NORMAL GENOMIC

• Capalbo D et al.
• Posterior reversible encephalopathy syndrome in a child during anaccelerated phase of a severe APECED phenotype due to an uncommon mutationof AIRE.
• Clin Endocrinol (Oxf). 2008; 69: 511-3

• Lintas C, Cappa M, Comparcola D, Nobili V, Fierabracci A
• An 8-year-old boy with autoimmune hepatitis and Candida onychosis as thefirst symptoms of autoimmune polyglandular syndrome (APS1): identificationof a new homozygous mutation in the autoimmune regulator gene (AIRE).
• Eur J Pediatr. 2008; 167: 949-53
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• An 8-year-old boy presented in 1995 with a 2-year history ofhypertransaminasemia and hypergammaglobulinemia. Afterwards the patientdisplayed onychosis with a positive culture test for Candida albicans(CA). Because of the persistence of hypertransaminasemia, a percutaneousliver biopsy was performed showing 'low grade chronic active autoimmunehepatitis' (AIH), positive for liver-kidney microsomal autoantibodies andantibodies to the hepatic autoantigen cytochrome P450-1A2.Immunosuppressive treatment was initiated. In 2003 he developed Addison'sdisease resulting in the diagnosis of autoimmune polyendocrinopathycandidiasis-ectodermal dysplasia (APECED) syndrome, also known asautoimmune polyendocrine syndrome type 1 (APS1). Anti-17OH hydroxylaseantibodies tested negative, anti-21-OH hydroxylase autoantibodies werepositive. Among the other relevant organ- and non organ- specificautoantibodies, aromatic L-amino acid decarboxylase (ADDC) autoantibodiesand anti-tryptophan hydroxylase autoantibodies were positive. The patientalso presented polyuria and polydypsia with diabetes insipidus. Because ofthe presence of two diagnostic criteria of APS1, mutations in theautoimmune regulator gene (AIRE) were performed, which revealed thepresence of a novel mutation (c1314- 1326 del 13/insGT) in exon 11. Inconclusion, the diagnosis of APECED should be suspected in any child withminimal hypertransaminasemia, anti-microsomal autoantibodies and Candidaalbicans onychosis.

• Ruan QG, Wang CY, Shi JD, She JX
• Expression and alternative splicing of the mouse autoimmune regulator gene(Aire).
• J Autoimmun. 1999; 13: 307-13
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• AIRE, the gene responsible for the autoimmune polyglandular syndrome type1 (APS1) or APECED, may act as a transcription factor according to itspredicated protein structure. Here we demonstrate the low expression levelof the mouse Aire gene as it is undetectable by Northern blot analyses.However, RT-PCR analyses revealed expression of Aire in mouse thymus,ovary, lung, testis, kidney and adrenal gland. Barely detectable level ofRT-PCR product was also found in thyroid gland and heart but noamplification was detected in pancreas, spleen and liver. CompetitiveRT-PCR assays demonstrated highest expression level of Aire mRNA inthymus. In addition to the complete cDNA (Aire or Aire-1a), we identified11 alternative splicing forms (designated as Aire-1b, Aire-1c, Aire-1d,Aire-2a, Aire-2b, Aire-2c, Aire-2d, Aire-3a, Aire-3b, Aire-3c andAire-3d). These forms result from combinations of four alternativesplicing units (exon 10, exon 11, 12 bp in exon 6 and 3 bp in exon 8). Therelative abundance of these splicing forms was also determined.

• Ward L et al.
• Severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy inan adolescent girl with a novel AIRE mutation: response toimmunosuppressive therapy.
• J Clin Endocrinol Metab. 1999; 84: 844-52
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• Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) isa rare autosomal recessive disorder for which the gene (AIRE) has recentlybeen identified on chromosome 21q22.3. We present the mutational analysesof a French-Canadian family with APECED, in which there are two affectedsiblings, as well as the response to cyclosporine A(CyA) therapy in theindex patient, the eldest sibling. Haplotype analysis suggested compoundheterozygozity at the AIRE locus. Direct sequencing of exon 8 revealed apreviously described mutation, a 13-bp deletion (1085-1097) of maternalorigin, found in the index patient, her affected sister, and herunaffected sister. A novel missense mutation characterized by a T-->Gtransversion at nucleotide position 398, resulting in a leu-->arg aminoacid substitution (L93R), was found in exon 2. The mutation was present inthe father, the brother, the index patient, and the affected sister. Thepresence of the mutation in the propositus was verified by cloning of PCRproducts from genomic DNA. The mutation destroys a PstI restriction enzymesite, as confirmed in the aforementioned patients. Screening of 50French-Canadian controls with PstI digestion did not show destruction ofthe restriction-enzyme site. The index patient's phenotype was severe,manifested by classic features of the illness (adrenal insufficiency,hypoparathyroidism, candidiasis, and keratoconjunctivitis with alopeciauniversalis), as well as by severe exocrine pancreatic insufficiency,diabetes mellitus, hepatic inflammation, growth hormone (GH) deficiencydue to lymphocytic hypophysitis, and primary ovarian failure. Oral CyA (5mg/kg/day) was initiated at 13 yr of age. After 8 months of therapy,stimulated pancreatic lipase increased 24-fold with normalization of stoolfat (from 31.5 g/day to 2.5 g/day, normal(N) < 5). There was completeresolution of her photophobia, and considerable hair regrowth wasdiffusely apparent. Minimal side effects were noted. Our experiencesupports the use of oral CyA for the treatment of severe APECED-associatedexocrine pancreatic failure and keratoconjunctivitis.