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

• Published in: The journal of clinical endocrinology and metabolism 2017-09, Vol.102 (9), p.3261-3267
• Main Authors: Han, Bing, Mohamed, Zainab, Estebanez, Maria Salomon, Craigie, Ross J, Newbould, Melanie, Cheesman, Edmund, Padidela, Raja, Skae, Mars, Johnson, Matthew, Flanagan, Sarah, Ellard, Sian, Cosgrove, Karen E, Banerjee, Indraneel, Dunne, Mark J
• Format: Article
• Language: English
• Subjects: Biopsy, Needle; Child, Preschool; Clinical s; Cohort Studies; Congenital diseases; Congenital Hyperinsulinism - genetics; Congenital Hyperinsulinism - pathology; Congenital Hyperinsulinism - surgery; Cytoplasm; Dehydrogenases; Female; Genetic Predisposition to Disease; Humans; Hyperplasia; Hypoglycemia; Immunohistochemistry; Infant; Insulin; Islet cells; Islets of Langerhans; Islets of Langerhans - pathology; Islets of Langerhans - secretion; Male; Mosaicism; Mutation; Nkx2.2 protein; Nuclear Proteins - genetics; Pancreas; Pancreatectomy - methods; Patients; Prognosis; Reference Values; Severity of Illness Index; Somatostatin; Surgery; Thyroid Nuclear Factor 1; Tissues; Transcription factors; Transcription Factors - genetics
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2017-00158

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 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. Atypical forms of congenital hyperinsulinism in infancy were found to be associated with a mosaic profile of immature islet cells. This was directly related to the altered expression of NKX2.2.