Type I Polyglandular Autoimmune Syndrome



Polyglandular autoimmune (PGA) syndromes (otherwise known as polyglandular failure syndromes) are constellations of multiple endocrine gland insufficiencies. Other descriptive terminologies, such as autoimmune polyendocrine syndrome (APS), also are used in the literature. In the classification of these syndromes, Roman numerals (eg, I and II) and Arabic numbers (eg, 1 and 2) have been variably used in the literature. For the purpose of consistency in this article, the term PGA and Roman numerals will be used.

Essentially, 2 types of PGA exist, type I and the more common type II, also known as Schmidt syndrome. A third type (type III), which occurs in adults, has been described. Type III does not involve the adrenal cortex, but it includes 2 of the following: thyroid deficiency, pernicious anemia, type 1A diabetes mellitus, vitiligo, and alopecia. Other disorders also have been described in association with the PGA syndromes; pulmonary hypertension in association with PGA syndrome type II (PGA-II) is one example.[1]

Historically, the interest in these syndromes began in the 19th century and essentially focused on the adrenal cortex. In 1849, Thomas Addison first described the clinical and pathologic features of adrenocortical failure in patients who also appeared to have coexisting pernicious anemia. Between 1849 and 1980, geneticists, immunologists, and endocrinologists generated a wealth of new information concerning the pathogenesis of the PGA syndromes and their component disorders.

In 1929, Thorpe and Handley recognized the association of mucocutaneous candidiasis with glandular failure, and case reports and case series have since appeared in the international literature. In 1981, Neufeld and colleagues distinguished 2 major PGA syndromes, and other authors subsequently began to add to our knowledge of these conditions.[2] In 2004, Eisenbarth and Gottlieb extended the discussion on the classification of these syndromes.[3] While they acknowledged the system that was adopted by the so-called splitters, dividing the syndromes into 4 subtypes (I, II, III, IV), Eisenbarth and Gottlieb recommended the system adapted by the "lumpers." The latter system "lumps" the syndromes into just 2 types, I and II. Finally, according to Eisenbarth and Gottlieb, the term polyendocrine is a misnomer, because these syndromes include a number of nonendocrine disorders.

PGA-I, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) or as Whitaker syndrome, is associated with candidiasis, hypoparathyroidism, and adrenal failure[4] (although PGA-I without mucocutaneous candidiasis has been reported in an adolescent).[5] A syndrome with these features was first described in 1946. It is a rare disorder, with sporadic autosomal recessive inheritance.


The evidence supporting the autoimmune etiology of polyglandular autoimmune (PGA) syndrome, type I, is based on the presence of chronic inflammatory infiltrates composed mainly of lymphocytes in the affected organs and on the presence of autoantibodies reacting to target tissue – specific antigens. The antibodies are believed to occur as a result of a breakdown in normal immunologic tolerogenesis or as a consequence of immunization with an environmental agent that has a similar antigenic molecular structure to a self-antigen.

The 3 main types of autoantibodies are directed to the surface receptor molecules, intracellular enzymes, and secreted proteins, such as hormones. Their pathogenic relevance is still unclear, and even measuring levels of these autoantibodies against endocrine glands or their components does not appear to be useful, because such antibodies may persist for years without the patient developing endocrine failure. Their primary function is to differentiate autoimmune causes and infectious/iatrogenic causes of endocrine insufficiency.

