Molecular and Clinical Analysis of Japanese Patients with Persistent Congenital Hyperinsulinism: Predominance of Paternally Inherited Monoallelic Mutations in the KATP Channel Genes

Background: Preoperative identification of the focal form of congenital hyperinsulinism is important for avoiding unnecessary subtotal pancreatectomy. However, neither the incidence nor the histological spectrum of the disease is known for Japanese patients. Aims: The aim of the study was to elucidate the molecular and histological spectrum of congenital hyperinsulinism in Japan. Subjects: Thirty-six Japanese infants with persistent congenital hyperinsulinism were included in the study. Methods: All exons of the ATP-sensitive potassium channel (KATP channel) genes (KCNJ11 and ABCC8), the GCK gene, and exons 6 and 7 and 10–12 of the GLUD1 gene were amplified from genomic DNA and directly sequenced. In patients with KATP channel mutations, the parental origin of each mutation was determined, and the results were compared with the histological findings of surgically treated patients. In one of the patients with scattered lesions, islets were sampled by laser capture microdissection for mutational analysis. Results: Mutations were identified in 24 patients (66.7%): five in GLUD1 and 19 in the KATP channel genes. Sixteen had a paternally derived, monoallelic KATP channel mutation predictive of the focal form. In 10 patients who underwent pancreatectomy, the molecular diagnosis correctly predicted the histology, more accurately than [18F]-3,4-dihydroxyphenylalanine positron emission tomography scans. Three patients showed focal lesions that occupied larger areas of the pancreas. Preferential loss of the maternal allele was observed in these islets. Conclusion: The majority of the Japanese patients with KATP channel hyperinsulinism (84.2%) demonstrated paternally inherited monoallelic mutations that accurately predicted the presence of the focal form. Most of the Japanese patients with congenital KATP-channel hyperinsulinism have the focal form.