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AP S Dr.Yassin M Al-saleh Dr.Mohammad Algufiliy

Autoimmune polyglandular syndromes

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Autoimmune polyglandular syndromes autoimmune polyendocrine syndrome APS-1,APS-2

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Page 1: Autoimmune polyglandular syndromes

APSDr.Yassin M Al-salehDr.Mohammad Algufiliy

Page 2: Autoimmune polyglandular syndromes

بسم الله الرحمن الرحيم

وما أوتيتم من )(العلم إال قليال

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OBJIECTIVES• Case.• Introduction.• Classification.• APS-1• Pathogenesis. • Presentation.• Management.• APS-2.• Other APS.

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Case

• rafal is 3 year old girl referred from MCH- Qasseem with hypoparathyrodisim.

• Where she presented with generalized convulsion .• found to have low ca 1.1 ,high phosporus 3.7 ,low

PTH 0.27 • Also patient having malabsorption in regular follow

up with GIT clinic . • Family history: consangious marriage.• father have DM and hemihypertorphy.• One cousin with APS-1.

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case

• On exam: • Wt:5th. Ht: 5th. Poor dentation,Hemihypertrophy.• Screeing done for her:• LFT:WNL .• U/E:WNL.• HbA1c:WNL.• ACTH,cortisol:WNL• TFT:WNL• Islet cell, throid,adrenal antibodies :negative.• AIRE gene mutation :positive.

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synonyms• autoimmune polyendorine syndromes (APS).• autoimmune polyglandular syndromes (APS).• polyglandular autoimmune syndromes (PAS)/ (PGAS).• autoimmune polyendocrinopathy.• polyglandular failure syndromes.

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introduction • Definition: • are a heterogeneous group of uncommon diseases

characterized by autoimmune activity against more than one organ (endocrine OR non-endocrine).

• The autoimmune polyglandular syndromes result from a loss of tolerance to self-antigens.

Maurizio Cutolo. Autoimmune polyendocrine syndromes. Autoimmunity Reviews 13 (2014) 85–89

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classification

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Autoimmune polyendocrine syndrome type 1 (APS-1)

• This condition is also termed as APECED autoimmune polyendocrinopathy candidiasis ectodermal dystrophy.

• Also called Whitaker's syndrome• Due to a monogenetic mutation • Males and females are equally affected

Dtsch Med Wochenschr. 2013 Feb;138(7):319-26; quiz 327-8. doi: 10.1055/s-0032-1327355. Epub 2013 Feb 7.[Autoimmune polyglandular syndromes].

introduction

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epidemiology• the disease is not common• an incidence of 1:100 000 . • The highest prevalence have been found in certain

populations with high degree of consanguinity .• in Iranian Jews (1:9,000) • in Finland (1:14,000)• in Sardinia (1:25,000) • In Norway (1:80,000)

George J Kahaly. Polyglandular autoimmune syndromes. European Journal of Endocrinology (2009) 161 11–20

Autoimmune polyendocrine syndrome type 1 (APS-1)

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pathogenesis• an autosomal recessive disease.• linked to mutation of the AIRE gene (Autoimmune

Regulator gene) on chromosome 21q22.3.

Autoimmune polyendocrine syndrome type 1 (APS-1)

MichelsAW: Autoimmune polyglandular syndromes.nat rev endocrinology. 2010 May;6(5):270-7. doi: 10.1038/nrendo.2010.40. Epub 2010 Mar 23.

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pathogenesis• AIRE gene is expressed mainly in the thymus.• Expressed in medullary thymic epithelial cells

(mTECS) .• But also in lymph nodes, liver, pancreas,

adrenal cortex, and testes.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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pathogenesis• More than 70 different mutations in the AIRE gene

have now been reported.• mutations can be confirmed in more than 95% of

patients with clinical diagnoses of APS I

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Pathogenesis

North American,

British, and Norwegian

Iranian Jews Sardinian

Finland

Autoimmune polyendocrine syndrome type 1 (APS-1)

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pathogenesis• several hypotheses have been put forward to explain how an

individual can lose its tolerance against self antigens.• the release of sequestered antigens.• environment-induced alterations of host membrane proteins.• crossreactivity between environmental agents and host

antigens.• A defect in the cells regulating the immune response

Corrado Betterle, Renato Zanchetta: Update on autoimmune polyendocrine syndromes (APS) .ACTA BIO MEDICA 2003; 74; 9-33