Another immunological feature is the presence of circulating neutralizing antibodies to cytokines in the peripheral blood of APECED patients. Neutralizing Abs to Th (T helper) cytokines are present in the peripheral blood of patients causing defective antifungal response, contributing to the development of mucocutaneous candidiasis.[6]  Virtually all the of patients with PGA-1 have been found to express autoantibodies reacting with interferon-omega and the great majority express autoantibodies reacting with interferon alpha.[7]

With regard to genetic susceptibility, PGA-I is unique among autoimmune endocrine disorders, because it has no HLA antigen association. However, an increased frequency of HLA-A28 and HLA-A3 has been documented in PGA-I, more so than in normal controls. The genetic locus responsible for the disease has been localized to the short arm of chromosome 21 near markers D21s49 and D21s171 on band 21p22.3. A Finnish study concluded that the mutation R257X is responsible for 82% of cases.[8]

A monogenic mutation of AIRE (autoimmune regulator), which codes for a putative transcription factor featuring 2 zinc motifs, is very strongly linked to PGA-I.[9]  In autoimmune disorders such as Addison's disease, patients without the PGA-1 syndrome, do not show AIRE mutations suggesting that the gene alterations are not involved in these more common diseases, but unique to PGA-1.

Studies on young, thymectomized mice have contributed significantly to the understanding of the pathophysiology of PGA-I, as neatly illustrated by Eisenbarth and Gottlieb in a 2004 review article.[3]



United States

In North America, polyglandular autoimmune (PGA) syndrome, type I, is extremely rare, and only scattered US case reports have been published. Most of the published literature has come from Europe, where the disease clusters in certain populations (see International Frequency, below). Frequency, therefore, is not well documented in the United States; the mixed ethnic makeup of the US population may explain the low rate of case clustering. The 2 largest case series from North America were published by Neufeld and colleagues in 1981 and by Heino and coauthors in 1999.[2, 10] In the latter report, 16 patients were described, including 13 white patients, 1 Hispanic individual, 1 Middle Eastern patient, and 1 Asian person.


Polyglandular autoimmune (PGA) syndrome, type I, is a very rare disorder; it clusters in certain homogeneous ethnic populations due to consanguineous marriages and/or clustering of descendants of common family founders. These populations include special groups of Finns, Sardinians, and Iranian Jews. Less frequent clustering has been reported from northern Italy, northern Britain, Norway, and Germany. Scattered case reports from various countries around the world have been published. The highest number of patient groups has notably been reported in Finland, in successive case series over the last few decades. The prevalence of PGA-I in Finland has been estimated to be 1 case per 25,000.[8] Known frequencies in other ethnic groups include 1 case per 14,400 in Sardinians and 1 case per 9,000 in Iranian Jews.[11, 12]


The mortality and morbidity associated with polyglandular autoimmune (PGA) syndrome, type I, appear to be equivalent to the individual components of the syndrome. Certainly morbidity and mortality can be reduced with improved case findings in relatives of index cases. In individual cases, early detection of life-threatening complications, such as adrenal crisis, hypocalcemia, and sepsis, is prudent.


As discussed in Frequency, ethnic clustering of polyglandular autoimmune (PGA) syndrome, type I, has been observed in certain ethnic populations. Sporadic cases reported around the world have most likely been caused by various isolated mutations, many of which have been identified.


The female-to-male ratio for polyglandular autoimmune (PGA) syndrome, type I, ranges from 0.8:1 to 1.5:1, as reported in earlier case series. Figures from 2003 indicate that this ratio is between 0.8:1 and 2.4:1, indicating some tendency toward female preponderance.[13] A sporadic report from Italy, by Iannello and colleagues, showed a rather exclusive female preponderance in an X-linked inheritance fashion.[14] In reports from around the world, however, autosomal recessive inheritance has been found to be the genetic mode of transmission in most families.


Polyglandular autoimmune (PGA) syndrome, type I, usually occurs in children aged 3-5 years or in early adolescence, but it always occurs by the early part of the third decade of life. A general trend has been noted in the order of appearance of the 3 major systemic manifestations, eg, candidiasis, hypoparathyroidism, and Addison disease. However, that is not always the case, and decades may pass before the appearance of newer syndromic components. Therefore, lifelong follow-up is prudent for early detection of additional components. This cannot be overemphasized, because unrecognized hypoparathyroidism or adrenal insufficiency can be life-threatening.


