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Autoimmune polyendocrinopathy syndromes
Arnold A. Asp
CHAPTER 52
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: n Hypoparathyroidism: 89% n Adrenal insufficiency: 60% n Gonadal failure: 45% n Thyroid disease: 12% n Diabetes mellitus type 1: 1% to 4% 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.
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430 CHAPTER 52 AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 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: n Adrenal insufficiency: 100% n Autoimmune thyroid disease: 70% n Diabetes mellitus type 1: 50% n Gonadal failure: 5% to 50% Very rarely, geriatric hypoparathyroidism may occur in elderly patients with APS type 2. 8. What is the most common presenting disorder in APS type 2? Adrenal insufficiency is the presenting disorder in 50% of cases, whereas adrenal insufficiency with diabetes mellitus or thyroid disease is present at the time of diagnosis in 20% of cases. In the remaining 30%, adrenal insufficiency occurs after other endocrine dysfunction. Between 69% and 90% of patients have circulating antibodies to 21-hydroxylase. 9. What thyroid disorders are associated with APS type 2? Thyroid disorders associated with APS type 2 include Graves’ disease (50%) and Hashimoto’s disease or atrophic thyroiditis (50%). As expected, thyroid-stimulating immunoglobulins (TSIs) are present in cases of hyperthyroidism, whereas antibodies to thyroid peroxidase or thyroglobulin are present in cases of hypothyroidism. 10. Summarize the significance of cytoplasmic islet-cell antibodies (ICAs) in APS type 2. Cytoplasmic ICAs are present in patients with APS type 2 and diabetes mellitus; however, the significance of these antibodies is questionable. Patients with APS type 2 who have ICAs but not diabetes may have no compromise of beta-cell function and subsequently develop diabetes at a rate of 2% per year, whereas ICA-positive first-degree relatives of non-APS, type 1 diabetic individuals develop diabetes at a rate of 8% per year. 11. How common is gonadal failure in APS type 2? Gonadal failure is more common in women than in men and is associated with antibodies to gonadal tissue. 12. Are nonendocrine abnormalities described in APS type 2? Yes. In about 5% of cases, other autoimmune disorders are found, including vitiligo, pernicious anemia, alopecia, myasthenia gravis, celiac disease, Sjögren’s syndrome, and rheumatoid arthritis. 13. How should kindreds with suspected APS type 2 be screened? Because APS type 2 appears in multiple generations and because 20 years may lapse between the development of various endocrine organ failures, affected patients should be screened by assessing levels of serum glucose, thyrotropin (TSH), and vitamin B12 every 3 to 5 years. Symptoms of adrenal insufficiency should be investigated by assessing levels of cosyntropin-stimulated cortisol. Firstdegree relatives of the proband should be educated about the syndrome and advised to undergo screening every 3 to 5 years. Antibodies to thyroid peroxidase or thyroglobulin are so common in the general population as to preclude their use as a screening test.
CHAPTER 52 AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 431 14. Explain the etiology of APS type 2. The genetic basis of APS type 2 is uncertain, although it appears to be associated with an HLA-DR3 phenotype that may be permissive for the development of autoimmunity. Organ-specific antibodies may cause organ dysfunction; for example, TSIs may cause Graves’ disease, and antiacetylcholine receptor antibodies may cause myasthenia gravis. Or, like antithyroglobulin antibodies, they may be epiphenomena of disease. The only consistent abnormality noted in affected patients is decreased function of T-suppressor cells. 15. What is POEMS syndrome? POEMS syndrome is a disorder of unknown origin, unrelated to either APS type 1 or APS type 2, that appears to have an immunologic basis. The acronym highlights the cardinal features of the syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal component, and skin changes. All the symptoms are considered to be secondary to overproduction of proinflammatory and other cytokines (most commonly vascular endothelial growth factor [VEGF]). This condition may represent plasma cell dyscrasia (monoclonal gammopathies of undetermined significance; plasmacytoma, osteosclerotic, osteolytic, or mixed myeloma).
KEY POINTS 1: AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 1. Autoimmune polyendocrinopathy syndrome (APS) type 1 is a pediatric syndrome marked by hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis. 2. APS type 1 is inherited in an autosomal recessive manner, is not human leukocyte antigen (HLA) associated, and is clinically apparent by 15 years of age. 3. APS type 2 consists of adrenal insufficiency, thyroid dysfunction, and diabetes mellitus type 1. 4. APS type 2–associated organ failure progresses over many years during adulthood and affects multiple generations. It is associated with HLA-DR3. 5. Both APS type 1 and APS type 2 manifest as nonendocrine organ dysfunction, primarily gastrointestinal and dermatologic diseases.
