1 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 Paediatrics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Endocrinology research center, Paediatrics, Moscow, Russian Federation;4 Morozovskaya Pediatric Municipal Clinical Hospital, Endocrinology, Moscow, Russian Federation5 Russian Children's Clinical Hospital, Endocrinology, Moscow, Russian Federation6 Russian Children's Clinical Hospital, Abdomen surgery, Moscow, Russian Federation7 Endocrinology research center, Paediatrics, Moscow, Russian Federation8 M. F. Vladimirsky regional clinical institute, Hystopathology, Moscow, Russian Federation9 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU10 Paediatrics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
Congenital hyperinsulinism (CHI) is a heterogeneous disease in terms of clinical presentation, genetics and histology. Mutations in eight genes are known to be a cause of CHI, of which ABCC8, KCNJ11 and GCK are among the most common. We investigated genotype-phenotype associations in a cohort of Russian patients with CHI by clinical characterization and bidirectional direct sequencing of the ABCC8, KCNJ11 and GCK genes. 33 children were identified, of which 18 (54,5%) responded to the medical therapy (diazoxide and/or somatostatine) and 15 (45,5%) were resistant and underwent subtotal or partial pancreatectomy. Histological examination of the removed pancreatic tissue revealed 7 (47%) diffuse, 7(47%) focal, and 1 (6%) atypical form of CHI. Among medically responsive, 4 children (22%) spontaneously recovered during one year after the diagnosis. Mutations were found in 12 patients (36%); 4 (22%) of the medical responsive and 8 (53%) of the medical resistant patients, Table 1. Ten (83%) of the mutations were found in the KATP-channel genes ABCC8 and KCNJ11. The same heterozygous, novel ABCC8 mutation Q444H was seen in 4 unrelated families, causing medically resistant focal form in 3 patients and diazoxide responsive form in 1. GCK mutations were medical responsive, and resistant, respectively. There were no mutation carriers among children with spontaneously recovery. Table 1. Gentotype-phenotype correlation in patients with mutations detected ABCC8 KCNJ11 GCK Number of patients 8 2 2 Mutations found in medically responsive cases R74L hetz Q444H hetz A96T homoz V91L hetz, de novo Mutations found in medically resistant cases of focal forms Q444H hetz, paternal Q444H hetz Q444H hetz R841P hetz, paternal R136AfsX5 hetz, de novo - Mutations found in medically resistant cases of diffuse forms R998X hetz delF1387 hetz, de novo - Y241C hetz Hetz – heterozygous; homoz – homozygous Conclusion: A genetic cause was detected in 23%, and 53%, of children with mild, and severe CHI, respectively, in Russia. The ABCC8 mutation Q444H was prevalent and found in both medical responsive and resistant patient. Further genetic investigations are pending.