Autoimmune polyendocrine syndrome type 1 (APS-1)

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pathogenesis• Also hypothesis is that organs deriving from a same

germ layer can express common germ-layer specific antigens that could serve as targets for the autoimmune responses in APS

• it has been suggested that an APS may be due to external agents sharing one or more epitopes with a common antigen in several endocrine tissues

Autoimmune polyendocrine syndrome type 1 (APS-1)

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pathogenesis• It has been hypothesized that mutations of the AIRE

gene cause loss of peripheral antigen expression in the thymus and probably decreased deletion of autoreactive T lymphocytes that target such peripheral antigens.

Autoimmune polyendocrine syndrome type 1 (APS-1)

De martinilo :APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors. Front immunology. 2013 Oct 23;4:331. eCollection 2013.

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pathogenesis

• AIRE gene function : expression of tissue specific antigen (self-antigin) to thymocytes

• which lead to self tolerance by elimination of the autoreactive T cells.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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T T-cell precursor or developing T-cell

A Auto reactive, self-reactive, pathological T-cell (CD4+ or CD8+)

Rn

Ri

Natural regulatory T-cell or suppressor

induced regulatory T-cell or suppressor

mTEC Medullary thymic epithelial cell

APC Antigen presenting cell

Antigen

CD4 H CD4+ helper cell

(CD4+,CD25+, FOXP3) R

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THYMUS CENTRAL TOLERANCE

TT-cell precursor

negative Selection(apoptosis)

T

mTEC + AIRE

A

A APC + AIREAanergyIgnorance

RiRi

AAA

A

AA

PERI

PHER

Y

Rn

Rn

Rn

positive selection

A

Rn

Rn

Rn

Rn

Rn

Rn

IPEX

APS1

CD4 H

CD4+ and CD8+

TCD4+ or CD8+

TEC

MHC

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Diagnosis of APS-1 • Clinical diagnosis requires the presence of two from three major

criteria (Whitaker’s triad) :• 1-mucocutaneous candidiasis.• 2-Hypoparathyroidism.• 3- Adrenocortical insufficiency (or autoantibodies against 21

hydroxylase)

• or If a sibling has the syndrome only one major is required

• diagnosis could be made by molecular genetics in presence of minors.

Proust- lemoine E. Polyglandular autoimmune syndrome type I. Presse Med .2012 Dec;41(12 P 2):e651-62. doi: 10.1016/j.lpm.2012.10.005. Epub 2012 Nov 23.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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• Different genotype lead to different phenotypes.

• Different genotype can lead to same phenotype. (overlaping)

• One genotype can lead to different phenotypes

presentation

Autoimmune polyendocrine syndrome type 1 (APS-1)

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presentation• Patients begin with CMC, followed by

hypoparathyrodism and finally by addison.• It has been observed that the earlier was the first

clinical presentation, greater will be the number of diseases that will develop during the life of a patient with APS-1

Sarinda Millar, Dennis Carson. Clinical phenotypes of autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy seen in the Northern Ireland

paediatric population over the last 30 years. Ulster Med J 2012;81(3):118-122

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Chronic mucocutaneous candidiasis CMC • is often the first condition detected .• The onset is usually before 5 years of age . • the first sign of APS I in 60% patients.• by 40 years of age 100% of patient with APS will

developed candidiasis .

Autoimmune polyendocrine syndrome type 1 (APS-1)

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CMC

• the etiology :due to a selective immunological deficiency of T cells towards Candida albicans.

• Humoral immunity B-cell function normal.

• Anticytokines autoantibodies against the Th17- related cytokines (IL-22,IL-17A and IL-17F) were implicated .

Sarinda Millar, Dennis Carson. Clinical phenotypes of autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy seen in the Northern Ireland

paediatric population over the last 30 years. Ulster Med J 2012;81(3):118-122

Autoimmune polyendocrine syndrome type 1 (APS-1)

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• Presentation:• Oral candidiasis (thrush)• Diaper rash.• vulvovaginal candidiasis at puberty in females.• Nail infection :leading to a darkened discoloration, thickening,

or erosion. • intestinal mucosal candidiasis :lead to intermittent abdominal

pain and diarrhea.

