ESPE Abstracts (2016) 86 P-P1-550

Persistent Ketotic Hypoglycemia as an Atypical Presentation of Heterozygous HNF4A Mutation

Julia von Oetting, John Mitchell, Daphné Cloutier & Daphne Yau


McGill University Health Center, Montreal, Quebec, Canada


Background: Heterozygous loss-of-function HNF4A mutations are known to lead to monogenic diabetes, and in infants to macrosomia and hyperinsulinemic hypoglycemia. We are reporting a patient with a heterozygous HNF4A mutation (c.997C>T p.ARG333Cys) presenting with persistent ketotic hypoglycemia.

Case report: In a 38 weeks’ gestation infant (birth weight 4.1 kg, pregnancy complicated by insulin-requiring gestational diabetes), hypoglycemia developed in the first hours of life. Initially diagnosed with hyperinsulinemic hypoglycemia due to gestational diabetes, treatment with diazoxide 7.5 mg/kg/day was initiated. Hyperglycemia and severe signs of fluid overload requiring intensive care developed and treatment was discontinued. During a lengthy hospitalization, high insulin and concurrently low C-peptide levels in the context of hypoglycemia were suggestive of exogenous insulin administration. A congenital hyperinsulinism genetic panel showed a likely pathogenic variant of HNF4A, but was not thought to be relevant in the context of suspected Munchausen by proxy. At age 7 months, the patient presented to our hospital with recurrent ketotic hypoglycemia. Hypoglycemia observed as soon as 1 h post-prandially persisted while hospitalized and while wearing a continuous glucose monitor at home. Critical samples during hypoglycemia showed appropriately low levels of insulin (1.1–5.2 pmol/l), and elevated ketone levels 1.30–2.30 mmol/l). Cortisol and growth hormone were 667 nmol/l and 4.2 mcg/l (maximum value), respectively. Glycemia rose <1.7 mmol/l in response to glucagon administration. Acylcarnitine profile, glycogen storage disease genetic panel and toxicology screen were negative. Therapeutic trials with corn starch and Octreotide failed. Despite prior side effects, Diazoxide at a dose of 5 mg/kg/day was retrialed in combination with hydrochlorothiazide, and hypoglycemia resolved.

Conclusion: Heterozygous HNF4A mutations may present as ketotic hypoglycemia, and laboratory investigations may not suggest hyperinsulinism. We considered dysregulated insulin secretion, down-regulation of GLUT2 as a result of the known HNF4A mutation vs. an additional condition predisposing to hypoglycemia as possible mechanism to explain this presentation.

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