At a Glance

Polyglandular autoimmune (PGA) syndrome (also abbreviated APS) is a disease in which the functions of multiple endocrine organs (i.e., thyroid, parathyroid, pancreatic islets, and adrenal gland) are affected by endogenous autoantibodies. Common manifestations of autoantibody activity are hyper- or hypothyroidism, Addison disease, hypoparathyroidism, and type I diabetes mellitus (DM). PGA syndrome is commonly divided into four main groups, designated APS-1, APS-2, APS-3, and APS-4. In addition to the endocrine manifestations of PGA, autoimmune damage of other organs may contribute to the clinical presentation. Examples of such coexisting autoimmune manifestations would include such entities as myasthenia gravis, autoimmune hepatitis, and primary ovarian insufficiency.

APS-1 (also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; APECED) is a pediatric disease caused by recessive mutations in the AIRE gene. This group commonly presents with mucocutaneous candidiasis and is also characterized by Addison disease, hypoparathyroidism, and type I DM. One clinical manifestation in the presence of known AIRE mutations is also sufficient for diagnosis.

APS-2 (also known as Schmidt’s syndrome) is a disease of adults that is associated with HLA-DR3 and HLA-DR4. It presents as Addison disease in the presence of other endocrinopathies, such as hyper- or hypothyroidism and type I DM. A variety of additional autoimmune manifestations may be seen, including celiac disease, alopecia, pernicious anemia, and myasthenia gravis.

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APS-3 exhibits autoimmune thyroid disease and other autoimmune disease (such as those listed above for APS-2) in the absence of specific conditions (Addison disease, hypoparathyroidism, candidiasis) characteristic of APS-1

APS-4 is the designation reserved for disease in patients who have at least two organ-specific autoimmune diseases but who do not meet the criteria for APS-1, -2, or -3.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Given its diverse manifestations, subtypes, and target organs, the testing regimen required in order to fully characterize PGA (APS) is very broad. The Laboratory tests and their limitations are the same as the constituent conditions and have the same limitations. The most critical clinical issue is making sure that all organ systems that may be affected by PGA are adequately assessed by laboratory testing.

Testing should include a basic metabolic panel including electrolytes (sodium, potassium, chloride, carbon dioxide, calcium, magnesium, phosphorus), BUN, creatinine, glucose. Additionally, at a minimum the organ-specific testing should include assays to assess adrenal function (cortisol, adrenocorticotropic hormone with consideration given to a possible stimulation test, aldosterone), parathyroid function (parathyroid hormone), pancreatic islet-cell function (oral glucose tolerance test or hemoglobin A1c), thyroid function (thyroid stimulating hormone, free T4), liver function (AST, ALT), and other relevant systems (B12, folate).

If other clinical symptoms suggest additional affected organ systems, appropriate testing may be indicated (e.g. follicle stimulating hormone and luteinizing hormone in a female with amenorrhea; an insulin-induced hypoglycemia test (ITT) or growth hormone releasing hormone (GHRH) +arginine stimulation test for possible growth hormone deficiency.

What Lab Results Are Absolutely Confirmatory?

APS-1 patients are characterized by recessive mutations in the AIRE gene, and over 60 such mutations have been reported.

100% of APS-1 patients have been reported to manifest specific anti-type 1 interferon antibodies, and this methodology may provide a more cost-effective testing strategy compared with AIRE mutation testing.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

Clinical mutation testing by gene sequencing is available from a number of laboratories. Such testing is most likely to be useful in order to determine the status of other family members who may carry the mutation but who have not yet been diagnosed. In such patients, increased surveillance via the testing described above (broad testing for endocrine and other organ system function) may be useful.

What Factors, If Any, Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

DNA testing for AIRE mutations is not affected by any medications.