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Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dysplasia

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Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dysplasia

Presented by Yoavanit Srivaro, MD.

November 6, 2015

Published in: Health & Medicine
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Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dysplasia

  1. 1. Autoimmune Polyendocrinopathy- Candidiasis–Ectodermal Dysplasia Yoavanit Srivaro M.D.
  2. 2. Outlines •Introduction •Epidemiology •Pathogenesis •Clinical Manifestations •Laboratory Evaluation •Diagnosis •Management •Prognosis
  3. 3. Introduction
  4. 4. 1st mentioned literature by Thorpe and Handley in 1929 CMC & HP 1929 1946 Clinical triad of 1.Chronic mucocutaneous candidiasis 2.Hypoparathyroidism 3.Adrenal insufficiency was reported 1956 Recognized as “Whitaker’s syndrome” 1980 Recognized as “APS-1” Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.
  5. 5. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350:2068-79.
  6. 6. 1st mentioned literature by Thorpe and Handley in 1929 CMC & HP 1929 1946 Clinical triad of 1.Chronic mucocutaneous candidiasis 2.Hypoparathyroidism 3.Adrenal insufficiency was reported 1956 Recognized as “Whitaker’s syndrome” 1980 Recognized as “APS-1” 1990 Acronym “APECED” was introduced by Finnish pediatrician Professor Jaakko Perheentupa Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.
  7. 7. 1994 1997 2002 Analysis 1st knockout mouse models: A role for AIRE in the development of both central& peripheral tolerance. Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53. APECED locus was mapped in the Finnish families to 21q22.3 A novel gene, AIRE was positionally cloned.
  8. 8. APECED •Monogenic autosomal recessive disease •Characterized by 1. Chronic candidiasis 2. Multiple autoimmune diseases •Loss-of-function mutations in the autoimmune regulator (AIRE) gene Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  9. 9. Burmester, Color Atlas of Immunology © 2003
  10. 10. Epidemiology
  11. 11. Country Prevalence Iranian Jews 1: 9,000 Sardinians 1:14,000 Finns 1:2,5000 Slovenia 1:43,000 Norway 1:80,000 Poland 1:129,000 Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  12. 12. Pathogenesis
  13. 13. Burmester, Color Atlas of Immunology © 2003
  14. 14. Burmester, Color Atlas of Immunology © 2003
  15. 15. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015 FIGURE 2-10 Morphology of the thymus.
  16. 16. FIGURE 8-18 Maturation of T cells in the thymus. Abbas AK, Lichtman AH, Pillai S. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015
  17. 17. Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. FIGURE 15-2 Central T cell tolerance.
  18. 18. FIGURE2Thymocyte-intrinsic pathways required for negative selection. Siggs OM, Makaroff LE, Liston A. The why and how of thymocyte negative selection. Curr Opin Immunol. 2006;18:175-83.
  19. 19. Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. FIGURE 15-2 Central T cell tolerance.
  20. 20. Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. FIGURE 15-3 The function of AIRE in deletion of T cells in the thymus.
  21. 21. Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015. FIGURE 15-3 The function of AIRE in deletion of T cells in the thymus.
  22. 22. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350:2068-79.
  23. 23. Abbas AK, Lichtman AH, Pillai Shiv. Cellular and molecular immunology. 8th ed.Philadelphia, W.B. Saunders Company.2015.
  24. 24. The AIRE gene is located in chromosome 21 region q22.3 Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  25. 25. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol. 2008;8:948-57. AIRE protein: 545–amino acid protein, molecular weight of 57.5 kDa
  26. 26. Figure 1 AIRE gene and AIRE 1 protein Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  27. 27. Figure 1 AIRE gene and AIRE 1 protein Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  28. 28. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. HSR NLS SAND PHD1 PRR PHD2 Homogeneously Staining Region Nuclear Localisation Signal DNA liaison domain Plant HomeoDomain Proline Rich Region Plant HomeoDomain LXXLL motifs: motifs of nuclear receptor liaison
  29. 29. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78. Fig. 1 In the medullary thymic epithelial cells (mTEC) AIRE promotes the expression of tissue specific antigens by interacting with large chromatin-associated complex.
