Autoimmune polyendocrinopathy broadly describes three main disorders in which deficient functioning of multiple endocrine organs occurs. The pathogenesis involves various autoimmune mechanisms and the following medical entities are enclosed in this group [1] [2] [3] [4] [5] [6]:

• Autoimmune polyendocrine syndrome type 1 (APS1) - APS1 arises from autosomal recessive mutations in the autoimmune regulator (AIRE) gene located on chromosome 21 [4] [5]. It is described as a rare disorder in clinical practice [4], with the presentation starting in early childhood, whereas virtually all patients develop complaints by the end of the first two decades of life [1] [4]. The three cardinal components of APS1 are hypothyroidism, adrenal insufficiency (Addison's disease), and mucocutaneous candidiasis, which is why the term autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is often used [1] [3] [4]. In a variable number of cases, additional features such as diabetes mellitus type 1, pituitary dysfunction, gonadal failure, asplenism, gastrointestinal malabsorption, dysplasia of enamel tissue, hepatitis, and alopecia are encountered [1] [2] [3] [6].
• Autoimmune polyendocrine syndrome type 2 (APS2) - Although Addison's disease is a constitutive feature of APS2, similarly to APS1, distinguishing characteristics are - a more frequent prevalence of diabetes (50% of all patients develop type 1 diabetes compared to only 20% in APS1), an adult-onset (third or fourth decade of life), a predilection toward female gender, and the absence of candidiasis or hypoparathyroidism [1] [2] [4]. Celiac disease, vitiligo, autoimmune gastritis and thyroid disease (eg. Hashimoto thyroiditis) are seen in APS2, but also in a proportion of APS1 individuals [1] [2] [4].
• Immunodysregulation polyendocrinopathy enteropathy X-Linked syndrome (IPEX) - A very early onset (up to 2 years of age) of chronic diarrhea is the hallmark of IPEX [1] [2]. Autoimmune-mediated enteropathy, thyroiditis (mainly hypothyroidism), glomerulonephritis, dermatitis (presenting as eczema), and diabetes mellitus are seen, with symptoms occurring in a relapsing and remitting course [1] [2].

• Candidiasis

  Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-93. • More rarely : Genitals candidiasis • 15 to 22% of cases:Oeosophageal candidiasis 50. Perheentupa J. [slideshare.net]

  Abstract Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disorder characterized by hypoparathyroidism, adrenal failure, chronic mucocutaneous candidiasis, and ectodermal dystrophies and other organ-specific [ncbi.nlm.nih.gov]

• Fatigue

  Addison disease can cause fatigue, muscle weakness, weight loss, low blood pressure, and changes in skin coloration. There are numerous other symptoms which can also occur in people with PAS-1. [counsyl.com]

  […] of circulating calcium Addison disease, an insufficiency of the adrenal glands, presenting with changes in skin pigmentation, loss of appetite and weight loss, fatigue, low blood pressure and fatigue. [dermnetnz.org]

  However, most people with endocrine disease complain of fatigue and weakness. Blood and urine tests to check your hormone levels can help your doctors determine if you have an endocrine disorder. [webmd.com]

  These include symptoms of AD (hyperpigmentation, fatigue), T1DM (polyuria, polydipsia and polyphagia), pernicious anemia (problems with coordination), hypothyroidism (fatigue, weight gain, hair changes), and celiac disease (abdominal pain, anemia) among [healio.com]

  Hypoparathyroidism can cause a tingling sensation in the lips, fingers, and toes; muscle pain and cramping; weakness; and fatigue. [ghr.nlm.nih.gov]

• Myxedema

  Autoimmune Syndrome, Type 2 [Nom commun] Polyglandular Deficiency Syndrome, Type 2 [Nom commun] Schmidt Syndrome [Nom commun] Syndrome, Schmidt [Nom commun] Autoimmune Polyendocrine Syndrome, Type 2 [Nom commun] Diabetes Mellitus, Addison's Disease, Myxedema [idref.fr]

