Diagnosing congenital hyperinsulinaemic hypoglycaemia requires careful testing to identify when the pancreas is producing too much insulin, leading to dangerously low blood sugar levels. Early and accurate diagnosis is crucial to prevent brain damage and ensure children receive the right treatment.

Introduction: Who Needs Diagnostic Testing

Any infant or child who experiences repeated episodes of low blood sugar should be evaluated for congenital hyperinsulinaemic hypoglycaemia. This condition most commonly shows itself in the first month of life, with about 60 percent of affected babies experiencing symptoms during this early period.^[2] However, some children may not develop symptoms until early childhood, making it important to remain vigilant even beyond the newborn period.

Newborns and infants who should undergo diagnostic testing include those showing signs such as poor feeding, unusual tiredness or lethargy (a state of extreme drowsiness and lack of energy), irritability, difficulty feeding, or breathing problems. More serious warning signs include seizures (sudden, uncontrolled electrical disturbances in the brain that can cause jerking movements) or loss of consciousness.^[1] Because the brain relies heavily on glucose as its primary fuel source, prolonged or repeated episodes of low blood sugar can lead to permanent brain damage, making prompt diagnosis essential.

During physical examination, doctors may notice certain physical signs that suggest hyperinsulinism. These can include cardiomyopathy (a condition where the heart muscle becomes enlarged or weakened) and hepatomegaly (an enlarged liver).^[1] Parents should seek immediate medical attention if their baby exhibits any unusual symptoms, particularly if episodes of low blood sugar occur not only during fasting but also after eating, which is characteristic of this condition.^[2]

Classic Diagnostic Methods

The foundation of diagnosing congenital hyperinsulinaemic hypoglycaemia begins with blood tests performed when the child’s blood sugar is low. The key finding is plasma glucose levels below 54 mg/dL (or less than 3.5 mmol/L) along with detectable levels of insulin and C-peptide (a substance released when insulin is made, which helps confirm that the body is producing insulin).^[1] These measurements must be taken at the same time to accurately assess whether insulin levels are inappropriately high for the amount of glucose present in the blood.

When doctors test blood during a low blood sugar episode, they also look for suppressed or very low levels of ketone bodies (substances the body normally makes from fat when glucose is low) and free fatty acids (fats released into the bloodstream for energy).^[1] In healthy individuals, when blood sugar drops, the body responds by reducing insulin production and creating ketone bodies as an alternative fuel source for the brain. In children with hyperinsulinism, however, the excessive insulin prevents the formation of these alternative fuels, leaving the brain dependent solely on glucose and at greater risk of injury.

The specific pattern of test results helps doctors distinguish congenital hyperinsulinism from other causes of low blood sugar in children. The diagnosis is confirmed when blood tests show low glucose alongside inappropriately elevated insulin, C-peptide, and proinsulin levels, while ketone bodies remain suppressed.^[3] This combination of findings is characteristic of hyperinsulinism and helps rule out other metabolic disorders that might cause similar symptoms.

Genetic Testing

Genetic mutation testing has become a standard part of care for diagnosing congenital hyperinsulinism and determining the best treatment approach. Mutations in at least nine different genes can cause this condition, with changes in the ABCC8 gene being the most common known cause, accounting for approximately 40 percent of affected individuals.^[2] Mutations in the KCNJ11 gene are the next most frequent cause, while changes in other genes account for smaller percentages of cases.

Modern genetic testing methods can now provide results much faster than in the past, sometimes within just a few days. This rapid turnaround is crucial because treatment decisions often need to be made quickly for severely ill infants.^[3] The genetic test results help doctors predict whether a child will respond to certain medications and whether the condition affects the entire pancreas or just a small area that might be removed surgically.

In approximately half of people with congenital hyperinsulinism, genetic testing does not identify a specific cause, suggesting that additional genes involved in the condition have yet to be discovered.^[2] Even when genetic testing does not reveal a mutation, other diagnostic tests can still help determine the best treatment approach.

Imaging Studies

The gold standard for determining whether a child has the focal or diffuse form of hyperinsulinism is fluorine-18-dihydroxyphenyloalanine PET scanning, commonly called 18F-DOPA PET.^[1] This specialized imaging test helps doctors see which parts of the pancreas are overproducing insulin. In the focal form, only a small area of the pancreas is abnormal, while in the diffuse form, the entire pancreas is affected.

The 18F-DOPA PET scan is considered the gold standard for preoperative differentiation between focal and diffuse disease and for locating the exact position of a focal lesion if one is present.^[3] This information is vital for surgical planning because children with focal disease can potentially be cured by removing only the affected area of the pancreas, while those with diffuse disease may require removal of most of the pancreas if medications do not work.

Other specialized procedures, such as portal and pancreatic venous sampling or intra-arterial calcium stimulation, may be used in some centers to help distinguish between focal and diffuse forms of the disease.^[3] However, these procedures are more invasive and are generally used less frequently now that 18F-DOPA PET scanning is available. These tests involve inserting catheters into blood vessels and taking samples from specific locations or injecting substances to stimulate insulin release, then measuring the response.

Additional Diagnostic Considerations

Doctors also perform other tests to fully understand a child’s condition and rule out other possible causes of symptoms. These may include measuring blood sugar levels at different times throughout the day, assessing how long a child can go without food before blood sugar drops dangerously low, and monitoring response to feeding.

The estimated incidence of congenital hyperinsulinism is approximately 1 in 50,000 live births in most populations, though it can be more common in certain groups, affecting up to 1 in 2,500 newborns in some communities.^[2] This relative rarity means that many healthcare facilities may see only one or two cases per year, making it important for affected children to receive care at specialized centers with experience in diagnosing and treating this condition.

Diagnostics for Clinical Trial Qualification

When considering enrollment in clinical trials for congenital hyperinsulinism, additional diagnostic testing may be required to ensure that participants meet specific inclusion criteria. Clinical trials testing new treatments for this condition typically require documentation of confirmed hyperinsulinism through the standard diagnostic blood tests showing inappropriately elevated insulin levels during documented hypoglycemia.

Genetic testing results are often required for clinical trial enrollment, as many studies focus on specific genetic forms of the disease or aim to evaluate how different genetic mutations affect treatment response. Complete genetic analysis may be necessary to determine eligibility, particularly for trials testing medications designed to work on specific cellular mechanisms affected by particular gene mutations.

Imaging studies, particularly 18F-DOPA PET scans when available, may be required to classify participants as having either focal or diffuse disease. This classification is important because some clinical trials may specifically enroll only children with diffuse disease who have not responded to standard medications, while others may focus on different subgroups of patients.

Documentation of previous treatment attempts and responses is also typically required for clinical trial qualification. This includes records showing whether the child responded to first-line treatment with diazoxide, the standard medication for this condition, and whether second-line treatments such as octreotide (a medication that mimics a natural hormone to help reduce insulin secretion) were tried and their effectiveness.^[1] Clinical trials often focus on children whose condition has proven difficult to manage with existing medications.

Baseline measurements of blood sugar patterns, including how frequently low blood sugar episodes occur and how severe they are, may need to be documented before trial enrollment. This information helps researchers understand the severity of each child’s condition and measure whether new treatments provide improvement. Some trials may use continuous glucose monitoring devices to collect detailed information about blood sugar patterns over several days or weeks.

Assessment of neurological function may also be part of pre-trial screening. Because untreated or poorly controlled hyperinsulinism can lead to brain damage, clinical trials may include cognitive and developmental testing to establish baseline function. This allows researchers to monitor whether new treatments help prevent further neurological complications and potentially improve outcomes.