA) has been described in some patients with APECED, the extent and timing of AA is not well established and extent and timing of concomitant vitiligo and hypothyroidism has not been described. We evaluated an APECED cohort followed at the National Institutes of Health for the timing of development of associated diseases. We found AA occurred earlier in those with APECED than in the general population, was rarely the first sign of APECED, and the timing of AA onset did correlate with the timing of onset of vitiligo or hypothyroidism which also occurred at high rates and early age.

Autoimmune adrenal insufficiency in children: a hint for polyglandular syndrome type 2?

BACKGROUND: Primary adrenal insufficiency (PAI) in childhood is a life-threatening disease most commonly due to impaired steroidogenesis. Differently from adulthood, autoimmune adrenalitis is a rare condition amongst PAI's main aetiologies and could present as an isolated disorder or as a component of polyglandular syndromes, particularly type 2. As a matter of fact, autoimmune polyglandular syndrome (APS) type 2 consists of the association between autoimmune Addison's disease, type 1 diabetes mellitus and/or Hashimoto's disease. CASE PRESENTATION: We report the case of an 8-year-old girl who presented Addison's disease and autoimmune thyroiditis at an early stage of life. The initial course of the disease was characterized by numerous crises of adrenal insufficiency, subsequently the treatment was adjusted in a tertiary hospital with improvement of disease control. CONCLUSIONS: APS type 2 is a rare condition during childhood, probably because it may remain latent for long periods before resulting in the overt disease. We recommend an early detection of APS type 2 and an adequate treatment of adrenal insufficiency in a tertiary hospital. Moreover, we underline the importance of a regular follow-up in patients with autoimmune diseases, since unrevealed and incomplete forms are frequent, especially in childhood.

SARS-CoV-2-induced adrenal crisis in a patient with autoimmune polyglandular syndrome type 1: case report.

Autoimmune polyglandular syndromes (APS) are rare disorders characterized by the coexistence of endocrine and non-endocrine dysfunctions mediated by autoimmune mechanisms. Autoimmune polyglandular syndrome type 1 is defined as coexistence of chronic mucocutaneous candidiasis, hypoparathyroidism, and autoimmune adrenal insufficiency. Addison's disease as the obligatory component is potentially life threatening.Herein, we demonstrate a case of a 44-year-old woman with APS-1 (hypoparathyroidism, adrenal insufficiency, hypergonadotropic hypogonadism) and SARS-CoV-2-induced adrenal crisis. The patient presented with the typical manifestations of hypotensive shock, electrolyte disturbances of hyponatremia and hyperkalemia, and hypoglycaemia.Our case report illustrates the increased risk of severe course of COVID-19 in APS-1 syndrome patients along with heightened exposure to medical complications. The case reinforced the significance of a timely diagnosis, appropriate treatment, and education of patients with such a rare condition like APS-1.

Successful live birth following a short course of glucocorticoid suppression in a patient with autoimmune polyglandular syndrome type 2 and premature ovarian insufficiency: A case report.

A 32-year-old nulliparous woman with premature ovarian insufficiency POI and autoimmune polyglandular syndrome type 2 (APS-2), presented to our fertility center with a 2.5-year history of amenorrhoea. Controlled ovarian hyperstimulation (COH), with high dose gonadotropins, failed to promote antral follicle growth. The patient was given a short, 4-week course of 2 mg dexamethasone prior to a repeat COH cycle, which resulted in the retrieval of good oocyte numbers and eventual live birth from a thawed embryo transfer.

[Autoimmune polyglandular syndrome type 3 diagnosed with cerebral venous sinus thrombosis: a case report].

