Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED): Single-Centre Experience
,
Abstract
Background: APECED is a rare autosomal recessive disease, caused by mutations in the AIRE-gene resulting in a failure of T-cell tolerance, clinically characterized by multiple autoimmunopathies. The objective of the study was to determine the clinical and genetic features and consequences of APECED in a single-centre Ukrainian cohort of patients.
Material and methods: Out of five families, eight patients with APECED were included in the study. Family history and clinical information of each patient was collected; laboratory studies aimed at identifying endocrine disorders, other autoimmunity, and infections was done. Genetic testing by NGS was performed in four out of five families. Patients were included in the study after the written informed consent had been signed by their parents/legal guardians.
Results: In most patients, the onset of the disease was noted in childhood with manifestations of hypoparathyroidism and/or candidiasis. Adrenal insufficiency was associated later. Diabetes mellitus, hypothyroidism and hypogonadism were observed as other endocrinopathies. Five of eight patients (62.5%) developed autoimmune hepatitis, two patients suffered from autoimmune lung lesions, and two developed enteropathy. Two patients were diagnosed with brain damage: psychosis and autoimmune encephalitis. All the patients that we examined were homozygous carriers of the Finn major mutation R257X (c.769C> T) of the AIRE gene.
Conclusion: One or two endocrinopathies in combination with recurrent candidiasis are the key to a diagnosis of APECED. Most patients also develop organ autoimmunopathy. The mutation R257X (c.769C> T) of the AIRE-gene is predominant in the population of western Ukraine.
1. Husebye ES, Anderson MS, Kämpe O. Autoimmune Polyendocrine Syndromes. N Engl J Med. 2018;378(12):1132-41.
2. Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17(4):399-403.
3. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17:393-8.
4. Orphanet: Autoimmune polyendocrinopathy type 1. [Internet] 2009 [retrieved 2021-03-26. Expert reviewers: E. Proust-Lemoine, J-L Wemeau. Last update: February 2009]; Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=3453
5. Giordano C, Modica R, Allotta ML, Guarnotta V, Cervato S, Masiero S, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Sicily: confirmation that R203X is the peculiar AIRE gene mutation, J Endocrinol Invest. 2012;35:384-8.
6. Constantine G, Lionakis MS. Lessons from Primary Immunodeficiencies: Autoimmune Regulator and Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy. Immunol Rev. 2019; 287(1):103-120.
7. Scarpino S, Di Napoli A, Stoppacciaro A, Antonelli M, Pilozzi E, Chiarle R, et al. Molecular background of polyendocrinopathy- candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence. Clin Genet. 2006;70:348-54.
8. Wolff AS, Erichsen MM, Meager A, Magitta NF, Myhre AG, Bollerslev J, et al. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab. 2007;92:595-603.
9. Bondarenko A, Chernyshova L, Hilfanova A, Niconez L, Sharapova S. Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy Syndrome (APECED) as Primary Immunodeficiency: Spectrum of Clinical Manifestations. Sovremennaya Pediatriya. 2017;3(83):84-90.
10. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol. 2008;8:948-57.
11. Anderson MS, Su MA. AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol. 2016;16(4):247-58.
12. Arstila TP, Jarva H. Human APECED; a Sick Thymus Syndrome? Front Immunol. 2013;4:313.
13. Fierabracci A. Recent insights into the role and molecular mechanisms of the autoimmune regulator (AIRE) gene in autoimmunity. Autoimmun Rev. 2011;10:137-43.
14. Huibregtse KE, Wolfgram P, Winer KK, Connor E. Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient. J Pediatr Endocrinol Metab. 2014;27(0): 1257-60.
15. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002;23:327.
16. Alimohammadi M, Dubois N, Sköldberg F, Hallgren A, Tardivel I, Hedstrand H, et al. Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc Natl Acad Sci USA. 2009;106:4396-401.
17. Browne SK, Holland SM. Anticytokine autoantibodies in infectious diseases: pathogenesis and mechanisms. Lancet Infect Dis. 2010;10:875.
18. Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol. 2011;41:1517-27.
19. Puel A, Döffinger 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.
20. Capalbo D, Improda N, Esposito A, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy from the pediatric perspective. J Endocrinol Invest. 2013;36:903.
21. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006; 91:2843-50.
