Congenital Hyperinsulinism

What is congenital hyperinsulinism (HI)?

Congenital hyperinsulinism (HI) is a genetic disorder in which the insulin cells of the pancreas, called beta cells, secrete too much insulin. Excess insulin causes low plasma sugar (hypoglycemia) or low blood sugar.

Ordinarily, beta cells secrete just enough insulin to keep the blood sugar in the normal range. In children with HI, the secretion of insulin is not properly regulated, causing excess insulin secretion and low blood sugar.

Low blood sugar can be very dangerous, because the brain needs a constant source of sugar. If the brain doesn't get the sugar it needs, it can lead to seizures, brain damage, and possibly death.

Congenital HI is a rare disease, affecting 1 in 25,000 to 50,000 babies. Since most children’s hospitals encounter only one or two cases a year, it is important to receive medical care from an experienced treatment center, such as the Congenital Hyperinsulinism Center at CHOP.

There are several forms of HI:

  • Diazoxide-Responsive and Diazoxide-Unresponsive Diffuse KATP HI: In diffuse KATP HI, potassium channels (named KATP channels) in the beta cell, which help regulate insulin secretion, do not work properly.
  • Focal KATP HI: For children with a KATP defect who have focal congenital HI, only an isolated or focal area of the pancreas is abnormal; the remainder of the pancreas is normal.
  • GDH-HI: In GDH-HI, excess insulin secretion causes low blood glucose with fasting or when the child eats protein. This form also causes higher ammonia levels and, in some people, may cause seizures.
  • Glucokinase HI: In glucokinase HI, the beta cells are not able to turn off insulin secretion when the blood glucose is too low.
  • HNF1a-HI and HNF4a-HI: These are rare forms of HI that progress to diabetes in adolescence and adulthood.
  • Exercise-induced HI: In this rare form of HI, exercise triggers insulin release, which results in low blood sugars
  • SCHAD-HI: SCHAD-HI is a type of HI caused by a very rare disorder of fatty acid metabolism.
  • UCP2-HI: UCP-2 HI is rare form of congenital HI that seems to be transient, meaning it is not a permanent condition, and eventually resolves over time.
  • FOXA2-HI: FOXA2 HI causes pituitary hormone problems in addition to HI.
  • LINE HI: Localized islet nuclear enlargement (LINE) HI is a rare form of HI caused by mosaic (not present in all cells) gene changes in the pancreas.
  • Syndromes That Include HI: Multiple genetic syndromes may also cause HI, including Beckwith-Wiedemann syndrome, Kabuki syndrome, Turner syndrome, Sotos syndrome, congenital disorders of glycosylation (types 1a and 1t) and Rubinstein-Taybi syndrome.

Causes of congenital hyperinsulinism (HI)

Congenital hyperinsulinism is caused by genetic mutations that result in inappropriate and excess insulin secretion from the beta cells of the pancreas. It is not related to anything that the mother did during pregnancy. Genetic testing can help to identify the cause of HI.

Symptoms of congenital hyperinsulinism (HI)

Congenital hyperinsulinism causes low plasma sugar (hypoglycemia).The symptoms of hypoglycemia in infants are often difficult to identify, as they can be similar to normal infant activities.

Common symptoms of hypoglycemia include:

  • irritability
  • sleepiness
  • lethargy
  • excessive hunger
  • rapid heart rate 

More severe symptoms, such as seizures and coma, can occur with a prolonged low plasma sugar or an extremely low plasma sugar. Common symptoms of hypoglycemia in older children include feelings of shakiness, weakness, tiredness, confusion, and rapid heart rate.

We consider a normal plasma sugar to be >70 mg/dL. Anything less than 60 mg/dL is low, although severe symptoms due to hypoglycemia are not likely unless the plasma sugar is less than 50 mg/dL. Prolonged or severe low plasma sugar can cause seizures and permanent brain damage. 

Diagnosis of congenital hyperinsulinism (HI)

The diagnosis of congenital hyperinsulinism is based on history, laboratory findings, and genetic testing. Prompt diagnosis and establishment of effective treatment are essential to avoid neurologic damage.


The history of the child is an important piece of the puzzle. This includes information such as when the low plasma sugars started, the timing of the low plasma sugars, whether the baby was born large for gestational age (LGA), any family history of low plasma sugar or unexplained infant deaths, seizures or SIDS.

Laboratory findings

Blood tests drawn when the plasma sugar is less than 50 mg/dL are essential to the diagnosis of HI. In congenital HI, with a plasma sugar < 50, you will see suppressed ketones and free fatty acids, an elevated insulin level (although this may not always be captured), and a glycemic response to glucagon, with the plasma sugar rising more than 30 mg/dL when glucagon is administered.

It is important that these samples at the time of a critically low plasma sugar be obtained in an experienced, controlled environment, as we do not want a child to be kept with a critically low plasma sugar longer than is absolutely necessary to make the diagnosis.

Genetic testing

The DNA from a blood sample from the child with congenital HI and each parent can be analyzed to screen for the mutations that cause the most common types of HI. This can be done at commercial laboratories and should be considered in any child suspected to have congenital HI. Contact us for more information on where to have this testing performed.

Treatment for congenital hyperinsulinism (HI)

Because congenital HI causes dangerously low blood sugars as a result of excess insulin, the treatment for this condition is to try and maintain blood sugars greater than 70 mg/dL. There are two options for treatment of congenital HI, medical therapy and surgical intervention. About 50 percent of children respond to medical therapy, while the other half require surgery for a partial or near total pancreatectomy.

Long-term outcomes for congenital hyperinsulinism (HI)

We are now tracking and compiling data on the long-term outlook for children with congenital hyperinsulinism. We know that with rapid diagnosis and appropriate treatment, keeping blood sugars >70 mg/dL, it is less likely that children with congenital HI will have long-term effects of hypoglycemia. With focal hyperinsulinism, 96.9 percent of children are cured with surgery.


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