A 67-year-old woman with a history of diabetes mellitus was admitted to our hospital with convulsions due to bilateral frontal subcortical hemorrhages. MR venography showed a defect in the superior sagittal sinus, and thrombi were demonstrated in the same lesion with head MRI three-dimensional turbo spin echo T1-weighted imaging. She was diagnosed with cerebral venous sinus thrombosis. As precipitating factors, we found high levels of free T3 and T4, low levels of thyroid stimulating hormone, anti-thyroid stimulating hormone receptor antibody, and anti-glutamic acid decarboxylase antibody with her. We diagnosed her with autoimmune polyglandular syndrome type 3 with Graves' disease and slowly progressive type 1 diabetes mellitus. Since she also had nonvalvular atrial fibrillation, she was treated with apixaban subsequently to intravenous unfractionated heparin in the acute phase, resulting in partial regression of the thrombi. Autoimmune polyglandular syndrome should be considered when multiple endocrine disorders are identified as precipitating factors for cerebral venous sinus thrombosis.

A Case of Autoimmune Poly Glandular Glandular Syndrome Type 2 (Schmidt's Syndrome).

INTRODUCTION: Autoimmune polyendocrine syndrome (APS) type II (Schmidt's syndrome) is defined by the coexistence of autoimmune Addison's disease with autoimmune thyroid disease and/or type 1 diabetes mellitus. Patients also present with other organ specific autoimmune disorders like hypergonodotropic hypogonadism, vitiligo, chronic atrophic gastritis, pernicious anaemia, autoimmune chronic hepatitis and celiac disease. Many circulating organ-specific antibodies directed against endocrine organs. MATERIALS: A 40 year old female presented to the casualty with multiple episodes of vomiting and giddiness. Patient known case of hypothyroidism since past 4 years but was not on medications recently 1 month back patient was started on Thyroxine supplementation. History of menopause 8 years back present (premature). On examination patient had cold clammy extremity with signs of dehydration. Hyperpigmentation of face and gums was noted. PR -120/min thready pulse BP- 70/50 mmhg. Blood pressure was stabilised with fluid resuscitation. On investigation hyponatremia with hyperkalemia was present. In view of adrenal insufficiency co-syntropin stimulation test was done which came in favour of PRIMARY ADRENAL INSUFFICIENCY. TSH > 100 and anti TPO was positive suggesting AUTOIMMUNE THYROIDITIS. FSH was elevated and estradiol was reduced in favour of HYPERGONADOTROPIC HYPOGONADISM.ANA IF was positive. Therefore diagnosis of APS type 2 was made and appropriate substitution therapy was initiated. RESULT: Autoimmune endocrine gland disorders may regularly coexist with other endocrine autoimmune diseases. Neufeld and Blizzard organized and classified these clinical conditions and defined them as polyglandular autoimmune diseases or autoimmune polyendocrine syndromes (APS). Oegle first reported the association between Addison's disease, caused by bilateral tuberculous destruction of the adrenal glands, and diabetes mellitus in 1886. Schmidt's excisional biopsy detected lymphocytic infiltration of the adrenal cortex and thyroid gland in a patient who died from adrenal insufficiency in 1926. From that time, the coexistence of Addison's disease and autoimmune thyroid disease has been known as Schmidt's syndrome. APS II typically occurs in early adulthood with a peak onset during the third or fourth decades and is three times more common in females than in males. CONCLUSION: Autoimmune poly glandular syndrome can be treated with respective substitution therapy. Thyroxine therapy when initiated first may precipitate Addisonian crisis in patients with Schmidt's syndrome through increasing cortisol clearance and metabolic rate as evident in our case. Early detection of the disease and appropriate management may reduce morbidity and mortality significantly in the patients with autoimmune poly glandular syndrome.

Autoimmune Polyglandular Syndrome with Refractory Gait Disturbance.

Autoimmune polyglandular syndrome (APS) causes autoimmune diseases of multiple organs and can also present with neurological symptoms. We here report a 58-year-old man who presented with progressive gait disturbance that had started 7 years ago. He had spasticity, reduced deep sensations, and truncal cerebellar ataxia. Laboratory examinations revealed autoantibody-related cobalamin deficiency and the presence of anti-thyroid antibodies and anti-glutamic acid decarboxylase antibodies. His gait worsened after cobalamin replenishment, but additional steroid therapy was effective. APS can cause refractory gait disturbance that requires not only cobalamin replenishment but also immunotherapy.

Recurrent venous thrombosis - an unusual first presentation of autoimmune polyendocrinopathy syndrome type 3B.

