ESPE Abstracts (2015) 84 P-3-1080

Severe Congenital Hyperinsulinism in a Neonate Homozygous for Two Novel Missense Mutations in the KCNJ11 Gene

Alev Ozona, Ayfer Alikasifoglua, Sian Ellardc, Sarah Flanaganc, Nazli Gonca, Diclehan Orhanb, Saniye Ekincid & Nurgun Kandemira


aDivision of Pediatric Endocrinology, Hacettepe University, Ankara, Turkey; bDivision of Pediatric Pathology, Hacettepe University, Ankara, Turkey; cInstitute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK; dDepartment of Pediatric Surgery, Hacettepe University, Ankara, Turkey


Background: Congenital hyperinsulinism (CHI) is a heterogenous disorder characterized by hyperinsulinaemic hypoglycaemia, and may present in the neonatal period in severe forms of the disease. Molecular defects involving eight genes has been described so far. Herein we report a case of severe, diazoxide unresponsive CHI caused by two homozygous novel missense mutations in the KCNJ11 gene.

Case report: An 8-day old girl was referred for hyperinsulinaemic hypoglycaemia. She was the first child of first degree cousins. She had hypoglycemia on the first day of life. Unresolved repeated hypoglycaemia despite high glucose infusion rates (GIR) and an elevated insulin (47 μIU/ml) suggested CHI and the patient was started on diazoxide (15 mg/kg per day). She continued to have boutes of hypoglycaemia, considered to be diazoxide unresponsive and referred for pancreatectomy. Upon arrival she had hepatomegaly, also ASD, PDA, pulmonary hypertension as well as concentric left ventricular hypertrophy was discovered on ECHO. Blood glucose was kept in the normal range initially using diazoxide (15 mg/kg per day), hydrochlorothiazide (2 mg/kg per day), octreotide (20–40 μg/kg per day) and glucose infusion (10–12 mg/kg per min on 20th postnatal day, she developed heart failure and was digitalized, diazoxide was replaced with glucagon (20 μg/kg per day). On 22nd day of life PDA was ligated, and 36th day of life near total pancreatectomy was carried out. Following pancreatectomy hypoglycaemia recurred and she was put on octreotide. Pathology showed diffuse hyperplasia, hypertrophy and nucleomegaly in the islet cells. Molecular analysis revealed that the patient was homozygous for two novel missense mutations (p.R221H and p.Q299H) in the KCNJ11 gene. Both parents were heterozygous for the same mutations.

Conclusion: Pathology and molecular findings suggested autosomal recessive CHI. The arginine residue at codon 221 and the glutamine residue at codon 299 are conserved across species. It is therefore likely that one or both of these mutations are pathogenic.

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