Autoimmune polyendocrine syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Autoimmune polyendocrine syndrome (APS) are a group of autoimmune disorders against multiple (poly) endocrine organs, although non endocrine organs may be affected. On the basis of organ involvement, autoimmune polyendocrine syndrome (APS) can be classified into APS type 1, APS type 2 and APS type 3. In APS there is loss of self tolerance or defective T cell regulation and the immune system attacks various endocrine and nonendocrine organs throughout the body. APS is seen in genetically susceptible individuals, when exposed to certain environmental triggers (such as infection) leads to autoimmunity. Common causes of autoimmune polyendocrine syndrome include mutation in AIRE gene, FOXP3 gene and certain HLA alleles such as DR3/DQ2, DR4/DQ8 and DRB1*0404. There are no established risk factors for autoimmune polyendocrine syndrome. However, patients with single autoimmune disorder are at an increased risk of having another autoimmune disorder. The most common symptoms of APS-1 include mucocutaneous candidiasis, hypoparathyroidism and Addison’s disease. The most common symptoms of APS-2 include Addison’s disease with autoimmune thyroiditis or diabetes mellitus type 1. The most common symptoms of APS 3 include autoimmune thyroiditis, diabetes mellitus type 1, pernicious anemia and/or with involvement of a nonendocrine organ. The diagnosis of autoimmune polyendocrine syndrome (APS) is made on the basis of presence of organ-specific antibodies (serological measurement) followed by functional testing. Medical therapy for autoimmune polyendocrine syndrome (APS) depends upon the subtype and the organ system involved. In APS the focus is to treat the presenting disorder.

In 19th century physicians first focussed their attention on constellation of symptoms associated with autoimmune polyendocrine syndrome. In 1855, Thomas Addison identified patients with Addison’s disease who also appeared to have coexisting pernicious anemia. In 1956, Roitt and Doniach found that patients with Hashimoto’s thyroiditis had circulating autoantibodies reacting with thyroid gland. In 1980, Neufeld and Blizzard first developed the classification for polyglandular failure and in 1982 categorised autoimmune polyendocrine syndrome into type 1 and type 2.

On the basis of organ involvement, autoimmune polyendocrine syndrome (APS) can be classified into APS type 1, APS type 2 and APS type 3. APS type 1 commonly presents with mucocutaneous candidiasis, hypoparathyroidism and Addison’s disease. APS type 2 commonly presents with Addison’s disease, autoimmune thyroiditis and diabetes mellitus type 1. APS type 3 commonly presents with autoimmune thyroiditis, diabetes mellitus type 1 and pernicious anemia.

Autoimmune polyendocrine syndrome (APS) is a group of autoimmune disorders against multiple (poly) endocrine organs, although non endocrine organs may be affected. Autoimmune polyendocrine syndrome is also known as polyglandular autoimmune syndrome and polyendocrine autoimmune syndrome. In autoimmune polyendocrine syndrome there is loss of self tolerance or defective T cell regulation and the immune system attacks various endocrine and nonendocrine organs throughout the body. APS is seen in genetically susceptible individuals who when exposed to certain environmental triggers (such as infection) leads to autoimmunity. The involvement of endocrine glands can be simultaneous or sequential. The autoimmune reaction can either be humoral or cell mediated which may lead to partial or complete destruction of the tissue involved. The common endocrine glands involved are parathyroids, adrenals, thyroid, and pancreas. However any other non endocrine gland/tissue of the body may be involved.

Common causes of autoimmune polyendocrine syndrome include mutation in AIRE gene, FOXP3 gene and certain HLA alleles such as DR3/DQ2, DR4/DQ8 and DRB1*0404.

Autoimmune polyendocrine syndrome (APS) must be differentiated from other similar conditions which lead to multiple endocrine disorders such as thymoma, Kearns–Sayre syndrome, POEMS syndrome, and Wolfram syndrome. APS should also be differentiated among its subtypes such as APS type 1, type 2 and type 3.

Autoimmune polyendocrine syndrome (APS) is a group of rare autoimmune disorders. APS type 2 is the most commonly seen autoimmune polyendocrine syndrome. The incidence of APS type 2 is estimated to be 1-2 per 100,000 individuals worldwide. The prevalence of APS type 2 is estimated to be 1-4 per 100,000 individuals worldwide. Most cases of APS type 1 and type 2 are symptomatic by early thirties, while APS type 3 is generally seen in 40-60 years of age. APS usually affects individuals of the caucasian race. In APS type 1, type 2 and type 3 females are more commonly affected than men.

There are no established risk factors for autoimmune polyendocrine syndrome. However, patients with single autoimmune disorder are at an increased risk of having another autoimmune disorder. Any autoimmune endocrine disorder such as Addison’s disease, type 1 diabetes mellitus, autoimmune thyroiditis, hypogonadism (usually autoimmune oophoritis), vitiligo, pernicious anemia, chronic atrophic gastritis, chronic active hepatitis may put the patient at an increased risk of autoimmune polyendocrine syndrome.

Screening is an important aspect in the early diagnosis and management of autoimmune polyendocrine syndrome (APS). The onset of APS is often with a single endocrine disorder and the subsequent involvement of other endocrine/non-endocrine organs may take up to years or decades. In patients of APS, high clinical suspicion should be maintained for presence of other autoimmune disorders. Once a patient has been diagnosed with a single autoimmune endocrine disorder, screening should be done for presence of other auto-antibodies such as 21- hydroxylase or 17-hydroxylase.

If left untreated, patients with autoimmune polyendocrine syndrome (APS) may progress to involve other endocrine and nonendocrine organs. APS can be a life threatening condition if vital hormone producing organs of the body are involved such as adrenal glands, thyroid, parathyroid glands. The complications of APS depend upon the subtype and organ system involved. Common complications of APS include those arising from hypoparathyroidism, Addison’s disease and autoimmune thyroiditis. The prognosis of APS is variable and depends upon the duration and severity of endocrine/non-endocrine organ involved. Patients of APS with endocrine involvement generally require lifelong hormone replacement therapy.

The diagnosis of autoimmune polyendocrine syndrome (APS) is made on the basis of presence of organ-specific antibodies (serological measurement) followed by functional testing. Few examples of organ specific antibodies include autoantibodies against 21-hydroxylase, 17-hydroxylase, GAD, islet cells, thyroglobulin, thyroid peroxidase, intrinsic factor and tyrosinase. Genetic analysis may be done in suspected patients of APS for AIRE or FOXP3 gene mutation. Patients presenting with a single endocrine pathology should always be considered for other endocrine organ dysfunction. Patients with autoimmune endocrine disorder are always at a risk of developing autoimmune conditions of other endocrine organs.

A detailed history may be helpful in the early diagnosis of the autoimmune polyendocrine syndrome (APS). Autoimmune polyendocrine syndrome patients generally have an early onset. In such cases, history from the caregivers may be obtained. An important aspect involves obtaining family history about the presence of APS in family members since APS can be transmitted in genetic mode. Patients with the autoimmune polyendocrine syndrome (APS) have varied symptoms depending on the subtype. The most common presentation of APS-1 include mucocutaneous candidiasis, hypoparathyroidism and Addison’s disease. The most common presentation of APS-2 include Addison’s disease with autoimmune thyroiditis or diabetes mellitus type 1. The most common presentation of APS 3 include autoimmune thyroiditis, diabetes mellitus type 1, pernicious anemia and/or with involvement of a nonendocrine organ.

The physical examination findings in autoimmune polyendocrine syndrome (APS) depend upon the subtype and the organ system involved. APS may present as hypotension, bradycardia, tetany, dry skin, coarse hair, and muscle weakness depending upon the organ affected such as adrenals, thyroid or pancreatic islet cells. Patients of APS usually appear fatigued and dehydrated.

Laboratory findings suggestive with the diagnosis of autoimmune polyendocrine syndrome (APS) include testing for the presence of autoantibodies (serology) followed by functional testing. Patients are tested for autoantibodies such as antibodies against 21-hydroxylase, 17-hydroxylase, glutamic acid decarboxylase (GAD), islet cell, thyroid peroxidase (TPO), TSH receptor and thyroid-stimulating immunoglobulins (TSI). Other tests include thyroid function test, adrenal function test, electrolytes, blood glucose, complete blood count (CBC) and vitamin B12.

An ECG may be helpful in the diagnosis of autoimmune polyendocrine syndrome (APS) associated hypoparathyroidism which may present with cardiac dysfunction due to hypocalcemia. EKG findings suggestive of cardiac dysfunction due to hypoparathyroidism include prolongation of QT interval.

There are no x-ray findings associated with autoimmune polyendocrine syndrome.

A CT scan may be helpful in the diagnosis of autoimmune polyendocrine syndrome (APS) associated hypoparathyroidism and Addison’s disease. Hypoparathyroidism on CT may present with increased volumetric bone mineral density (vBMD) of both cortical and trabecular bones. Addison’s disease on CT scan may present with small adrenal remnants bilaterally (suggestive of autoimmune adrenalitis) or as atrophied adrenal glands.

Brain MRI may be helpful in the diagnosis of autoimmune polyendocrine syndrome associated hypopituitarism and hypogonadism. Findings on MRI suggestive of hypopituitarism may include decreased size of the pituitary gland and empty sella may also be noticed in some cases.

