Endocrine Abstracts

Introduction: Persistent endogenous hyperinsulinemic hypoglycemia in neonates (congenital hyperinsulinism; CHI) is usually due to monogenetic gene variants affecting the insulin secretion. The genetic cause is known in about 50% of patients. We present a new variant within the short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADH) gene causing CHI in two cousins.

Methods: The cases of two patients with CHI are presented with a follow-up of >30 years.

Results/Case Reports: A 32-year-old man (patient 1) and his 30-year-old cousin (patient 2) with CHI were referred to the outpatient clinic for treatment. According to the pediatric notes, the first hospitalization was at day 17 after birth in patient 1 (apnea with cyanosis during breastfeeding) and at day 10 in patient 2 (muscular hypotonia and sucking weakness). The diagnosis of CHI was established in both patients during the first hospitalization. A therapy with Diazoxide was initiated. The growth charts of both patients documented a disproportionate increase in weight in relation to height in childhood and adolescence, mainly due to recurrent hypoglycemic events with snacking of carbohydrates. In adulthood, the frequencies of hypoglycemic episodes increased leading to the referral. The patients belong to consanguineous family.

Investigation: 1) A genetic analysis was performed in the ABCC8, KCNJ11 and HADH genes resulting in a novel homozygous pathogenic variant in the HADH gene (HADH-variant c.796G > T). The disease is autosomal recessive. 2) Based on the finding an acylcarnitine-profile was performed showing an increased plasma 3-OHButyryl-carnitine, consistent with a dysfunction of the HADH enzyme. 3) Histologically, CHI is associated with pancreatic nesidioblastosis, which can be focal, atypical or diffuse. We have previously shown that nesidioblastosis can be morphologically characterized by targeting GLP-1 receptors, which are overexpressed. Therefore, a GLP-1-receptor-PET/CT with ⁶⁸Gallium-DOTA-exendinwas performed showing significantly increased uptake in the whole pancreas in both patients compatible with a diffuse form of nesidioblastosis. A surgical procedure was, therefore, not a therapeutic option.

Therapy: Intermittent monitoring with continuous glucose monitoring system and a somatostatin analogue was administered in addition to Diazoxide resulting in a significant decrease in hypoglycemic events. Patient 1 lost 24 kg within 9 months due to a decrease in snacking.

Conclusion: ● A genetic work-up is mandatory in patients with CHI.

● The increased uptake of the GLP-1-receptor-PET/CT indicates an overexpression of GLP-1 receptor in this condition. The pathophysiological role of this finding is unclear.

● Therapy with Diazoxide and Octreotide has to be evaluated in adults with CHI and recurrent hypoglycaemias.