Autoimmune Polyendocrine Syndrome, Type Ii

Description

Autoimmune polyendocrine syndrome type II (APS2), or Schmidt syndrome, is characterized by the presence of autoimmune Addison disease in association with either autoimmune thyroid disease or type I diabetes mellitus, or both. Chronic candidiasis is not present. APS2 may occur at any age and in both sexes, but is most common in middle-aged females and is very rare in childhood (summary by Betterle et al., 2004).

See 240300 for a phenotypic description of autoimmune polyendocrine syndrome type I (APS1).

Clinical Features

Carpenter et al. (1964) reviewed the literature on Schmidt syndrome and reported 15 new cases. Of the 15, 10 also had diabetes mellitus, 13 had circulating antibodies against thyroid tissue, and 9 had antibodies against adrenal tissue.

Phair et al. (1965) reported 2 patients with diabetes mellitus in whom Addison disease and myxedema developed 3 and 16 years after the onset of diabetes, respectively. In a sib of 1 of the patients, adrenal insufficiency preceded diabetes mellitus by 15 years. In the 2 cases tested, antibodies against the adrenal were demonstrable. One also had antithyroid antibodies, and the other had antibodies against the parathyroid in spite of clinically normal parathyroid function.

Anderson et al. (1980) reported 3 brothers who were found to have Schmidt syndrome with clinically apparent adrenal and thyroid hypofunction. Age at onset ranged from 18 to 38 years. Three of their sibs, although clinically normal, had notable levels of circulating antiadrenal and antithyroid antibodies. Various other autoimmune disorders were detected in the sibship, including pernicious anemia, vitiligo, and alopecia.

Butler et al. (1984) studied an Indiana kindred in which various manifestations of Schmidt syndrome occurred over 4 generations. Features included hypo- and hyperthyroidism, insulin-dependent diabetes mellitus, Addison disease, noninsulin-dependent diabetes, and pernicious anemia.

Lechuga-Gomez et al. (1988) described a 26-year-old woman in whom APS type II was diagnosed 3 years after the acute onset of insulin-dependent diabetes mellitus.

Meyerson et al. (1988) reviewed the clinical, immunologic, and genetic features of Schmidt syndrome. Slightly over half of the patients present initially with insulin-dependent diabetes mellitus.

Schmidt syndrome can be associated with interstitial myositis, an inflammatory myopathy which can be pathologically distinguished from idiopathic polymyositis and inclusion body myositis (IBM). Heuss et al. (1995) concluded that perifascicular denervation is a characteristic feature of this interstitial myositis by virtue of exclusive perifascicular expression of the leu19 antigen.

Eisenbarth and Gottlieb (2004) compared the features of 3 autoimmune polyendocrine syndromes: autoimmune polyendocrine syndrome type I (240300), autoimmune polyendocrine syndrome type II, or Schmidt syndrome, and X-linked polyendocrinopathy with immune dysfunction and diarrhea (304790).

Mapping

Eisenbarth et al. (1978) found evidence of an association of HLA-B8 (see HLA-B, 142830) with the polyglandular failure syndrome in 3 generations of a family. The 10 unaffected individuals did not have B8, and only 1 of 7 members with B8 escaped the syndrome.

Butler et al. (1984) found no linkage between HLA-B8 and Schmidt syndrome in a 4-generation kindred.

Maclaren and Riley (1986) found that autoimmune Addison disease was strongly associated with HLA-DR3 and -DR4 (see HLA-DRA, 142860); relative risks were 6.0, 4.6, and 26.5 for DR3, DR4, and DR3/DR4, respectively. This is similar to the findings for insulin-dependent diabetes. Patients with type I autoimmune polyglandular syndrome did not show the association.

In the majority of cases, Addison disease is a component of an autoimmune polyendocrine syndrome, or APS (Gambelunghe et al., 1999). The major histocompatibility complex class I chain-related MICA (600169) and MICB (602436) genes are located on chromosome 6 between the HLA-B and the B-associated transcript (see 142560) genes. Gambelunghe et al. (1999) evaluated the association of APS2-Addison disease with both MICA and MICB gene polymorphism in 28 autoimmune (21-hydroxylase autoantibody-positive) Addison disease patients and in 75 healthy subjects from central Italy. The authors concluded that susceptibility to autoimmune Addison disease is linked to the MICA microsatellite allele 5.1 and that both MICA5.1 and HLA-DR3/DQ2 (see HLA-DQ, 146880) are necessary to confer increased genetic risk for Addison disease.

Inheritance

The transmission pattern of APS2 in the family reported by Butler et al. (1984) was consistent with autosomal dominant inheritance.

In a review, Betterle et al. (2002) noted that APS2 often occurs in many generations of the same family in an autosomal dominant pattern with incomplete penetrance.

Population Genetics

Betterle et al. (2004) stated that APS2 is a rare disorder, being described in about 1.4 to 4.5 per 100,000 individuals.