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Histopathology of Congenital Hyperinsulinism: Retrospective Study with Genotype Correlations

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Pediatric and Developmental Pathology

Abstract

The majority of the most severe cases of congenital hyperinsulinism (HI) are caused by defects in the β-cell adenosine triphosphate (ATP)-sensitive potassium channel and usually require pancreatectomy to control blood sugar levels. In contrast to the recent advances in understanding the pathophysiology and genetic bases of HI, the histologic classification of this condition remains controversial. A recent proposal to classify the HI pancreata into diffuse and focal forms has drawn much interest because of its relative simplicity and its good correlation with the genetic abnormalities. We undertook a retrospective study to determine whether this classification scheme could be applied to 38 pancreata resected for HI at our institution. We also obtained leukocyte genomic DNA from 29 cases and screened the exons of ABCC8 and KCNJ11 genes for the presence of mutations. Nineteen cases (50.0%) were histologically classified as diffuse HI and 14 cases (36.8%) were categorized as focal form. The mutational analysis revealed that 14 of the 16 diffuse cases analyzed had either homozygous or compound heterozygous mutations of ABCC8 or KCNJ11 and 7 of 10 focal cases had only the paternally inherited mutations, consistent with the previous observations. Two patients (5.3%) had normal pancreatic histology but had persistent hypoglycemia postoperatively, leaving the possibility of residual focal lesion. Three of 38 cases (7.9%) did not fit well into either diffuse or focal category. Two cases differed from the described pattern for the diffuse form in that the nuclear enlargement was confined to a single area of the pancreas. The other case had a focal lesion but β-cell nuclear enlargement was present in nonadjacent areas. Mutations for typical diffuse or focal HI were not identified in two of these three equivocal cases. We conclude from this study that nearly 90% of HI cases can be classified into either a diffuse or a focal form. However, a small percentage of cases represented a diagnostic challenge.

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Acknowledgements

This work was supported, in part, by grants from the National Institutes of Health (MO1 RR-00240, RO1 DK56268 (C.A.S.) and the American Diabetes Association Research Award (C.A.S.). We thank Carol Buckingham, Joanne Mauger, and Diana Rosini for their technical assistance.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA

    Mariko Suchi & Eduardo D. Ruchelli

  2. Department of Pediatrics, Division of Endocrinology/Diabetes, The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA

    Courtney MacMullen, Paul S. Thornton & Charles A. Stanley

  3. Department of Genetics, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA

    Arupa Ganguly

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  1. Mariko Suchi
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Correspondence to Mariko Suchi.

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Suchi, M., MacMullen, C., Thornton, P. et al. Histopathology of Congenital Hyperinsulinism: Retrospective Study with Genotype Correlations . Pediatr. Dev. Pathol. 6, 322–333 (2003). https://doi.org/10.1007/s10024-002-0026-9

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