Background: Congenital Hyperinsulinism (CHI), a condition characterised by dysregulation of insulin secretion from the pancreatic beta cells, remains one of the most common causes of hyperinsulinemic, hypoketotic hypoglycaemia in the newborn period. Mutations in ABCC8 and KCNJ11 constitute the majority of genetic forms of CHI. Biallelic inactivating mutations (homozygous or compound heterozygous) in ABCC8 and KCNJ11 are known to result in severe, diffuse, diaxoxide unresponsive hypoglycaemia. We report a neonate with CHI due to compound heterozygous mutations in ABCC8 and completely responsive to diazoxide.
Case: A term macrosomic male baby, birth weight 4.81 kg, born to non-consanguineous parents, presented on day 1 of life with severe and persistent hypoglycaemia. Apart from polyhydramnios during the antenatal period, the pregnancy was otherwise uneventful. Normoglycaemia (blood glucose>3.5mmol/L) was achieved with a peak glucose infusion rate (GIR) of 20mg/kg/minute. The hypoglycaemia screen showed an inappropriately raised plasma insulin 50.4mIU/L when the plasma blood glucose level was 0.5mmol/L with suppressed free fatty acids and beta-hydroxy butyrate, confirming the diagnosis of CHI. Following a normal baseline echocardiogram, diazoxide was commenced initially at a dose 5mg/kg/day in conjunction with chlorothiazide. The intravenous fluids were weaned and normoglycaemia was sustained with a high dose of diazoxide (15mg/kg/day) and enteral nasogastric formula feeding 150ml/kg/day. Molecular genetic analysis of the proband confirmed biallelic ABCC8 mutations: missense c.4079C>T (pathogenic) and splicing c.4122+1G>A (pathogenic) variants inherited from the unaffected father and mother respectively. The proband is currently 4 months old and continues to show a sustained response to his current diazoxide dose 7.5mg/kg/day and formula feeding (4 hourly) via naso-gastric tube due to vomiting on oral feeds. The MRI brain showed a deep medullary sinus thrombosis which is being managed conservatively. The investigations to look for the causes of persistent vomiting on oral feeds are currently underway.
Discussion: Rapid genetic analysis is integral in the management of CHI as a tool to identify patients who may not respond to standard therapy of diazoxide, and those who may need F-DOPA PET scan and possible pancreatectomy. Although the majority of biallelic ABCC8 mutations cause diazoxide unresponsive CHI, very rarely they can show a complete response to diazoxide treatment. The molecular interaction behind this is currently unclear. An accurate assessment to diazoxide responsiveness is therefore warranted before considering alternative therapies.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology