Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease

Objectives: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. Methods: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. Results: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. Conclusions: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.