ESPE Abstracts (2022) 95 P1-289

ESPE2022 Poster Category 1 Fetal, Neonatal Endocrinology and Metabolism (30 abstracts)

Novel Mutations in GLIS3/TRMT10a As A Cause Of Congenital Hyperinsulinism

Mansa Krishnamurthy 1 , Lily Deng 1 , Claudia Lozano 2 , Jonathan Kraus 3 & James Wells 1

1Cincinnati Children's Hospital Medical Center, Cincinnati, USA; 2Universidad de La Frontera, Temuco, Chile; 3Luis Calvo Mackenna Children´s Hospital, Santiago, Chile

Introduction: Congenital hyperinsulinism (CHI) is a heterogeneous group of disorders characterized by hypoglycemia and inappropriate insulin secretion. Prompt identification of CHI and its genetic causes are essential to minimize the risk of permanent neurological damage as well as guide treatment options for these patients. Although, there are 15 known monogenic forms of CHI, there remain 50% of patients without an identified genetic diagnosis, suggesting that there are genetic loci that remain yet to be discovered.

Case: We describe a 4 month old male presenting with new-onset seizures due to hypoglycemia. Lab evaluation was consistent with hyperinsulinism and a trial of diazoxide was pursued. He developed severe thrombocytopenia and was switched to octreotide and continuous feeds. A 98% pancreatectomy was performed and the resected pancreas was consistent with diffuse CHI.

Results: Targeted genetic evaluation was negative and whole exome sequencing of the patient and parents revealed a novel heterozygous mutation in GLIS3 (c.835G>A, p.Glu279Lys) and an extra copy of TRMT10a (entire coding sequence). Using the resected pancreas, we performed deep histological characterization to better understand changes in islet architecture and alterations in transcription factor expression profiles when compared to age matched islet controls. We observed a significant increase in insulin positive cells, along with an increase in polyhormonal cells expressing insulin/glucagon and insulin/somatostatin. Moreover, there was a reduction in pancreatic polypeptide expressing cells. Interestingly, we also observed an increase in ductal marker CK19 expression throughout all regions of the pancreas and increased co-expression of CK19 with single insulin positive cells consistent with nesidioblastosis. Proliferative index through Ki67 labelling was much higher in beta cells of the resected pancreas when compared to age matched controls. Finally, we observed a statistically significant increase in key beta cell transcription factors including FOXA2, PDX1 and NKX6.1.

Conclusion: For the first time, we demonstrate the connection between GLIS3/TRMT10a and CHI, expanding the list of known genetic causes. This case highlights the utility of whole exome sequencing in further identifying novel genetic causes for CHI and the benefits of deep histological characterization to better understand changes in islet architecture and gene expression.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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