SUN-269 Novel Mutation of the HNF1A Gene in a Patient with Congenital Hyperinsulinism

Background. Hyperinsulinism (HI) is diagnosed based on biochemical evidence of hypoglycemia associated with increased insulin secretion/action. Few individuals with HI harbor mutations in the HNF1A gene; they are hypoglycemic and responsive to diazoxide early in life, but a few of them develop diabetes mellitus later in life. Clinical case. R.B. was delivered at 38 6/7 weeks by repeat C-section and was large for gestational age with birthweight of 4160 grams. Her mother had a history of diabetes diagnosed at 17 years of age and treated with insulin. R.B. developed hypoglycemia at DOL1 with blood glucose in the 20’s which normalized with IV dextrose. At DOL4, IV dextrose was discontinued and she maintained normal blood glucose levels on PO feeds. She underwent an 8-hour fast at DOL12 but developed hypoglycemia with blood glucose of 47 mg/dl at the end of the fast. A critical sample was obtained which showed cortisol of 12 mcg/dl (6.2-19.4), insulin of 7.2 uIU/ml (2.6-24.9), GH of 27.4 ng/dl (0.0-10.0), betahydroxybutyrate of 3.5 mg/dl (0.2-2.8), and free fatty acid of 0.6 mEq/L (0.1-0.6). Based on these laboratory results, the diagnosis of hyperinsulinism was made and she was started on diazoxide (7.5 mg/kg/day). On treatment, her blood glucose normalized (pre-feed glucose of > 70 mg/dl). Diazoxide was subsequently weaned when she started having blood glucose of 170-180 mg/dl and then discontinued at 1 month of age. She remained euglycemic (pre-feed blood glucose > 70 mg/dl) off diazoxide until 4 months of age, when hypoglycemia recurred (blood glucose of 49 mg/dl). An ACTH stimulation test excluded adrenal insufficiency (peak cortisol of 42 mcg/dl). She was then restarted on diazoxide (5 mg/kg/day) and maintained normal blood glucose levels after an 8-hour fast. Genetic testing demonstrated a nucleotide change of c.341 G>A in exon 2 of HNF1A gene that resulted in an amino acid change p. Arg114His located in a domain of the HNF1A protein that is known to be functional. Conclusion. Our patient presented with HI associated with a mutation in the HNF1A gene, which has been described in patients with MODY 3 but has not been described in patients with congenital HI. Genetic testing of her diabetic mother, which is currently being pursued, will likely confirm the maternal origin of our patient’s mutation as well suggest an increased risk for our patient to develop DM later in life. Interestingly, she had ketosis at the time of hypoglycemia, which is atypical in HI but has been previously reported in a patient with HI associated with a different HNF1A gene mutation. Although the underlying mechanism is not clear, this association suggests that the presence of ketosis in patients with hypoglycemia and other features of increased insulin secretion/action does not exclude hyperinsulinism. As a result, in patients with HI and ketosis, HNF1A genetic analysis must be considered while performing a diagnostic work-up.