24-hour iodine-123 uptake may be helpful in the diagnosis of autoimmune thyroiditis associated with autoimmune polyendocrine syndrome (APS). Autoimmune thyroiditis can be seen in any subtype of APS but is more commonly seen in type 3 and type 2. Patients of APS with autoimmune thyroiditis present with decreased uptake of iodine-123, which can help in differentiating hypothyroidism seen in autoimmune thyroiditis from other causes.

Other diagnostic studies for autoimmune polyendocrine syndrome (APS) include endoscopy with biopsy of upper GI tract. Patients of APS may develop atrophic gastritis or celiac disease from autoantibodies against parietal cells or tissue transglutaminase. In patients with positive autoantibodies, endoscopy with biopsy may be helpful in the early diagnosis of atrophic gastritis or celiac disease.

Medical therapy for autoimmune polyendocrine syndrome (APS) depends upon the subtype and the organ system involved. In APS, the focus is to treat the presenting disorder which can either be mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency or autoimmune thyroiditis. The goal of treatment is to correct hormone deficiencies, prevent complications, and reduce morbidity. Treatment includes monitoring of glandular functions for early detection of glandular failure, lifelong hormone replacement therapy for established glandular failure, and familial screening.

Surgical intervention is not recommended for the management of autoimmune polyendocrine syndrome.

Effective measures for the primary prevention of autoimmune polyendocrine syndrome (APS) include patient education and screening. Autoimmune polyendocrine syndrome may be inherited in autosomal recessive (APS type 1), autosomal dominant (APS type 2) or X linked fashion (APS type 3) and therefore educating the relatives about the importance of a positive family history is necessary. In addition, screening should be done for first degree relatives of patients (parents, siblings or children) with APS for the presence of autoantibodies.

Effective measures for the secondary prevention of autoimmune polyendocrine syndrome (APS) include patient education and periodic screening. In APS the time interval between involvement of one endocrine organ to other endocrine/nonendocrine organ may take years. Thus, patient should be informed about signs and symptoms of commonly associated conditions/disorders with APS. In addition, periodic screening at an interval of 6-12 months should be done to detect the presence of any autoantibody such as antibodies against 21-hydroxylase or islet cells.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

In 19th century physicians first focussed their attention on constellation of symptoms associated with autoimmune polyendocrine syndrome. In 1855, Thomas Addison identified patients with Addison’s disease who also appeared to have coexisting pernicious anemia. In 1956, Roitt and Doniach found that patients with Hashimoto’s thyroiditis had circulating autoantibodies reacting with thyroid gland. In 1964, Carpenter described the association between adrenocortical failure, thyroiditis and insulin-dependent diabetes mellitus. In 1980, Neufeld and Blizzard first developed the classification for polyglandular failure and in 1982 categorized autoimmune polyendocrine syndrome into type 1 and type 2.

The history associated with autoimmune polyendocrine syndrome is as below:^{[1][2][3][4][5]}

• In 19th century physicians first focussed their attention on constellation of symptoms associated with autoimmune polyendocrine syndrome.
• In 1855, Thomas Addison identified patients with Addison’s disease who also appeared to have coexisting pernicious anemia.
• In 1908, Claude and Gougerot described patients with Addison’s disease and pernicious anemia to have a common pathogenesis in their paper titled “Insufficence pluriglandulaire endocrinnienne”.
• In 1926, Schmidt described the relationship between adrenocortical failure and thyroiditis.
• In 1929, Thorpe and Handley first described the case of mucocutaneous candidiasis with glandular failure in a 4.5-year-old girl.
• In 1956, Roitt and Doniach found that patients with Hashimoto’s thyroiditis had circulating autoantibodies reacting with thyroid gland.
• In 1959, Beaven et al extensively reviewed relationship between Addison’s disease and diabetes mellitus.
• In 1964, Carpenter described the association between adrenocortical failure, thyroiditis and insulin-dependent diabetes mellitus.
• In 1974, Bottazzo and Doniach described autoantibodies against islet cells in patients with type 1A diabetes.
• In 1980, Neufeld and Blizzard first developed the classification for polyglandular failure.
• In 1981, Neufeld and colleagues categorized autoimmune polyendocrine syndrome into type 1 and type 2.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Autoimmune polyendocrine syndrome (APS) can be classified into APS type 1, APS type 2 and APS type 3 on the basis of organ involvement. APS type 1 commonly presents with mucocutaneous candidiasis, hypoparathyroidism and Addison’s disease. APS type 2 most commonly presents with Addison’s disease, autoimmune thyroiditis and diabetes mellitus type 1. APS type 3 usually presents with autoimmune thyroiditis, diabetes mellitus type 1 and pernicious anemia.