  Información en español Title Other Names: Diabetes mellitus, Addison's disease, myxedema; Multiple endocrine deficiency syndrome, type 2; Polyglandular autoimmune syndrome, type 2; Diabetes mellitus, Addison's disease, myxedema; Multiple endocrine deficiency [rarediseases.info.nih.gov]

• Male Hypogonadism

  Self-Abs against scc, but not 17 α -OH, were associated with hypogonadism (16). Researches revealed that the testis-expressed protein TSGA10 is also a target of immune reactions in male hypogonadal patients (59). [doi.org]

• Abdominal Pain

  He had no associated diarrhoea, abdominal pain, or fever and there was no history of recent travel, contact with unwell persons or consumption of unusual foods. [endocrine-abstracts.org]

  View/Print Table TABLE 2 Diagnosis of Adrenal Insufficiency Symptoms Common: fatigue, weakness, anorexia, nausea, vomiting Less common: abdominal pain, salt craving, diarrhea, constipation, syncope Signs Weight loss, cutaneous and mucosal pigmentation [aafp.org]

  On further review of symptoms, you note the patient has persistent polydipsia, headaches, nausea/vomiting, intermittent abdominal pain, and hyperpigmentation. [healio.com]

  Other symptoms consistent with adrenal insufficiency include dizziness and orthostasis, anorexia, weakness, nausea, emesis and abdominal pain, salt craving [1]. [hopkinsguides.com]

  Recurrent diarrhea, morning nausea, and intermittent abdominal pain occurred from age 9, and he became Cushingoid because of frequent stress doses of hydrocortisone. [pediatrics.aappublications.org]

• Nausea

  View/Print Table TABLE 2 Diagnosis of Adrenal Insufficiency Symptoms Common: fatigue, weakness, anorexia, nausea, vomiting Less common: abdominal pain, salt craving, diarrhea, constipation, syncope Signs Weight loss, cutaneous and mucosal pigmentation [aafp.org]

  The patient began to suffer from nausea, vomiting, and visual disturbances, and she was transferred to Tampere University Hospital. [edmcasereports.com]

  Recurrent diarrhea, morning nausea, and intermittent abdominal pain occurred from age 9, and he became Cushingoid because of frequent stress doses of hydrocortisone. [pediatrics.aappublications.org]

  Deficiencies of these hormones may lead to weakness, muscle cramps, faintness, diarrhea, nausea and vomiting, low blood pressure, dehydration, and salt craving. [rarediseases.org]

  Other symptoms consistent with adrenal insufficiency include dizziness and orthostasis, anorexia, weakness, nausea, emesis and abdominal pain, salt craving [1]. [hopkinsguides.com]

• Failure to Thrive

  Severe autoimmune enteropathy manifests with intractable secretory diarrhea leading to malabsorption, electrolyte disturbance and failure to thrive. Vomiting, ileus, gastritis or colitis can also be observed. [orpha.net]

  It can cause failure to gain weight and grow at the expected rate (failure to thrive) and general wasting and weight loss (cachexia). People with IPEX syndrome frequently develop inflammation of the skin, called dermatitis. [ghr.nlm.nih.gov]

  Symptoms of diarrhoea and failure to thrive began during the first year of life and led to a biopsy confirmed diagnosis of coeliac disease at 18 months of age. [jmg.bmj.com]

• Hypotension

  In patients with addisonian crisis, the initial goal is to reverse hypotension and electrolyte abnormalities, and to treat shock when it occurs. [aafp.org]

  Decreased insulin requirements, hypotension, weight loss, hyperpigmentation, and vitiligo may be present. [hopkinsguides.com]

  […] polydipsia 多飲 polyglandular autoimmune syndrome 多腺性自己免疫症候群 polyneuropathy 多発ニューロパチー polyneuropathy 多発神経障害 polyphagia 多食 polyunsaturated fatty acid 多価不飽和脂肪酸 polyunsaturated fatty acid / saturated fatty acid ratio 多価不飽和脂肪酸/飽和脂肪酸比 polyuria 多尿 postural hypotension [jds.or.jp]

