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

OBJECTIVE Congenital hyperinsulinism (CHI) may be due to diffuse or focal pancreatic disease. The diffuse form is associated with an increase in the size of beta-cell nuclei throughout the whole of the pancreas and most commonly results from recessive ATP-sensitive K(+) channel (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 beta-cell nuclei confined to the focal lesion. Some "atypical" cases defy classification and show pancreatic beta-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 analyzed 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 and 50% in normal pancreatic sections but between 64 and 74% in abnormal sections. Microsatellite analysis showed mosaic interstitial paternal uniparental isodisomy (UPD) for chromosome 11p15.1. CONCLUSIONS We report a novel genetic mechanism to explain atypical histological diffuse forms of CHI due to mosaic UPD in patients with dominantly inherited ABCC8 (or KCNJ11) gene mutations.