Polyglandular deficiency syndromes have been given many different names, reflecting the wide spectrum of disorders that have been associated with these syndromes and the heterogeneity of their clinical presentations. The name used in this chapter for this group of disorders is autoimmune polyendocrine syndrome (APS). In general, these disorders are divided into two major categories, APS type 1 (APS-1) and APS type 2 (APS-2). Some groups have further subdivided APS-2 into APS type 3 (APS-3) and APS type 4 (APS-4) depending on the type of autoimmunity involved. For the most part, this additional classification does not clarify our understanding of disease pathogenesis or prevention of complications in individual patients. Importantly, there are many nonendocrine disease associations included in these syndromes, suggesting that although the underlying autoimmune disorder predominantly involves endocrine targets, it does not exclude other tissues. The disease associations found in APS-1 and APS-2 are summarized in Table 382-1. Understanding these syndromes and their disease manifestations can lead to early diagnosis and treatment of additional disorders in patients and their family members.
TABLE 382-1Disease Associations with Autoimmune Polyendocrine Syndromes ||Download (.pdf) TABLE 382-1 Disease Associations with Autoimmune Polyendocrine Syndromes
|Autoimmune Polyendocrine Syndrome Type 1 ||Autoimmune Polyendocrine Syndrome Type 2 ||Other Autoimmune Polyendocrine Disorders |
|Endocrine ||Endocrine ||IPEX (immune dysfunction polyendocrinopathy X-linked) |
| Addison’s disease ||Addison’s disease ||Thymic tumors |
| Hypoparathyroidism ||Type 1 diabetes ||Anti-insulin receptor antibodies |
| Hypogonadism ||Graves’ disease or autoimmune thyroiditis ||POEMS syndrome |
| Graves’ disease or autoimmune thyroiditis ||Hypogonadism ||Insulin autoimmune syndrome (Hirata’s syndrome) |
| Type 1 diabetes || ||Adult combined pituitary hormone deficiency (CPHD) with anti-Pit1 autoantibodies |
| || ||Kearns-Sayre syndrome |
| || ||DIDMOAD syndrome |
|Nonendocrine ||Nonendocrine ||Congenital rubella associated with thyroiditis and/or diabetes |
| Mucocutaneous candidiasis ||Celiac disease, dermatitis herpetiformis || |
| Chronic active hepatitis ||Pernicious anemia || |
| Pernicious anemia ||Vitiligo || |
| Vitiligo ||Alopecia || |
| Asplenism ||Myasthenia gravis || |
| Ectodermal dysplasia ||IgA deficiency || |
| Alopecia ||Parkinson’s disease || |
| Malabsorption syndromes ||Idiopathic thrombocytopenia || |
| IgA deficiency || || |
APS-1 (Online Mendelian Inheritance in Man [OMIM] 240300) has also been called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). Mucocutaneous candidiasis, hypoparathyroidism, and Addison’s disease form the three major components of this disorder. However, as summarized in Table 382-1, many other organ systems can be involved over time. APS-1 is rare, with fewer than 500 cases reported in the literature.
The classical form of APS-1 is an autosomal recessive disorder caused by mutations in the AIRE gene (autoimmune regulator gene) found on chromosome 21. This gene is most highly expressed in thymic medullary epithelial cells (mTECs) where it appears to control the expression of tissue-specific self-antigens (e.g., insulin). Deletion of ...