Chronic mucocutaneous candidiasis CMC

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Chronic mucocutaneous candidiasis CMC • Retrosternal pain occurring in patients with

confirmed oral candidiasis suggests esophageal candidiasis which may lead to stricture and dysphagia.

• epithelial carcinoma of the oral mucosa, tongue or esophagus with its high mortality is well described in APS I patients with chronic mucosal candidiasis.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Chronic hypoparathyroidism• usually presents before puberty.• Pathology:• an atrophy and infiltration of the parathyroid glands with

mononuclear cells. • clinically patient may present with paresthesias, hypereccitability,

hypotension, carbopedal spasim , laryngospasm and generalized seizures.

• These symptoms may, however, be masked in the presence of adrenal insufficiency.

• Papilledema and calcification of the basal ganglia are other signs of chronic hypocalcaemia.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Chronic hypoparathyroidism• hypocalcemia ,Hyperphosphatemia with a low

parathyroid hormone(PTH) level is diagnostic. • Recently, in patients with APS-1 and

hypoparathyrodisim, autoantibodies against calcium-sensing receptors and other autoantibodies have been reported

• Antibodies aginest NALP5 have been found in 49% of patient with APS-1.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Addison disease • is found in more than 85% of APS I• adrenocortical failure usually has its peak onset before

adolescence.• Pathology:• showed atrophy of the glands and lymphocyte

infiltration• Deficiencies of cortisol, aldosterone, and adrenal

andogens may present simultaneously or may evolve over months to several years.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Addison disease • Clinical Presentation• The initial clinical features are often non specific• These include fatigue, weight loss, myalgias,

arthralgias, behavioral changes, nausea and vomiting, abdominal pain, weight loss and diarrhea.

• Hyperpigmentation and postural hypotension • Adrenal crises with hyponatremia, hyperkalemia, and

hypoglycemia .

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Other associated diseases (Minor)

Mohammed Al-Owain :Renal Failure Associated with APECED and Terminal 4q Deletion:Evidence of Autoimmune Nephropathy Case Report. Clinical and Developmental Immunology Volume 2010, Article ID 586342, 7 pages

watanbe M .Myopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Uscle nerve. 2012 Jun;45(6):904-8.

hyposplenism or asplenia . Gonadal failure.policlonal hypergammaglobulinemia autoimmune thyroiditis.IgA deficiency. autoimmune hepatitis.Vasculitis. type 1 diabetes.sublenticular cataract. Cholelithiasis.calcification of basal ganglia. Atrophic gastritis.tympanic membranes calcification. Malabsorption.

rheumatoid arthritis Dental enamel hypoplasia.pure red cell aplasia . Vitiligo.Cerebellar Degeneration . Alopecia.

Keratoconjunctivitis Pericarditis.Sjögren’s syndrome. Pernicious anemia.Polyneuropathy. pulmonary disease.Myopathy* IDA Autoimmune Nephropathy* Encephalopathy.

(APS-1)

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gonadal failure (Hypergonadotropic hypogonadism)• more common in females.• 50% of women with APS I develop ovarian failure by 20

years of age.• In most cases presents usually as secondary amenorrhoea

although in some cases as primary Amenorrhoea • Also menstrual irregularities, polycystic ovaries, or infertility• Less than 30% of men with APS I develop testicular failure.• In 60-80% of patients with APS-1, steroid-producing cell

antibodies (StCA) have been detected .

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Autoimmune thyroid diseases• Autoimmune thyroid diseases (ATD) occur in 4- 36%

of cases .• between 9-32 years of age and usually as chronic

thyroiditis • Anti-microsomial (anti-peroxidase) and/or anti-

thyroglobulin antibodies are detected in most patients with autoimmune thyroid diseases

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Autoimmune hepatitis• Autoimmune Hepatitis occurs in 10% to 31% of APS I.• Subclinical to fulminant hepatic failure.• the leading cause of death in these patients.• all patients suspected of having APS I should have their liver

function regularly monitored.• Autoimmune hepatitis in APS-1 correlates with positive

antibodies against liver and kidney microsomes (anti-LKM)• Anti-LKM antibodies are present even in 25% without

alterations in their liver function tests.