On the basis of organ involvement, autoimmune polyendocrine syndrome (APS) can be classified into APS type 1, APS type 2 and APS type 3.^[1][2][3]

Autoimmune polyendocrine syndrome (APS)

Autoimmune polyendocrine syndrome type 1

Autoimmune polyendocrine syndrome type 2

Autoimmune polyendocrine syndrome type 3

•Mucocutaneous candidiasis •Hypoparathyroidism •Addison’s disease

•Addison’s disease •Autoimmune thyroiditis •Diabetes mellitus type 1

•Autoimmune thyroiditis •Diabetes mellitus type 1 •Pernicious anemia

Autoimmune polyendocrine syndrome type 3A

Autoimmune polyendocrine syndrome type 3B

Autoimmune polyendocrine syndrome type 3C

•Autoimmune thyroiditis •Immune mediated diabetes mellitus

•Autoimmune thyroiditis •Pernicious anemia

•Autoimmune thyroiditis •Vitiligo/Alopecia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Autoimmune polyendocrine syndrome (APS) is a group of autoimmune disorders against multiple (poly) endocrine organs, although non-endocrine organs may be affected. Autoimmune polyendocrine syndrome is also known as polyglandular autoimmune syndrome and polyendocrine autoimmune syndrome. In autoimmune polyendocrine syndrome there is loss of self tolerance or defective T cell regulation and the immune system attacks various endocrine and non-endocrine organs throughout the body. APS is seen in genetically susceptible individuals who when exposed to certain environmental triggers (such as infection) leads to autoimmunity. The involvement of endocrine glands can be simultaneous or sequential. The autoimmune reaction can either be humoral or cell mediated which may lead to partial or complete destruction of the tissue involved. The common endocrine glands involved are parathyroids, adrenals, thyroid, and pancreas. However any other non endocrine gland/tissue of the body may be involved.

The pathogenesis in autoimmune polyendocrine syndrome (APS) includes:^{[1][2][3][4][5]}

• APS can be defined as a group of rare autoimmune disorders against multiple (poly) endocrine glands, although non-endocrine gland/tissues may be affected.
• In APS, there is either defective regulation of T cells or loss of self tolerance which causes the immune system to attack various endocrine and non-endocrine organs throughout the body.
• APS can be categorized into two major types namely:
  • Type 1 (also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
  • Type 2 (also known as Schmidt syndrome)
  • Other rare types of APS include APS type 3 [IPEX (Immune Dysfunction Polyendocrinopathy X-linked syndrome) and APS type 4.
• In APS, the involvement of endocrine glands can be either simultaneous or sequential.
• The common endocrine glands involved are parathyroids, adrenals, thyroid, and pancreas. However any other endocrine/non-endocrine tissue of the body may be involved.
  • The autoimmune reaction can either be humoral or cell mediated.
  • Depending upon the inflammation and the lymphocytic infiltration of the endocrine and non-endocrine tissue, there may be partial or complete destruction of the tissue involved.

Autoimmune polyendocrine syndrome type 1 (APS type 1)

The major mechanism behind the pathogenesis of APS type 1 is as follows:^[6][7][8][9]

• The APS type 1 is primarily related to mutation in the AIRE (Autoimmune Regulator) gene on chromosome 21.
• Normal function of AIRE, a transcription factor, appears to confer immune tolerance for antigens present in the body.
• In patients of APS type 1, mutated AIRE gene leads to loss of peripheral antigen expression in the thymus.
• The decreased exposure of self antigens in thymus causes decreased deletion or apoptosis of self reactive T lymphocytes which leads to autoimmunity.
• Patients with APS type 1 have autoantibodies against endocrine and non-endocrine organs throughout the body. These antibodies may be directed against surface receptor proteins, intracellular structures and secreted products.
• The most commonly associated autoantibody is anti-adrenal antibody (against enzyme; 21-hydroxylase) which leads to Addison’s disease.
• The second most commonly associated autoantibody is against parathyroid specific protein, NALP5 which leads to hypoparathyroidism.
• Autoantibody against enzyme, glutamic acid decarboxylase (GAD)of pancreas may lead to insulin deficiency.
  • Patients with typical type 1 diabetes also have anti-GAD antibodies but can be differentiated from anti-GAD antibodies seen in APS type 1 with the help of western blot.
  • Patients with anti-GAD antibodies in APS type 1 react with GAD on western blot and leads to inhibition of GAD enzyme activity. This is not present in typical patients with diabetes mellitus type I.
• Other antibodies include anti-cytokine autoantibodies such as anti-IL17A, IL-17F and IL-22.
• The presence of anti-cytokine antibodies predispose to defective antifungal response, which may lead to mucocutaneous candidiasis. APS type 1 is also termed as APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) from the symptom complex associated with this condition.
• Recent studies have indicated that almost all patients with APS type 1 have antibodies against interferon-omega (IFN-ω) and interferon alpha (IFN-α).

