Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder of immune-cell dysfunction with multiple autoimmunities. It presents as a group of symptoms including potentially life-threatening endocrine gland and gastrointestinal dysfunctions. Autoimmune disorders occur when antibodies and immune cells are launched by the body against one or several antigens of its tissues. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. HLA-DR/DQ genes also play a role in predisposing to which of the component autoimmune disease the patient develops.
APS-1 needs to be distinguished from the unrelated but more common APS-2 which is characterized by type-1 diabetes and autoimmune thyroid diseases.
Causes
APS-1 is caused by mutations in the AIRE gene. To date, more than 60 mutations in the AIRE gene have been identified in people with APS-1.
The AIRE gene is responsible for the production of a protein called ‘autoimmune regulator’ which is highly expressed in the thymus gland and generates thymus-derived or T lymphocytes. If this protein is deficient, then those T-cells which have receptors capable of interacting with self-antigens can escape into the circulation (instead of being destroyed in the thymus and not released) and result in autoimmunities. For reasons that are still unclear, defects of the autoimmune regulator protein seem to mostly affect endocrine (hormone-producing) glands.
APS-1 is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Diagnosis
APS-1 is diagnosed definitively through DNA analysis (via blood test) of mutations in the AIRE gene. The diagnosis should be strongly considered in people under 30 years of age who present with at least two of the three typical disease components (CMC, hypoparathyroidism, and/or Addison’s disease). Recently, typical AIRE mutations have been identified in patients who have only one of these three cardinal features but have other less common APS-1-associated autoimmunities. Since virtually all APS-1 patients have interferon autoantibodies, such antibodies when more freely available will serve as a less expensive diagnostic test.
Clinical history and physical exam that suggests more than one endocrine disorder, with or without CMC, should prompt the physician to obtain serum endocrine autoantibody blood tests.
Treatment
Treatment of APS-1 is currently directed toward the specific diseases that are apparent in each patient. In general, replacement therapy of the endocrine hormones that may be lacking, and patient education about the signs and symptoms of these deficiencies, are integral to treatment success. The educational aspect is of extreme importance, as this allows the patient to self-monitor, hopefully avoiding a life-threatening situation.
Addison’s disease is treated with drugs such as hydrocortisone and fludrocortisone to replace the cortisol and aldosterone that are deficient in such patients.
Hypoparathyroidism is treated with oral calcium supplements and activated forms (1, 25 dihydroxy) of vitamin D such as Calcitriol or Rocaltrol. Recently, the parathyroid hormone has become available as a treatment.
For chronic mucocutaneous candidiasis, oral fluconazole (Diflucan) is prescribed.
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