Autoimmune polyendocrine syndrome

In medicine, autoimmune polyendocrine syndromes are a heterogeneous group of rare diseases characterised by autoimmune activity against more than one endocrine organs, although non-endocrine organs can be affected.

There are three "autoimmune polyendocrine syndromes", and a number of other diseases which have endocrine autoimmunity as one of their features.

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The syndromes

Type 1

Autoimmune polyendocrine syndrome, type 1 is also known as the candidiasis-hypoparathyroidism-Addison's disease-syndrome after its main features:

• A mild immune deficiency, leading to persistent mucosal and cutaneous infections with candida yeasts. There is also decreased function of the spleen (asplenism).
• Autoimmune dysfunction of the parathyroid gland (leading to hypocalcemia) and the adrenal gland (Addison's disease: hypoglycemia, hypotension and severe reactions in disease).
• Other disease associations are:
  • hypothyroidism
  • hypogonadism and infertility
  • vitiligo (depigmentation of the skin)
  • alopecia (baldness)
  • malabsorption
  • pernicious anemia
  • chronic active (autoimmune) hepatitis

As opposed to type 2, this syndrome inherits in an autosomal recessive fashion and is due to a defect in AIRE ("autoimmune regulator"), a gene located on the 21st chromosome. Normal function of AIRE, a transcription factor, appears to be to confer immune tolerance for antigens from endocrine organs.

A EU-funded consortium is currently doing translational research on this condition and has established a webpage at EurAPS.

Type 2

Autoimmune polyendocrine syndrome, type 2 (also known as "Schmidt's syndrome") is more heterogeneous, occurs more often and has not been linked to one gene. Rather, patients are at a higher risk when they carry a particular HLA genotype (DQ2, DQ8 and DRB1*0404).

Features of this syndrome are:

• Addison's disease
• hypothyroidism
• diabetes mellitus (type 1)
• less common associations:
  • hypogonadism
  • vitiligo

Some researchers favour splitting this syndrome into three distinct syndromes (numbering 2, 3 and 4), but research evidence for these distinct combinations is not convincing.

XPID

The most serious but rarest form is the X-linked polyendocrinopathy, immunodeficiency and diarrhea-syndrome, also called IPEX. This is due to mutation of the FOXP3 gene on the X chromosome. Most patients develop diabetes and diarrhea as neonates and many die due to autoimmune activity against many organs. Boys are affected, while girls are carriers and might suffer mild disease.

Other diseases

Other diseases featuring polyendocrine autoimmunity:

• Chromosomal abnormalities (Down's syndrome) increase the risk of endocrine autoimmunity
• POEMS syndrome - the E is for endocrinopathy; the cause is a paraprotein excreted by a plasmacytoma or multiple myeloma; other features are polyneuropathy, organomegaly (hepatomegaly and splenomegaly), M-protein (paraprotein) and skin changes.
• Several very rare diseases.

Management

In principle, the component diseases are managed as usual. The challenge is to detect the possibility of any of the above syndromes, and to anticipate other manifestations. For example, in a patient with known Type 2 autoimmune polyendocrine syndrome but no features of Addison's disease, regular screening for antibodies against 21-hydroxylase (a feature of Addison's) may prompt early intervention and hydrocortisone replacement to prevent characteristic crises.

Sources

• Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med 2004;350:2068-79. PMID 15141045.