Atypical Forms of Congenital Hyperinsulinism In Infancy are Associated with Mosaic Patterns of Immature Islet Cells

Objectives. We aimed to characterise mosaic populations of pancreatic islet cells from patients with atypical CHI (CHI-A) and the expression profile of NKX2.2, a key transcription factor expressed in β-cells but suppressed in δ-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 to quantify the proportions of insulin-secreting β-cells and somatostatin-secreting δ-cells in atypical islets and the results compared to CHI-D (n=3) and age-matched control tissue (n=3). Results. In CHI-A tissue, islets had a heterogeneous profile. In resting / quiescent islets - identified by a condensed cytoplasm and nuclear crowding, β-cells were reduced to <50% of the total cell numbers in n=65/70 islets, whereas δ-cell numbers were increased with 85% of islets (n=49/57) containing >20% δ-cells. In comparison, all islets in control tissue (n=72) and 99% of CHI-D islets (n=72) were composed of >50% β-cells and >20% δ-cells were only found in 12% of CHI-D (n=8/66), and 5% of control islets (n=3/60). Active islets in CHI-A tissue contained similar proportions of β-cells and δ-cells as control and CHI-D islets. Finally, when compared to active islets, quiescent islets had a 2-fold higher prevalence of SOM+/NKX2.2+ co-expressed cells. Conclusions. Marked increases in NKX2.2 expression combined with increased numbers of δ-cells, strongly imply that an immature δ-cell profile contributes to the pathobiology of atypical CHI.