Final Diagnosis -- Polyglandular Autoimmune Syndrome Type II




This case represent an unusual clinical presentation of polyglandular autoimmune syndrome (PAS). PAS is characterized by the coexistence of several autoimmune diseases, affecting predominantly the endocrine glands. The concept of polyglandular disease was initiated about 80 years ago by reports of patients with coexistent nontuberculous adrenal insufficiency and lymphocytic thyroiditis. Subsequent reports confirmed an association of Addison's disease with lymphocytic thyroiditis. In 1926. Schmidt noted the relation between adrenal and thyroid failure with or without diabetes mellitus which has now become a syndrome recognized as PGS II. Regardless of definition the key element of the PGA II syndrome is adrenal insufficiency. Recent study of 151 patients with PGS II by Ferster et al. showed that the most common clinical presentation is diabetes mellitus type I, followed by Hashimoto's thyroiditis and Addison' s disease. Vitiligo, alopecia, pernicious anemia and hypogonadism were less common. The most common combination was diabetes mellitus type I with thyroiditis (33% of patients). IgA deficiency , myasthenia gravis and Sjogren's syndrome have also been reported in isolated cases. The time between manifestation of each disease was highly variable. Diabetes mellitus was the first manifestation in half the cases. Similar to other reports females were more commonly affected than males.

The initial lesion and precipitating events that result in the syndrome are unknown, but immunogenetic and immunological similarities are present, with regard to both the time course and the pathogenesis of each of the component disorders. Most of the principal components of PGA II are individually strongly associated with the presence of certain HLA genes in major histocompatibility complex. HLA-D subgroup DR3 and HLA-B8 have been found to be associated with PGS II. It appears that susceptibility to the syndrome rather than specific disease is inherited. A degree of genetic polymorphism in the expression of the HLA-DR antigen subgroup may also account for variability among families in the expression of this syndrome. There was an attractive theory proposing that patients with PGS II have certain susceptibility genes that are closely linked to an HLA haplotype, thereby predisposing to a defect in immune control. Environmental triggering factors, such as viral infections or stress-precipitating events could also be involved in the development of this autoimmune disease.

Approximately 50% of cases of Schmidt's syndrome are familial, but the mode of disease transmission varies from family to family. A single gene mutation transmitted in an autosomal recessive pattern is suggested by some studies. However, there are also other studies showing autosomal dominant inheritance or polygenic inheritance.

. Many circulating organ-specific antibodies to endocrine organs are detected in a high proportion of patients with PGA II. Approximately 70% of patients will have antithyrogloblin antibodies and thyroidal antimicrosomal antibodies. However, those antibodies are also present in the absence of clinically overt disease and are also common in normal relatives of affected individuals, many of whom will not progress to overt disease. According to Seissler et al. a high prevalence of antibodies to 21-hydroxylase was observed in patients with isolated Addison's disease (76%) and patients suffering from PGS II (85%). They also showed that antibodies to 17-alpha-hydorxilase (17 OH) and side chain cleavage enzyme (SCC) are more often associated with PGN II than with isolated Addison's disease. Other autoantibodies associated with PGN such as gastric (antiparietal cell and/or anti-intrinsic factor) are reported in about 40% of patients. Islet cell antibodies are present in 25% of type II PGA (in 16% of those who do not have diabetes mellitus, and in 50% of patients with insulin-treated diabetes mellitus). These findings suggest that the simultaneous occurrence of antibodies that react with multiple organs with various affinities may account for the observed variation in severity and clinical manifestations. Overall, circulating-organ and cell-specific autoantibodies are frequently detected in patients with this syndrome and may be a marker of future organ failure. Early recognition and replacement therapy can be life-saving, particularly when there is adrenal or thyroid insufficiency.


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  2. Baker JR. Autoimmune Endocrine Disease. JAMA 1997;278:1931-37.
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  4. Forster G, Krummenauer F, Kuhn I, Beyer J, Kahaly G. Polyglandular autoimmune syndrome type II: epidemiology and forms of manifestation. Btsch Med Wochenschr 1999; 124:1476-81.
  5. Seissler J, Schott M, Steinbrenner H, Peterson P, Scherbaum WA. Autoantibodies to adrenal cytochrome P450 antigens in isolated Addison's disease and autoimmune plolyendocrine syndrome type II. Exp Clin Endocrinol Diabetes 1999;107:208-13.

Contributed by Sanja Dacic, MD, PhD


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