Autoimmune polyendocrine syndrome type 2 (APS type 2)

The pathogenesis of APS type 2 includes:

• The pathogenesis of APS type 2 is related to MHC class II, primarily DQ2 and DQ8.
• The strongest association for APS type 2 is with HLA DR3/DQ2, DR4/DQ8 and DRB1*0404.
• APS type 2 is seen in genetically susceptible individuals who develop autoimmunity when exposed to certain environmental factors (such as viral infection).
• As seen in type 1, APS type 2 also has a loss of self tolerance to intrinsic antigenic proteins in the body.
• The autoantibodies are directed against various endocrine and non-endocrine organs.
• The classic triad of APS type 2 includes Addison’s disease, autoimmune thyroiditis and type 1A diabetes.
• As compared to type 1, APS type 2 is more varied in its manifestations and is the most common type of APS.
• Other HLA DR3 and HLA B8 associated APS type 2 conditions include selective IgA deficiency, juvenile dermatomyositis, dermatitis herpetiformis, alopecia, scleroderma, autoimmune thrombocytopenic purpura, hypophysitis, metaphyseal osteopenia, serositis and premature ovarian failure.

Autoimmune polyendocrine syndrome type 3 (APS type 3)

Studies demonstrate that environmental factors, genetic factors and autoimmunity play an important role in the parthenogenesis of APS type 3.^[10][11][12]

• As seen in APS type 1 and type 2, APS type 3 is also seen in genetically susceptible individuals who develop autoimmunity when exposed to certain environmental factors (such as viral infections).
• Patients of APS type 3 have a defect in regulatory T cells.
  • Normally, T-regulatory cells have a vital role in creating and maintaining self tolerance.
  • Self tolerance is the mechanism by which immune system recognize body’s own proteins/antigens as ‘self’ and prevent the immune system from mounting an attack against them.
  • In patients of APS type 3, defective function of regulatory T cells leads to loss of self tolerance which leads to autoimmunity.
• Recent case reports also suggest that, patients of APS type 3 have defective IL-2 and gamma-interferon production which leads to increased susceptibility to infections from bacterial, viral, and fungal organisms.
• Compared with APS type 1 and 2, APS type 3 does not involve the adrenal cortex. Instead autoimmune thyroiditis is the most commonly involved endocrine organ in APS type 3.

The genes involved in the pathogenesis of APS include:

• APS type I: APS type 1 is inherited in an autosomal recessive fashion and is due to a defect in AIRE (autoimmune regulator), a gene located on chromosome 21.^[13][14]
  • The genetic locus is on short arm (p) of chromosome 21 at 21p22.3.
  • The normal function of AIRE gene is to confer immune tolerance for antigens present in the body.
  • The mutated AIRE gene results in the loss of self tolerance – a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus.
  • APS-1 has been associated with more than 60 different mutations of AIRE gene, the majority of which results in truncated and non-functional AIRE.
  • The two common mutations of AIRE gene include R257X and 1094-1106del.
  • According to a Finnish study, the mutation R257X is responsible for 82% of cases in Finland.
  • It is also observed that patients with APS type 1 have an increased frequency of HLA-A28 and HLA-A3.

• ‘APS type’ 2 : APS type 2 is not a single gene disorder and has a complex inheritance pattern.^[15][16][17]
  • APS type 2 patients commonly have Addison’s disease, autoimmune thyroiditis and type I diabetes mellitus. Each one of these conditions involve multiple genes which is responsible for the complex inheritance pattern seen in APS type 2.
  • The highest genetic risk for APS type 2 maps to the HLA locus. Other low risk genes include CLTA4 and PTPN22.
    • The strongest association for APS type 2 is with HLA DR3/DQ2 (DQ2:DQA1*0501, DQB1*0201), DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302), DRB1*0404 and this syndrome exhibits an autosomal dominant inheritance.
    • It has been observed that patients of APS type 2 with DR3 is often introduced into the family by more than one relative.

• APS type 3 or XPID: This is due to a mutation in the FOXP3 gene on the X chromosome.^[18][19]
  • The FOXP3 gene is located on chromosome Xp11.3-q13.3
  • FOXP3 plays a critical role in the function of CD4+ CD25+ T regulatory cells.
  • Since XPID is an ‘X’ linked condition, males are commonly affected. Females are carriers and may have mild disease.

