ESPE Abstracts (2014) 82 P-D-1-1-182

Clinical and Histological Heterogeneity of Congenital Hyperinsulinism Due to Paternally Inherited Heterozygous ABCC8/KCNJ11 Mutations

Ved Bhushan Aryaa,b, Maria Guemesa,b, Azizun Nessaa, Syeda Alamb, Pratik Shaha,b, Clare Gilbertb, Senthil Senniappana,b, Sarah E Flanaganc, Sian Ellardc & Khalid Hussaina,b


aClinical and Medical Genetics Unit, UCL Institute of Child Health, London, UK; bLondon Centre for Paediatric Endocrinology, Great Ormond Street Hospital NHS Foundation Trust, London, UK; cInstitute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK


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 DOPA–PET 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 DOPA–PET CT scan in 3/18 children showed diffuse disease. The remaining 35 (67%) children were diazoxide unresponsive and either had PVS (7) or 18F DOPA–PET 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.