ESPE Abstracts (2014) 82 FC9.4

Clinical Characteristics and Molecular Genetics Analysis of 20 Patients with Neonatal Diabetes Mellitus from a Single Centre of the South-Eastern Region of Turkey

Huseyin Demirbileka,c, Ved Bhushan Aryaa,b, Mehmet Nuri Ozbekc, Jayne Houghtond, Riza Taner Baranc, Selahattin Tekkese, Deborah Mackayf, Sarah E Flanagand, Sian Ellardd & Khalid Hussaina,b

aDepartment of Paediatric Endocrinology, Great Ormond Street Hospital For Children NHS Trust, London, UK; bInstitute of Child Health, University College London, London, UK; cDepartments of Paediatric Endocrinology, Children State Hospital, Diyarbakir, Turkey; dInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; eDepartment of Medical Biology and Genetics, Dicle University, Diyarbakir, Turkey; fFaculty of Medicine, Princess Anne Hospital, University of Southampton, Southampton, UK

Background: Neonatal diabetes mellitus (NDM), either transient (TNDM) or permanent (PNDM), is a rare form of monogenic diabetes, and usually presents in the first 6 months of life.

Objective and Hypotheses: To describe the clinical characteristics and molecular genetics of a large Turkish cohort of NDM from a single centre.

Method: NDM patients presenting to Diyarbakır Children State Hospital between 2010 and 2013 were prospectively recruited and phenotyped. Molecular genetic analysis (conventional or targeted next generation analysis, tNGS) was performed

Results: Twenty patients (60% males) presented with NDM (five TNMD and 15 PNDM) during this period. In 5 (100%) TNDM and 13 (86.7%) PNMD patients families were consanguineous. Molecular genetic analysis identified the cause of NDM in 18 (90%) patients. In 13 PNDM patients, 11 homozygous (GCK (n=4), EIF2AK3 (n=3), PTF1A (n=3), and INS (n=1)) and two heterozygous (KCNJ11) mutations were identified. All patients with an EIF2AK3 mutation had liver dysfunction and/or skeletal dysplasia. Pancreatic exocrine dysfunction was observed in the three patients with mutations in the distal enhancer region of PTF1A. One patient with a KCNJ11 mutation responded well to oral sulfonylureas whilst the second patient with the same mutation was unable to transfer from insulin. A genetic diagnosis was possible for all five TNDM patients. Three had 6q24 methylation abnormalities and 2 patients were homozygous for mutations in ABCC8 and INS. A variable phenotype was associated with the c.−331C>A INS mutation, which was identified in both a PNDM and TNDM patient.

Conclusion: We present the largest cohort of NDM from a single paediatric centre. Homozygous mutations in GCK, EIF2AK3 and the distal enhancer region of PTF1A were the commonest causes of NDM in our cohort. The underlying genetic cause could be established in up to 90% of NDM patients. This high pick-up rate is likely to reflect enrichment for consanguinity within our cohort.