Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations

in European Journal of Endocrinology
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  • 1 Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • | 2 Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, Oregon, USA
  • | 3 Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • | 4 Department of Radiology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • | 5 Department of Radiology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • | 6 Department of Surgery, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • | 7 Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  • | 8 Department of Pathology, , The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • | 9 Department of Genetics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

Correspondence should be addressed to D D De Leon; Email: deleon@chop.edu
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Objective

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI.

Design

The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined.

Methods

We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK).

Results

Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic.

Conclusion

These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
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