Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency

Diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency is a rare form of congenital hyperinsulinism (CHI) characterized by inappropriate and excessive insulin secretion from a discrete focal lesion within the pancreas. It is caused by a paternally inherited mutation in the ABCC8 gene, which encodes the sulfonylurea receptor 1 (SUR1) subunit of the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. The focal form arises when a paternal ABCC8 mutation is combined with somatic loss of the maternal 11p15 region in a clonal population of beta cells, leading to a localized area of abnormal insulin secretion. This condition primarily affects the endocrine pancreas and, through its metabolic consequences, the central nervous system. Patients typically present in the neonatal or early infantile period with severe, persistent hypoglycemia that does not respond to diazoxide therapy — the first-line medical treatment for hyperinsulinism. Symptoms of hypoglycemia include seizures, lethargy, poor feeding, jitteriness, and, if untreated, can lead to permanent brain damage. The hallmark of this condition is the resistance to diazoxide, which works by opening KATP channels; because the SUR1 protein is dysfunctional, diazoxide cannot exert its therapeutic effect. Diagnosis involves biochemical confirmation of hyperinsulinemic hypoglycemia, genetic testing of the ABCC8 gene, and 18F-DOPA PET/CT scanning to localize the focal lesion within the pancreas. The key advantage of identifying focal disease is that it is potentially curable through limited surgical resection (focal lesionectomy), which removes only the affected area of the pancreas while preserving the remainder of normal pancreatic tissue. This is in contrast to diffuse forms of the disease, which may require near-total pancreatectomy. Prior to surgery, patients often require intensive medical management including frequent feeding, intravenous glucose infusions, and octreotide or glucagon to maintain euglycemia. Early diagnosis and appropriate surgical intervention are critical to preventing neurodevelopmental complications from recurrent hypoglycemia.

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