Congenital isolated hyperinsulinism

Congenital isolated hyperinsulinism (CHI), also known as congenital hyperinsulinism (CHI), persistent hyperinsulinemic hypoglycemia of infancy (PHHI), or nesidioblastosis, is a group of rare genetic disorders characterized by inappropriate and excessive secretion of insulin by the pancreatic beta cells, leading to severe and recurrent episodes of hypoglycemia (low blood sugar). It is the most common cause of persistent hypoglycemia in neonates and infants. The condition primarily affects the endocrine system, specifically the insulin-regulating mechanisms of the pancreas, but the resulting hypoglycemia can have devastating effects on the central nervous system, potentially causing seizures, intellectual disability, and permanent brain damage if not promptly recognized and treated. Clinically, affected individuals present with symptoms of hypoglycemia including lethargy, poor feeding, irritability, jitteriness, seizures, and in severe cases, coma. The disease can manifest in two major histological forms: diffuse disease, where all beta cells throughout the pancreas are affected, and focal disease, where the abnormality is limited to a discrete region of the pancreas. Distinguishing between these forms is critical for treatment planning. Multiple genetic subtypes have been identified, with mutations in the ABCC8 and KCNJ11 genes (encoding the components of the beta-cell ATP-sensitive potassium channel) being the most common causes. Other causative genes include GCK, GLUD1, HADH, HNF4A, HNF1A, SLC16A1, and UCP2, among others. Treatment aims to maintain blood glucose within a safe range to prevent neurological damage. First-line medical therapy typically involves diazoxide, which inhibits insulin secretion. Patients unresponsive to diazoxide, particularly those with KATP channel mutations, may require octreotide (a somatostatin analog) or continuous glucose infusions. For focal forms of the disease, limited surgical resection (partial pancreatectomy) of the affected area can be curative. In severe diffuse disease unresponsive to medical management, near-total pancreatectomy may be necessary, though this carries a high risk of subsequent diabetes mellitus and exocrine pancreatic insufficiency. 18F-DOPA PET/CT scanning has become an important tool for differentiating focal from diffuse disease preoperatively. Long-term follow-up is essential, as patients may develop diabetes later in life and require monitoring for neurodevelopmental outcomes.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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