Background: Atypical forms of congenital hyperinsulinism in infancy (CHI-A) represent a novel subgroup of patients who present later in the neonatal period; have poor responses to medical intervention; an unremarkable histopathology and no known genetic cause of disease.
Objective and hypotheses: To compare the expression profiles of insulin and somatostatin in islets from patients with CHI-A, diffuse CHI (CHI-D) and age-matched control tissue.
Methods: CHI tissues were obtained following pancreatectomy, and control tissue following autopsy. CHI-D patients were positive for defects in ABCC8; CHI-A was not associated with defects in CHI-associated genes. Insulin- (INS+) and somatostatin-expressing cells (SOM+) were identified by immunohistochemistry and quantified following digitization of paraffin-embedded tissue samples; Ki67 is a marker of cell proliferation and NKX2.2 is a marker of cell fate determination in islets.
Results: We examined n=380 islets from CHI-A and compared to control and CHI-D islets. In CHI-A, 49.5% of the islets (n=188) had a quiescent profile associated with condensed cytoplasm, nuclear crowding and reduced numbers of centrally-located INS+ cells. In control and CHI-D, >90% of islets were composed of >70% INS+ cells and <20% SOM+ cells (n=91). In contrast, >70% of quiescent CHI-A islets had less than 30% INS+ cells and >65% had more than 20% SOM+ cells; with 30% of islets composed of >50% δ-cells (n=20). Surprisingly, quiescent islets had twofold higher rates of proliferation than unaffected islets from the same tissue, and >60% δ-cells were positive for NKX2.2; a transcription factor that was only present in a limited number of δ-cells in control islets.
Summary/conclusion: NKX2.2 maintains a β-cell phenotype and has a limited expression profile in δ-cells following birth. Marked increases in NKX2.2 expression in CHI-A δ-cells combined with increased numbers of SOM+ cells and rates of proliferation, strongly imply that an immature δ-cell profile contributes to the pathobiology of CHI.
Funding: National Institute of Health Sciences.
01 - 03 Oct 2015
European Society for Paediatric Endocrinology