Autosomal dominant hyperinsulinism due to Kir6.2 deficiency

Autosomal dominant hyperinsulinism due to Kir6.2 deficiency is a rare genetic form of congenital hyperinsulinism (CHI) caused by heterozygous activating mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This condition is also referred to as autosomal dominant hyperinsulinemic hypoglycemia type 2 or KATP channel-related dominant congenital hyperinsulinism due to Kir6.2 mutations. The KATP channel plays a critical role in regulating insulin secretion in response to blood glucose levels. When the channel is dysfunctional, beta cells release insulin inappropriately, leading to persistent hyperinsulinemic hypoglycemia — dangerously low blood sugar levels caused by excessive insulin production. The condition primarily affects the endocrine system, specifically the insulin-secreting beta cells of the pancreas, but the consequences of recurrent or severe hypoglycemia can significantly impact the central nervous system. Key clinical features include recurrent episodes of hypoglycemia that may present in the neonatal period or infancy, with symptoms such as seizures, lethargy, poor feeding, jitteriness, and in severe cases, developmental delay or brain injury if hypoglycemia is not promptly treated. The dominant form tends to be milder than the recessive forms of KATP-related hyperinsulinism and is more often associated with diffuse disease of the pancreas rather than focal lesions. Treatment options include dietary management with frequent feeding and carbohydrate supplementation, as well as pharmacological therapy. Diazoxide, which acts on the KATP channel to suppress insulin secretion, is the first-line medical treatment, though responsiveness can vary depending on the specific mutation. Some patients with dominant Kir6.2 mutations may show partial or good response to diazoxide. Octreotide (a somatostatin analog) may be used as a second-line agent. In medically unresponsive cases, near-total pancreatectomy may be considered, though this carries the risk of subsequent diabetes mellitus. Long-term follow-up is essential to monitor for neurodevelopmental outcomes and glycemic control.

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