Congenital hyperinsulinism phenotypes, genotypes linked to response to therapy

medwireNews: Researchers have characterised the pathogenesis, prognosis, treatment, neurological sequelae and prevalence of congenital hyperinsulinism (CHI) in children born in Norway, finding genetic alterations to ABCC8 to be the most common cause of the condition.

The team reviewed medical records for children referred to the National Treatment Service of CHI at Haukeland University Hospital in Bergen between 2002 and 2023 with persistent hypoglycaemia unexplained by prematurity, gestational diabetes or prenatal stress.

Pål Njølstad (University of Bergen, Norway) and co-workers identified 98 children with suspected CHI; 21 of these cases were subsequently given a different diagnosis, such as idiopathic ketotic hypoglycaemia or syndromic hyperinsulinism.

The remaining 77 (79%) patients met the CHI diagnostic criteria of “persistent hypoglycemic episodes concurrent with detectable serum insulin or C-peptide”, the researchers say, after excluding cases of syndromic CHI, such as Sotos syndrome.

Among the patients diagnosed with CHI, 46 had a pathogenic or likely pathogenic genetic alteration, or a variant of uncertain significance, to one of seven genes that justified the diagnosis and 23 were diagnosed from clinical phenotype without confirmation of a genetic variant, giving 69 verified cases. There were eight patients who had some clinical features consistent with CHI but no genetic markers and their CHI diagnosis was classified as “uncertain”, the team says.

Forty of the patients with a genetic finding had an alteration to ABCC8, a gene encoding the beta-cell ATP-sensitive potassium channel, with 31 unique variants identified including five mutations that were previously unreported.

Generally, patients with an ABCC8 alteration had a severe phenotype with early disease onset, affecting 69% and 89% within 1 day and 1 week of birth, respectively, and only 24% of the 27 patients given diazoxide responded to treatment. However, patients with dominant inheritance of ABCC8 alterations were more likely to have a mild phenotype that responded to diazoxide than those with recessive or compound heterozygous inheritance, the researchers say.

One patient with an ABCC8 alteration also had a pathogenic variant in GCK that was considered the likely “underlying cause for disease,” while the ABCC8 alteration was thought to contribute to the patient’s “severe phenotype with unresponsiveness to medical treatment”, Njølstad et al comment.

The remaining patients had alterations to five other genes; the beta-cell ATP-sensitive potassium channel gene KCNJ11 (n=1), and four genes for enzymes that alter insulin secretion in the beta cell, GLUD1 (n=2), HADH (n=1), HK1 (n=1) and HNF4A (n=1). These patients had varying disease severity and response to treatment with diazoxide.

Patients with any identified genetic marker were significantly more likely to have disease onset within 1 week of birth than the 23 patients with verified CHI but no genetic diagnosis. Sixteen of the latter patients were given diazoxide and 11 were responsive, and three underwent subtotal pancreatectomy, two of whom developed diabetes and one had elevated glycated haemoglobin.

The investigators highlight that, overall, 43% of the 40 patients who were managed without surgery experienced phenotype resolution and none developed diabetes, leading them to recommend that “medical therapy should always be considered as a long-term treatment alternative” to surgery where feasible.

The team also reports that “[n]eurologic sequela was a recurrent characteristic” for patients with CHI. Of the 58 patients with neurological status available, 53% had one or more developmental delay, suspected or confirmed epilepsy, a concentration or learning disability, brain tissue damage, multifunctional disability, or visual or hearing impairment.

Children who developed neurological sequelae were three times more likely to have had seizures than those who did not (58 vs 19%) and although the rate of loss of consciousness was similar (21 vs 19%), four of the five children who experienced both seizures and loss of consciousness developed sequelae.

“Because we have not evaluated severity or length of the seizures, we speculate that those who had seizures without developing neurologic sequela had fewer, shorter, and milder seizures”, the researchers write. “Clinically, we stress the importance of avoiding seizures and unconscious episodes in patients with CHI.”

And although there was no association between subtotal pancreatectomy and likelihood of neurological sequela, they hypothesize that this may be due to “pancreatectomies being initiated after severe hypoglycemic episodes (and possibly seizures) have occurred, too late to prevent neurologic affection.”

Finally, Njølstad and co-authors estimate that the minimum prevalence of CHI in Norway between 2013 and 2022 was one case per 19,400 live births but suggest that this rate may be higher as they were unable to account for unidentified or misdiagnosed patients, affected relatives of the patients identified in the current study and those with syndromic CHI.

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

Citation(s)
J Clin Endocrinol Metabol 2024; doi:10.1210/clinem/dgae459
Martin Savage
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