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An ABCC8 gene mutation and mosaic uniparental isodisomy resulting in atypical diffuse congenital hyperinsulinism

¹Departments of Endocrinology
³Histology
⁵Surgery, Great Ormond Street Hospital for Children NHS Trust and the Institute of Child Health, University College London WC1N 1EH
²Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
⁴Department of Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK

Objective: Congenital hyperinsulinism may be due to diffuse or focal pancreatic disease. The diffuse form is associated with an increase in the size of ß-cell nuclei throughout the whole of the pancreas and most commonly results from recessive K_ATP channel mutations. Focal lesions are the consequence of somatic uniparental disomy for a paternally inherited K_ATP channel mutation with enlargement of the ß-cell nuclei confined to the focal lesion. Some "atypical" cases defy classification and show pancreatic ß-cell nuclear enlargement confined to discrete regions of the pancreas. We investigated an atypical case with normal morphology within the tail of the pancreas but occasional enlarged endocrine nuclei in parts of the body and head.

Research Design and Methods: The KCNJ11 and ABCC8 genes encoding the K_ATP channel subunits and microsatellite markers on chromosome 11 were analysed in DNA samples from the patient and her parents.

Results: A mosaic ABCC8 nonsense mutation (Q54X) was identified in the proband. The paternally inherited mutation was present at 90% in lymphocytes, 50% in normal pancreatic sections but between 64 and 74% in abnormal sections. Microsatellite analysis showed mosaic interstitial paternal uniparental isodisomy for chromosome 11p15.1.

Conclusion: We report a novel genetic mechanism to explain atypical histological diffuse forms of congenital hyperinsulinism due to mosaic uniparental isodisomy in patients with dominantly inherited ABCC8 (or KCNJ11) gene mutations.

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