Context: Congenital hyperinsulinism (CHI) has two main histological types diffuse and focal. Diffuse CHI is due to recessive or dominant mutations in ABCC8/KCNJ11. Focal disease is due to somatic maternal allele loss of 11p15 in pancreatic β-cells along with paternally inherited germline ABCC8/KCNJ11 mutation. Fluorine-18 L-3, 4-dihydroxyphenylalanine positron emission tomography computerized tomography (18F DOPAPET CT) scan and pancreatic venous sampling (PVS) can differentiate the two subtypes. Heterozygous paternally inherited ABCC8/KCNJ11 mutations (depending upon whether recessive or dominant acting and occurrence of somatic maternal allele loss) can give rise to variable phenotype.
Objective: To describe the variable clinical phenotype observed in CHI patients due to heterozygous paternally inherited ABCC8/KCNJ11 mutations.
Design: A retrospective case-notes review of the children diagnosed with CHI due to heterozygous paternally inherited ABCC8/KCNJ11 mutations from 2000 to 2013 was conducted.
Results: During this period, paternally inherited heterozygous ABCC8/KCNJ11 mutations were identified in 53 patients. Of these, 18 (34%) either responded to diazoxide or resolved spontaneously. 18F DOPAPET CT scan in 3/18 children showed diffuse disease. The remaining 35 (67%) children were diazoxide unresponsive and either had PVS (7) or 18F DOPAPET CT (28) to differentiate between focal and diffuse disease. Diffuse disease was found in 12 (23%) and focal disease in 22 (42%) patients. Differentiation between focal and diffuse disease was not possible in one patient studied by PVS. No recurrence of hypoglycaemia was noticed in 95% (20/21) patients with focal CHI after removal of the focal lesion. Diazoxide-unresponsive diffuse CHI patients were managed with either near-total pancreatectomy (9) or octreotide therapy (3).
Conclusions: Paternally inherited heterozygous ABCC8/KCNJ11 mutations can manifest as a wide spectrum of CHI with variable PET/histological findings and clinical outcomes. Focal CHI patients were completely cured after surgery.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology