Every day, researchers learn more about congenital hyperinsulinism (HI) and how to improve care for children and families living with this condition. We’re highlighting five studies from our team here at Children's Hospital of Philadelphia (CHOP) that are helping families better understand the genetics, biology and long-term outcomes of HI.

Understanding Life with Hyperinsulinism Hyperammonemia (HI/HA)

A new study led by Dr. Elizabeth Rosenfeld and the Congenital Hyperinsulinism Center here at CHOP looked at children and adults with hyperinsulinism hyperammonemia syndrome (HI/HA), a rare form of HI caused by changes in the GLUD1 gene. By combining medical record review with information directly shared by families through patient registries, researchers were able to better understand how this condition affects people over time.

The study found that many individuals continue to need treatment well beyond infancy, often into adolescence or adulthood. Researchers also found that learning differences, attention challenges and neurologic concerns may occur even when blood sugar is being managed.

What does this mean for patients and families?

HI/HA is often more than just a blood sugar condition. Ongoing developmental, neurological and educational support may be an important part of long-term care. This study also highlights how powerful family participation in research can be.

Research takeaway

Long-term follow up matters and family voices are helping shape the future of care.  

Why Does Beckwith-Wiedemann Syndrome Cause Hyperinsulinism?

Children with Beckwith-Wiedemann syndrome (BWS) sometimes develop severe HI, but doctors have not fully understood why. In this new study from the De León-Crutchlow Laboratory, led by Dr. Christine Juliana, researchers examined pancreatic tissue from children with BWS who needed surgery for severe hypoglycemia.

They found that insulin-producing cells in the pancreas can become overactive and release insulin too easily. The study also identified changes in genes that may help explain why some children with BWS develop severe low blood sugars.

What does this mean for patients and families?

This research gives us a better understanding of what is happening inside the pancreas in BWS. Over time, these discoveries may help doctors develop more personalized treatment approaches.

Research takeaway

Understanding what is happening inside the pancreas at a cellular level may lead to more personalized (targeted) therapies.

Finding Hidden Genetic Causes: The HK1 Story

Some families are told that genetic testing did not identify a cause for their child’s HI (genetics negative cases). In a new study from the De León-Crutchlow Laboratory, led by Kara Boodhansingh, our team found that hidden changes in a gene called HK1 may explain some of these previously genetics-negative cases.

Researchers identified HK1-related changes in about 6% of patients without a prior genetic diagnosis. Some children had mild diseases that responded well to medication, while others had more severe forms requiring surgery.

What does this mean for patients and families?

More advanced genetic testing may provide answers for families who previously didn't have them. A genetic diagnosis can help guide treatment decisions and provide important information for other family members.

Research takeaway

Sometimes the answer is there—it just takes better tools to find it.

When Focal and Diffuse HI Happen Together

Doctors usually classify HI as either affecting one small area of the pancreas (focal) or the entire pancreas (diffuse). In a surprising new report written by our HI genetic counselor, Victoria Sanders, and colleagues, we described children who had both types simultaneously.  

After surgery to remove the focal lesion, some children continued to have low blood sugars because diffuse disease was also present. Fortunately, many responded well to medication after surgery.

What does this mean for patients and families?

If children continue to experience low blood sugar levels after focal surgery, it does not always mean the surgery “didn’t work.” Some children may have a more complex form of HI that still responds well to medical treatment.

Research takeaway

HI can be more complex than expected and personalized care remains essential.

Predicting HI Severity in Beckwith-Wiedemann Syndrome

In the largest study of its kind, a multidisciplinary team of physicians and scientists from the Beckwith-Wiedemann and Overgrowth Genetics Clinic and the Congenital Hyperinsulinism Center at CHOP studied 85 children with both BWS and HI to understand why some children have mild disease while others require surgery.

The team found that certain genetic patterns were strongly associated with more severe HI and a reduced response to medications such as diazoxide.

What does this mean for patients and families?

Genetic testing may help predict how severe a child’s HI may become and whether medical treatment is likely to work. This could help families and care teams make treatment decisions earlier.

Research takeaway

Genetics may help predict the road ahead and guide earlier, more personalized care.

Looking Ahead

Research like this brings us closer to a future where every child with congenital HI receives care tailored to their specific biology, genetics and family needs. To the patients and families who participate in research studies, share your stories, and contribute to patient registries – thank you. Your partnership is helping move the field forward!

Articles reviewed

1. Rosenfeld E, Taylor O, Mitteer LM, Boodhansingh KE, Pasquini TLS, Raskin J, Rafferty D, Thornton PS, De León DD (2026). Natural history of the hyperinsulinism hyperammonemia syndrome – a retrospective review incorporating patient-centered data. Hormone Research in Paediatrics. DOI: 10.1159/000551535.  
2. Juliana CA, Li C, Chai J, Boodhansingh KE, Mitteer LM, Kalish JM, Bhatti TR, Adzick NS, De León DD (2026). Functional evaluation of pancreatic islets from patients with Beckwith-Wiedemann syndrome and congenital hyperinsulinism. Journal of Endocrine and Metabolism. DOI: 10.1210/clinem/dgag050.  
3. Boodhansingh KE, Lord K, Sigal L, Benjet JE, Chen P, Juliana CA, Mitteer LM, Bhatti T, Stanley CA, De León DD, Ganguly A (2026). Non-coding variants in intron 2 of HK1 associated with hyperinsulinism with variable clinical phenotype. Journal of Endocrine and Metabolism. DOI: 10.1210/clinem/dgag108.  
4. Sanders VR, Lord K, Sigal W, McKnight H, Wilkinson E, Mitteer LM, Boodhansingh KE, Adzick NS, States LJ, Bhatti T, De León DD (2026). Double trouble: When focal and diffuse hyperinsulinism occur simultaneously. Hormone Research in Paediatrics. DOI: 10.1159/000550909.  
5. George AM, Viswanathan A, Sussman JH, Hathaway ER, Casalnova A, Nesbitt S, Boodhansingh KE, Stewart NM, McKnight HJ, Lord K, De León DD, Stanley CA, Adzick NS, Ganguly A, Kalish JM. Determinants of Hyperinsulinism Severity in Children with Beckwith-Wiedemann Syndrome. J Clin Endocrinol Metab. 2026 Feb 7:dgag053. doi: 10.1210/clinem/dgag053.