Clinical Heterogeneity in Patients With FOXP3 Mutations Presenting With Permanent Neonatal Diabetes
- Oscar Rubio-Cabezas, MD12,
- Jayne A.L. Minton, PHD1,
- Richard Caswell, PHD3,
- Julian P. Shield, MD4,
- Dorothee Deiss, MD5,
- Zdenek Sumnik, MD, PHD6,
- Amely Cayssials, MD7,
- Mathias Herr, MD58,
- Anja Loew, MD9,
- Vaughan Lewis, MD10,
- Sian Ellard, PHD, MRCPATH1 and
- Andrew T. Hattersley, DM, FRCP1
- 1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K.
- 2Department of Endocrinology, Hospital Infantil Universitario Niño Jesus, Madrid, Spain
- 3School of Biosciences, Cardiff University, Cardiff, U.K.
- 4Department of Pediatric Endocrinology, Bristol Royal Hospital for Children, Bristol, U.K.
- 5Department of Pediatric Diabetology and Endocrinology, Charite Campus, Virchow Childrens Hospital, Berlin, Germany
- 6Department of Pediatrics, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
- 7Department of Pediatrics, Hospital Italiano de Buenos Aires, Argentina
- 8Klinik für Kinder- und Jugendmedizin, DRK-Kliniken Berlin Westend, Germany
- 9Kinderklinik Dritter Orden, Munich, Germany
- 10Department of Pediatrics, Royal Devon and Exeter Foundation Trust, Exeter, U.K.
- Corresponding author: Prof. Andrew T. Hattersley, andrew.hattersley{at}pms.ac.uk
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.
CONCLUSIONS—FOXP3 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.
Footnotes
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Published ahead of print at http://care.diabetesjournals.org on 17 October 2008.
O.R.-C. and J.A.L.M. contributed equally to this work.
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.
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- Accepted September 30, 2008.
- Received July 1, 2008.
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