Overview of clinical features

Mucocutaneous candidiasis


Adrenocortical failure (Addison disease)

Less common clinical manifestations


Physical findings in polyglandular autoimmune (PGA) syndrome, type I, are dependent on the components of the syndrome that are clinically manifested at the time of examination.




Laboratory Studies

The diagnosis of polyglandular autoimmune (PGA) syndrome, type I is usually made with two or three of the following conditions: mucocutaneous candidiasis, hypoparathyroidism and/or adrenal insufficiency. In diagnosing PGA-1, a clinical history and examination that suggest evidence of more than 1 endocrine deficiency should prompt the use of the following tests:

Serum endocrine autoantibody screen[7, 16]

Since the different components of this disease develop over years to decades, once there is clinical suspicion, surveillance is essential for other associated autoimmune disorders.

End-organ function tests are necessary to confirm the diagnosis.

Depending on the presentation, liver function tests along with antibodies to the liver, kidney, and spleen (autoimmune hepatitis) may be considered because of their occasional association with PGA-I.

Malabsorption and atrophic gastritis occasionally are associated with PGA-I, and patients with suggestive clinical features may require endoscopic biopsies to prove the diagnosis.

Imaging Studies

Perform a computed tomography (CT) scan of the adrenal glands to exclude hemorrhage and fungal infections as the cause of primary adrenal insufficiency.

Other imaging studies depend on the syndrome components or other associated disorders present at the time of the evaluation.

Other Tests

Other tests depend on the syndrome components or other associated disorders present at the time of the evaluation.


Endoscopies with biopsies of the stomach and small bowel are used to rule out atrophic gastritis and celiac disease.

Other procedures depend on the syndrome components or other associated disorders present at the time of the evaluation.

Histologic Findings

Histology depends on the organ that has been affected. There usually is chronic inflammatory cell infiltration of the affected organs. Examples are as follows:

Medical Care

The treatment for polyglandular autoimmune (PGA) syndrome, type I, is targeted at whatever organ is affected. It is always best to identify and treat the respective autoimmunity before any significant morbidity can develop.

For the most part, replacement therapy and patient education about the chronic diseases are integral to treatment success. The educational aspect is extremely important, because it helps the patient with the early detection of any new autoimmune states and aids in the adequate treatment of this chronic syndrome.

Mucocutaneous candidiasis


Adrenal insufficiency (Addison disease)

Surgical Care

No specific surgical interventions exist that are unique to the management of polyglandular autoimmune (PGA) syndrome, type I. However, complications from a component of the syndrome may require therapeutic procedures or surgical interventions, as for example, in the case of a patient requiring intubation and other critical care therapeutic interventions after going into adrenal crisis culminating in septic/hypovolemic shock.


See the list below:


A high-salt diet is beneficial to patients with adrenal insufficiency.

If coexisting diabetes is present, institute a diabetic diet.


As tolerated.

Medication Summary

The drugs listed here are used primarily for the replacement of deficient hormones and electrolytes (except for ketoconazole). The medications detailed in this list are the major, well-established drugs available for each category. However, newer agents, especially in the antifungal category, have been introduced; these may be administered by qualified physicians, especially to critically ill patients in the ICU.

Hydrocortisone (Cortef, A-Hydrocort, Solu-Cortef)

Clinical Context:  DOC because of mineralocorticoid activity and glucocorticoid effects. Useful for treatment of many diseases, especially autoimmune and inflammatory diseases. Used in PGA-I for primary adrenal failure.


Clinical Context:  Partial replacement therapy for primary and secondary adrenocortical insufficiency. Most commonly prescribed synthetic mineralocorticoid. Possesses glucocorticoid qualities. Encourages sodium reabsorption at distal renal tubules, GI mucosa, and the sweat and salivary glands.

Class Summary

These are used for adrenocortical insufficiency replacement. Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.


Clinical Context:  First azole used in clinical practice. Imidazole broad-spectrum antifungal agent that inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death. Also acts on several P450 enzymes including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. May inhibit ACTH secretion when used at therapeutic doses. Possess narrow therapeutic index.

