Partial diazoxide responsiveness in a neonate with hyperinsulinism due to homozygous ABCC8 mutation

Abstract

SummaryWe report a case of partial diazoxide responsiveness in a child with severe congenital hyperinsulinaemic hypoglycaemia (CHI) due to a homozygous ABCC8 mutation. A term baby, with birth weight 3.8 kg, born to consanguineous parents presented on day 1 of life with hypoglycaemia. Hypoglycaemia screen confirmed CHI. Diazoxide was commenced on day 7 due to ongoing elevated glucose requirements (15 mg/kg/min), but despite escalation to a maximum dose (15 mg/kg/day), intravenous (i.v.) glucose requirement remained high (13 mg/kg/min). Genetic testing demonstrated a homozygous ABCC8 splicing mutation (c.2041-1G>C), consistent with a diffuse form of CHI. Diazoxide treatment was therefore stopped and subcutaneous (s.c.) octreotide infusion commenced. Despite this, s.c. glucagon and i.v. glucose were required to prevent hypoglycaemia. A trial of sirolimus and near-total pancreatectomy were considered, however due to the significant morbidity potentially associated with these, a further trial of diazoxide was commenced at 1.5 months of age. At a dose of 10 mg/kg/day of diazoxide and 40 µg/kg/day of octreotide, both i.v. glucose and s.c. glucagon were stopped as normoglycaemia was achieved. CHI due to homozygous ABCC8 mutation poses management difficulties if the somatostatin analogue octreotide is insufficient to prevent hypoglycaemia. Diazoxide unresponsiveness is often thought to be a hallmark of recessively inherited ABCC8 mutations. This patient was initially thought to be non-responsive, but this case highlights that a further trial of diazoxide is warranted, where other available treatments are associated with significant risk of morbidity.Learning points:Homozygous ABCC8 mutations are commonly thought to cause diazoxide non-responsive hyperinsulinaemic hypoglycaemia.This case highlights that partial diazoxide responsiveness in homozygous ABCC8 mutations may be present.Trial of diazoxide treatment in combination with octreotide is warranted prior to considering alternative treatments, such as sirolimus or near-total pancreatectomy, which are associated with more significant side effects.

Clinical characteristics, outcome, and predictors of neurological sequelae of persistent congenital hyperinsulinism: A single tertiary center experience

“…Combined diazoxide and octreotide use was successful in controlling hypoglycaemia in five cases with biparental homozygous ABCC8 mutation even though, this mutation commonly causes diazoxide unresponsiveness 24 . Diazoxide responsiveness after combination with octreotide has been reported in a single case report and the authors encouraged trial of this approach in cases with homozygous ABCC8 mutation before proceeding to sirolimus and/or surgery 27 …”

Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous ABCC8 mutation

“…1,6 Alternatively, a few cases with partial diazoxide responsiveness despite biallelic ABCC8 mutations were reported. [7][8][9][10] Herein, we report a case series with CHI from unrelated two families caused by an identical homogenous variant of a 1-bp deletion mutation of ABCC8 which was not reported previously; however, these cases exhibited markedly distinct phenotypes, including differing hypoglycaemia severity and diazoxide response.…”

Possible New Strategies for the Treatment of Congenital Hyperinsulinism

“…Noteworthy, nifedipine has been used for the treatment of diazoxide-unresponsive CHI (19,29), but due to reported hypotension in patients with mutations in the ABCC8 gene, it is not commonly recommended for the treatment of CHI (29,86). Diazoxide is usually effective in all forms of CHI including severe cases caused by mutations in the genes encoding K ATP channels (ABCC8 and KCNJ11), e.g., in (2,67,87,88). Our sample cohort was derived from patients harboring ABCC8 missense mutations (patients 1, 6, and 7), a mutation affecting splicing (patient 3) and two nonsense mutations (patients 4,5).…”

“…However, they do not necessarily lead to diazoxide unresponsiveness. Response to diazoxide is even observed in patients in whom non-response would be predicted (67). Moreover, focal CHI is clinically heterogeneous and responsiveness or resistance to diazoxide was reported for patients with the same mutation in K ATP channels (68).…”