  The patient was anuric and hypotensive, and i.v. fluids were administered. During the next few days, she experienced headache and dizziness. Diuresis restarted on day six after the onset of fever. [edmcasereports.com]

  Addison’s disease •Characteristic symptoms include :Fatigue, salt craving, hypotension, weight loss and an increased pigmentation of the skin and mucous membranes Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. [slideshare.net]

• Alopecia

  Other autoimmune conditions may be associated, such as hypothyroidism, hypogonadism, insulin-dependent diabetes mellitus, chronic active hepatitis, pernicious anemia, vitiligo, alopecia, biliary cirrhosis, and ectodermal dysplasia. [ncbi.nlm.nih.gov]

  Alopecia areata is strongly associated with DQB1*03 and DRB1*1104, which appear to be markers of general susceptibility to alopecia areata. [emedicine.medscape.com]

• Eczema

  Autoimmune-mediated enteropathy, thyroiditis (mainly hypothyroidism), glomerulonephritis, dermatitis (presenting as eczema), and diabetes mellitus are seen, with symptoms occurring in a relapsing and remitting course. [symptoma.com]

  The symptoms of IPEX syndrome include severe diarrhea, diabetes, skin conditions (such as eczema, erythroderma, or psoriasis ), and thyroid disease ( thyroiditis ). [rarediseases.info.nih.gov]

  Skin involvement consists of a generalized pruriginous eruption resembling eczema, psoriasis, and/or atopic or exfoliative dermatitis. Less frequently, alopecia or onychodystrophy can be observed. [orpha.net]

  Clinical features are highly variable and include early onset type 1 diabetes, hypothyroidism, severe enteropathy, eczema, anaemia and thrombocytopenia. Haemopoietic stem cell transplantation has sometimes been effective in its treatment. [diapedia.org]

• Arthralgia

  Indeed, in a restricted number of cases a maculopapular, or morbilliform, or urticaria-like skin rash, eventually accompanied by fever, splenomegaly and arthralgia, has been reported [ 2, 3, 6 – 18 ]. [doi.org]

• Seizure

  Seizure 0001250 Steatorrhea Fat in feces 0002570 Tetany Intermittent involuntary muscle spasm 0001281 Thymoma 0100522 Type II diabetes mellitus Noninsulin-dependent diabetes Type 2 diabetes Type II diabetes [ more ] 0005978 Showing of 30 | Last updated [rarediseases.info.nih.gov]

  In turn, this can lead to a host of clinical findings, including muscle cramping and spasms, rigidity (tetany) and even seizures. (For further information on hypoparathyroidism, see Related Disorders Section of this report.) [rarediseases.org]

  Case Report A 32-year-old man, born of a non-consanguineous marriage, with a history of chronic plaque psoriasis and seizure disorder, presented with multiple thick crusted plaques all over the body, associated with burning sensation and fever, of 15 [ijdvl.com]

  TABLE 1 Clinical Components of APECED With Associated Antibodies Case Report A 5-year-old boy presented with a hypocalcemic seizure caused by primary hypoparathyroidism. [pediatrics.aappublications.org]

  Her older brother had been identified with hypocalcemia (calcium 5.2 mg/ dL) when he was 8 years old; his presentation was with seizures. [omicsonline.org]

• Tingling

  An underactive parathyroid gland can cause numerous symptoms including tingling in the lips, fingers, and toes; muscle cramps; pain in the abdomen, face, legs, and feet; weakness or fatigue; and dry hair and skin. [counsyl.com]

  APS1 is based on three main clinical features: Mucocutaneous candidiasis affecting the skin and mucous membranes Hypoparathyroidism, resulting in numbness and tingling in the face and limbs, muscle cramps and aches, weakness and fatigue due to low levels [dermnetnz.org]

  Hypoparathyroidism can cause a tingling sensation in the lips, fingers, and toes; muscle pain and cramping; weakness; and fatigue. [ghr.nlm.nih.gov]

