Background: Hyperinsulinaemic hypoglycaemia (HH) is the most frequent cause of severe and persistent hypoglycaemia in infancy. Prompt recognition and successful management are critical to ensure prevention of hypoglycaemic brain injury and neurological sequelae. The incidence of HH varies from 1:50,000-1:2,500, and mutations in at least 12 different genes involved in β-cell insulin release have been described. Recently, the spectrum of genetic causes for HH has been extended, with the reported co-existence of HH and congenital polycystic kidney disease (PCKD) in 17 children, caused by a promoter mutation in the phosphomannomutase 2 gene (PMM2). Previous reports have documented the effectiveness of L-type calcium channel blockers, such as nifedipine, for treating different forms of HH. In some cases nifedipine was introduced to avoid the side-effects of other medications such as diazoxide/octreotide, or with a concomitant antihypertensive purpose. Closure of adenosine triphosphate (ATP)-sensitive potassium channels (KATP channels) channels in the membrane of pancreatic β-cells initiates depolarisation of the cell membrane and opening of calcium channels. This results in an influx of calcium, and the rise in intracellular calcium triggers insulin release.
Objective: To report the first trial of nifedipine therapy in 3 patients with HH due to mutations in PMM2.
Methods: Nifedipine was initiated at a dose of 0.5 mg/kg/day and increased to 1 mg/kg/day after 48 hours, with close blood pressure monitoring. Glycaemic response was assessed by a blood glucose profile and fast test.
Results: Treatment with nifedipine enabled Patient 1 to come off overnight feeds and fast for 16 hours (6 hours prior to treatment), with no hypoglycaemic episodes on profile. Furthermore, his diazoxide dose was weaned by 20%. Patient 2 had an increase in fast tolerance from 13 to 16 hours with no hypoglycaemia on treatment. Patient 3 was able to fast for 18 hours with no hypoglycaemia on profile, and his dose of diazoxide was weaned by ~40% on Nifedipine.
Conclusions: This is the first report of glycaemic response to nifedipine therapy in 3 patients with HH due to mutations in PMM2. Nifedipine therapy has enabled these patients to achieve a stable blood glucose profile with increased fast tolerance, and to wean diazoxide. Furthermore, control of blood pressure improved to the extent that, in one case, nifedipine is now used as monotherapy. Nifedipine may therefore prove useful as first line therapy in patients with HH and PCKD due to mutations in PMM2.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology