Hyperinsulinism in a child with an insulin gene variant. causative or co-INS-idence?

Louise Apperley; Zoe Yung; Kelly Cassidy; Sophie Lennon; Jayne Houghton; Sarah Flanagan; Joanne Blair; Poonam Dharmaraj; David Cullingford; Renuka Ramakrishnan; Senthil Senniappan; Mohammed Didi; Julie Park

doi:10.1530/endoabs.111.P131

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Endocrine Abstracts (2025) 111 P131 | DOI: 10.1530/endoabs.111.P131

BSPED2025 Poster Presentations Miscellaneous/Other 2 (9 abstracts)

Hyperinsulinism in a child with an insulin gene variant. causative or co-INS-idence?

Louise Apperley ¹ , Zoe Yung ¹ , Kelly Cassidy ¹ , Sophie Lennon ¹ , Jayne Houghton ² , Sarah Flanagan ³ , Joanne Blair ¹ , Poonam Dharmaraj ¹ , David Cullingford ¹ , Renuka Ramakrishnan ¹ , Senthil Senniappan ¹ , Mohammed Didi ¹ & Julie Park ¹

Author affiliations

¹Alder Hey Children’s Hospital, Liverpool, United Kingdom; ²Royal Devon and Exeter Foundation NHS Trust, Exeter, United Kingdom; ³University of Exeter Medical School, Exeter, United Kingdom

Introduction: The human insulin gene (INS) encodes pre-proinsulin, which is processed into the peptide hormone, insulin. Pathogenic INS variants classically lead to permanent neonatal diabetes (PNDM) with a few rare reports describing hyperinsulinaemia and insulin-resistant diabetes in adults. To our knowledge, INS variants have not been described to cause hyperinsulinaemic hypoglycaemia. We report a neonate with a pathogenic INS variant that is predicted to cause PNDM, but who instead presented with congenital hyperinsulinaemic hypoglycaemia.

Case Report: A term female infant (birth weight [BW] 4.5 kg) was admitted at 48-hours with poor feeding, lethargy, and hypothermia (32.9^oC). A hypoglycaemia screen with a plasma glucose 2.6 mmol/l showed insulin 149pmol /l, C peptide 884pmol /l, 3 hydroxybutyrate <100 µmol/l and free fatty acids <275 µmol/l confirming hyperinsulinaemia hypoglycaemia. She required a glucose infusion rate of 9.8 mg/kg/min and a glucagon infusion to maintain normoglycaemia. Mother had a normal antenatal oral glucose tolerance test. Father and paternal grandmother have diabetes mellitus. They were diagnosed at 5 and 3 years, respectively, with BW of 3.02 kg and 4.55 kg. Diazoxide (15 mg/kg/day) and Chlorothiazide (10 mg/kg/day) are required, with ongoing evidence of occasional hypoglycaemia down to 3.4 mmol/l at 9-weeks. Hyperglycaemia episodes have resolved with feed adjustments. Trio next generation sequencing performed within the national Generation Study, a broad research-based neonatal genomic screening programme, identified a heterozygous variant in the INS gene (c.188-31G>A, p.?) which has been confirmed. This variation is a well-established cause of PNDM. Routine diagnostic screening of the known congenital hyperinsulinism genes did not identify a second pathogenic variant.

Conclusion: This case highlights a novel observation between hyperinsulinaemic hypoglycaemia and a pathogenic INS variant. The mechanism is not fully understood, so a causative relationship cannot be confirmed. The variant was identified via an antenatal research study and the result became available following hospitalisation. Further research is required to establish whether this INS variant is causal, but these findings may potentially broaden the spectrum of INS-related disease to include hyperinsulinism. This would require further investigation including the identification of additional cases with a bi-phasic phenotype to establish causality. Our patient will be closely monitored as she is high risk of developing diabetes.