• Diabetes mellitus type 1
• Common variable immunodeficiency (CVID)
• Pure red cell aplasia
• Autoimmune thyroiditis
• Hypogonadism (usually autoimmune oophoritis)
• Hypopituitarism
• Vitiligo
• Pernicious anemia
• Parkinson disease
• Chronic atrophic gastritis
• Chronic active hepatitis
• Idiopathic thrombocytopenic purpura
• Myasthenia gravis

On gross pathology the characteristic findings include:^[20][21]

• The endocrine gland is usually diffusely enlarged and firm.
• Chronically inflamed glands can be irregularly shrunken.

Autoimmune polyendocrine syndrome can involve a variety of endocrine and non-endocrine organs. On microscopic histopathological analysis, the following features can be seen:^[22]

• Chronic inflammatory cell infiltration
• Lymphocytic/plasma cell infiltration (cell mediated autoimmunity)
• Extensive fibrosis and atrophy
• Sparing of adjacent non-target tissue
• Renal involvement may exhibit the following histopathological findings:^[23]
  • Moderate inflammation
  • Tubular atrophy
  • Dilated tubuli with proteinaceous periodic acid-Schiff-positive material
  • Fibrosis 

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Common causes of autoimmune polyendocrine syndrome include mutation in AIRE gene, FOXP3 gene and certain HLA alleles such as DR3/DQ2, DR4/DQ8 and DRB1*0404.

Autoimmune polyendocrine syndrome is caused by a mutation in:

• APS type I: APS type 1 is due to a defect in AIRE (autoimmune regulator), a gene located on chromosome 21.^[1][2]
  • The genetic locus is on short arm (p) of chromosome 21 at 21p22.3.
  • The normal function of AIRE gene is to confer immune tolerance for antigens present in the body.
  • The mutated AIRE gene results in the loss of self tolerance – a process by which developing T cells with potential reactivity for self-antigens are eliminated during early differentiation in the thymus.
  • According to a Finnish study the mutation R257X (in AIRE gene) is responsible for 82% of APS type 1 cases in Finland.

• APS type 2: APS type 2 is not a single gene disorder and has a complex inheritance pattern.^[3][4][5]
  • The highest genetic risk for APS type 2 maps to the HLA locus. Other low risk genes include CLTA4 and PTPN22.
    • The strongest association for APS type 2 is with HLA DR3/DQ2 (DQ2:DQA1*0501, DQB1*0201), DR4/DQ8 (DQ8:DQA1*0301, DQB1*0302), DRB1*0404 and this syndrome inherits in an autosomal dominant fashion.

• APS type 3 or XPID: This is due to a mutation in the FOXP3 gene on the X chromosome.^[6][7]
  • The FOXP3 gene is located on chromosome Xp11.3-q13.3
  • FOXP3 plays a critical role in the function of CD4+ CD25+ T regulatory cells.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Autoimmune polyendocrine syndrome (APS) must be differentiated from other similar conditions which lead to multiple endocrine disorders such as thymoma, Kearns–Sayre syndrome, POEMS syndrome, and Wolfram syndrome. APS should also be differentiated among its subtypes such as APS type 1, type 2 and type 3.

Different types of autoimmune polyendocrine syndrome should be differentiated from each other. The following table characterizes the differences among various sub-types of APS.^{[1][2][3][4][5][6][7]}

Characterstic	Autoimmune polyendocrine syndrome type 1	Autoimmune polyendocrine syndrome type 2	Autoimmune polyendocrine syndrome type 3
Inheritance	Autosomal recessive	Autosomal dominant	X-linked
Gene(s) involved	AIRE (transcription factor)	Polygenic	FOXP3 (transcription factor)
HLA genotype	HLA-D3 and HLA-D4	HLA-DQ2 and HLA-DQ8; HLA-DRB1*0404	None
Pathogenesis	Autoreactive T cells escape negative selection	Unknown	Defective T cell regulation leading to T cell activation and proliferation
Age of onset	Infancy	Infancy and adulthood	Neonatal
Clinical features (most common)	Candidiasis Hypoparathyroidism Addison’s disease	Addison’s disease Diabetes mellitus type 1A Autoimmune thyroiditis	Autoimmune thyroiditis Neonatal diabetes Malabsorption
Diabetes	18%	20-50%	>60%
Other manifestations	Hepatitis, malabsorption, asplenism, oophoritis, alopecia and vitiligo	Autoimmune gastritis, celiac disease, oophoritis and vitiligo	Autoimmune thyroiditis, haemolytic anemia, thrombocytopenia and lymphadenopathy
Gender predisposition	Equal in males and females	Females>males	Males (X-linked)
Immunodeficiency	Immunodeficienct	No defined immunodeficiency	Immunodeficient
Prevalence	Rare	Common	Very rare

