Clinical presentation and treatment response to diazoxide in two siblings with congenital hyperinsulinism as a result of a novel compound heterozygous ABCC8 missense mutation.
BACKGROUND
Congenital hyperinsulinism (CHI) can present with considerable clinical heterogeneity which may be due to differences in the underlying genetic etiology. We present two siblings with hyperinsulinaemic hypoglycaemia (HH) and marked clinical heterogeneity caused by compound heterozygosity for the same two novel ABCC8 mutations.


METHODS
The index patient is a 3-year-old boy with hypoglycaemic episodes presenting on the first day of life. HH was diagnosed and treatment with intravenous glucose and diazoxide was initiated. Currently he has normal physical and neurological development, with occasional hypoglycaemic episodes detected following continuous fasting on treatment with diazoxide. The first-born 8-year-old sibling experienced severe postnatal hypoglycaemia, generalised seizures and severe brain damage despite diazoxide treatment. The latter was stopped at 6-months of age with no further registered hypoglycaemia. Genetic testing showed that both children were compound heterozygotes for two novel ABCC8 missense mutations p.I60N (c.179T>A) and p.G1555V (c.4664G>T).


CONCLUSIONS
These ABCC8 missense mutations warrant further studies mainly because of the variable clinical presentation and treatment response.
Department of Paediatrics, Medical University of Varna, 55 Marin Drinov street, Varna 9002.
Sonya
S
Galcheva
Department of Paediatrics, Medical University of Varna, Varna.
Violeta
V
Iotova
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter.
Sian
S
Ellard
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter.
Sarah E
SE
Flanagan
Department of Paediatrics, Medical University, Pleven.
Irina
I
Halvadzhiyan
Department of Paediatrics, Medical University, Pleven.
Chayka
C
Petrova
Genetics and Epigenetics in Health and Disease Genetics and Genomic Medicine Programme, UCL Institute Child Health, London.
Khalid
K
Hussain
D000959:Antihypertensive Agents / Q000627:therapeutic use*; D002675:Child, Preschool; D044903:Congenital Hyperinsulinism / Q000188:drug therapy / Q000235:genetics*; D003981:Diazoxide / Q000627:therapeutic use*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011379:Prognosis; D035781:Siblings; D064233:Sulfonylurea Receptors / Q000235:genetics*
C577507:ABCC8 protein, human; D000959:Antihypertensive Agents; D064233:Sulfonylurea Receptors; D003981:Diazoxide
ABCC8 gene; congenital hyperinsulinism (CHI); mutation; neonatal hypoglycaemia