• Encephalopathy

  Analysis of muscle mitochondrial DNA (mtDNA) revealed a 2,532-bp deletion of the type seen in Kearns-Sayre syndrome as well as a heteroplasmic A3243G mutation in the tRNA-Leu(UUR) gene of the type seen in mitochondrial myopathy, encephalopathy, lactic [ncbi.nlm.nih.gov]

  During the year before his bone marrow transplant (BMT), he had experienced intractable hypertension with encephalopathy, probably resulting in a residual left posterior temporal lesion identified by MRI scan of the brain, and life threatening central [jmg.bmj.com]

• Paresthesia

  She had initiated the neurological symptoms with paresthesia in the lower limbs, ascending and progressive, in the hallux region which advanced gradually to the thoracic region. [scielo.mec.pt]

  Hypoparathyroidism •Symptoms are related to hypocalcemia : Muscle cramps, mild paresthesia and clumsiness Husebye ES, Perheentupa J, Rautemaa R, Kampe O. [slideshare.net]

  Many symptoms of hypocalcemia are nonspecific, such as paresthesias and muscle cramps. Seizures may occur in more severe cases. Hypomagnesemia is common and may complicate the condition (12). [doi.org]

• Convulsions

  In history, it was learned that 1 year ago, she was admitted to another hospital for lethargy and convulsions. The diagnosis of hypoparathyroidism was made and subsequently, she was put on calcitriol and calcium therapy. [jcor.in]

The diagnosis of autoimmune polyendocrinopathy syndromes can be made through a detailed clinical, laboratory, and genetic assessment. The physician should obtain a history that will assess the age of symptom onset, presenting complaints, and associated endocrine abnormalities, which may provide useful clues into discriminating between the different types of autoimmune polyendocrinopathy syndromes. After a meticulous laboratory investigation, the detection of multiple abnormalities of endocrine tissue must raise suspicion toward this disorder. The presence of multiple autoantigens (islet cells, thyroid-stimulating hormone receptors, gastric intrinsic factor, gliadin, tyrosinase, etc.) and autoantibodies (antigonadal, antiadrenal, anti-islet, and other organ-specific antibodies) is highly specific for all syndromes belonging to this group of conditions, and is one of the main laboratory criteria [2] [4] [5] [6]. A definite diagnosis, however, rests on genetic studies. Identification of mutations in the AIRE gene on chromosome 21 confirms autoimmune polyendocrine syndrome type 1 as the underlying cause [4] [5]. For IPEX, detection of mutations in the FOX3 gene on chromosome X is diagnostic [1]. Unfortunately, the entire pathogenesis model for APS type 2 remains to be elucidated [1].

• Hyponatremia

  Schmidt’s syndrome and severe hyponatremia: report of an unusual case and review of the related literature. Endocr Pract. 2003;9:384–388 doi:10.4158/EP.9.5.384 [CrossRef]. Rallison ML, Dobyns BM, Meikle AW, et al. [healio.com]

  […] deficiency. ( 19968812 ) Quintos J.B....Salas M. 2010 13 Genetics of the autoimmune polyglandular syndrome type 3 variant. ( 20578896 ) Dittmar M....Kahaly G.J. 2010 14 Autoimmune polyglandular syndrome type 3 complicated by mineralocorticoid-responsive hyponatremia [malacards.org]

  Hypotension, hypoglycemia, and hyponatremia are fairly late manifestations. Ovarian failure occurs in 10 percent of women with APS II, 7 so amenorrhea in a woman younger than 40 years may warrant consideration of this diagnosis. [aafp.org]

  Investigations revealed anemia, leucocytosis, hyponatremia, hypochloremia, severe hypocalcemia, hyperphosphatemia, and hypoalbuminemia, all of which normalized with adequate treatment except serum calcium, which remained persistently low ( AIRE gene analysis [ijdvl.com]

  Associated lab findings include hyponatremia, hyperkalemia, hypoglycemia, anemia, eosinophilia, elevated thyrotropin and low thyroxine. Signs and symptoms of related autoimmune conditions (e.g. alopecia, celiac disease ) may be present. [hopkinsguides.com]