  30. 30. AIRE Protein •Restricted expression pattern 1. Mainly present in :Medullary thymic epithelial cells (mTECs) 2. Rare present in :Dendritic-like cells in the lymph nodes & tonsils Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257:821–5. Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, et al. Human peripheral lymphoid tissues contain
  31. 31. Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.
  32. 32. Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.
  33. 33. FIG. 1. Expression of AIRE in thymus medulla Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257:821-5.
  34. 34. FIG. 2. Intracellular expression of AIRE in vivo and in vitro. Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257:821-5.
  35. 35. AIRE Gene Mutation •More than 50 mutations : Deletions : Insertions : Missense point mutations : Nonsense point mutations Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  36. 36. Finnish mutation English mutation Sardinain mutation
  37. 37. Anderson MS, Casanova JL. More than Meets the Eye: Monogenic Autoimmunity Strikes Again. Immunity. 2015;42:986-8.
  38. 38. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  39. 39. Clinical Manifestations
  40. 40. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  41. 41. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  42. 42. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  43. 43. Chronic Mucocutaneous Candidiasis • Heterogeneous group of syndromes 1. Common features : Chronic noninvasive Candida infections of the skin,nails, and mucous membranes 2. Associated autoimmune manifestations
  44. 44. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 88 69 84 77 100 97 33 5 31 18 27 39 31 22
  45. 45. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  46. 46. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  47. 47. Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-93.
  48. 48. Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-93. • Less than 10% of cases : limited to the skin & often localized. • Up to 100% of cases :mainly affects the oral mucous membranes. • 2/3 of cases : mainly affects the nails.
  49. 49. Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-93. • More rarely : Genitals candidiasis • 15 to 22% of cases:Oeosophageal candidiasis
  50. 50. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  51. 51. Milner JD, Holland SM. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat Rev Immunol. 2013;13:635-48. FIGURE 4 Defects in immunity to Candida albicans.
  52. 52. Milner JD, Holland SM. The cup runneth over: lessons from the ever-expanding pool of primary immunodeficiency diseases. Nat Rev Immunol. 2013;13:635-48. FIGURE 4 Defects in immunity to Candida albicans.
  53. 53. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010;207:291-7.
  54. 54. Gouda MR, Al-Amin A, Grabsch H, Donnellan C. A multidisciplinary approach to management of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). BMJ Case Rep. 2013;2013.
  55. 55. Sivabalan S, Mahadevan S, Srinath MV. Recurrent oral thrush. Indian J Pediatr. 2014;81:394-6.
