Nesidioblastosis is the most common cause of persistent hypoglycaemia in neonates. It is characterized by inappropriately high levels of serum insulin, C-peptide, and proinsulin. In HHF2, this defective regulation of insulin secretion is caused by the abnormal function or regulation of the ATP-dependent potassium (K_ATP) channel of the pancreatic beta cells. The disorder can be of 2 types: a diffuse form, caused by beta cell abnormality spread throughout the pancreas, and the focal form of HHF2 with clusters of nodular hyperplasia.

While the global incidence of Nesidioblastosis is 1 in 50,000 individuals, in Saudi Arabia it has been found to affect 1 in 2675 live births. It is a congenital disorder and depending on severity, may present in the early days of infancy or early childhood. Infants with HHF2 are large for their gestational age and exhibit islet cell hyperplasia. Symptoms may also include jitteriness, lethargy, cyanosis, seizures, hypotonia, poor feeding and apnea. Recurrent episodes of prolonged sublethal hypoglycemia can result in permanent neurological damage, including developmental delay and mental retardation.

Diagnosis can be made based on elevated serum insulin levels with low serum ketone bodies and an increased glucose response to glucagon administration. Treatment involves dietary interventions and the administration of beta cell potassium channel agonists such as diazoxide. Patients unresponsive to medication may require a partial pancreatectomy to resolve their persistent hypoglycaemia.

HHF2 is caused by mutations in the KCNJ11 gene that encodes the Kir6.2 subunit of the ATP sensitive, inward rectifier potassium ion channel. Mutations can result in deficiency of the protein, failure of the protein to be incorporated into the plasma membrane or failure to respond appropriately to ATP signals.

While HHF2 has generally been shown to follow an autosomal recessive pattern of inheritance, rare autosomal dominant forms have also been reported. Focal forms of the disorder have been found to occur due to a paternally inherited mutation and loss of the normal maternal allele in hyperplastic regions of the pancreas.