Clinical Pearls & Morning Reports

By Carla Rothaus

Published March 21, 2018


What are some of the features of autoimmune polyendocrine syndrome type 1?

Autoimmune polyendocrine syndromes comprise a diverse group of clinical conditions characterized by functional impairment of multiple endocrine glands due to loss of immune tolerance. These syndromes can be broadly categorized as rare monogenic forms, such as autoimmune polyendocrine syndrome type 1 (APS-1), and a more common polygenic variety, autoimmune polyendocrine syndrome type 2 (APS-2). Read the latest NEJM Review Article here.

Clinical Pearls

Q: Are the manifestations of the autoimmune polyendocrine syndromes limited to conditions affecting the endocrine glands?

A: These syndromes also frequently include conditions such as alopecia, vitiligo, celiac disease, and autoimmune gastritis with vitamin B 12 deficiency that affect nonendocrine organs.

Q: Are all the components of any given autoimmune polyendocrine syndrome evident by early adulthood?

A: Autoimmune polyendocrine syndromes are insidious and are characterized by circulating autoantibodies and lymphocytic infiltration of the affected tissues or organs, eventually leading to organ failure. The syndromes can occur in patients from early infancy to old age, and new components of a given syndrome can appear throughout life.

Morning Report Questions

Q: What are some of the features of autoimmune polyendocrine syndrome type 1 (APS-1)?

A: APS-1, also named autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy, is a rare autosomal recessive disease caused by mutations in the autoimmune regulator gene (AIRE). APS-1 is characterized by the development of at least two of three cardinal components during childhood — chronic mucocutaneous candidiasis, hypoparathyroidism, and primary adrenal insufficiency (Addison’s disease). Other typical components include enamel hypoplasia and enteropathy with chronic diarrhea or constipation. Primary ovarian insufficiency, affecting approximately 60% of women with APS-1 before they reach 30 years of age, is common. Wide variation in presentation and symptomatology makes the diagnosis of APS-1 challenging. As an early marker of T-cell–mediated loss of immune tolerance in patients with APS-1, disease-associated organ-specific autoantibodies may appear, often targeting intracellular proteins that have key functions in affected organs. Many of the autoantibodies are fairly specific to APS-1. Other autoantibodies observed in APS-1 also appear in more common autoimmune diseases, such as those targeting glutamic acid decarboxylase 65 in type 1 diabetes, 21-hydroxylase in Addison’s disease, and side-chain cleavage enzyme in autoimmune primary ovarian insufficiency, pointing to possible commonality in the pathogenesis of these various entities.

Q: What are some of the features of autoimmune polyendocrine syndrome type 2 (APS-2)?

A: The onset of APS-2 typically occurs in young adulthood, later than the onset of APS-1. Patients with APS-2 have courses characterized by at least two of the following three endocrinopathies: type 1 diabetes, autoimmune thyroid disease, and Addison’s disease. Women predominate among patients with APS-2. In many affected patients, other autoimmune conditions develop, including celiac disease, alopecia, vitiligo, primary ovarian insufficiency, and pernicious anemia. The picture emerging from genetic studies of APS-2 is that the same genes and single-nucleotide polymorphisms are associated with several organ-specific autoimmune diseases. Thus, there are more similarities than specific differences when it comes to genetic associations. In general, associations are mostly to genes coding for key regulatory proteins in the adaptive and innate immune system, particularly in the major histocompatibility complex. For example, patients with APS-2 who are at risk for celiac disease generally have variants in DR3-DQ2 and DR4-DQ8, and these same haplotypes confer a risk of type 1 diabetes, autoimmune thyroid disease, and Addison’s disease. This explains why all four diseases may develop in the same patient.

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