  56. 56. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  57. 57. Burmester, Color Atlas of Immunology © 2003
  58. 58. Endocrine Manifestations •Hypoparathyroidism •Adrenocortical failure •Hypergonadotropic hypogonadism •Type 1 diabetes •Autoimmune thyroiditis •Pituitary failure and growth hormone deficiency Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  59. 59. Burmester, Color Atlas of Immunology © 2003
  60. 60. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 88 69 84 77 100 97 33 5 31 18 27 39 31 22
  61. 61. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  62. 62. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  63. 63. Hypoparathyroidism •Symptoms are related to hypocalcemia : Muscle cramps, mild paresthesia and clumsiness Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  64. 64. Endocrine Manifestations •Hypoparathyroidism •Adrenocortical failure •Hypergonadotropic hypogonadism •Type 1 diabetes •Autoimmune thyroiditis •Pituitary failure and growth hormone deficiency Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  65. 65. Burmester, Color Atlas of Immunology © 2003
  66. 66. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 84 69 88 77 100 97 33 5 31 18 27 39 31 22
  67. 67. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  68. 68. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  69. 69. Addison’s disease •Mediated by autoreactive cytotoxic T-cells •Adrenal hormone deficiencies do not manifest clinically until at least 90 % of the functional adrenocortical cells have been destroyed Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  70. 70. Addison’s disease •Characteristic symptoms include :Fatigue, salt craving, hypotension, weight loss and an increased pigmentation of the skin and mucous membranes Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  71. 71. Endocrine Manifestations •Hypoparathyroidism •Adrenocortical failure •Hypergonadotropic hypogonadism •Type 1 diabetes •Autoimmune thyroiditis •Pituitary failure and growth hormone deficiency Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  72. 72. Burmester, Color Atlas of Immunology © 2003
  73. 73. Hypergonadotropic hypogonadism •Ovarian insufficiency •Testicular insufficiency Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  74. 74. Ovarian insufficiency •Start early with arrested pubertal development •Manifest as premature menopause Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  75. 75. Testicular insufficiency •Less frequent •Affects approximately 10 % of male patients •Usually develops during adulthood Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  76. 76. Endocrine Manifestations •Hypoparathyroidism •Adrenocortical failure •Hypergonadotropic hypogonadism •Type 1 diabetes •Autoimmune thyroiditis •Pituitary failure and growth hormone deficiency Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  77. 77. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 80 69 87 77 100 97 33 5 31 22 39 18 27 31
  78. 78. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  79. 79. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  80. 80. Endocrine Manifestations •Hypoparathyroidism •Adrenocortical failure •Hypergonadotropic hypogonadism •Type 1 diabetes •Autoimmune thyroiditis •Pituitary failure and growth hormone deficiency Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  81. 81. Autoimmune thyroiditis •Hypothyroidism also develops during adulthood :Dx in one-fourth of patients •Hyperthyroidism is very rare and transient Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  82. 82. Endocrine Manifestations •Hypoparathyroidism •Adrenocortical failure •Hypergonadotropic hypogonadism •Type 1 diabetes •Autoimmune thyroiditis •Pituitary failure and growth hormone deficiency Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  83. 83. Pituitary failure and Growth hormone deficiency •Rare manifestations •Higher prevalence in certain populations Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114–24.
  84. 84. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24. Sardinians 25 %
  85. 85. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  86. 86. Gastrointestinal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  87. 87. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 80 69 87 77 100 97 33 5 31 18 27 39 31 22
  88. 88. Gastrointestinal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  89. 89. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 80 69 87 77 100 97 33 5 31 18 27 39 31 22
  90. 90. Gastrointestinal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  91. 91. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  92. 92. Gastrointestinal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  93. 93. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  94. 94. Ectodermal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  95. 95. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 80 69 87 77 100 97 33 5 31 18 27 39 31 22
  96. 96. FIGURE. 6-13 Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome. A.Erythematous candidiasis diffusely involving the dorsal tongue of a 32- year-old man. B.Same patient showing nail dystrophy. C.Corneal keratopathy http://pocketdentistry.com/6-fungal-and-protozoal-diseases
  97. 97. Ectodermal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  98. 98. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  99. 99. FIGURE 2 Dental Enamel hypoplasia Winer KK, Merke DP. Picture of the month. Autoimmune polyglandular syndrome type 1. Arch Pediatr Adolesc Med. 2000;154:745-6.
  100. 100. Ectodermal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  101. 101. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 80 69 87 77 100 97 33 5 31 18 27 39 31 22
  102. 102. Fig 3a: hyperpigmentation and periorificial vitiligo in a 23 year-old female patient Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  103. 103. FIGURE 1 Depigmented patchs around both eyes were noted Winer KK, Merke DP. Picture of the month. Autoimmune polyglandular syndrome type 1. Arch Pediatr Adolesc Med. 2000;154:745-6.
  104. 104. FIGURE 1 Dermatological manifestations of autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy syndrome Oral candidiasis Halo naevi Candidal onychomycosis & paronychia Poliosis Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-93.
