Autoimmune polyendocrinopathy syndromes
1. Define the autoimmune polyendocrinopathy syndromes (APSs). How many clinical forms are there?
The APSs are disorders in which two or more endocrine glands are simultaneously hypofunctional or hyperfunctional as the result of autoimmune dysfunction. It is theorized that a defect in the T-suppressor cell subset inadvertently permits activation of the cellular and humoral arms of the immune system. The nature of this dysfunction is unknown. The two widely recognized clinical forms are appropriately designated APS type 1 and APS type 2. The common clinical link between the syndromes is adrenal insufficiency.
2. Is evidence of nonendocrine autoimmune dysfunction associated with APSs?
Yes. Connective tissue diseases and hematologic and gastrointestinal autoimmune disorders are commonly associated with the APSs.
3. What constitutes APS type 1?
APS type 1 is a pediatric disorder manifested by the presence of a combination of two of the following three disorders: hypoparathyroidism, adrenal insufficiency, and chronic mucocutaneous candidiasis. Usually, hypoparathyroidism and candidiasis manifest by age 5 years. Adrenal insufficiency occurs by age 12 years, and all manifestations are present by age 15 years. Some affected individuals develop only one manifestation. Other endocrine conditions may also occur; the largest series of patients had the following endocrine manifestations:
4. Are nonendocrine manifestations associated with APS type 1?
Yes. Chronic mucocutaneous candidiasis occurs in 75% of patients, celiac disease in 25%, alopecia in 20%, pernicious anemia in 16%, and chronic autoimmune hepatitis in 9%. Dystrophy of the dental enamel, vitiligo, keratopathy, and hypoplasia of the teeth and nails also may occur, thus prompting the alternative designation for APS type 1: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).
5. Explain the etiology of APS type 1.
Mutations of the autoimmune regulator (AIRE) gene on chromosome 21 cause APS type 1, which is inherited in an autosomal recessive pattern. There appears to be no human leukocyte antigen (HLA) association. The cause of the candidiasis is not known, although delayed hypersensitivity is defective in affected patients. Antibodies to adrenal enzymes (21-hydroxylase, an enzyme in the biosynthetic pathway for aldosterone and cortisol) and to poorly characterized parathyroid antigens have been described by some groups.
6. What therapy can be offered?
Annual screening of levels of serum calcium, cosyntropin-stimulated cortisol, and liver-associated enzymes is performed in affected sibships until age 15 years. Adrenal insufficiency and hypoparathyroidism are treated with glucocorticoids and with oral calcium and vitamin D supplementation, respectively. Mucocutaneous candidiasis is treated with fluconazole. Use of prophylactic immunosuppressives, such as cyclosporine, is not recommended.
7. What disorders are associated with APS type 2?
APS type 2 occurs in adulthood and consists of autoimmune adrenal insufficiency with autoimmune thyroid disease and/or diabetes mellitus type 1. The age of onset tends to be between 20 and 30 years; one half of the cases are sporadic, and one half are familial. Endocrine organ involvement is as follows:
Autoimmune thyroid disease: 70%