22. Husebye ES, Perheentupa J, Rautemaa R, Kämpe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514-29.
23. Kluger N, Jokinen M, Krohn K, Ranki A. Gastrointestinal manifestations in APECED syndrome. J Clin Gastroenterol. 2013;47:112-20.
24. 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.
25. Abraham A, Ziv I, Steinmetz A, Groshar D, Djaldetti R. Autoimmune polyendocrine syndrome type I and brain calcinosis. Parkinsonism Relat Disord. 2010;16:101-4.
26. Barthel A, Benker G, Berens K, Diederich S, Manfras B, Gruber M, et al. An update on Addison’s disease. Exp Clin Endocrinol Diabetes. 2019;127:165-70.
27. Borchers J, Eero Pukkala E, Outi Mäkitie O, Laakso S. Patients with APECED have increased early mortality due to endocrine causes, malignancies and infections. J Clin Endocrinol Metab. 2020;105(6):2207-13.
28. Betterle C, Ghizzoni L, Cassio A, Baronio F, Cervato S, Garelli S, et al. Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy in Calabria: clinical, immunological and genetic patterns. J Endocrinol Invest. 2012;35:877-81.
29. Al-Owain M, Kaya N, Al-Zaidan H, Bin Hussain I, Al-Manea H, Al-Hindi H. Renal failure associated with APECED and terminal 4q deletion: evidence of autoimmune nephropathy. Clin Dev Immunol. 2010;2010:586342.
30. Alimohammadi M, Dubois N, Sköldberg F, Hallgren A, Tardivel I, Hedstrand H, et al. Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc Natl Acad Sci USA. 2009;106:4396-401.
31. De Luca F, Valensize M, Alaggio R, Arrigo T, Crisafuli G, Salzano G, et al. Sicilian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and lethal lung disease in one of the affected brothers. Eur J Ped. 2008;167:1283-8.
32. Chang B, Brosnahan D, McCreery K, Dominguez M, Costigan C. Ocular complications of autoimmune polyendocrinopathy syndrome type 1. J AAPOS. 2006;10:515-20.
33. Kopczak A, Schumacher A-M, Nischwitz S, Kumpfel T, Stalla GK, Auer MK. GAD antibody-associated limbic encephalitis in a young woman with APECED. Endocrinol Diabetes Metab Case Rep. 2017;2017:17-0010.
34. Meloni A, Corda G, Saba L, Ferri G-L, Maroitti S, Cocco C. Reduction of total brain and cerebellum volumes associated with neuronal autoantibodies in patients with APECED. J Clin Endocrinol Met. 2019;104(1):150-62.
35. Shin Y-W, Lee S-T, Park K-I, Jung K-H, Jung K-Y, Lee S, Chu K. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord. 2018;11:1-19.
2. Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17(4):399-403.
3. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17:393-8.
4. Orphanet: Autoimmune polyendocrinopathy type 1. [Internet] 2009 [retrieved 2021-03-26. Expert reviewers: E. Proust-Lemoine, J-L Wemeau. Last update: February 2009]; Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=3453
5. Giordano C, Modica R, Allotta ML, Guarnotta V, Cervato S, Masiero S, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Sicily: confirmation that R203X is the peculiar AIRE gene mutation, J Endocrinol Invest. 2012;35:384-8.
6. Constantine G, Lionakis MS. Lessons from Primary Immunodeficiencies: Autoimmune Regulator and Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy. Immunol Rev. 2019; 287(1):103-120.
7. Scarpino S, Di Napoli A, Stoppacciaro A, Antonelli M, Pilozzi E, Chiarle R, et al. Molecular background of polyendocrinopathy- candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence. Clin Genet. 2006;70:348-54.
8. Wolff AS, Erichsen MM, Meager A, Magitta NF, Myhre AG, Bollerslev J, et al. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab. 2007;92:595-603.
9. Bondarenko A, Chernyshova L, Hilfanova A, Niconez L, Sharapova S. Autoimmune Polyendocrinopathy with Candidiasis and Ectodermal Dystrophy Syndrome (APECED) as Primary Immunodeficiency: Spectrum of Clinical Manifestations. Sovremennaya Pediatriya. 2017;3(83):84-90.
10. Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat Rev Immunol. 2008;8:948-57.
11. Anderson MS, Su MA. AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol. 2016;16(4):247-58.
12. Arstila TP, Jarva H. Human APECED; a Sick Thymus Syndrome? Front Immunol. 2013;4:313.
13. Fierabracci A. Recent insights into the role and molecular mechanisms of the autoimmune regulator (AIRE) gene in autoimmunity. Autoimmun Rev. 2011;10:137-43.