  105. 105. FIGURE 1 Dermatological manifestations of autoimmune polyendocrinopathy–candidiasis– ectodermal dystrophy syndrome Oral candidiasis Halo naevi Candidal onychomycosis & paronychia Poliosis Collins SM, Dominguez M, Ilmarinen T, Costigan C, Irvine AD. Dermatological manifestations of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Br J Dermatol. 2006;154:1088-93.
  106. 106. Ectodermal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  107. 107. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62. Finn Sardinian 2006 2012 91 (%) 22 (%) 80 69 87 77 100 97 33 5 31 18 27 39 31 22
  108. 108. Fig 3 b: alopecia of the scalp (note the absence of eyelashes and eyebrows) in a 34 year-old subject Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  109. 109. Ectodermal Manifestations Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  110. 110. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  111. 111. FIGURE 3 Nail pitting Winer KK, Merke DP. Picture of the month. Autoimmune polyglandular syndrome type 1. Arch Pediatr Adolesc Med. 2000;154:745-6.
  112. 112. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  113. 113. Tubulo-Interstitial Nephritis •Serious but rare manifestation •Affecting up to 10 % of patients • Serum Cr , ESR, Abn UA , Proteinuria & Glycosuria •Permanent renal dysfunction, H/D, KT •Biopsy T cell infiltration & antiproximal tubular autoab. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  114. 114. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  115. 115. Interstitial Lung Disease •Rare ,Affecting less than 5%of patients •It can lead to chronic respiratory failure •Chronic cough, dyspnea, thoracic pain & recurrent LRTI •Lung bx severe peribronchiolar lymphoid infiltrate •Two autoantibodies :KCNRG, BPIFB1 Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  116. 116. • Chronic Mucocutaneous Candidiasis • Endocrine Manifestations • Gastrointestinal Manifestations • Ectodermal Manifestations • Tubulo-Interstitial Nephritis • Interstitial Lung Disease • Other Manifestations
  117. 117. Other Manifestations •Asplenia •Chronic inflammatory demyelinating polyneuropathy •Sjögren’s syndrome •Rheumatoid arthritis •Cutaneous vasculitis Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  118. 118. Other Manifestations •Scleroderma •Metaphyseal osteodysplasia •Amyotrophic lateral sclerosis •Retinal pigment degeneration •Celiac disease Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  119. 119. Asplenia •Presenting in up to 20 % of adult patients •Impaired immune responses to encapsulated bacteria •Pathogenesis of asplenia remains unknown Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  120. 120. Rash with fever •One of the first signs of APECED •It usually develops before the age of 5 years •Skin bx : Presence of vasculitis Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  121. 121. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  122. 122. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  123. 123. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  124. 124. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  125. 125. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24. • 22 patients from 17 Sardinian families with APS1 • Female/male :13/9 • Median current age : 30.7yr (1.8–46yr) • Median early disease onset : 3.5 yr (0.3–10 yr)
  126. 126. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24.
  127. 127. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24. • Classic triad : 58% • First sign with CMC : 18 patients • First sign with HP : 3 patients • CMC : 95% • HP :77% • AD :68%
  128. 128. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24. • Major nonsense mutation, R139X :93% • Died during follow-up : 3 patients :Hyperacute AIH (aged 5–12 yr) : 2 patients :Unrelated HIV infection: 1 patients
  129. 129. Laboratory Evaluation
  130. 130. • Immunologic Evaluation • Endocrine Work Up • Gastrointestinal Work Up • Serum autoantibody Work Up
  131. 131. • Immunologic Evaluation • Endocrine Work Up • Gastrointestinal Work Up • Serum autoantibodies Work Up
  132. 132. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015.
