Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency

Diazoxide-resistant focal hyperinsulinism due to Kir6.2 deficiency is a rare form of congenital hyperinsulinism (CHI) caused by pathogenic variants in the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This condition is characterized by inappropriate and excessive secretion of insulin from a discrete focal lesion within the pancreas, leading to severe and persistent hypoglycemia (low blood sugar). The focal nature of the disease means that only a localized region of the pancreas is affected, typically due to a paternally inherited KCNJ11 mutation combined with somatic loss of the maternal allele in the affected tissue. Because the KATP channels are dysfunctional, the beta cells continuously release insulin regardless of blood glucose levels. Clinical presentation typically occurs in the neonatal or early infantile period with symptoms of severe hypoglycemia, including seizures, lethargy, poor feeding, jitteriness, and, if untreated, potential brain damage. The hallmark of this condition is resistance to diazoxide, the first-line medical therapy for hyperinsulinism, because diazoxide works by opening KATP channels — channels that are non-functional in this disease. Diagnosis involves biochemical confirmation of hyperinsulinemic hypoglycemia, genetic testing of KCNJ11, and 18F-DOPA PET/CT scanning to localize the focal lesion within the pancreas. The primary treatment for focal hyperinsulinism is surgical resection (focal lesionectomy) of the affected pancreatic tissue, which can be curative. Unlike diffuse forms of congenital hyperinsulinism, where near-total pancreatectomy may be required, patients with focal disease can achieve normoglycemia after limited surgery with preservation of the majority of pancreatic tissue. Accurate preoperative localization using 18F-DOPA PET/CT and intraoperative frozen section analysis are critical for successful surgical outcomes. Octreotide and continuous glucose infusions may be used as bridging therapies to manage hypoglycemia prior to surgery.

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