Endocrine Abstracts

JOINT3300

Introduction: In cases of hypoketotic hypoglycemia mimicking hyperinsulinism, pathogenic variants in post-receptor signaling cascades lead to autonomous activation of insulin signaling in target tissues, causing severe hypoglycemia with low or undetectable insulin. This report highlights the challenges in diagnosis and management of hypoinsulinemic hypoketotic hypoglycemia (HHH) and discusses available treatment options.

Case Report: A male neonate was born at 33 weeks gestation to non-consanguineous parents, with a weight of 2440 g (+2.2 SDS), mild dysmorphic features and a cleft palate. A capillary blood glucose (BG) on day 12 was 29 mg/dL and a critical blood sample taken during this hypoglycemic episode revealed serum glucose of 32mg/dL, insulin of 0.65mIU/l, c-peptide of 0.285ng/ml, ketones of 0.2mmol/l and adequate counter-regulatory hormone levels (cortisol 21.9µg/dL, growth hormone 10.9µg/L). Glucagon elicited glucose response without lactate elevation. The patient exhibited cyclical hypo/hyperglycemic episodes during 2-hourly feeding with continuous glucose-monitoring (27-383 mg/dL; time in 55-140 mg/dL range: below 4% and above 9%). Persistent hypoglycemia despite a glucose infusion rate (GIR) of up to 8 mg/kg/min required diazoxide and hydrochlorothiazide. Hypoglycemia persisted despite GIR of 17 mg/kg/min, suggesting diazoxide unresponsiveness. Despite treatment including methylprednisolone (2 mg/kg/day), octreotide (40 mg/kg/day), nifedipine (4x100 mg/kg/dose) and glucagon infusion (1 mg/kg/hour), hypo/hyperglycemia cycling persisted, necessitating continuous nasogastric feeding and octreotide by pump, successfully stabilizing BG. Rapid genetic testing for ABCC8 and KCNJ11 variants at Exeter were unremarkable. Next-generation sequencing analysis for ABCC8, AKT2, CACNA1C, CACNA1D, CREBBP, DNTTIP1, EP300, FOCAD, FOXA2, GCK, GLUD1, GPC3, HADH, HNF1A, HNF4A, INSR, KCNJ11, KDM6A, KMT2D, MAFA, MAGEL2, NSD1, PHOX2B, PMM2, RNF10, SLC16A1, TRMT10A, and HK1 variants were also unremarkable. Whole exome sequencing re-analysis for hypoglycemia-associated conditions has been initiated. On continuous feeding at three months old the baby had an episode of hypoglycemia (48.9 mg/dL) with concurrent insulin <0.04 mIU/L and c-peptide 0.03 ng/ml confirming HHH. The patient died due to septic shock from complications of influenza pneumonia.

Discussion and Conclusion: HHH is a rare and heterogeneous disorder that can clinically resemble congenital hyperinsulinism (CHI) or other metabolic diseases and may be misdiagnosed, as in this case\. Pathogenic variants in the phosphoinositide-3-kinase (PI3K)-AKT-mTOR signaling cascade, have been implicated in HHH, and should be considered in cases of CHI with low measurable insulin levels. Continuous feeding systems, which have demonstrated efficacy in recent reports of HHH ultimately achieved euglycemia in the presented case, although the mTOR inhibitor, sirolimus, has also been effective in some cases.