Autoimmune polyendocrine syndrome type 1 (APS-1)

Bialkosowska J: Hepatitis and the polyglandular autoimmune syndrome, type 1.Aech med sci . 2011 Jun;7(3):536-9. doi: 10.5114/aoms.2011.23427. Epub 2011 Jul 11.

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malapsorption• Many ossotiated condition implicated including: • Coeliac disease ,cystic fibrosis, pancreatic

insufficiency ,intestinal infections from Candida Albicans, intestinal lymphangectasia , idiopathic cholecystokinin deficiency

• In some patients cause unknown “idiopathic malabsorption”

• in 48% of patients with APS-1 the tryptophan hydroxylase autoantibodies were detected.

• TPH-Abs are absent in patients with gastrointestinaldisorders but unaffected by APS-1

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Management

Autoimmune polyendocrine syndrome type 1 (APS-1)

Specific organ autoantibody

screening

assessment of endocrine function

Genetic study + general antibodies

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screening• In hypothyroid patients with confirmed APS,

evidence for adrenal autoimmunity must also be sought before starting thyroid hormone replacement therapy

• Usually, sudden hypercalcemia in hypoparathyroid individuals may signal the beginning of adrenal insufficiency

Autoimmune polyendocrine syndrome type 1 (APS-1)

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screening• Any patients with APS-1 should be seen and screen

for autoantibodies at 6-month intervals.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Meloni A, Furcas Met al. Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2008;93:4389–97

• Studies showed that upto 100% of patients with APS-1 have been found to express autoantibodies reacting with interferon-omega .

• also the great majority express autoantibodies reacting with interferon alpha.

• their role in pathogenesis still controversy.

PathogenesisAutoimmune polyendocrine syndrome type 1 (APS-1)

(Anti-IFN-ω and Anti-IFN-α)

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jaaskelainen j ,Perheentupa Autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy (APECED)--a diagnostic and therapeutic challenge. endocrinology review 2009 Dec;7(2):15-28.

• search for autoantibodies against interferon-omega, enables proof or exclusion of APECED with more certainty than gene analysis.

• It is highly specific and sensitive for APECED if thymoma and myasthenia gravis are excluded

• Its present early in course of the disease and persist for years

Autoimmune polyendocrine syndrome type 1 (APS-1)

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screening

• Any patient with suspected APS should be screened with a panel of autoantibodies :

• type I interferons autoantibodies (α and ω) • adrenal cortex cytoplasmic autoantibodies.• 21 hydroxylase autoantibodies.• GADA, IA-2A, IAA,ZnT8 andICA• thyroid microsomal/thyroperoxidase autoantibodies.• thyroglobulin autoantibodies.• steroidal cell autoantibodies.• P450 1A2 and AADC autoantibodies• Anti-LKM antibodies.• endomysial or transglutaminase autoantibodies.• Internisic factor.• H+ K+ ATPase autoantibodies.• Parital cell autoantibodies.• Autoantibodies against tyrosine hydroxylase• Complement-fixing melanocyte antibodies

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Assessment of end-organ function• Assessment of end-organ function in any patient with

autoantibodies is recommended annually.Investigation

early morning cortisol levels

electrolyte :sodium, potassium

renins

Fasting blood glucose testing

calcium, phosphate, and PTH

TSH level,FT4

Investigation

FSH and LH levels

Testesteron , estradiol

hemoglobin and hematocrit

mean corpuscular volume

vitamin B12 level

Liver function tests

Autoimmune polyendocrine syndrome type 1 (APS-1)

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Treatment of APS-1 • will depend upon the autoimmune disorder identified .• Candidiasis: antifungal.• aggressive therapy of oral is indicated in order to prevent

the late complication of epithelial carcinoma.• Fluconazole is preferred over ketconazole. • Hypoparathyrodisim: calcium and one alph.• Addision : hydrocortison or prednisolone +

fludrocortisone.• Type 1 DM: insulin.

