Focal Congenital Hyperinsulinism

Peter Tieh, MD; Isabel Kwan, MD; Catherine S. Mao, MD; Soina K. Dargan, MS, MD; and Jennifer K. Yee, MD

A full-term girl was born to a 21-year-old gravida 2 para 2 mother who had had adequate prenatal care and no pregnancy complications. The delivery was uncomplicated, and the results of the infant’s initial physical examination were unremarkable. However, on day 2 of life, the girl exhibited lethargy and poor tone. Blood glucose was measured with a chemically treated paper strip (Dextrostix), and concentration was 35 mg/dL just prior to transport for higher level of care. 

The infant was treated with dextrose 10% water boluses and maintenance intravenous fluids, but hypoglycemia persisted despite a glucose infusion rate up to 20 mg/kg/min. A critical blood sample analysis resulted in the following: blood glucose 37 mg/dL, insulin 12.3 µIU/mL, C-peptide 2.33 ng/dL, β-hydroxybutyrate 0.1 mmol/L, and urinalysis without ketones. Hypoglycemic events were not reducted by diazoxide treatment up to 15 mg/kg/day. Intravenous octreotide initiated at 10 mcg/kg/day ultimately stabilized the infant’s blood glucose levels. During the process of glucose stabilization, the patient experienced 1 episode of supraventricular tachycardia, which resolved with treatment. 

The patient had normal acylcarnitine and urine organic acid concentrations. However, next-generation sequencing of genes involved in hyperinsulinism showed a heterozygous nonsense mutation causing a premature-stop codon in the adenosine triphosphate (ATP)–binding cassette subfamily C member 8 (ABCC8) gene, affecting the sulfonylurea receptor–1 subunit of the potassium-ATP channel in pancreatic β-cells. 

Pancreatic β-cells are neuroendocrine cells known to take up and decarboxylate amino acid precursors, and therefore 18F-fluoro-L-DOPA positron emission tomography with computed tomography (PET-CT) was performed (Figure), revealing focal enhancement in the tail of the pancreas. The patient subsequently underwent partial pancreatectomy of the focal region identified on imaging. Postoperatively, glucose concentrations became stable on oral feedings, and the infant was discharged home without medications. She continued developmental assessments as an outpatient because vision impairment was identified. 


Neonatal hypoglycemia is a common problem, with up to 30% of infants at high risk for the condition.1 Currently, no consensus exists on the range of plasma glucose levels that defines hypoglycemia in the newborn period, but cutoff values in the literature range from 40 to 47 mg/dL.2 Dextrostix is not part of routine newborn care, and the diagnosis of hypoglycemia is often made after the infant becomes symptomatic. Although most cases of neonatal hypoglycemia may be transient, the neonatal health care provider must be aware of those that are persistent and know when to evaluate for specific causes. 

In the case of our patient, the persistence and severity of hypoglycemia along with a high glucose infusion rate (reference range for normal term infant, 4-6 mg/kg/min)3 indicated more than a transient phenomenon. Congenital
hyperinsulinism is the most frequent cause of persistently decreased glucose levels in the newborn.4,5 It is often caused by a mutation in the ATP-sensitive potassium (KATP) channel. Under physiologic conditions in the β-cell, KATP channels close in response to glucose uptake, leading to membrane depolarization, calcium influx into the cell, and subsequent insulin release. 

Mutations that cause loss or permanent closure of KATP channels result in continuous membrane depolarization and insulin release even under conditions of hypoglycemia. While diazoxide is the first-line therapy used to treat hyperinsulinism,6,7 mutations in the ABCC8 genes are usually unresponsive to diazoxide. The ABCC8 and the KCNJ11 genes comprise the highest percentage of cases of diagnosed congenital hyperinsulinism (approximately 36%) and are responsible for more than 87% of diazoxide-unresponsive cases.8 

Second-line treatments include octreotide, a somatostatin analogue that decreases insulin secretion by acting on somatostatin receptors 2 (SSTR2) and 5(SSTR5).7,9,10 Ultimately, after genetic and imaging confirmation of focal hyperinsulinism, our patient underwent definitive surgical resection.7 In focal congenital hyperinsulinism, 94% of patients are cured after surgery and have no further issues with glucose control.4 


Our patient’s hypoglycemia completely resolved after surgery and she remained euglycemic without medications. The patient’s vision impairment was possibly a result of subclinical hypoglycemic seizures. 

