The Critical Role of Accurate Testing in Identifying Children with Focal Hyperinsulinism

An HI diagnosis at birth 

Patient D, born at 37 weeks with a birth weight of 3200 gm, presented with hypoglycemia at birth. He was noted to have tight nuchal cord and APGARS of 7 and 9, and his initial glucose was 15 mg/dL. He received three dextrose gels and was admitted to the birth hospital’s NICU. Due to persistent hypoglycemia, he was placed on dextrose containing fluids, which were titrated up to a GIR of 12 mg/kg/min.  

A critical sample was obtained, which showed:  

• A plasma glucose of 42 mg/dL
• Betahydroxybutyrate (BOHB) of 0.1 mmol/L
• Insulin 3 uIU/mL and
• Cortisol 37 mcg/dL 

He was diagnosed with hyperinsulinism and started on diazoxide. Despite increasing the diazoxide to the maximum dose of 15 mg/kg/day, he continued to require an IV GIR of 8.5 mg/kg/min to maintain euglycemia. Given the lack of response, the diazoxide was discontinued. Rapid exome sequencing found a paternally inherited recessive mutation in ABCC8, concerning for the focal form of hyperinsulinism (HI).  

At six weeks old, he transferred to a tertiary children’s hospital for imaging to localize the focal lesion. He underwent a 68Ga-DOTATATE PET/CT, which showed diffuse update throughout the pancreas. The team considered medical therapy with octreotide but ultimately agreed to transfer to our center at Children’s Hospital of Philadelphia (CHOP) for additional imaging.

Diagnostic findings at CHOP 

Patient D was transferred to CHOP at 10 weeks old. He was still requiring an IV GIR of 8.5 mg/kg/min to manage his hypoglycemia. He underwent an 18F-DOPA PET/CT, which demonstrated focal uptake in the pancreatic neck. At surgery, the focal lesion was identified in the neck of the pancreas, and he underwent a 20% pancreatectomy to remove the lesion. Histologic findings consisted of a 0.6 cm area of increased endocrine tissue with no abnormal endocrine tissue identified at the resection margins.

Determined to recover

After recovery in our Newborn/Infant Intensive Care Unit (N/IICU), Patient D returned to the endocrinology unit to undergo a “cure fast.” He fasted 12 hours while maintaining glucoses > 70 mg/dL and ended the fast with a plasma glucose of 62 mg/dL, BOHB 1.8 mg/dL, insulin < 2 mIU/mL and c-peptide 0.1 ng/mL. He was determined to be cured of his hyperinsulinism and was discharged home.

The importance of the correct testing 

Congenital hyperinsulinism (HI) is the most common hypoglycemic disorder in infants and children. It results from dysregulated insulin secretion by the pancreatic beta cells. Inactivating mutations of ABCC8 and KCNJ11, which encode the ATP-sensitive potassium (KATP) channel, cause the most common and severe form of HI. Most patients with KATP-HI do not respond to the first-line treatment for HI, diazoxide, which is a KATP channel agonist.  

KATP-HI occurs in two distinct histologic types:  

1. A diffuse form, in which beta cells throughout the pancreas oversecrete insulin,
2. and a focal form, in which there is a localized area of beta cell overgrowth. Children with the focal form of HI are cured with resection of the focal lesion. Therefore, it is crucial to identify patients with the focal form.   

This case illustrates the importance of selecting the correct tests during a diagnostic evaluation. After a diagnosis of HI was made, the team appropriately started treatment with diazoxide. Failure to respond to diazoxide suggests KATP-HI and accordingly, expediated genetic testing was sent when the patient did not respond to diazoxide. Genetic testing is the best method of identifying children with focal HI. In patients with diazoxide unresponsive HI, a paternally inherited recessive mutation in ABCC8 or KCNJ11 has a 94% positive predictive value for the focal form. 

Pre-operative localization of the focal lesion is also critical to ensure a successful cure. Focal lesions are not detected on conventional imaging studies, such as CT or MRI. The 18F-DOPA PET/CT revolutionized the care of HI patients by providing accurate pre-operative localization of focal lesions. In one large study, 100% of focal lesions were correctly localized. While other radio-nucleotide tracers, such as 68Ga-DOTATATE, are available for pancreatic imaging, they have not been widely studied for focal HI. Current literature suggests that they are inferior to the 18F-DOPA PET/CT in the detection of focal lesions. For our case, the 68Ga-DOTATATE PET/CT missed the focal lesion, and our patient almost missed being cured of a severe disorder.  

Key points  

• The most common and severe form of HI is due to inactivating mutations of the KATP channel encoded by ABCC8 and KCNJ11. Children with KATP-HI do not respond to diazoxide, which acts on the KATP channel. KATP-HI occurs in the diffuse and focal form. Focal HI is cured with surgical resection of the focal lesion.
• Genetic testing offers the best means of distinguishing between the focal and diffuse forms of HI. A paternally inherited recessive mutation in ABCC8 or KCNJ11 has a 94% positive predictive value for the focal form. Expedited genetic sequencing of ABCC8 and KCNJ11 should be performed in a child with diazoxide unresponsive HI.
• The 18F-DOPA PET/CT is the gold standard for localizing focal lesions in the pancreas and allows for a successful cure. Other types of PET/CTs may not correctly identify a focal lesion and can result in a child being mis-diagnosed and receiving unnecessary therapy.