Congenital Hyperinsulinism Due to a Novel Activating Glucokinase Mutation: A Case Report and Literature Review

Background: Congenital Hyperinsulinism (CHI) constitutes a major cause of persistent and recurrent hypoglycemia, especially in the neonatal period, showing notable phenotypical heterogeneity among affected subjects. Activating mutations of the Glucokinase gene (GCK) are responsible for mild forms of hypoglycemia, due to CHI, usually easily medically managed. Case report: We present a patient at the age of 3.5 years old investigated for persistent hypoglycemia. Laboratory evaluation showed hyperinsulinism during the hypoglycemic episode with a required glucose infusion rate greater than 8-10 mg/kg/min to maintain normoglycemia. Targeted gene panel sequencing revealed an activating missense novel mutation p.Val71Ala in exon 3 of GCK gene, dominantly inherited by his mother. In silico, analysis of this novel missense variant assessed its pathogenicity as being of uncertain significance Conclusions: GCK gene mutations result in varying phenotypic characteristics and responsiveness to diazoxide depending on the type of activating mutation.

Raised blood glucose due to heterozygous glucokinase gene mutation (GCK-MODY) diagnosed for the first time in pregnancy: The dilemmas and successful management – Case report and review of literature

Glucokinase mutation (GCK-MODY) is frequently misdiagnosed as either type I or type II diabetes mellitus, especially if presented for the first time during pregnancy. Generally GCK-MODY affects 1–2% of individuals with a diagnosis of diabetes. The defect in the glucose sensing mechanism in GCK-MODY results in a higher set point for maintenance of glucose homeostasis. Treatment is not recommended outside the pregnancy; however, in pregnancy, fetal abdominal circumference helps to decide about the likelihood of the fetus having inherited the condition and therefore whether insulin is required in pregnancy. We present a case in which GCK-MODY was diagnosed for the first time after pregnancy; the subsequent pregnancy was uneventful. Genetic testing is mandatory to establish the diagnosis. Here the implications of MODY and its subtypes, along with the pattern of inheritance and management aspects are discussed.

Adult-onset hyperinsulinaemic hypoglycaemia in clinical practice: diagnosis, aetiology and management

Objective In adults with hyperinsulinaemic hypoglycaemia (HH), in particular those with insulinoma, the optimal diagnostic and management strategies remain uncertain. Here, we sought to characterise the biochemical and radiological assessment, and clinical management of adults with HH at a tertiary centre over a thirteen-year period. Design Clinical, biochemical, radiological and histological data were reviewed from all confirmed cases of adult-onset hyperinsulinaemic hypoglycaemia at our centre between 2003 and 2016. In a subset of patients with stage I insulinoma, whole-exome sequencing of tumour DNA was performed. Results Twenty-nine patients were identified (27 insulinoma, including 6 subjects with metastatic disease; 1 pro-insulin/GLP-1 co-secreting tumour; 1 activating glucokinase mutation). In all cases, hypoglycaemia (glucose ≤2.2 mmol/L) was achieved within 48 h of a supervised fast. At fast termination, subjects with stage IV insulinoma had significantly higher insulin, C-peptide and pro-insulin compared to those with insulinoma staged I–IIIB. Preoperative localisation of insulinoma was most successfully achieved with EUS. In two patients with inoperable, metastatic insulinoma, peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE rapidly restored euglycaemia and lowered fasting insulin. Finally, in a subset of stage I insulinoma, whole-exome sequencing of tumour DNA identified the pathogenic Ying Yang-1 (YY1) somatic mutation (c.C1115G/p.T372R) in one tumour, with all tumours exhibiting a low somatic mutation burden. Conclusion Our study highlights, in particular, the utility of the 48-h fast in the diagnosis of insulinoma, EUS for tumour localisation and the value of PRRT therapy in the treatment of metastatic disease.