16. What eponym is associated with POEMS syndrome? Another name for the disorder is Crow-Fukase syndrome. 17. How does POEMS syndrome usually manifest? Most patients with POEMS syndrome are men 45 to 55 years old. The most common presentation is that of distal, symmetric peripheral sensorimotor neuropathy. There is usually loss of pinprick and vibratory sense and decreased deep tendon reflexes, predominantly in the lower extremities. The neuropathy is slowly progressive. Findings of electromyograms and nerve biopsies are most consistent with both demyelination and axonal degeneration. Autonomic neuropathy has not been observed. Papilledema is present in 40% to 80% of cases. Nerve damage may result from myelin cross-reactivity with monoclonal immunoglobulin A (IgA) or IgG M proteins produced by plasmacytomas in sclerotic bone lesions, but evidence of intraneural immunoglobulin deposition has not been found in all series. 18. How does the organomegaly manifest? Hepatomegaly (uncommon in multiple myeloma), splenomegaly, or both can be noted in approximately two thirds of patients with POEMS syndrome. The hepatomegaly may be associated with fibrosis and liver dysfunction.
432 CHAPTER 52 AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 19. Which endocrine systems are involved? Primary hypogonadism is the most common endocrine manifestation, followed by primary hypothyroidism. Diabetes mellitus type 2 is less commonly encountered; rarely, adrenal insufficiency is reported. Antibodies to the thyroid or adrenal glands have not been consistently detected. 20. What skin changes have been encountered? Skin changes include sclerosis, hypertrichosis, hyperpigmentation, and hyperhidrosis. 21. How is POEMS syndrome treated? Treatment of POEMS syndrome is based on elimination of plasmacytomas and osteosclerotic lesions with radiation or chemotherapy, which, if successful, results in amelioration of the polyneuropathy and reduction in organomegaly. Endocrine deficiencies are treated with replacement hormones.
BIBLIOGRAPHY Ahonen P, Myllarniemi S, Sipila I, et al: Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients, N Engl J Med 322:1829–1836, 1990. Chatila TA. Regulatory T cells: key players in tolerance and autoimmunity, Endocrinol Metab Clin North Am 38:265–272, 2009. Dittmar M, Kahaly GJ: Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up, J Clin Endocrinol Metab 88:2983–2992, 2003. Eisenbarth GS: Autoimmune polyendocrine syndromes, Adv Exp Med Biol 55:2204–2218, 2004. Gandhi GY, Basu R, Dispenzieri A, et al: Endocrinopathy in POEMS syndrome: the Mayo Clinic experience, Mayo Clin Proc 82:836–842, 2007. Gavalas NG, Kemp EH, Krohn KJ, et al: The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1, J Clin Endocrinol Metab 92:2107–2114, 2007. Gianani R, Eisenbarth GS: Autoimmunity to gastrointestinal endocrine cells in autoimmune polyendocrine syndrome type 1 [editorial], J Clin Endocrinol Metab 88:1442–1444, 2003. Husebye ES, Bratland E, Bredholt G, et al: The substrate-binding domain of 21-hydroxylase, the main autoantigen in autoimmune Addison’s disease, is an immunodominant T-cell epitope, Endocrinology 147:2411–2416, 2006. Mhyre AG, Halonen M, Eskelin P, et al: Autoimmune polyendocrine syndrome, Clin Endocrinol 45:211–217, 2001. Owen CJ, Cheetham TD: Diagnosis and management of polyendocrinopathy syndromes, Endocrinol Metab Clin North Am 38:419–436, 2009. Perheentupa J: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, J Clin Endocrinol Metab 91: 2843–2850, 2006. Shikama N, Nusspaumer G, Hollander GA: Clearing the AIRE: on the pathological basis of the autoimmune polyendocrinopathy syndrome type-1, Endocrinol Metabol Clin North Am 38:273–288, 2009. Soubrier M, Sauron C, Souweine B, et al: Growth factors and proinflammatory cytokines in the renal involvement of POEMS syndrome, Am J Kidney Dis 34:633–638, 1999.
