Atypical forms of congenital hyperinsulinism in infancy are associated with mosaic patterns of immature islet cells

Abstract

Objectives: We aimed to characterize mosaic populations of pancreatic islet cells from patients with atypical congenital hyperinsulinism in infancy (CHI-A) and the expression profile of NKX2.2, a key transcription factor expressed in b-cells but suppressed in d-cells in the mature pancreas. Patients/Methods: Tissue was isolated from three patients with CHI-A following subtotal pancreatectomy. CHI-A was diagnosed on the basis of islet mosaicism and the absence of histopathological hallmarks of focal and diffuse CHI (CHI-D). Immunohistochemistry was used to identify and quantify the proportions of insulin-secreting b-cells and somatostatin-secreting d-cells in atypical islets, and results were compared with CHI-D (n = 3) and age-matched control tissues (n = 3). Results: In CHI-A tissue, islets had a heterogeneous profile. In resting/quiescent islets, identified by a condensed cytoplasm and nuclear crowding, b-cells were reduced to,50% of the total cell numbers in n = 65/70 islets, whereas d-cell numbers were increased with 85% of islets (n = 49/57) containing .20% d-cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI-D islets (n = 72) were composed of .50% b-cells, and .20% d-cells were found only in 12% of CHI-D (n = 8/66) and 5% of control islets (n = 3/60). Active islets in CHI-A tissue contained proportions of b-cells and d-cells similar to those of control and CHI-D islets. Finally, when compared with active islets, quiescent islets had a twofold higher prevalence of somatostatin/NKX2.2+ coexpressed cells. Conclusions: Marked increases in NKX2.2 expression combined with increased numbers of d-cells strongly imply that an immature d-cell profile contributed to the pathobiology of CHI-A.