Autoimmune polyendocrine syndrome type 1 (APS-1)

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• Hypothyrodisim: levothyroxine.• Hypergonadotropic hypogonadism: testosterone in

male, estrogen and progestrone in female.• asplenia :vaccinations and prophylactic antibiotic. • Autoimmune hepatitis : immunosuppresent.• Keratoconjunctivitis : immunosuppresent.• Malabsorption : immunosuppresent.• pure red cell aplasia : immunosuppresent.

Treatment of APS-1

Autoimmune polyendocrine syndrome type 1 (APS-1)

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• APS-2 is the most common autoimmune polyendocrine syndrome.

• incidence of 1:20 000• more common in females than in males.• onset in adulthood.• particularly during the third or fourth decades.

Dtsch Med Wochenschr. 2013 Feb;138(7):319-26; quiz 327-8. doi: 10.1055/s-0032-1327355. Epub 2013 Feb 7.[Autoimmune polyglandular syndromes].

Autoimmune polyendocrine syndrome type 2 (APS-2)

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pathogenesis of APS II• the precise aetiology is unknown.• cases occur sporadically or within families.• inheritance of PAS II is complex.• Within some families, it appears to be inherited as an

autosomal dominant.• genes on chromosome 6 playing a predominant role.

this chromosome contains the major histocompatibility loci.

George J Kahaly. Polyglandular autoimmune syndromes. European Journal of Endocrinology (2009) 161 11–20

Autoimmune polyendocrine syndrome type 2 (APS-2)

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pathogenesis• patients with APS II have HLA associations similar to

those of patients with type 1 diabetes..• The primary association of APS-2, appears to be with

class II HLA alleles with DR3/DQ2 and DR4/DQ8• Primary adrenal insufficiency in type 2, but not in

type 1 APS, is strongly associated with both HLADR3 and HLA-DR4

Autoimmune polyendocrine syndrome type 2 (APS-2)

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Diagnosis of APS II

• is defined by the coexistence of :• Autoimmune adrenocortical insufficiency or serologic evidence of

adrenalitis with one or more of the following :• 1- autoimmune thyroiditis or serologic evidence of thyroid autoimmunity.• 2- type 1 diabetes mellitus or islet autoimmunity.

• (Schmidt syndrome) : adrenocortical insufficiency + autoimmune thyroiditis

• (Carpenter syndrome) Schmidt syndrome + type 1 diabetes

Autoimmune polyendocrine syndrome type 2 (APS-2)

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Presentation • Adrenocortical failure is the intial presentation in

approximately 50% of APS II cases.• autoimmune thyroid disease (AITD) coexists in 80–

90% of females with Addison disease. • Type 1 diabetes coexists in nearly 50% of patients

with Addison disease.

Autoimmune polyendocrine syndrome type 2 (APS-2)

Ali Y: Polyglandular autoimmune syndrome type 2: diagnosed in the intensive care unit. Ther Adv Endocrinol Metab. 2013 Dec;4(6):170-2. doi: 10.1177/2042018813515698.

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• Vitiligo.• autoimmune lymphocytic

gastritis.• Alopecia.• Gonadal failure.• Hypophysitis.• empty sella syndrome.• ulcerative colitis.• primary biliary cirrhosis.

• Sarcoidosis.• Achalasia.• neuropathy. • Thrombocytopenic purpura• IgA deficiency.• juvenile dermatomyositis• dermatitis herpetiformis,• scleroderma,

Other associated diseases

Autoimmune polyendocrine syndrome type 2 (APS-2)

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APS-2

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Other APS• IPEX.• Thymic tumor

disease.• POEMS syndrome.• Hirata syndrome.• Adult combined

pitutary hormone deficincy(CPHD).

• Kearn-sayre syndrome.

• DIDMOAD syndrome.

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IPEX

• IPEX (immune dysfunction, polyendocrinopathy, and enteropathy, X-linked).

• also called XLAAD (X-linked autoimmunity and allergic dysregulation)• fatal autoimmune lymphoproliferative disease.• rare X-linked recessive.• Due to the absence of normal FoxP3 expression• Neonatal onset type 1 diabetes,dermatitis, enteropathy, thyroiditis,

hemolytic anemia, and thrombocytopenia.• long-term immunosuppression or bone marrow transplantation

appears to be the only effective therapy for IPEX.

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Sperling’s MCQs

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انها رب يا األطفال ضحكة وصناعشبا الرمل موحش في غردت ما إذا

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