Management and treatment The only curative treatment for IPEX is hematopoietic stem cells transplantation (HSCT), which is much more successful when performed in the early stages of the disease. [orpha.net]

In the case of low growth rate, GH should be evaluated by dynamic tests and, if GH deficiency is detected, treatment with hGH must be initiated. [ncbi.nlm.nih.gov]

You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments. [rarediseases.info.nih.gov]

This review focuses on the clinical and immunological features of APECED, summarizes the current knowledge on the function of AIRE and discusses the importance of autoantibodies in disease diagnosis and prognosis. [ncbi.nlm.nih.gov]

The clinical presentation, onset of symptoms, organs involved, and the prognosis depends on the underlying subtype. The diagnosis rests on a thorough physical examination, a comprehensive history, and a detailed laboratory assessment. [symptoma.com]

What is the prognosis for a person with Polyglandular Autoimmune Syndrome Type 1? The prognosis for a person with PAS-1 varies depending on the number and severity of his or her symptoms. [counsyl.com]

In addition, the patient developed progressive muscular atrophy of unknown etiology at the beginning of the third decade, and is bedridden at the present time. [ncbi.nlm.nih.gov]

Etiology IPEX syndrome is caused by mutations in the FOXP3 gene (Xp11.23). [orpha.net]

Etiology The etiology is most often autoimmune. [merckmanuals.com]

Rhabdomyolysis: a review of clinical presentation, etiology, diagnosis, and management. Pediatr Emerg Care. 2008;24(4):262–268 doi:10.1097/PEC.0b013e31816bc7b7 [CrossRef]. Egan JJ, Davies AJ, Jones MK. [healio.com]

The presence of antithyroid antibodies (e.g. anti-thyroglobulin antibodies, anti-microsomal antibodies, thyroid stimulating immunoglobulins) can be useful for confirming autoimmune etiology (see thyroid function tests module). [hopkinsguides.com]

Expanded epidemiological investigations based on AIRE gene sequencing are necessary to verify the relevancy of the novel mutation to APECED etiopathogenesis in the Lithuanian population and to prove its diagnostic efficacy in association with clinical [ncbi.nlm.nih.gov]

Epidemiology Frequency United States Approximately 14-20 people per million population are affected by polyglandular autoimmune syndrome type II. [emedicine.medscape.com]

In this article, we discuss the role of AIRE in autoimmune polyendocrine syndrome type-1 and identify issues that still need to be addressed to fully understand the molecular pathophysiology of this complex syndrome. [ncbi.nlm.nih.gov]

Chapters cover both basic pathophysiology informed by studies of animal models as well as current understanding of multiple related clinical diseases—their pathophysiology, diagnosis, and therapy. [books.google.de]

The pathophysiological aspects of this syndrome are discussed. © 1982 S. [karger.com]

Autoimmunity, environmental factors, and genetic factors are the 3 major factors that should be considered in the pathophysiology of PAS III. [emedicine.medscape.com]

We will summarize how AIRE contributes to immunological tolerance, and thus to the prevention of autoimmunity. [ncbi.nlm.nih.gov]

Funding and Disclosures Supported by grants from the National Institutes of Health (DK32083, AI39213, DK55969, DK62718, AI95380, DK32493, DK59097, DK63518, AI46374, and DK61926; a Diabetes Endocrine Research Center grant [P30 DK57516]; an Autoimmunity Prevention [oadoi.org]

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2. Anderson MS. Update in Endocrine Autoimmunity. J Clin Endocrinol Metab. 2008;93:3663–3670.
3. Perheentupa J. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. J Clin Endocrinol Metab. 2006;91:2843–2850
4. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol. 2009;161:11–20.
5. Alimohammadi M, Björklund P, Hallgren A, et al. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N Engl J Med. 2008;358:1018–1028.
6. Bensing S, Fetissov SO, Mulder J, et al. Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(3):949-954.