Autoimmune polyendocrine syndrome (APS) must be differentiated from other similar conditions which lead to multiple endocrine disorders such as POEMS syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.^{[8][9][10][11][12]}

Disease	Addison’s disease	Type 1 diabetes mellitus	Hypothyroidism	Other disorders present
APS type 1	+	Less common	Less common	Hypoparathyroidism Candidiasis Hypogonadism
APS type 2	+	+	+	Hypogonadism Malabsorption
APS type 3	–	+	+	Malabsorption
Thymoma	+	–	+	Myasthenia gravis Cushing syndrome
Chromosomal abnormalities (Turner syndrome, Down’s syndrome)	–	+	+	Cardiac dysfunction
Kearns–Sayre syndrome	–	+	–	Myopathy Hypoparathyroidism Hypogonadism
Wolfram syndrome	–	+	–	Diabetes insipidus Optic atrophy Deafness
POEMS syndrome	–	+	–	Polyneuropathy Hypogonadism Plasma cell dyscrasias

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Autoimmune polyendocrine syndrome (APS) are a group of rare autoimmune disorders. APS type 2 is the most commonly seen autoimmune polyendocrine syndrome. The incidence of APS type 2 is estimated to be 1-2 per 100,000 individuals worldwide. The prevalence of APS type 2 is estimated to be 1-4 per 100,000 individuals worldwide. Most cases of APS type 1 and type 2 are symptomatic by early thirties, while APS type 3 is generally seen in the fourth to sixth decade of life. APS usually affects individuals of the Caucasian race. In APS type 1, type 2 and type 3 females are more commonly affected than men.

The epidemiology and demographics of autoimmune polyendocrine syndrome (APS) is as follow:^{[1][2][3][4][5][6]}

• The incidence of autoimmune polyendocrine syndrome (APS) type 2 is estimated to be 1-2 per 100,000 individuals worldwide.
• The most common autoimmune polyendocrine syndrome seen among the general population is APS type 2.
• APS type 1 and type 3 are very rare and extremely rare conditions respectively. Therefore no precise data is available for their incidence.

• The prevalence of autoimmune polyendocrine syndrome (APS) type 2 is estimated to be 1-4 per 100,000 individuals worldwide.
• APS type 1 and type 3 are very rare and extremely rare conditions respectively. Therefore no precise data is available for their prevalence.
• APS type 1 is a very rare disorder and seen mostly in Iran, Sardinia and Finland.
  • The prevalence of APS type 1 is estimated to be 11 cases per 100,000 in Iranian Jews.
  • The prevalence of APS type 1 is estimated to be 7 cases per 100,000 in Sardinians.
  • The prevalence of APS type 1 is estimated to be 4 cases per 100,000 in Finland.

• Autoimmune polyendocrine syndrome (APS) type 1 commonly affects children of age group 3-5 years or in 13-15 years of age.
• Autoimmune polyendocrine syndrome (APS) type 2 commonly affects adults in the third and fourth decade of life.
• Autoimmune polyendocrine syndrome (APS) type 3 commonly affects elderly women during fourth to sixth decades of life but may occur at any age.
• Most cases of autoimmune polyendocrine syndrome (APS) type 1 and type 2 are symptomatic by early thirties.

• Autoimmune polyendocrine syndrome (APS) usually affects individuals of the Caucasian race.

• In autoimmune polyendocrine syndrome type 1, type 2 and type 3 females are more commonly affected than men.

• The majority of autoimmune polyendocrine syndrome type 1 cases are reported in Finland, Sardinia and Iran. It can be attributed to consanguineous marriages and/or clustering of descendants of common family founders. Other less frequent regions include Norway, Germany, northern Italy and northern Britain.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

There are no established risk factors for autoimmune polyendocrine syndrome. However, patients with single autoimmune disorder are at an increased risk of having another autoimmune disorder. Any autoimmune endocrine disorder such as Addison’s disease, type 1 diabetes mellitus, autoimmune thyroiditis, hypogonadism (usually autoimmune oophoritis), vitiligo, pernicious anemia, chronic atrophic gastritis, chronic active hepatitis may put the patient at an increased risk of autoimmune polyendocrine syndrome.

There are no established risk factors for autoimmune polyendocrine syndrome. However, patients with single autoimmune disorder are at an increased risk of having another autoimmune disorder. The following is the list of autoimmune disorders which may put a patient at an increased risk for autoimmune polyendocrine syndrome.^[1][2]

• Addison’s disease
• Type 1 diabetes mellitus
• Autoimmune thyroiditis
• Hypogonadism (usually autoimmune oophoritis)
• Vitiligo
• Pernicious anemia
• Chronic atrophic gastritis
• Chronic active hepatitis
• Idiopathic thrombocytopenic purpura
• Myasthenia gravis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

Screening is an important aspect in early diagnosis and management of autoimmune polyendocrine syndrome (APS). The onset of APS is often with a single endocrine disorder and the subsequent involvement of other endocrine/non-endocrine organs may take up to years or decades. In patients of APS, high clinical suspicion should be maintained for presence of other autoimmune disorders. Once a patient has been diagnosed with a single autoimmune endocrine disorder, screening should be done for presence of other auto-antibodies such as 21- hydroxylase or 17-hydroxylase.

