Abstract
Background: Autoimmune polyglandular syndrome type 1 (APS-1) (OMIM 240300) is a rare autosomal recessive disorder associated with three major manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. There are, however, multiple minor components of APS-1 that induce significant phenotype variability. Subsequently, the diagnosis of APS-1 during early stages is often challenging. Aim: We aimed to provide clinical and mutational data for a large number of APS-1 patients in the Russian population. Methods: We analyzed clinical variations and component prevalence in APS-1 patients. DNA screening for autoimmune regulator (AIRE) gene mutations was performed in established APS-1 patients and in patients with the single components of chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, or alopecia. Results: We identified 46 patients from 42 families with APS-1. Eighteen different components were present in the patients, including very rare conditions – bone dysplasia and retinitis pigmentosa. We identified 10 different mutations, 3 of which were novel (M1T, E298K, c1053_1060del). The common Finnish mutation, R257X, was the most frequent in our population, present in 64/92 (70%) of the alleles. Conclusion: We found that the R257X AIRE mutation is common in Russian APS-1 patients. The majority of children with hypoparathyroidism and chronic mucocutaneous candidiasis were carriers of the AIRE mutations.
References
1.
The 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;17:399–403.
2.
Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJE, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N: Positional cloning of the APECED gene. Nat Genet 1997;17:393–398.
3.
Perheentupa J: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab 2006;91:2843–2850.
4.
Wolff ASB, Erichsen MM, Meager A, Magitta NF, Myhre AG, Bollerslev J, Fougner KJ, Lima K, Knappskog PM, Husebye ES: Autoimmune polyendocrine syndrome type 1 (APS I) in Norway – Phenotypic variation, autoantibodies and novel mutations in the autoimmune regulator (AIRE) gene. J Clin Endocrinol Metab 2007;92:595–600.
5.
Myhre AG, Halonen M, Eskelin P, Ekwall O, Hedstrand H, Rorsman F, Kampe O, Husebye ES: Autoimmune polyendocrine syndrome type 1 (APS I) in Norway. Clin Endocrinol (Oxf) 2001;54:211–217.
6.
Buzi F, Badolato R, Mazza C, Giliani S, Notarangelo LD, Radetti G, Plebani A: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome: time to review diagnostic criteria? J Clin Endocrinol Metab 2003;88:3146–3148.
7.
Betterle C, Greggio NA, Volpato M: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab 1998;83:1049–1055.
8.
Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D: The cellular mechanism of Aire control of T cell tolerance. Immunity 2003;23:227–239.
9.
Kumar PG, Laloraya M, She JX: Population genetics and functions of the autoimmune regulator (AIRE). Endocrinol Metab Clin North Am 2002;31:321–338.
10.
Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kampe O, Eskelin P, Pelo- Huikko M, Peltonen L: Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 2002;11:397–409.
11.
Rosatelli MC, Meloni A, Devoto V, Cao A, Scott HS, Peterson P, Krohn KJ, Nagamine K, Kudoh J, Shimizu N, Antonarakis SE: A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-actodermal dystrophy patients. Hum Genet 1998;103:428–434.
12.
Chiakova D, Trebusak K, Heino M, Fadeev F, Tuilpakov A, Battelino T, Tar A, Halasz Z, Blumel P, Tawfik S, Krohn K, Lebl J, Peterson P, the MEWPE-APECED Study Group: Novel AIRE mutations and P450 cytochrome autoantibodies in central and Eastern European patients with APECED. Hum Mutat 2001;18:225–232.
13.
Podkrajsek KT, Bratanic N, Krizsnik C, Battelino T: Autoimmune regulator-1 messenger ribonucleic acid analysis in a novel intronic mutation and two additional novel AIRE gene mutations in a cohort of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. J Clin Endocrinol Metab 2005;90:4930–4935.
14.
Harris M, Howlett R, Tobias V, Walker J: Autoimmune polyglandular syndrome type 1 associated with metaphyseal osteosclerosis. Pediatr Res 2001;49:25A.
15.
Soderberg A, Myhre AG, Ekwall O, Gebre-Medhin G, Hedstrand H, Landgren E, Miettinen A, Eskelin P, Halonen M, Tuomi T, Gustafsson J, Husebye ES, Perheentupa J, Gylling M, Manns MP, Rorsman F, Kampe O, Nilson T: Prevalence of clinical association of 10 defined autoantibodies in autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2004;89:557–562.