  133. 133. • Immunologic Evaluation • Endocrine Work Up • Gastrointestinal Work Up • Serum autoantibodies Work Up
  134. 134. Endocrine Work Up
  135. 135. • Immunologic Evaluation • Endocrine Work Up • Gastrointestinal Work Up • Serum autoantibodies Work Up
  136. 136. Gastrointestinal Work Up Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  137. 137. • Immunologic Evaluation • Endocrine Work Up • Gastrointestinal Work Up • Serum autoantibodies Work Up
  138. 138. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  139. 139. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  140. 140. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24.
  141. 141. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24.
  142. 142. Diagnosis
  143. 143. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  144. 144. Management
  145. 145. Treatment •Require continuous hormone replacement therapy •Calcium and vitamin D supplements •Systemic antibiotics for candidal infections •Immunosuppressive therapy Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.
  146. 146. Hormone replacement therapy •Hydrocortisone 20 mg /day (divided in three dose) •Cortisone acetate 25 mg /day (divided in three dose) Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  147. 147. Calcium and vitamin D supplements •Elementary Ca 100–500 mg 2–3 daily doses •Ca-citrate is preferable Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  148. 148. Calcium and vitamin D supplements •Dihydrotachysterol (T½ 7 days) •Alphacalcidol (T½ 2 days) •Calcitriol (T½ 1 day) Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  149. 149. Antibiotics for candidal infections •Oral mucositis : First, 1–2 mL of nystatin suspension oral 4 times daily : Then, Amphotericin B lozenge oral 4 times daily for 4 to 6 weeks or for at least 1 week after the resolution of symptoms Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  150. 150. Antibiotics for candidal infections •Recurrent candidosis : Pulse prophylaxis : 1-week course of either of the polyenes q 3 week. : 3 mL of nystatin suspension oral 3 times daily : Chlorhexidine mouth rinse 2 times daily Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  151. 151. Antibiotics for candidal infections •Infected corners of the mouth : Natamycin : Amorolphine hydrochloride cream : Nonalcoholic chlorhexidine gel : Miconazole gel several times daily continuing for 4–5 days after the corners have healed. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  152. 152. Antibiotics for candidal infections •Failure of the topical therapy & Severe oral mucositis :Fluconazole adults 200–300 mg once daily for 1-week course of high dose Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  153. 153. Antibiotics for candidal infections •Fingernail candidosis :Amorolphine nail lacquer 40% :Urea paste with the help of a podiatrist. :Itraconazole continued for up to 6 weeks. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  154. 154. Immunosuppressive treatments •Hepatic involvement •Severe malabsorption Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41:e651-62.
  155. 155. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  156. 156. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. J Clin Immunol. 2015;35:463-78.
  157. 157. Immunization • Live virus vaccines must be avoided Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.
  158. 158. General considerations on follow-up •Regular follow-up serum alanine aminotransferase (ALT) activity to monitor liver function Peltonen-Palotie L, Halonen M, Perheentupa J. Autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy. In: Ochs HD, Smith CI, Puck JM, editors. Primary immunodeficiency diseases: a molecular and genetic approach. 2nd ed. New York: Oxford University Press; 2007. p. 342-53.
  159. 159. General considerations on follow-up • F/U with endocrinologist and an oral specialist at least once annually •An SOS Emergency Bracelet •Need professional support to avoid depression, social isolation and alcoholism. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29
  160. 160. Prognosis
  161. 161. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  162. 162. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91:2843 50
  163. 163. Meloni A, Willcox N, Meager A, Atzeni M, Wolff AS, Husebye ES, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114-24.
  164. 164. Take Home Message •Rare autosomal recessive disease •Autoimmune Regulator (AIRE) gene mutations
  165. 165. Take Home Message •Diagnosis :based on presence of at least two out of three ‘‘majors’’ criterions 1. Candidiasis 2. Autoimmune hypoparathyroidism 3. Adrenal insufficiency
  166. 166. Take Home Message •Hormone replacement therapy •Candidiasis and other infections should be carefully screened and treated
  167. 167. Take Home Message •Potentially letal components :treated by immunosuppressors :Hepatitis :Intestinal malabsorption
  168. 168. Thank You

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