Severe autoimmune polyendocrinopathy candidiasis ectodermal dystrophy in an adolescent girl with a novel AIRE mutation: Response to immunosuppressivetherapy

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder for which the gene (AIRE) has recently been identified on chromosome 21q22.3. We present the mutational analyses o f a French-Canadian family with APECED, in which there are two affected sib lings, as well as the response to cyclosporine A(CyA) therapy in the index patient, the eldest sibling. Haplotype analysis suggested compound heterozygozity at the AIRE locus. Dir ect sequencing of exon 8 revealed a previously described mutation, a 13-bp deletion (1085-1097) of maternal origin, found in the index patient, her af fected sister, and her unaffected sister. A novel missense mutation charact erized by a T-->G transversion at nucleotide position 398, resulting in a l eu-->arg amino acid substitution (L93R), was found in exon 2. The mutation was present in the father, the brother, the index patient, and the affected sister. The presence of the mutation in the propositus was verified by clo ning of PCR products from genomic DNA. The mutation destroys a PstI restric tion enzyme site, as confirmed in the aforementioned patients. Screening of 50 French-Canadian controls with PstI digestion did not show destruction o f the restriction-enzyme site. The index patient's phenotype was severe, manifested by classic features of the illness (adrenal insufficiency, hypoparathyroidism, candidiasis, and k eratoconjunctivitis with alopecia universalis), as well as by severe exocri ne pancreatic insufficiency, diabetes mellitus, hepatic inflammation, growt h hormone (GH) deficiency due to lymphocytic hypophysitis, and primary ovar ian failure. Oral CyA (5 mg/ kg/day) was initiated at 13 yr of age. After 8 months of therapy, stimulated pancreatic lipase increased 24-fold with nor malization of stool fat (from 31.5 g/day to 2.5 g/day, normal(N) < 5). Ther e was complete resolution of her photophobia, and considerable hair regrowt h was diffusely apparent. Minimal side effects were noted. Our experience s upports the use of oral CyA for the treatment of severe APECED-associated e xocrine pancreatic failure and keratoconjunctivitis.