Sarah Flanagan

Atypical Forms of Congenital Hyperinsulinism in Infancy Are Associated With Mosaic Patterns of Immature Islet Cells

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 &bgr;‐cells but suppressed in &dgr;‐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 &bgr;‐cells and somatostatin‐secreting &dgr;‐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, &bgr;‐cells were reduced to <50% of the total cell numbers in n = 65/70 islets, whereas &dgr;‐cell numbers were increased with 85% of islets (n = 49/57) containing >20% &dgr;‐cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI‐D islets (n = 72) were composed of >50% &bgr;‐cells, and >20% &dgr;‐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 &bgr;‐cells and &dgr;‐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 &dgr;‐cells strongly imply that an immature &dgr;‐cell profile contributed to the pathobiology of CHI‐A.

Clinical Diversity in Focal Congenital Hyperinsulinism in Infancy Correlates With Histological Heterogeneity of Islet Cell Lesions

Background: Congenital Hyperinsulinism (CHI) is an important cause of severe and persistent hypoglycaemia in infancy and childhood. The focal form (CHI-F) of CHI can be potentially cured by pancreatic lesionectomy. While diagnostic characteristics of CHI-F pancreatic histopathology are well-recognized, correlation with clinical phenotype has not been established. Aims: We aimed to correlate the diversity in clinical profiles of patients with islet cell organization in CHI-F pancreatic tissue. Methods: Clinical datasets were obtained from 25 patients with CHI-F due to ABCC8/KCNJ11 mutations. 18F-DOPA PET-CT was used to localize focal lesions prior to surgery. Immunohistochemistry was used to support protein expression studies. Results: In 28% (n = 7) of patient tissues focal lesions were amorphous and projected into adjoining normal pancreatic tissue without clear delineation from normal tissue. In these cases, severe hypoglycaemia was detected within, on average, 2.8 ± 0.8 (range 1–7) days following birth. By contrast, in 72% (n = 18) of tissues focal lesions were encapsulated within a defined matrix capsule. In this group, the onset of severe hypoglycaemia was generally delayed; on average 46.6 ± 14.3 (range 1–180) days following birth. For patients with encapsulated lesions and later-onset hypoglycaemia, we found that surgical procedures were curative and less complex. Conclusion: CHI-F is associated with heterogeneity in the organization of focal lesions, which correlates well with clinical presentation and surgical outcomes.