Known major sequelae of hyperinsulinism include cortical blindness, developmental delays, and intellectual disability.7 Future evaluations are required to screen for and manage potential developmental and cognitive impairments.

Peter Tieh, MD, is a fellow in pediatric endocrinology at Harbor-UCLA Medical Center in Torrance, California. 

Isabel Kwan, MD, is a resident in the Department of Pediatrics at Harbor-UCLA Medical Center in Torrance, California.

Catherine S. Mao, MD, is a professor of pediatrics in the Division of Pediatric Endocrinology at Harbor-UCLA Medical Center in Torrance, California.

Soina K. Dargan, MS, MD, is an assistant professor of pediatrics in the Division of Neonatology at Harbor-UCLA Medical Center in Torrance, California.

Jennifer K. Yee, MD, is an associate professor of pediatrics in the Division of Endocrinology at Harbor-UCLA Medical Center in Torrance, California.


The authors would like to thank the following colleagues for their assistance with this article:

Lisa J. States, MD, who is with Children’s Hospital of Philadelphia and is an associate professor of clinical radiology at the Perelman School of Medicine at the University of Pennsylvania.

Daniel DeUgarte, MD, an associate professor of surgery in the Division of Pediatric Surgery at Harbor-UCLA Medical Center in Torrance, California.

Steven Lee, MD, an associate professor of surgery in the Division of Pediatric Surgery at Harbor-UCLA Medical Center in
Torrance, California.


1. McKinlay CJ, Alsweiler JM, Ansell JM, et al. Neonatal glycemia and neurodevelopmental outcomes at 2 years. N Engl J Med. 2015;373(16):1507-1518.

2. Committee of Fetus and Newborn; Adamkin DH. Postnatal glucose homeostasis in late-preterm and term infants. Pediatrics. 2011;127(3):575-579.

3. Sweet CB, Grayson S, Polak M. Management strategies for neonatal hypoglycemia. J Pediatr Pharmacol Ther. 2013;18(3):199-208. 

4. Lord K, Dzata E, Snider KE, Gallagher PR, De Leon DD. Clinical presentation and management of children with diffuse and focal hyperinsulinism: a review of 223 cases. J Clin Endocrinol Metab. 2013;98(11):E1786-E1789.

5. Hardy OT, Hernandez-Pampaloni M, Saffer JR, et al. Accuracy of [18F]fluorodopa positron emission tomography for diagnosing and localizing focal congenital hyperinsulinism. J Clin Endocrinol Metab. 2007;92(1):4706-4711.

6. Arya VB, Aziz Q, Nessa A, Tinker A, Hussain K. Congenital hyperinsulinism: clinical and molecular characterisation of compound heterozygous ABCC8 mutation responsive to Diazoxide therapy. Int J Pediatr Endocrinol. 2014;(1):24.

7. Yorifuji T. Congenital hyperinsulinism: current status and future perspectives. Ann Pediatr Endocrinol Metab. 2014;19(2):57-68.

8. Kapoor RR, Flanagan SE, Arya VB, Shield JP, Ellard S, Hussain K. Clinical and molecular characterisation of 300 patients with congenital hyperinsulinism. Eur J Endocrinol. 2013;168(4):557-564.

9. Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital hyperinsulinism: current trends in diagnosis and therapy. Orphanet J Rare Dis. 2011;6:63.

10. Demirbilek H, Shah P, Arya VB, et al. Long-term follow-up of children with congenital hyperinsulinism on octreotide therapy. J Clin Endocrinol Metab. 2014;99(10):3660-3667.