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      Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes

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          Abstract

          OBJECTIVE—Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM).

          RESEARCH DESIGN AND METHODS—The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes.

          RESULTS—We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes ( P = 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy ( n = 2) or nephrotic syndrome ( n = 1) and survival to 12–15 years.

          CONCLUSIONSFOXP3 mutations result in ∼4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.

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          Diabetes

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              JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome.

              X-linked autoimmunity-allergic disregulation syndrome (XLAAD) is an X-linked recessive immunological disorder characterized by multisystem autoimmunity, particularly early-onset type 1 diabetes mellitus, associated with manifestations of severe atopy including eczema, food allergy, and eosinophilic inflammation. Consistent with the allergic phenotype, analysis of two kindreds with XLAAD revealed marked skewing of patient T lymphocytes toward the Th2 phenotype. Using a positional-candidate approach, we have identified in both kindreds mutations in JM2, a gene on Xp11.23 that encodes a fork head domain-containing protein. One point mutation at a splice junction site results in transcripts that encode a truncated protein lacking the fork head homology domain. The other mutation involves an in-frame, 3-bp deletion that is predicted to impair the function of a leucine zipper dimerization domain. Our results point to a critical role for JM2 in self tolerance and Th cell differentiation.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                January 2009
                : 32
                : 1
                : 111-116
                Affiliations
                [1 ]Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.
                [2 ]Department of Endocrinology, Hospital Infantil Universitario Niño Jesus, Madrid, Spain
                [3 ]School of Biosciences, Cardiff University, Cardiff, U.K.
                [4 ]Department of Pediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, U.K.
                [5 ]Department of Pediatric Diabetology and Endocrinology, Charite Campus, Virchow Childrens Hospital, Berlin, Germany
                [6 ]Department of Pediatrics, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
                [7 ]Department of Pediatrics, Hospital Italiano de Buenos Aires, Argentina
                [8 ]Klinik für Kinder- und Jugendmedizin, DRK-Kliniken Berlin Westend, Germany
                [9 ]Kinderklinik Dritter Orden, Munich, Germany
                [10 ]Department of Pediatrics, Royal Devon and Exeter Foundation Trust, Exeter, U.K.
                Author notes

                Corresponding author: Prof. Andrew T. Hattersley, andrew.hattersley@ 123456pms.ac.uk

                Article
                321111
                10.2337/dc08-1188
                2606841
                18931102
                fe204bee-8051-4099-991b-c9196f906eef
                Copyright © 2009, American Diabetes Association

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 1 July 2008
                : 30 September 2008
                Categories
                Pathophysiology/Complications

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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