Congenital hyperinsulinism (CHI) results from inappropriate insulin secretion most commonly caused by mutations in the ABCC8 and KCNJ11 genes which encode for the pancreatic β-cells-ATP-sensitive-potassium channel (KATP) subunits SUR1 and KIR6.2 respectively. Diagnosis of CHI is based on the presence of detectable plasma insulin during hypoglycemia, suppressed β-hydroxybutyrate and NEFA. Diazoxide is the major treatment for CHI, sirolimus had also been used. Focal/diffuse disease are differentiated by 18F-DOPA-PET-CT scanning. In the former a lesionectomy can resolve hyperinsulinism. Monoallelic recessively-acting ABBCC8/KCNJ11 mutations predict focal disease with 6997% sensitivity. Within a focal lesion uniparental disomy unmasks the paternal mutation. Objective: To report a retrospective series of 8 patients with CHI, describing clinical outcome, laboratory, genetic an 18F-DOPA-PET-CT findings.
Materials and methods: A clinical diagnosis was made in the presence of glucose<50 mg/dl (2.8 mmol/l), with detectable plasma insulin. Transient and syndromic forms were excluded. Age, laboratory results, response to treatment, side effects, ABCC8/KCNJ11 sequencing and 18F-DOPA-PET-CT results were recorded. Response to diazoxide was considered positive if normoglycemia was maintained after 6 hours of fast (maximum dose of 15 mg/kg per day).
Results: Eight patients presented with hypoglycemia (640 mg/dl), within 648 hours of life (except one detected at 5 months). Maximum glucose infusion rate required was: 821 mg/kg minutes. Laboratory during hypoglycemia: insulin: 560.6 uUI/l, β-hydroxybuturate: 0.070.30 mmol/l(NV:0.030.35), NEFA:0.130.5 mmol/l (NV:0.10.9), normal ammonia. Four patients responded to diazoxide, one presented with fluid retention. One patient treated with sirolimus presented persistent diarrhea, vomiting without improvement in glucose levels. Six patients had 18F-DOPA-PET-CT evaluation, 4 had diffuse and 2 had focal disease. ABCC8 mutations were detected in 6 of 8 patients; 3 of the 4 diazoxide-responsive patients and 3 of the 4 diazoxide-unresponsive. Two diazoxide-unresponsive patients had a monoallelic recessive ABCC8 mutation; one had focal disease whereas the other had diffuse disease. In the later LOH of pancreatic DNA to exclude a giant focal lesion was not performed. In one patient with focal disease analysis of leukocyte DNA did not identify a mutation, although a somatic mutation within the pancreas was not excluded. Hypoglycemia was not detected in patients with focal disease after the surgical remove of the lesion, whereas incidental hypoglycemia was found in patients under medical treatment.
Conclusions: The small pancreatic resection guided by 18F-DOPA-PET-CT in the focal disease allowed normal blood glucose homeostasis. Patients receiving medical treatment should maintain long-term surveillance to avoid hypoglycemia.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology