Background: Congenital hyperinsulinism (CHI) is a rare, heterogeneous disease with a transient, recurrent or persistent course. Transient CHI (tCHI) is considered to be caused by non-genetic risk factors e.g. birth asphyxia and intrauterine growth restriction (IUGR), while persistent hyperinsulinism is known to be caused by mutations in at least nine genes: ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A and UCP2.
Objective and hypotheses: The aim of the study is to investigate genetic causes in children with tCHI, not secondary to maternal diabetes, who has been treated at Odense University Hospital, Denmark, from 1994 to 2016.
Method: Retrospective hospital file review to determine i) the phenotype of tCHI patients defined as patients with clinical remission of hypoglycemia before 1 year of age and ii) the genotype in tCHI patients and their parents. Risk factors of tCHI (ultrasound-verified IUGR; severe asphyxia defined as APGAR score 1 and 5 min <4 or <7, respectively, or cord pH <7,0) and adverse neurological outcome were recorded.
Results: In 70 patients with tCHI, 10 (14%) of the patients had a mutation, ABCC8; n=2, KCNJ11; n=4, HNF1A; n=3, HNF4A; n=1. Seven of the mutations were known pathogenic; three had predicted pathogenicity. Affected family members were discovered in seven. Only 11 (16%) had a tCHI risk factor (severe asphyxia, n=6, IUGR, n=5), of whom one had a KCNJ11 mutation and asphyxia. Relapse was documented in five (7%), of whom one had a HNF1A mutation. Seven patients (10%) with tCHI developed neurological sequelae (cerebral palsy; n=3, microcephaly; n=1, mental retardation; n=1, epilepsy; n=2), of whom none had a genetic mutation or hypoglycemia relapse.
Conclusion: Transient CHI is not only caused by fetal life events, but also by CHI mutations in at least four different genes. Genetic testing may improve treatment and individual prognosis for tCHI patients and their families.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology