ESPE Abstracts

Background: Congenital hyperinsulinism possesses considerable clinical heterogeneity attributed partly to its diverse genetic causes.

Objective: To present a boy with diazoxide unresponsive hyperinsulinaemic hypoglycaemia due to a homozygous recessive ABCC8 missense mutation, previously reported to be dominant acting and being inherited by his unaffected heterozygous parents.

Material and results: The boy was a third preterm child of a 27-year-old mother, born at 37 weeks of gestation with a weight of 3600 g (+1.49 SDS) and retarded cardiopulmonary adaptation. Hypoglycaemic episodes with generalized seizures had appeared in the first hours after birth and the baby had been commenced on i.v. glucose infusions. Although the high glucose infusion rate (GIR) (above 8 mg/kg/min), the blood glucose values had varied between 1.0-2.0 mmol/l and at the age of 14 days the patient was referred to our Endocrine center for further investigations and treatment. He had normal cardiopulmonary function, with no liver enlargement or hemihypertrophy and did not display any features of syndromic hyperinsulinism. A “critical sample” was obtained at blood glucose level of 1.3 mmol/l showing increased insulin (31.4 mIU/ml), undetectable ketone bodies, normal cortisol and growth hormone concentrations at the time of hypoglycaemia. All other laboratory and imaging tests were normal. We commenced treatment with i.v. glucose with GIR of 8.5 mg/kg/min, diazoxide and chlorothiazide. However, the patient did not respond to this therapy and i.v. glucagon was initiated in order to control the blood glucose above 3.5 mmol/l. At the age of 1 month the patient was successfully commenced on octreotide therapy (18.5 mcg/kg/day) given as 4 s.c. injections. A genetic testing with sequence analysis of ABCC8 and KCNJ11 genes was performed showing that the boy was homozygous for a ABCC8 missense mutation (p.Gly92Asp) inherited from his unaffected parents. They were heterozygous for the same mutation which has previously been reported as a dominant one.

Discussion: The result of our patient is consistent with the diagnosis of autosomal-recessive congenital hyperinsulinism due to a homozygous loss-of-function mutation in the SUR1 subunit of the ATP-sensitive potassium channel confirming the diazoxide unresponsive diffuse disease. Further genotype-phenotype association studies in congenital hyperinsulinism are needed due to the variability in its inheritance and clinical presentation.