A 69 year old male was referred with a 60 year history of recurrent hypoglycaemia. Over the previous 12 months he had several episodes of severe hypoglycaemia, which necessitated emergency treatment from paramedics. He had been diagnosed with a hypoglycaemic disorder at the age of 9 years, but no underlying cause had been identified. He had no other previous history of note, though he was macrosomic at birth with a birth weight of approximately 5.9 kg. His mother was diagnosed with diabetes shortly after delivery. His maternal grandmother also had diabetes. The patients younger son was diagnosed with diabetes aged 33 and was treated with metformin; he was not overweight. His son weighed approximately 4.3 kg at 38 weeks and had issues with hypoglycaemia after birth. The patient was fitted with continuous flash glucose monitoring which confirmed interstitial glucose levels below 4 mmol/l virtually every night and sometimes unrecordable levels associated with symptoms of hypoglycaemia. Genetic testing confirmed that both the patient and his son were heterozygous for a pathogenic nonsense mutation (c.421C>T;p.(Arg141*)) in exon 4 of the HNF4A gene. The patient was commenced on Diazoxide therapy which had a transformative effect and abolished all episodes of severe hypoglycaemia. In offspring with HNF4A mutations birth weight is increased by an average of 700 g, and 50% are born macrosomic. Transient neonatal hyperinsulinaemic hypoglycaemia is reported in 10% of cases. After a period of normoglycaemia Maturity Onset Diabetes of the Young (MODY) develops in adolescence or early adulthood and is sensitive to low dose sulfonylurea therapy. Our patients phenotype of severe hypoglycaemia in adulthood without diabetes is not one that has been previously described. There are reports of two other families with this nonsense mutation; one family had no history of hyperinsulinaemia and the other proband had a child with macrosomia and transient neonatal hypoglycaemia. Nonsense mutations in HNF4A are not expected to have a genotype-phenotype correlation since they will result in degradation of the HNF4A mRNA transcript as a result of nonsense-mediated decay. However, the severity and duration of hypoglycaemia can be highly variable in individuals with different HNF4A mutations due to other modifying genetic effects and environmental factors. This very unusual case highlights that some genetic causes of neonatal hypoglycaemia can be associated with diabetes or hypoglycaemia in later life or in other family members and detailed family history and genetic studies can prove useful in establishing the diagnosis.
16 - 18 Apr 2018
Society for Endocrinology