ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P597

New clinical features and detailed genetic analysis of heterozygous 17q12 deletion syndrome, leading to loss of TCF2 and MODY5

Klemens Raile1, Theda Wessel1, Dorothee Deiss1, Dominik Mueller2, Denise Horn3, Wolfgang Riebel4, Reinhard Ullmann5, Eva Klopocki3 & Annette Grueters1

1Institute for Experimental Pediatric Endocrinology and Diabetes, Charité Campus Virchow, Berlin, Germany; 2Department of Paediatric Nephrology, Charité, Campus Virchow, Berlin, Germany; 3Institute of Medical Genetics, Charité Campus Virchow, Berlin, Germany; 4Department of Paediatric Radiology, Berlin, Germany; 5Max-Plack-Institute for Molecular Genetics, Berlin, Germany.

Objective: MODY5 is caused by abnormalities in the TCF2 gene encoding the transcription factor HNF1β. We investigated cases of MODY5 for the underlying type of TCF2 anomaly.

Case presentations: From 623 children and adolescents with diabetes mellitus followed at our diabetes clinic in 2006, 64 were negative for islet cell autoantibodies (GAD, IA-2, ICA) within the first year of diagnosis and out of these, four patients presented clinical features of MODY5. These features were in all patients: renal disease (single cysts, cystic dysplasia or uretero-pelvic obstructions), elevated liver enzymes, reduced birth weight and reduced postnatal growth as well as diabetes with adolescent onset. Additional features in some patients were pancreas dysplasia and exocrine insufficiency (2/4), genital malformation (3/4), and mental retardation (2/4). Single cases presented also extreme pre- and postnatal growth deficit, congenital cholestasis with bile duct dysplasia, immune defect (CVID) or cataract at diabetes onset.

Results: DNA of the patients was analysed for TCF2 point mutations and if normal by QMPSF for gene deletions. All MODY5 patients found in our cohort had no TCF2 mutation but had monoallelic loss of the entire TCF2 gene. Array CGH and FISH analysis confirmed a large genomic deletion of ~1.5–1.7 Mb in size that was not detected in any of the patients’ parents.

Conclusion: The phenotype of patients with 17q12 deletion syndrome is highly variable. Up to now, 17q12 deletion syndrome was claimed to be one of the few contiguous gene deletion syndromes without mental retardation but our two cases with mental retardation question this hypothesis. The molecular defect identified in all cases was a 1.5–1.7 Mb deletion and paired, segmental duplications along with breakpoints were most likely involved in this recurrent chromosomal microdeletion.