ESPE Abstracts (2014) 82 P-D-3-1-874

Clinical Characteristics and Phenotype-Genotype Analysis in Turkish Patients with Congenital Hyperinsulinism; Predominance of Recessive KATP Channel Mutations

Huseyin Demirbileka,c, Ved Bhushan Aryaa,b, Mehmet Nuri Ozbekd, Aysehan Akincie, Murat Doganf, Fatma Demirelc, Jayne Houghtong, Sultan Kabaf, Fatma Guzelc, Riza Taner Baranc, Sema Unalc, Selahattin Tekkesh, Sarah E Flanagang, Sian Ellardg & Khalid Husssaina,b

aDepartment of Paediatric Endocrinology, Great Ormond Street Hospital for Children NHS Trust, London, UK; bThe Institute of Child Health, University College London, London, UK; cDepartments of Paediatric Endocrinology, Ankara Pediatric Hematology and Oncology Research and Training Hospital, Ankara, Turkey; dDepartments of Paediatric Endocrinology, Children State Hospital, Diyarbakir, Turkey; eDepartments of Paediatric Endocrinology, Inönü University, Malatya, Turkey; fDepartments of Paediatric Endocrinology, Yüzüncü Yıl University, Van, Turkey; gInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; hDepartment of Medical Biology and Genetics, Dicle University, Diyarbakir, Turkey

Background: Congenital hyperinsulinism (CHI) is the most common cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy, and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous.

Objective and hypotheses: To describe the clinical characteristics, analyse the genotype–phenotype correlations and describe the treatment outcome of Turkish CHI patients.

Method: Thirty-five patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected.

Results: Diazoxide-unresponsiveness was observed in nearly-half of the patients (n=17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%). Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype–phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512del) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared to non-consanguineous families (87.5 vs 21%; P<0.0001). Among diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydrate rich feeds and six patients underwent subtotal pancreatectomy. There was high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients.

Conclusion: This is the largest study to report genotype–phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the most common causes of CHI in Turkish patients (48.6%). There is higher likelihood of a genetic diagnosis in patients with early age of presentation, higher birth weight and those from consanguineous pedigrees.