CHAPTER 52
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: n Hypoparathyroidism: 89% n Adrenal insufficiency: 60% n Gonadal failure: 45% n Thyroid disease: 12% n Diabetes mellitus type 1: 1% to 4% 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.
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430 CHAPTER 52 AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 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: n Adrenal insufficiency: 100% n Autoimmune thyroid disease: 70% n Diabetes mellitus type 1: 50% n Gonadal failure: 5% to 50% Very rarely, geriatric hypoparathyroidism may occur in elderly patients with APS type 2. 8. What is the most common presenting disorder in APS type 2? Adrenal insufficiency is the presenting disorder in 50% of cases, whereas adrenal insufficiency with diabetes mellitus or thyroid disease is present at the time of diagnosis in 20% of cases. In the remaining 30%, adrenal insufficiency occurs after other endocrine dysfunction. Between 69% and 90% of patients have circulating antibodies to 21-hydroxylase. 9. What thyroid disorders are associated with APS type 2? Thyroid disorders associated with APS type 2 include Graves’ disease (50%) and Hashimoto’s disease or atrophic thyroiditis (50%). As expected, thyroid-stimulating immunoglobulins (TSIs) are present in cases of hyperthyroidism, whereas antibodies to thyroid peroxidase or thyroglobulin are present in cases of hypothyroidism. 10. Summarize the significance of cytoplasmic islet-cell antibodies (ICAs) in APS type 2. Cytoplasmic ICAs are present in patients with APS type 2 and diabetes mellitus; however, the significance of these antibodies is questionable. Patients with APS type 2 who have ICAs but not diabetes may have no compromise of beta-cell function and subsequently develop diabetes at a rate of 2% per year, whereas ICA-positive first-degree relatives of non-APS, type 1 diabetic individuals develop diabetes at a rate of 8% per year. 11. How common is gonadal failure in APS type 2? Gonadal failure is more common in women than in men and is associated with antibodies to gonadal tissue. 12. Are nonendocrine abnormalities described in APS type 2? Yes. In about 5% of cases, other autoimmune disorders are found, including vitiligo, pernicious anemia, alopecia, myasthenia gravis, celiac disease, Sjögren’s syndrome, and rheumatoid arthritis. 13. How should kindreds with suspected APS type 2 be screened? Because APS type 2 appears in multiple generations and because 20 years may lapse between the development of various endocrine organ failures, affected patients should be screened by assessing levels of serum glucose, thyrotropin (TSH), and vitamin B12 every 3 to 5 years. Symptoms of adrenal insufficiency should be investigated by assessing levels of cosyntropin-stimulated cortisol. Firstdegree relatives of the proband should be educated about the syndrome and advised to undergo screening every 3 to 5 years. Antibodies to thyroid peroxidase or thyroglobulin are so common in the general population as to preclude their use as a screening test.
CHAPTER 52 AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 431 14. Explain the etiology of APS type 2. The genetic basis of APS type 2 is uncertain, although it appears to be associated with an HLA-DR3 phenotype that may be permissive for the development of autoimmunity. Organ-specific antibodies may cause organ dysfunction; for example, TSIs may cause Graves’ disease, and antiacetylcholine receptor antibodies may cause myasthenia gravis. Or, like antithyroglobulin antibodies, they may be epiphenomena of disease. The only consistent abnormality noted in affected patients is decreased function of T-suppressor cells. 15. What is POEMS syndrome? POEMS syndrome is a disorder of unknown origin, unrelated to either APS type 1 or APS type 2, that appears to have an immunologic basis. The acronym highlights the cardinal features of the syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal component, and skin changes. All the symptoms are considered to be secondary to overproduction of proinflammatory and other cytokines (most commonly vascular endothelial growth factor [VEGF]). This condition may represent plasma cell dyscrasia (monoclonal gammopathies of undetermined significance; plasmacytoma, osteosclerotic, osteolytic, or mixed myeloma).
KEY POINTS 1: AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 1. Autoimmune polyendocrinopathy syndrome (APS) type 1 is a pediatric syndrome marked by hypoparathyroidism, adrenal insufficiency, and mucocutaneous candidiasis. 2. APS type 1 is inherited in an autosomal recessive manner, is not human leukocyte antigen (HLA) associated, and is clinically apparent by 15 years of age. 3. APS type 2 consists of adrenal insufficiency, thyroid dysfunction, and diabetes mellitus type 1. 4. APS type 2–associated organ failure progresses over many years during adulthood and affects multiple generations. It is associated with HLA-DR3. 5. Both APS type 1 and APS type 2 manifest as nonendocrine organ dysfunction, primarily gastrointestinal and dermatologic diseases.
