Non-insulinoma persistent hyperinsulinaemic hypoglycaemia caused by an activating glucokinase mutation: hypoglycaemia unawareness and attacks.

OBJECTIVE: Adult-onset non-insulinoma persistent hyperinsulinaemic hypoglycaemia (NI-PHH) and the variant NI-pancreatogenous hypoglycaemia syndrome (NIPHS) are genetically unexplained diseases, without reports of hypoglycaemia unawareness or familial inheritance. DESIGN AND PATIENTS: In a prospective 8-year follow-up, a boy (i) with NI-PHH since age 14 years, his mother (ii), the mother's brother (iii) and his daughter (iv) were studied.
RESULTS: Patient (i) was characterized by especially postprandial hypoglycaemia down to 1.6 mmol/l and pronounced variability in diazoxide need with obesity; (ii) had asymptomatic blood glucose down to 2.9 mmol/l, but a severe hypoglycaemic postprandial attack after a slimming diet; (iii) had moderate hypoglycaemic symptoms since childhood and need of frequent eating; and (iv) was asymptomatic until a hypoglycaemic accident in the age of 24. After a slimming diet, symptomatic fasting, but especially postprandial hypoglycaemia occurred (blood glucose 1.9 mmol/l after 19 h fasting; 1.6 mmol/l 3.5 h after OGTT). By CT-scan/endoscopic ultrasound in three of the individuals, insulinoma could not be detected. In all four individuals, an activating glucokinase (GCK) mutation A456V was found. No mutations were found in the ABCC8 or KCNJ11 genes. The patients responded to treatment with diazoxide or octreotide long acting release.
CONCLUSION: This is the first report to highlight a genetic cause to adult-onset NI-PHH/NIPHS. The activating GCK mutation was dominantly inherited, but only after year-long follow-up and investigations, other family members were diagnosed symptomatic. Hypoglycaemia unawareness seems to be a prominent feature, but hypoglycaemic attacks occur after slimming, especially postprandially. PHH-GCK was medical responsive.