16.
Heino M, Peterson P, Kudoh J, Shimizu N, Antonarakis SE, Scott HS, Krohn K: APECED mutations in the autoimmune regulator (AIRE) gene. Hum Mutat 2001;18:205–211.
17.
Pearce SH, Cheetham T, Imrie H, Vaidya B, Barnes ND, Bilous RW, Carr D, Meeran K, Shaw NJ, Smith CS, Toft AD, Williams G, Kendall-Taylor P: A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1. Am J Hum Genet 1998;63:1675–1684.
18.
Tawfik S: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy presenting with severe keratopathy in an Egyptian patient with homozygous R139X mutation. Horm Res 2005;64:96–99.
19.
Harris M, Kecha O, Deal C, Howlett RC, Deiss D, Tobias V, Simoneau-Roy J, Walker J: Reversible metaphyseal dysplasia, a novel bone phenotype, in two unrelated children with autoimmunepolyendocrinopathy-candidiasis-ectodermal dystrophy: clinical and molecular studies. J Clin Endocrinol Metab 2003;88:4576–4585.
20.
Merenmies L, Tarkkanen A: Chronic bilateral keratitis in autoimmune polyendocrinopathy-candidiadis-ectodermal dystrophy (APECED). A long-term follow-up and visual prognosis. Acta Ophthalmol Scand 2000;78:532–535.
21.
Chang B, Brosnahan D, McCreery K, Dominguez M, Costigan C: Ocular complications of autoimmune polyendocrinopathy syndrome type 1. J AAPOS 2006;10:515–520.
22.
Boe AS, Knappskog PM, Myhre AG, Sorheim JI, Husebye ES: Mutational analysis of the autoimmune regulator (AIRE) gene in sporadic autoimmune Addison’s disease can reveal patients with unidentified autoimmune polyendocrine syndrome type I. Eur J Endocrinol 2002;146:519–522.
23.
Vaidya B, Imrie H, Geatch DR, Perros P, Ball SG, Baylis PH, Carr D, Hurel SJ, James RA, Kelly WF, Kemp EH, Young ET, Weetman AP, Kendall-Taylor P, Pearce SH: Association analysis of the cytotoxic T lymphocyte antigen-4 (CTLA-4) and autoimmune regulator-1 (AIRE-1) genes in sporadic autoimmune Addison’s disease. J Clin Endocrinol Metab 2000;85:688–691.
24.
Meyer G, Donner H, Herweg J, Bohles H, Usadel KH, Badenhoop K: Screening for an AIRE-1 mutation in patients with Addison’s disease, type 1 diabetes, Graves’ disease and Hashimoto’s thyroiditis as well as in APECED syndrome. Clin Endocrinol (Oxf) 2001;54:335–338.
25.
Tazi-Ahnini R, Cork MJ, Gawkrodger DJ, Birch MP, Wengraf D, McDonagh AJ, Messenger AG: Role of the autoimmune regulator (AIRE) gene in alopecia areata: strong association of a potentially functional AIRE polymorphism with alopecia universalis. Tissue Antigens 2000;60:489–495.
26.
Meager A, Visvalingam K, Peterson P, Möll K, Murumägi A, Krohn K, Eskelin P, Perheentupa J, Husebye E, Kadota Y, Willcox N: Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med 2006;3:289.
27.
Oftedal BE, Wolff AS, Bratland E, Kämpe O, Perheentupa J, Myhre AG, Meager A, Purushothaman R, Ten S, Husebye ES: Radioimmunoassay for autoantibodies against interferon omega; its use in the diagnosis of autoimmune polyendocrine syndrome type I. Clin Immunol 2008;129:163–169.
28.
Meloni A, Furcas M, Cetani F, Marcocci C, Falorni A, Perniola R, Pura M, Bøe Wolff AS, Husebye ES, Lilic D, Ryan KR, Gennery AR, Cant AJ, Abinun M, Spickett GP, Arkwright PD, Denning D, Costigan C, Dominguez M, McConnell V, Willcox N, Meager A: Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 2008;93:4389–4397.
© 2010 S. Karger AG, Basel
2010
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.