Fluconazole (Diflucan)

Clinical Context:  Fungistatic activity. Synthetic oral antifungal (broad-spectrum bis-triazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Class Summary

These drugs treat mucocutaneous candidiasis. Their mechanism of action may involve an alteration of ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Calcitriol (Vectical, Rocaltrol)

Clinical Context:  Active metabolite of vitamin D that binds to and activates the vitamin D receptor in kidney, parathyroid gland, intestine, and bone. The active form of vitamin D stimulates intestinal calcium transport and absorption. This medication is essential in individuals with hypoparathyroidism.

Ergocalciferol (Calciferol, Drisdol, Calcidol)

Clinical Context:  Stimulates absorption of calcium and phosphate from small intestine and promotes release of calcium from bone into blood. Precursor of active form of vitamin D (calcitriol). Because it is a precursor, a significant delay between dose administration and effect exists. Liver must be intact for intermediate to be formed (calcidiol, 25-hydroxy vitamin D). Many drugs may affect this step. Has lipid storage, so overdoses may cause prolonged hypercalcemia.

Measure of efficacy is serum calcium concentration.

Calcium carbonate (Oystercal, Caltrate)

Clinical Context:  Calcium moderates nerve and muscle performance by regulating action potential excitation threshold. For hypoparathyroidism, use a supplementation of at least 2 g of elemental calcium/d.

Class Summary

These are used as nutritional supplements.

Further Outpatient Care

Apart from the usual medications, enforce the following measures:

Further Inpatient Care

If evidence of hypothyroidism is present, perform an adrenal evaluation before any thyroid replacement. If replacement of thyroid hormones is urgent, draw blood for later adrenal evaluation, and administer steroids before starting thyroid replacement dosing.

Inpatient & Outpatient Medications

These medications depend on the components present in individual patients and range from agents used for hormone replacement to medications employed to manage fungal infections and other complications/deficiencies.


Strongly advise patients to wear medical alert bracelets indicating that they have adrenal insufficiency.

Provide patients with increased steroid coverage before surgeries or periods of stress (for example, in the case of a febrile illness).



Addison disease

Other complications include the following:


The prognosis is variable, depending on how organs are affected and the severity of the disease.

Patient Education

Outpatient management should include patient education on the various components of polyglandular autoimmune (PGA) syndrome, type I, and the need to screen close relatives as appropriate. An important aspect of patient education is the provision of information about adrenal deficiency; subtle deficiency that goes unnoticed in normal, daily-life situations may become life-threatening in stressful situations.

See Further Outpatient Care.


Saleh A Aldasouqi, MD, FACE, ECNU, Associate Professor of Medicine, Vice Chief of Endocrinology Division, Department of Medicine, Michigan State University College of Human Medicine

Disclosure: ReceivReceived honoraria from Janssen for speaking; Received honoraria from Invokana for speaking.


Naveen Kakumanu, MD, Assistant Professor, Department of Endocrinology, Michigan State University College of Human Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Arthur B Chausmer, MD, PhD, FACP, FACE, FACN, CNS, Professor of Medicine (Endocrinology, Adj), Johns Hopkins School of Medicine; Affiliate Research Professor, Bioinformatics and Computational Biology Program, School of Computational Sciences, George Mason University; Principal, C/A Informatics, LLC

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Additional Contributors

Olakunle P A Akinsoto, MD, MB, BCh, Consulting Staff, Family Health Center

Disclosure: Nothing to disclose.

Serge A Jabbour, MD, FACP, FACE, Professor of Medicine, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University

Disclosure: Nothing to disclose.


I would like to thank Jinie Shirey at the Department of Medicine, College of Human Medicine, Michigan State University, East Lansing for manuscript assistance and preparation, and Laura Smith at the Medical Library, Sparrow Hospital, Lansing, Michigan, for assistance in reference retrieval.


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