P0875 ATYPICAL AUTOIMMUNENTEROPATHY WITH UNCOMMON FOXP-3 MUTATION: SUCCESSFUL TREATMENT WITH SIROLIMUS

Abstract

Introduction: Autoimmune enteropathy (AIE) due to FOXP-3 mutations usually presents in the neonatal period, accompanied by endocrine disorders (IPEX-syndrome). The prognosis is poor. We describe a patient with an uncommon FOXP3 mutation and atypical AIE, succesfully treated with sirolimus.History: Eleven years old male, admitted with secretory diarrhoea of unexplained etiology requiring TPN. Onset of GI-symptoms (diarrhea and colitis) at 7 yrs. Colectomy at 9 yrs of age due to colitis, unresponsive to prednisone. Eczema since 4 years of age, interstitial nephritis at 9 years. Previous trials with cyclosporine and with tacrolimus were stopped due to renal failure.Findings: IgE elevated (2116 KU/l), normal levels of IgG, IgA and IgM and vaccination antibodies. Lymphocyte function testing: Normal mitogen/antigen/MLC-stimulation. Marked decrease in the proportion of CD19+B-cells. Positive enterocyte antibodies (R.Mirakian, London). Negative findings for autoantibodies against gliadin, mitochondria, LKM, SMA, Parietal cells, reticuline fibers, basal membranes, cardiolipin, ANAs including soluble nuclear antibodies, ds.DNA-antibodies, thyreoglobuline A and ANCA. Borderline levels of AMA-Elisa (M2). Normal plasma values for gastrin, VIP, cortisole, f-thyroxine,parathormone, TSH, insuline and C-peptide. Methods: Immunosuppressive treatment with prednisone (2mg/kg/day i.v.; tapered to 0.2mg/kg/day), methotrexate (15mg/m2 /week), sirolimus (Rapamune®) to achieve serum levels of 5–15μg/l. Genotyping: FOXP3 gene sequencing on ABI Prism 377 of the coding sequence and the intronexon junctions of the gene in the patient, his mother and 100 healthy controls (by DHPLC). Results: Secretory diarrhoea subsided within 8 days of immunosuppressive treatment. Duodenal biopsies before treatment disclosed subtotal villous atrophy, crypt elongation and dense mononuclear and polymorphnuclear infiltration of the lamina pro-pria with an increased proportion of CD8 lymphocytes. A renal biopsy showed chronic interstitial nephritis, no deposits of complement, IgA and IgG. After treatment the duodenal biopsies showed only minor residual villous atrophy. With exception of mild hypertriglyceridemia (232mg/dl) no side effects were observed. Remission is sutained for 3 years now. FOXP-3 genotyping: A nucleotide variation (677–20A>C) was found, located 20bp upstream of exon 8, not detectable in the mother and in controls. Conclusion: We present the first case of atypical AIE successfully treated with Sirolimus. The relevance of the FOXP3 mutation, affecting intron 8, deserves further investigations (m-RNA measurements). Our patient would be the first patient with atypical IPEX with late onset and lack of endocrine disorders.