A 45-year-old female presented with unprovoked recurrent venous thromboembolism (VTE), in unusual sites, and pancytopenia, posing a complex diagnostic challenge. Work-up for inherited thrombophilia, antiphospholipid syndrome (APLS) and paroxysmal nocturnal haemoglobinuria were unremarkable. Investigations revealed autoimmune thyroid disease, and a mixed iron/vitamin B12 deficiency due to pernicious anaemia and resultant atrophic gastritis. Hyperhomocysteinaemia due to vitamin B12 deficiency was identified as a potential contributor to her recurrent VTE. This case highlights the unusual initial presentation of autoimmune polyendocrinopathy syndrome type 3B (APS-3B) with recurrent thromboembolism, and emphasises the importance of considering hyperhomocysteinaemia in unprovoked and atypical VTE cases.

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

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Recurrent Hypokalemia and Adrenal Steroids in Patients With APECED.

Context: Hypokalemia is a common finding in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) but its exact cause often remains unknown. Objective: To explore the prevalence and etiology of hypokalemia and the role of adrenal steroids therein in a cohort of patients with APECED. Methods: We performed a cross-sectional assessment and retrospective data collection on 44 Finnish patients with APECED to identify subjects with episodes of hypokalemia. Also 68 healthy matched controls attended the cross-sectional evaluation. Factors associating with a tendency for hypokalemia were analyzed by reviewing medical records during 1960-2021 and performing a cross-sectional analysis of serum adrenal steroids. Results: In total 14 of the 44 APECED patients (32%) had episodes of hypokalemia; 2 presented with hypokalemia at cross-sectional evaluation and 12 had a history of hypokalemia before the cross-sectional evaluation. Hypokalemic episodes started at the median age of 14.1 years; 12/14 (86%) had primary adrenal insufficiency (PAI). The median number of hypokalemic periods per year was 0.3 (range 0.04-2.2); the frequency correlated positively with the number of clinical APECED manifestations at the time of cross-sectional evaluation (r=0.811, p<0.001). Etiologies of hypokalemia varied but episodes often occurred when new clinical manifestations developed and during hospitalizations. Three patients had kidney defects, also associated with electrolyte imbalances. Severity of hypokalemia varied (range 2.2-3.2 mmol/L), but no severe complications were observed. At cross-sectional evaluation, patients with PAI (n = 30) had significantly lower median plasma potassium and higher sodium concentration than controls, suggesting that fludrocortisone treatment contributed to hypokalemia. Detailed analysis of adrenal steroids provided no conclusive differences between patients with and without episodes of hypokalemia. Conclusions: In APECED, hypokalemia is common and varies in terms of frequency, etiology, and severity. PAI and kidney disease predispose to hypokalemia. In addition, hypokalemic periods seem to be more common in patients with more severe phenotype of APECED.

Multiple endocrine neoplasia type 2 and autoimmune polyendocrine syndromes (type 1 diabetes mellitus and Graves' disease) in a 16-year-old male with Kabuki syndrome.

Multiple endocrine neoplasia type 2A (MEN2A) is caused by germline pathogenic variants in the RET proto-oncogene and is characterized by medullary thyroid cancer (MTC), pheochromocytoma, and hyperparathyroidism. Autoimmune polyendocrine syndromes (APS) are defined as multiple endocrine gland insufficiency associated with loss of immune tolerance. APS type 2 (APS-2) consists of at least two of the following diseases: type 1 diabetes mellitus (T1DM), autoimmune thyroid disease, and Addison's disease. We describe the clinical, molecular, and biochemical findings of MEN2A, APS-2, and Kabuki syndrome (KS) in a 16-year-old male. Whole exome sequencing was performed to identify the genetic cause of the pheochromocytoma and syndromic features including facial dysmorphism, developmental delay, and epilepsy. RET pathogenic variant and KMT2D pathogenic variant were identified, and he was diagnosed with MEN2A and KS. This is the first case of association between MEN2 and APS in adolescence and the second proven case in humans. In addition, this is the first report of MEN2 and APS in KS.