The Congenital Hyperinsulinism Center at Children’s Hospital of Philadelphia, with a high volume of approximately 80 congenital hyperinsulinism (HI) cases a year, sees a large share of unusual cases. 

In the last six years, the center has treated three children with the exceedingly rare presentation of two focal lesions — representing about 1% of focal cases. All three children were cured with partial pancreatectomy that fully excised the lesions. 

Determining whether a diazoxide non-responsive patient has focal or diffuse disease is critical, and the type can’t be distinguished by clinical presentation alone. Focal HI has a 97% cure rate with resection of the lesion(s). Diffuse disease is ameliorated with surgery, but not cured. Also, children with diffuse disease face longer term risks of diabetes and pancreatic insufficiency with near-total pancreatectomy. Approximately 50% of non-medication responsive patients who undergo surgery have focal HI. 

Genetic testing that identifies a single paternally inherited recessive KATP channel gene mutation is the most accurate predictor of focal disease, and an 18F-L-Fluoro-DOPA PET/CT scan, pioneered at CHOP, can identify the location of focal lesions. CHOP’s HI Center has performed more 18F-DOPA PET/CT scans than any other hospital in the United States — more than 480. 

Interestingly, genetic testing of individual lesions in two of the cases revealed that the two lesions in these children arose from independent somatic events. Focal lesions result from a paternally inherited recessive KATP channel mutation plus somatic loss of maternal 11p chromosome region. In these cases, the two lesions showed a different break point for the loss of maternal 11p, demonstrating that the two events were distinct. 

Patient S.S. 

S.S. is a male born at 38 weeks gestation and found to have plasma glucose level of 28 mg/dL shortly after birth. He was unresponsive to diazoxide. Genetic testing revealed a single heterozygous paternally inherited recessive ABCC8 mutation. An 18F-L-Fluoro-DOPA PET/CT scan showed one lesion preoperatively, located in the inferior pancreatic head, extending into the uncinate region. During surgery, after removing that 1 cm lesion, a second lesion (0.4 cm) was found by palpitation in the pancreatic body and excised. In total, 20% of the pancreas was removed. 

Because the lesions were in different parts of the pancreas and were different sizes, it suggested they were formed separately and were from distinct somatic events. Pancreatic tissue was analyzed genetically. Chromosomal SNP array analysis revealed differences in the regions of chromosome 11 with loss of heterozygosity between the two lesions, confirming that they arose from independent somatic events. 

After surgery, S.S. underwent a fasting test that demonstrated he was cured. 

Patient E.D. 

E.D. is a female born at 39 weeks large for gestational age with a birth weight of 4.15 kg. Screening for hypoglycemia showed low, persistent plasma glucose levels (44 mg/dL). She was incompletely responsive to diazoxide and octreotide. Genetic testing revealed a paternally inherited deletion of a single exon of the ABCC8 gene in both blood and pancreas DNA. A second intronic variant in ABCC8 was identified in pancreas DNA, parent of origin unknown. 

A PET/CT scan showed two separate areas of increased uptake of 18F-DOPA — one from the posterior pancreatic body and one on the medial pancreatic head. E.D. underwent a 10% pancreatectomy to remove the 0.9 cm lesion in the body and 0.8 cm lesion in the head. 

Pancreatic tissue was analyzed genetically. Chromosomal SNP array analysis revealed differences in the regions of chromosome 11 with loss of heterozygosity between the two lesions, confirming that they arose from independent somatic events. 

E.D. passed her cure fast during this same admission and was discharged. 

Patient S.H. 

S.H. is a male born a 38w2d gestation. He was born at 3.62 kg, which is at the upper limit of average for gestational age. Shortly after birth, he showed signs of hypoglycemia (cyanotic and floppy at birth, but improved with resuscitation), transferred to NICU at 5 hours of life due to respiratory distress. In the NICU, he was found to have a plasma glucose level of <20 mg/dL. He was unresponsive to diazoxide. Genetic testing revealed a single paternally inherited recessive ABCC8 mutation, indicating likely focal disease. 

An 18F-L-Fluoro-DOPA PET/CT scan was ordered. 

In S.H.’s case, the PET/CT scan showed two lesions — one in the body and one in the neck — as potentially separate or possibly connected. During surgery, the two lesions were found to be side by side connected with a narrow strip of tissue. Both were excised during the 10% pancreatectomy. S.S. passed a cure fast and was discharged. 

S.H.’s connected lesions have not yet been genetically analyzed. 

In addition to the above cases, two prior CHOP patients were found to have a focal lesion in the pancreas and a second lesion ectopic intestinal — another extremely rare presentation. 

These cases illuminate the pivotal role of collaboration across fields of endocrinology, genetics, radiology, surgery and pathology to optimize care for patients with HI. 

References 

Rosenfeld E,  Mitteer L, Boodhansingh K, Becker, McKnight H, Boyajian L, Ackermann A, Kalish J, Bhatti T, States L, Adzick NS, Lord K, De León D. Case report: two distinct focal congenital hyperinsulinism lesions resulting from separate genetic events. Front Pediatr. 2021;16;9:699129. 

K E Snider, S Becker, L Boyajian, S-L Shyng, C MacMullen, N Hughes, K Ganapathy, T Bhatti, C A Stanley, A Ganguly. Genotype and phenotype correlations in 417 children with congenital hyperinsulinism. J Clin Endocrinol Metab. 2013;98(2):E355-363.