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 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 quantify the proportions of insulin-secreting β-cells and somatostatin-secreting δ-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, 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 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 β-cells and δ-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 δ-cells strongly imply that an immature δ-cell profile contributed to the pathobiology of CHI-A.

Therapies and outcomes of congenital hyperinsulinism‐induced hypoglycaemia

“…Importantly, atypical CHI has not been associated with any known genetic cause [29,30]. Here, mosaic patterns of hyperfunctioning islets are present with islands of apparently normal-appearing islets.…”

“…Although atypical CHI has been described in several papers, there is no agreement on its clinical, biochemical and histological characteristics. Importantly, atypical CHI has not been associated with any known genetic cause [29,30].…”

Update of variants identified in the pancreatic β‐cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes

“…Rarely, giant focal lesions have been described where virtually the whole of the pancreas is affected (Ismail et al, 2012). Atypical mosaic disease has also been reported in a small number of cases (Han et al, 2017; Houghton et al, 2019; Hussain et al, 2008; Sempoux et al, 2011).…”

Complexities in the medical management of hypoglycaemia due to congenital hyperinsulinism

“…Diffuse CHI implies a specific histopathological phenotype with a higher frequency of islet cells with enlarged, often misshapen nuclei, nucleomegaly and foamy cytoplasm spread throughout the pancreas . There have also been some descriptions of mosaic phenotypes . However, practically the term diffuse CHI is used to indicate nonfocal CHI where medical therapy should be prioritized over pancreatic surgery where possible.…”

“…In β‐cells, these are thought to be coupled to different elements of stimulus secretion coupling mechanisms including the activation of voltage‐dependent K + channels, inhibition of voltage‐dependent Ca 2+ channels and lowering the intracellular concentration of cAMP. The paracrine regulation of glucagon and insulin release by somatostatin is physiologically important as decreased numbers of δ‐cells and immature δ‐cell profiles have been associated with the pathology of CHI.…”