ESPE Yearbook of Paediatric Endocrinology

In Brief: The authors review advances in our understanding of congenital hyperinsulinism (CHI), including newly described molecular mechanisms, new treatments, and improved understanding of long-term outcomes.

Comment: We apologise for the absence of the chapter on neonatal endocrinology in this year’s edition of the yearbook. It will be back next year! In the meantime, this review provides an excellent update on new advances in CHI, covering new molecular discoveries through to new treatments.

The authors reflect that while there are >20 genes known to cause CHI, its aetiology remains unknown in >20% of all cases, and in ~50% of diazoxide-responsive CHI cases. This year mutations in the gene HK1 encoding hexokinase were discovered by whole genome sequencing (see paper 13.8 in this chapter). Other recent studies reported mutations in SLC25A36 as a cause of the CHI-hyperammonemia phenotype, characterized by both fasting and protein-induced hypoglycemia and persistent hyperammonemia (1). SLC25A36 encodes a carrier that transports pyrimidine and guanine nucleotides across the inner mitochondrial membrane. Uridine supplementation was given to one child, resulting in improved glycemic control and also normalized thyroid function and growth.

There have been advances in CHI imaging. Current best practice in multidisciplinary hyperinsulinism centres is ¹⁸F-DOPA PET/CT, which has >90% sensitivity to detect focal pancreatic lesions. However, more accurate imaging would potentially allow even more cases to be treated by surgery. There is promising data that 68Ga-NODAGA-exendin-4 PET/CT imaging may have even greater sensitivity and at lower radiation doses.

Continuous glucose monitoring (CGM) is a promising management tool. However despite its large evidence base in patients with type 1 (see paper 13.5 in this chapter) and type 2 diabetes, its use in CHI is still limited to small case series, and reliable detection of hypoglycemia appears more challenging than detection of hyperglycemia (2).

Diazoxide remains the only FDA approved medication for the treatment of CHI, 40 years after its first reported use. A recent paper describes that lanreotide, a synthetic version of somatostatin, significantly improved fasting tolerance and 42% of this large series of 58 CHI patients were able to discontinue other CHI treatments (3). New potential treatments in the testing pipeline include a soluble Glucagon analogue, a GLP-1 receptor antagonist, and an allosteric inhibitor of the insulin receptor.

Reference: 1. Shahroor MA, Lasorsa FM, Porcelli V, et al. PNC2 (SLC25A36) deficiency associated with the hyperinsulinism/hyperammonemia syndrome. J Clin Endocrinol Metab 2022; 107:1346–1356. 2. Worth C, Dunne MJ, Salomon-Estebanez M, et al. The hypoglycaemia error grid: a UK-wide consensus on CGM accuracy assessment in hyperinsulinism. Front Endocrinol (Lausanne) 2022; 13:1016072. 3. Cuff H, Lord K, Ballester L, et al. The use of lanreotide in the treatment of congenital hyperinsulinism. J Clin Endocrinol Metab 2022; 107:e3115–e3120.