Novel Homozygous AIRE Mutation in a German ...

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Autoimmune polyendocrinopathy-candidiasis ectodermal ... autoimmune Addison's disease, type 1 diabetes ... variably accompanied by other symptoms, These.
Journal of Pediatric Endocrinology & Metabolism, 21,1003-1009 (2008)

A), within the conserved splice donor sequence. This mutation probably introduces a frameshift after amino acid 154 (p.ProI54fs) by skipping exon 4. In addition, we analyzed five other family members out of three generations for the AIRE gene mutation and for polymorph­ isms in the cytotoxic T lymphocyte antigen 4 (CTLA4) gene region and lymphoid protein tyrosine phosphatase (PTPN22) gene, which are associated with the occurrence of sporadic autoimmune Addison's disease, type 1 diabetes mellitus, and generalized vitiligo.

APECED, AIRE, enterochromaffin cells, CTLA4, PTPN22, multiple sclerosis

Repr int address: Dr. J. v. Schnurbein Sektion Padiatrische Endokrinologie und Diabetologie Klinik fllr Kinder- und Jugendrnedizin Universiuit Ulm Eythstr.24 89075 Ulm, Germany e-mail: [email protected] VOLUME 21, NO. 10,2008

INTRODUCTION

Autoimmune polyendocrinopathy-candidiasis­ ectodermal dystrophy (APECED) is a rare auto­ somal recessive disorder. Historically, it is defined by the presence of at least two symptoms of ~e classical triad of chronic mucocutaneous candi ­ diasis, hypoparathyroidism and adrenal failure variably accompanied by other symptoms, These include hypothyroidism, diabetes mellitus, gonadal failure, hypophysitis, diarrhea with malabsorption, vitiligo, alopecia, pitted nail dystrophy, arthritis, and pernicious anemia. Since 1997, APECED is known to be caused by a mutation in the AIRE gene 1•2 • Some secluded populations, such as the Finns or Iranian Jews, have an increased prevalence of APECED with one founder mutation found in nearly all affected membersf". Today over 60 mutations are known world-wide. The mutations are spread throughout the coding region of the AlRE gene, yet most mutations are localized in exons 2, 8 and 10. The AIRE gene product has been shown to be a transcription factor responsible for the regulation of antigen presentation in the thymus and thus regulating central tolerance'', However, despite intensive research and extensive knowledge gathered by AIRE-knockout mice experiments, the pathological background of this disease is not yet Abbreviations AJRE = autoimmune regulator gene ; APECED = autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; CTLA4 = cytotoxic T lymphocyte antigen 4; HLA = human leukocyte antigen; MS = multiple sclerosis; PCR = polymerase chain reaction; PTPN22 = protein tyrosine phosphatase 22 gene. 1003

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fully understood. Apart from reduced self-tolerance, some additional T-lymphocyte defect must also be present since patients with APECED are extremely susceptible to Candida infections. There are large variations in the extent of manifestations, even between siblings with a similar genetic background carrying the same mutation? However, the genetic background does seem to be important, since certain HLA types exert some influence on the phenotype. Halonen et al. found an increased risk for the development of adrenal failure in patients with HLA DR3, for alopecia in patients with HLA DR4, and a negative correlation between HLA DRl5 and diabetes mellitus? Interestingly, these are the same associations established for those diseases in the absence of APECED. In other auto­ immune diseases, polymorphisms are also known to influence phenotype. A polymorphism in the gene encoding lymphoid protein tyrosine phospha­ tase 22 confers susceptibility to generalised vitiligo and is associated with an increased risk for diabetes mellitusv". Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region also confer susceptibility to vitiligo as well as to Addison's disease'?'!'. The polymorphisms in the CTLA4 gene region are also associated with the occurrence of additional autoimmune diseases in families with multiple sclerosis (MS)12. We report here a novel homozygous AIRE mutation at the end of exon 3 in a German girl with severe APECED. PATIENT REPORT

The index patient (f11-2), a 5 year-old girl, is the second child of two non-sanguineous parents (Fig. 1). Her mother (11-2) suffers from MS; her father (II-I) and her older brother (III-I) are both healthy. Her paternal grandmother also suffers from MS, otherwise there is no history of further autoimmune disease in her family. Our index patient was born after an uneventful pregnancy. She became first symptomatic at the age of one year with recurrent episodes of fever, accompanied by rash, enteritis, and hand swelling. Additional elevation of the rheumatoid factor led to the diagnosis of systemic juvenile arthritis. Treat­ ment with methotrexate and prednisolone success­

fully suppressed further episodes of fever and arthritis. Under this treatment, however, her serum transaminases were slightly elevated. This elevation and chronic mucocutaneous candidiasis were attri­ buted to the treatment with methotrexate. After immunosuppressive therapy was terminated, how­ ever, candidiasis persisted and transaminases rose to over 1,000 Ull. At the age of 3 years, elevated antinuclear antibodies, smooth muscle antibodies, and progressive liver inflammation in repeated liver biopsies led to the diagnosis of autoimmune hepatitis, which improved under treatment with azathioprine. At the age of 4 years, the girl also developed nail mycosis, hypothyroidism (antibody negative), and profuse diarrhea with malabsorption. There was no evidence of failure of the exocrine pancreas (stool elastase 377 ug/g, normal range >200 ug/g) or impaired disaccharidases activity (saccharidase, maltase, isomaltase, lactase activities within the normal range). Anti-tryptophan hydroxy­ lase antibodies were elevated (antibody ratio 444.3, normal value