16. What eponym is associated with POEMS syndrome? Another name for the disorder is Crow-Fukase syndrome. 17. How does POEMS syndrome usually manifest? Most patients with POEMS syndrome are men 45 to 55 years old. The most common presentation is that of distal, symmetric peripheral sensorimotor neuropathy. There is usually loss of pinprick and vibratory sense and decreased deep tendon reflexes, predominantly in the lower extremities. The neuropathy is slowly progressive. Findings of electromyograms and nerve biopsies are most consistent with both demyelination and axonal degeneration. Autonomic neuropathy has not been observed. Papilledema is present in 40% to 80% of cases. Nerve damage may result from myelin cross-reactivity with monoclonal immunoglobulin A (IgA) or IgG M proteins produced by plasmacytomas in sclerotic bone lesions, but evidence of intraneural immunoglobulin deposition has not been found in all series. 18. How does the organomegaly manifest? Hepatomegaly (uncommon in multiple myeloma), splenomegaly, or both can be noted in approximately two thirds of patients with POEMS syndrome. The hepatomegaly may be associated with fibrosis and liver dysfunction.
432 CHAPTER 52 AUTOIMMUNE POLYENDOCRINOPATHY SYNDROMES 19. Which endocrine systems are involved? Primary hypogonadism is the most common endocrine manifestation, followed by primary hypothyroidism. Diabetes mellitus type 2 is less commonly encountered; rarely, adrenal insufficiency is reported. Antibodies to the thyroid or adrenal glands have not been consistently detected. 20. What skin changes have been encountered? Skin changes include sclerosis, hypertrichosis, hyperpigmentation, and hyperhidrosis. 21. How is POEMS syndrome treated? Treatment of POEMS syndrome is based on elimination of plasmacytomas and osteosclerotic lesions with radiation or chemotherapy, which, if successful, results in amelioration of the polyneuropathy and reduction in organomegaly. Endocrine deficiencies are treated with replacement hormones.
BIBLIOGRAPHY Ahonen P, Myllarniemi S, Sipila I, et al: Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients, N Engl J Med 322:1829–1836, 1990. Chatila TA. Regulatory T cells: key players in tolerance and autoimmunity, Endocrinol Metab Clin North Am 38:265–272, 2009. Dittmar M, Kahaly GJ: Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up, J Clin Endocrinol Metab 88:2983–2992, 2003. Eisenbarth GS: Autoimmune polyendocrine syndromes, Adv Exp Med Biol 55:2204–2218, 2004. Gandhi GY, Basu R, Dispenzieri A, et al: Endocrinopathy in POEMS syndrome: the Mayo Clinic experience, Mayo Clin Proc 82:836–842, 2007. Gavalas NG, Kemp EH, Krohn KJ, et al: The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1, J Clin Endocrinol Metab 92:2107–2114, 2007. Gianani R, Eisenbarth GS: Autoimmunity to gastrointestinal endocrine cells in autoimmune polyendocrine syndrome type 1 [editorial], J Clin Endocrinol Metab 88:1442–1444, 2003. Husebye ES, Bratland E, Bredholt G, et al: The substrate-binding domain of 21-hydroxylase, the main autoantigen in autoimmune Addison’s disease, is an immunodominant T-cell epitope, Endocrinology 147:2411–2416, 2006. Mhyre AG, Halonen M, Eskelin P, et al: Autoimmune polyendocrine syndrome, Clin Endocrinol 45:211–217, 2001. Owen CJ, Cheetham TD: Diagnosis and management of polyendocrinopathy syndromes, Endocrinol Metab Clin North Am 38:419–436, 2009. Perheentupa J: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, J Clin Endocrinol Metab 91: 2843–2850, 2006. Shikama N, Nusspaumer G, Hollander GA: Clearing the AIRE: on the pathological basis of the autoimmune polyendocrinopathy syndrome type-1, Endocrinol Metabol Clin North Am 38:273–288, 2009. Soubrier M, Sauron C, Souweine B, et al: Growth factors and proinflammatory cytokines in the renal involvement of POEMS syndrome, Am J Kidney Dis 34:633–638, 1999.