Screening is an important aspect in early diagnosis and management of autoimmune polyendocrine syndrome (APS). The onset of APS is often with a single endocrine disorder and the subsequent involvement of other endocrine/non-endocrine organs may take up to years or decades. In patients of APS, high clinical suspicion should be maintained for presence of other autoimmune disorders:^{[1][2][3][4][5][6]}

• In APS type 1, the time interval between onset of mucocutaneous candidiasis and hypoparathyroidism may take upto five years and further involvement of adrenal glands may take upto ten years. Thus, a high degree of clinical suspicion is necessary in patients with a single autoimmune endocrine disorder.
• Once a patient has been diagnosed with a single autoimmune endocrine disorder, screening should be done for presence of other auto-antibodies such as 21- hydroxylase, 17-hydroxylase, thyroid peroxidase, parietal cell, anti-intrinsic factor and islet cell antibodies.
• Recent research has shown that in APS, autoantibodies can develop at any age and there is insufficient evidence to suggest optimum interval between testing. For example patients of celiac disease are often asymptomatic and are detected only after screening for transglutaminase autoantibodies. Thus, individuals with single autoimmune disorder should be rescreened for autoantibodies for other autoimmune conditions at appropriate intervals even if their initial autoantibody tests are negative.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Akshun Kalia M.B.B.S.[2]

If left untreated, patients with autoimmune polyendocrine syndrome (APS) may progress to involve other endocrine and non-endocrine organs. APS can be a life-threatening condition if vital hormone producing organs of the body are involved such as adrenal glands, thyroid, parathyroid glands. The complications of APS depend upon the subtype and organ system involved. Common complications of APS include those arising from hypoparathyroidism, Addison’s disease and autoimmune thyroiditis. The prognosis of APS is variable and depends upon the duration and severity of endocrine/non-endocrine organ involved. Patients of APS with endocrine involvement generally require lifelong hormone replacement therapy.

• If left untreated, patients with autoimmune polyendocrine syndrome (APS) may progress to involve other endocrine and nonendocrine organs.
• In APS, involvement of one organ is followed by autoimmune disorder of other endocrine-nonendocrine organs. Thus presentation of APS is highly variable and can lead to involvement of wide variety of organs.
• If untreated, APS can be life threatening condition since it may involve vital hormone producing endocrine glands such as adrenal glands, thyroid, parathyroid or pancreas.

The complications of autoimmune polyendocrine syndrome (APS) depends upon the subtype and endocrine/non-endocrine organ involved.

APS type 1

• Common complications of APS type 1 include those arising from hypoparathyroidism such as:^[1][2][3][4]
  • Renal complications (nephrolithiasis, nephrocalcinosis, impaired renal function, symptomatic hypocalcemia)
  • Posterior subcapsular cataracts
  • Basal ganglia calcifications^[5]
  • Complications of intravenous calcium extravasation
  • Hypocalcemic seizure
  • Dilated cardiomyopathy
  • Pathological fractures
  • Depression and other types of neuropsychiatric diseases
  • Increased risk of infections
• Other common complications of the APS type 1 include Addison’s disease

APS type 2

• Common complications of APS type 2 include those arising from Addison’s disease such as:^[6]
  • Hypoglycemia
  • Addisonian crisis
  • Hypoxia
  • Hypovolemic shock
  • Cardiac arrest
  • Stroke
• Other common complications of the APS type 2 include autoimmune thyroiditis and type 1 diabetes mellitus

APS type 3

• Common complications of APS type 3 include those arising from autoimmune thyroiditis such as:^{[7][8][9][10][11]}
  • Hypothyroidism
  • Hyperthyroidism
  • Heart failure
  • Myxedema Coma
  • Tracheal and/or esophageal compression
  • Papillary thyroid carcinoma (PTC)
  • Thyroid lymphoma
• Other common complications of the APS type 3 include pernicious anemia

• The prognosis of autoimmune polyendocrine syndrome is variable and depends upon the duration and severity of endocrine/non-endocrine organ involved.
• Patients of APS with endocrine involvement generally require lifelong hormone(s) replacement therapy.
• Patients with family history of APS who are screened and diagnosed early have a good prognosis. In other patients, the prognosis depends upon the component diseases.

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