Objective: To report a patient with an unusual presentation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and severe keratopathy. Case History: An Egyptian male sustained an injury to the left eye at 13 years of age and was found to have corneal damage which was attributed to the injury. Subsequently, however, he continued to have sore eyes with photophobia. A year later he became weak with pigmentation and episodes of collapse, and investigation showed that he had Addison’s disease together with mucocutaneous candidiasis. At 15 years of age he developed carpo-pedal spasm and was found to have hypoparathyroidism with intracranial calcification. At 20 years of age the ophthalmic diagnosis was revised to keratopathy by which time the patient had corneal opacity and problems with visual acuity, especially in the right eye. Investigation at 22 years of age showed that he was homozygous for an R139X mutation in the gene encoding the AIRE protein, a mutation which to date has only been found in Sardinian patients. Conclusions: Keratopathy can be an early and severe manifestation of APECED, requiring expert ophthalmic care. Its presence should prompt a search for other components of APECED, some of which are life-threatening.

Keywords:
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, Addison’s disease, Hypoparathyroidism, Mucocutaneous candidiasis, Keratopathy
1.
Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J: Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 1990;322:1829–1836.
2.
Perheentupa J: APS-1/APECED: the clinical disease and therapy. Endocrinol Metab Clin North Am 2002;31:295–320.
3.
Wingvist O, Karlsson FA, Kampe O: 21-Hydroxylase, a major autoantigen in idiopathic Addison’s disease. Lancet 1992;339:1559–1562.
4.
Krohn K, Uibo R, Aavik E, Peterson P, Savilahti K: Identification by molecular cloning of an autoantigen associated with Addison’s disease as steroid 17 alpha-hydroxylase. Lancet 1992;339:770–773.
5.
Uibo R, Aavik E, Peterson P, Perheentupa J, Aranko S, Pelkonen R, Krohn K: Autoantibodies to cytochrome P450scc, P450c17, and P450c21 in autoimmune polyglandular disease type I and II and in isolated Addison’s disease. J Clin Endocrinol Metab 1994;78:323–328.
6.
Husebye ES, Gebre-Medhin G, Tuomi T, Perheentupa J, Laden-Olsson M, Gustafsson J, Rorsman F, Kämpe O: Autoantibodies against aromatic acid decarboxylase in autoimmune polyendocrine syndrome type I. J Clin Endocrinol Metab 1997;82:147–150.
7.
Clemente MG, Meloni A, Obermayer-Straub P, Frau F, Manns MP, De Virgiliis S: Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1. Gastroenterology 1998;114:324–328.
8.
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;17:393–397.
9.
An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. The Finnish-German-APECED Consortium. Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy. Nat Genet 1997;17:399–403.
10.
Pitkanen J, Peterson P: Autoimmune regulator: from loss of function to autoimmunity. Genes Immun 2003;4:12–21.
11.
Halonen M, Eskelin P, Myhre A-G, Perheentupa J, Husebye ES, Kampe O, Rorsman F, Peltonen L, Ulmanen I, Partanen J: AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab 2002;87:2568–2574.
12.
Tarkkanen A, Merenmies L: Corneal pathology and outcome of keratopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Acta Ophthalmol Scand 2001;79:204–207.
13.
Perheentupa J, Miettinen A: Type 1 autoimmune polyglandular disease. Ann Med Intern 1999;150:313–325.
14.
Merenmies L, Tarkkanen A: Chronic bilateral keratitis in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Acta Ophthalmol Scand 2000;78:532–535.
15.
Freeman JV, Cole TJ, Chinn S, Jones PRM, White EM, Preece MA: Cross sectional stature and weight reference curves for the UK 1990. Arch Dis Child 1995;73:17–24.
16.
Tanner JM. Growth at Adolescence, ed 2. Oxford, Blackwell, 1962.
17.
Scott HS, Heino M, Peterson P, Mittaz L, Lalioti MD, Betterle C, Cohen A, Seri M, Lerone M, Romeo G, Collin P, Salo M, Metcalfe R, Weetman A, Papasavvas MP, Rossier C, Nagamine K, Kudoh J, Shimizu N, Krohn KJ, Antonarakis SE: Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins. Mol Endocrinol 1998;12:1112–1119.
18.
Tarkkanen A, Merenmies L, Perheenntupa J: Ocular changes in autoimmune-polyendocrinopathy-candidiasis dystrophy syndrome. R Soc Med Int Congr Symp Ser 1981;50:677–681.
19.
Rosatelli MC, Meloni A, Meloni A , Devoto M, Cao A, Scott HS, Peterson P, Heino M, Krohn KJ, Nagmane K, Kudoh J, Shimizu N, Antonarakis SE: A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. Hum Genet 1998;103:428–434.
20.
Soderbergh 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, Nillsson T: Prevalence and clinical associations of 10 defined autoantibodies in autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab 2004;89:557–562.
21.
Ward L, Paquette J, Seidman E, Huot C, Alvarez F, Crock P, Delvin E, Kämpe O, Deal C: Severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in an adolescent girl with a novel mutation: response to immunosuppressive therapy. J Clin Endocrinol Metab 1999;84:844–852.
22.
Wagman RD, Kazdan JJ, Kooh SW, Frazer D: Keratitis associated with the multiple endocrine deficiency, autoimmune disease, and candidiasis syndrome. Am J Ophthalmol 1987;103:569–575.
23.
Manderieux N, Putteunau M, Braunea R, de-Prost Y, Grant C, Dufier JL, Haye C: Prévention du rejet de greffon et de la récidive de la maladie par la cyclosporine A dans la kératite du syndrome de Whitaker. Bull Soc Ophtalmol Fr 1990;90:461–463.
© 2005 S. Karger AG, Basel
2005
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.