Background: Congenital hyperinsulinism (CHI) is a rare disease mostly due to loss-of-function mutations of the ABCC8 or KCNJ11 genes, encoding the two subunits of the KATP channel. Gain-of-function mutations in glutamate dehydrogenase 1, encoded by the GLUD1 gene, are the second most common cause of CHI.
Objective and hypotheses: The majority of patients with a GLUD1 CHI respond to diazoxide, but little is known about the consequences of fetal diazoxide exposure.
Method: We report the neonatal outcome after fetal diazoxide exposure (50 mg t.i.d) and maternal CHI.
Results: Whole exome sequencing with bioinformatical targeted analysis of 10 genes known to cause CHI (ABCC8, KCNJ11, GLUD1, GCK, HADH, HNF1A, HNF4A, SLC16A1, UCP2, CDKN1C) revealed a maternal novel heterozygous missense GLUD1 variant c.1496G>T; p.(Gly499Val), predicted to be pathogenic. The baby was born by cesarean section at 40 weeks of gestation with intrauterine growth restriction (IUGR), birth weight 2300 g (<−2 S.D.), length 46 cm (<−2 S.D.), head circumference 32.5 cm (<-2 S.D.). The genetic analysis showed that he was not carrying the maternal GLUD1 variant. No malformations were visible. No structural anomalies were identified on the brain MRI done on day of life 10.
Conclusion: This newborn had a 50% risk to inherit CHI and was exposed to diazoxide in utero. Diazoxide passes the placenta and fetal concentration is supposed to be the same as in the mother. Intravenous diazoxide has been used in pregnant women for its hypotensive action with risks of placental hypoperfusion, fetal death and neonatal hyperglycemia. We did not find such adverse effects; however the newborn presented with IUGR, which could be secondary to maternal hypoglycemia or to a direct effect of diazoxide. No structural brain anomalies attributable neither to teratogenicity of diazoxide nor to IUGR were observed, however this child is at risk of neurodevelopmental impairment.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology