title: Sirolimus therapy in a patient with severe hyperinsulinaemic hypoglycaemia due to a compound heterozygous ABCC8 gene mutation.
abstract: BACKGROUND
  Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of severe diazoxide unresponsive HH involves near total pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. mTOR inhibitors are used in cancer patients and recently found to be effective in the treatment of insulinoma and HH patients.
  
  
  METHODS
  A 36 weeks large for gestational age neonate presented with severe hypoglycaemia on day 1 of life. The hypoglycaemia screen confirmed HH and genetic testing revealed compound heterozygous ABCC8 mutation, confirming diffuse disease. He was unresponsive to the maximal dose of diazoxide (15 mg/kg/day), hence needed treatment with higher concentration of intravenous glucose (25 mg/kg/min), intravenous glucagon and subcutaneous octreotide (30 μg/kg/day) infusions to maintain normoglycaemia. Sirolimus, a mTOR inhibitor, was commenced at 9 weeks of age following which he showed a marked improvement in his glycaemic control. After 4 weeks of sirolimus therapy, he was discharged home on subcutaneous octreotide injection (20 μg/kg/day) and oral sirolimus, thereby avoiding the need for a near total pancreatectomy.
  
  
  CONCLUSIONS
  We report the first case of compound heterozygous ABCC8 mutation causing severe diffuse HH that responded to therapy with a mTOR inhibitor.
authors.forename: Pratik
authors.initials: P
authors.lastname: Shah
authors.forename: Ved Bhushan
authors.initials: VB
authors.lastname: Arya
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Kate
authors.initials: K
authors.lastname: Morgan
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Senthil
authors.initials: S
authors.lastname: Senniappan
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
mesh_terms: D044903:Congenital Hyperinsulinism / Q000188:drug therapy* / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000097:blood*; D008297:Male; D009154:Mutation; D020123:Sirolimus / Q000627:therapeutic use*; D064233:Sulfonylurea Receptors / Q000235:genetics*
chemical_list: C577507:ABCC8 protein, human; D007328:Insulin; D064233:Sulfonylurea Receptors; D020123:Sirolimus