Coexistence in the Same Family of Both Focal and Diffuse Forms of Hyperinsulinism

Neonatal hyperinsulinism is the most important cause of hypoglycemia in infancy (1,2). The inappropriate oversecretion of insulin is responsible for profound hypoglycemia, requiring aggressive treatment to prevent brain damage (1–3). Neonatal hyperinsulinism is often resistant to medical therapy (1–4), and pancreatectomy is required for many sufferers (1,5–6). The histopathological lesions associated with neonatal hyperinsulinism may be described as diffuse or focal (7–8). Focal adenomatous islet cell hyperplasia is sporadic and has been demonstrated to arise in individuals who have a germline mutation in the paternal allele of the sulfonylurea receptor 1 ABCC8 gene (9,10) or the inward-rectifying potassium channel Kir6.2 (KCNJ11) (10) in addition to a somatic loss of the maternally derived chromosome region 11p15 in adenomatous pancreatic β-cells (9–11). Diffuse hyperinsulinism may be familial and arises from the autosomal recessive inheritance of mutations in both ABCC8 (12) and KCNJ11 (13–14) genes. The therapeutic outcome for the patients is heavily dependent on distinguishing between the two histopathological lesions. Diffuse hyperinsulinisms, which are unresponsive to medical treatment, require extensive pancreatectomy, with a high risk of diabetes (5,15–16). Conversely, focal hyperinsulinism can be cured by limited pancreatectomy (6,17). Genetic counseling is dramatically different, as focal hyperinsulinism is considered a sporadic molecular event with a very low recurrence risk (10,18), while diffuse …