14. Huibregtse KE, Wolfgram P, Winer KK, Connor E. Polyglandular autoimmune syndrome type I – a novel AIRE mutation in a North American patient. J Pediatr Endocrinol Metab. 2014;27(0): 1257-60.
15. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002;23:327.
16. Alimohammadi M, Dubois N, Sköldberg F, Hallgren A, Tardivel I, Hedstrand H, et al. Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc Natl Acad Sci USA. 2009;106:4396-401.
17. Browne SK, Holland SM. Anticytokine autoantibodies in infectious diseases: pathogenesis and mechanisms. Lancet Infect Dis. 2010;10:875.
18. Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol. 2011;41:1517-27.
19. Puel A, Döffinger 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.
20. Capalbo D, Improda N, Esposito A, et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy from the pediatric perspective. J Endocrinol Invest. 2013;36:903.
21. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006; 91:2843-50.
22. Husebye ES, Perheentupa J, Rautemaa R, Kämpe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514-29.
23. Kluger N, Jokinen M, Krohn K, Ranki A. Gastrointestinal manifestations in APECED syndrome. J Clin Gastroenterol. 2013;47:112-20.
24. 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.
25. Abraham A, Ziv I, Steinmetz A, Groshar D, Djaldetti R. Autoimmune polyendocrine syndrome type I and brain calcinosis. Parkinsonism Relat Disord. 2010;16:101-4.
26. Barthel A, Benker G, Berens K, Diederich S, Manfras B, Gruber M, et al. An update on Addison’s disease. Exp Clin Endocrinol Diabetes. 2019;127:165-70.
27. Borchers J, Eero Pukkala E, Outi Mäkitie O, Laakso S. Patients with APECED have increased early mortality due to endocrine causes, malignancies and infections. J Clin Endocrinol Metab. 2020;105(6):2207-13.
28. Betterle C, Ghizzoni L, Cassio A, Baronio F, Cervato S, Garelli S, et al. Autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy in Calabria: clinical, immunological and genetic patterns. J Endocrinol Invest. 2012;35:877-81.
29. Al-Owain M, Kaya N, Al-Zaidan H, Bin Hussain I, Al-Manea H, Al-Hindi H. Renal failure associated with APECED and terminal 4q deletion: evidence of autoimmune nephropathy. Clin Dev Immunol. 2010;2010:586342.
30. Alimohammadi M, Dubois N, Sköldberg F, Hallgren A, Tardivel I, Hedstrand H, et al. Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc Natl Acad Sci USA. 2009;106:4396-401.
31. De Luca F, Valensize M, Alaggio R, Arrigo T, Crisafuli G, Salzano G, et al. Sicilian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and lethal lung disease in one of the affected brothers. Eur J Ped. 2008;167:1283-8.
32. Chang B, Brosnahan D, McCreery K, Dominguez M, Costigan C. Ocular complications of autoimmune polyendocrinopathy syndrome type 1. J AAPOS. 2006;10:515-20.
33. Kopczak A, Schumacher A-M, Nischwitz S, Kumpfel T, Stalla GK, Auer MK. GAD antibody-associated limbic encephalitis in a young woman with APECED. Endocrinol Diabetes Metab Case Rep. 2017;2017:17-0010.
34. Meloni A, Corda G, Saba L, Ferri G-L, Maroitti S, Cocco C. Reduction of total brain and cerebellum volumes associated with neuronal autoantibodies in patients with APECED. J Clin Endocrinol Met. 2019;104(1):150-62.
35. Shin Y-W, Lee S-T, Park K-I, Jung K-H, Jung K-Y, Lee S, Chu K. Treatment strategies for autoimmune encephalitis. Ther Adv Neurol Disord. 2018;11:1-19.
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| Issue | Vol 4, No 1 (2021) | |
| Section | Original Article | |
| DOI | https://doi.org/10.18502/igj.v4i1.8388 | |
| Keywords | ||
| Polyendocrinopathies APS-1 Autoimmune Encephalitis Clinical Presentation | ||
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How to Cite
1.
Kostyuchenko L, Hrytsiuk I, Romanyshyn Y, Boyko Y, Sakovich I. Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy (APECED): Single-Centre Experience. Immunol Genet J. 2021;4(1):35-45.
