Glucokinase (GCK)-MODY (Maturity-onset diabetes of the young) is the most common monogenic forms of diabetes. Glucokinase (GCK)-MODY, caused by an autosomal dominant, heterozygous loss‐of‐function mutation in the GCK gene, affects 0.4-1% of women diagnosed with gestational diabetes. It is characterised by impaired pancreatic glucose sensing, resulting in a higher threshold for glucose-stimulated insulin secretion.
A 42-year-old Caucasian woman (gravida 11, para 5), diagnosed with GCK-MODY in 2015, attended the diabetes clinic at 16 weeks gestation. Review of her genetic testing confirmed a pathogenic heterozygous frameshift mutation in exon 8 of the GCK gene (p.Asn313fs, c.938del). Her second child (daughter) carried the same mutation and her four other children (sons) had not been tested. Outside pregnancy, her fasting blood glucose concentrations were ~6.0mmol/L and post-meal were 6-9mmol/L. She began Protaphane 10 units nocte at 12 weeks and took folic acid 5mg and aspirin 150mg. The patient chose not to undergo foetal genetic testing. With the foetal genetic status unknown, adjusted glycaemic targets aimed to minimise potential harm irrespective of foetal genetic inheritance. Altered glycaemic targets were fasting 4.6-6.2mmol/L and 2-hour post meal 4.6-7.7mmol/L, 1mmol/L above standard hospital targets for diabetes in pregnancy. The initial growth ultrasound at 23+5 weeks showed normal foetal development, with abdominal circumference (AC) at the 51st percentile and estimated foetal weight (EFW) at the 61st percentile, and these glycaemic targets were continued. Subsequent ultrasounds at 27+4 weeks and 32 weeks confirmed consistent trajectories, with AC at the 51st percentile on both and EFW at the 58th and 61st percentiles, respectively. Insulin requirements gradually increased to Protaphane 22-26 units nocte and Novorapid 24-26 units TDS by 36+6/40 gestation. An uncomplicated elective Caesarean section at 38+5/40 gestation delivered a healthy 3.2 kg baby boy with no neonatal hypoglycaemia reported.
This case highlights the challenges of glycaemic management in pregnant women with GCK-MODY when the foetal genotype is unknown. Knowledge of foetal genotype informs management decisions, where if the foetus inherits the GCK variant, maternal hyperglycaemia may not require treatment. Conversely, if the foetus does not inherit the variant, maternal insulin therapy may be necessary to prevent excessive foetal growth. Foetal genetic testing, using cell-free DNA in maternal blood, offers high sensitivity (100%) and specificity (96%) for prenatal GCK-MODY diagnosis. In cases where maternal preference precludes testing and foetal genetic status remains uncertain, modified glycaemic targets and ultrasound monitoring can safely manage maternal GCK-MODY without complications. Guidelines for managing such cases would help optimise maternal and foetal outcomes.