Congenital Hyperinsulinism: Current Laboratory-Based Approaches to the Genetic Diagnosis of a Heterogeneous Disease

Abstract

Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in isolation, or present as a feature of syndromic disease. Establishing the underlying aetiology of the hyperinsulinism is critical for guiding medical management of this condition especially in children with diazoxide-unresponsive hyperinsulinism where the underlying genetics determines whether focal or diffuse pancreatic disease is present. Disease-causing single nucleotide variants affecting over 30 genes are known to cause persistent hyperinsulinism with mutations in the KATP channel genes (ABCC8 and KCNJ11) most commonly identified in children with severe persistent disease. Defects in methylation, changes in chromosome number, and large deletions and duplications disrupting multiple genes are also well described in congenital hyperinsulinism, further highlighting the genetic heterogeneity of this condition. Next-generation sequencing has revolutionised the approach to genetic testing for congenital hyperinsulinism with targeted gene panels, exome, and genome sequencing being highly sensitive methods for the analysis of multiple disease genes in a single reaction. It should though be recognised that limitations remain with next-generation sequencing with no single application able to detect all reported forms of genetic variation. This is an important consideration for hyperinsulinism genetic testing as comprehensive screening may require multiple investigations.

Congenital hyperinsulinism – Case report

“…Congenital hyperinsulinism (CH) is a rare disease, characterized by a group of clinical, genetic and morphological disorders that occur with inappropriate insulin secretion by pancreatic β cells (DEMIRBILEK et al, 2017;ROŽENKOVÁ et al, 2015); affects about 1 in every 30,000 to 50,000 live births (SBP, 2022), but in some isolated communities where founder mutations have been reported, and in populations with high rates of consanguinity, the incidence can increase to approximately 1 in every 3,000 live births ( HEWAT, JOHNSON and FLANAGAN, 2022). It is the most common cause of persistent and severe neonatal hypoglycemia in early childhood (BANERJEE et al, 2018;SBP, 2022).…”

Congenital Hyperinsulinaemic Hypoglycaemia—A Review and Case Presentation

“…It should be considered in diazoxide-unresponsive cases before performing (18)F-DOPA PET. The biallelic or single dominant K ATP channel disease-causing variant confirms the diffuse form of HH, while a paternally inherited recessive K ATP channel variant is linked to the focal form with a sensitivity of 97% [ 15 , 16 , 17 ].…”

KATP channel mutations in congenital hyperinsulinism: Progress and challenges towards mechanism-based therapies

“…Severe cases show symptoms of hypoglycemia early in the neonatal life, while milder forms are usually diagnosed later in infancy or childhood with recurrent attacks of hypoglycemia, which manifest following prolonged fasting or other health stress. CHI was first named as “idiopathic hypoglycemia of infancy” ( 5 ), which is no longer used after many genetic causes of the disease have been identified ( 6 , 7 ). It was also once referred to as “nesidioblastosis” based on an early suggestion that the increased insulin secretion is secondary to budding of pancreatic islets observed in histological samples from patients with CHI ( 8 ).…”

“…Another discontinued historical term is persistent hyperinsulinemic hypoglycemia of infancy or PHHI, as it is now understood that the disease can be neonatal, infantile or childhood and can persist to adulthood ( 11 ). In addition to prototypical CHI, hyperinsulinism can be a pathology of a syndromic disease, including Beckwith-Wiedemann syndrome, Perlman syndrome, Kabuki syndrome, Turner syndrome, Sotos syndrome, and others ( 7 , 12 ).…”