MODY1 is a rare condition that can complicate pregnancy. This case highlights the importance of diagnosis and utility of non-invasive prenatal testing to guide management.
A 25-year-old primigravida presented to a tertiary obstetric centre at 6 weeks gestation. She had a history of Type 2 diabetes (T2DM), diagnosed age 17, treated with metformin. Preconception HbA1c was 7.3%. Co-morbidities included PCOS with insulin resistance and hyperandrogenism, but without fertility complications. Her family history was significant for diabetes in her father and paternal grandmother. Early pregnancy BMI was 22.2kg/m2. Following commencement of insulin, she was noted to have labile blood glucose levels. Type 1 diabetes antibodies were negative. C-peptide was normal 0.80 nmol/L (NR 0.4-1-5 nmol/L). Maturity Onset Diabetes of the Young (MODY) was suspected. Genetic testing revealed heterozygous splice site mutation at the HNF4A gene, pathogenic for MODY 1. Interestingly, she was also diagnosed with a heterozygous missense mutation at the insulin receptor (INSR), associated with type A insulin resistance. Non-invasive prenatal testing using cell-free foetal DNA revealed foetal inheritance of the HFN4A, but not the INSR, mutation. The mother was treated with insulin reaching 1.1 U/kg with a stable dose of Protaphane, increasing doses of Novorapid and the resumption of metformin. Foetal ultrasounds showed progressive increase in abdominal circumference to the 86th centile at 33 weeks. She underwent preterm premature rupture of membranes at 34 weeks, requiring vacuum-assisted delivery. Neonatal weight at delivery was 2.86kg (90-95th centile) and birth was complicated by neonatal hypoglycaemia of 0.9mmol/L requiring NICU admission, IV dextrose and diazoxide. Neonatal bloods showed elevated insulin levels of 11mIU/L, but normal cortisol, ACTH and GH. A fasting challenge was performed at 2 weeks of age which allowed cessation of diazoxide. Following delivery, insulin was ceased, metformin continued and euglycaemia maintained while breastfeeding.
The young age at diagnosis, ‘normal’ BMI and family history raised suspicion of MODY. The INSR mutation likely accounted for some of the features of PCOS. This mutation results in type A insulin resistance featuring hirsutism, acanthosis nigricans and high insulin requirements. Foetal genetic testing is useful as maternal and foetal genotype guides management to mitigate macrosomia and informs risk of neonatal hypoglycaemia. An affected foetus is at risk of macrosomia and persistent and severe hypoglycaemia which needs to be monitored for. Affected mothers require management of maternal hyperglycaemia to avoid additive effect on growth in an affected foetus and mitigation of possible peri-partum morbidity.