Genotype and phenotype analysis of a cohort of patients with congenital hyperinsulinism based on DOPA-PET CT scanning

Abstract

Congenital hyperinsulinism (CHI) is a clinically, genetically, and morphologically heterogeneous disorder. 18 F DOPA-PET CT scanning greatly improves its clinical outcome. Here, we presented the first Chinese 18 F DOPA-PET CT scanning–based CHI cohort highlighting the variable ethic clinical phenotypes and genotypes. Fifty CHI patients were recruited. Median age at presentation was 2 days. Median fasting time was 2 h. Mean insulin level was 25.6 μIU/ml. Fifty-two percent of patients were diazoxide-unresponsive with significantly shorter fasting tolerance time and higher serum insulin level compared with the responsive patients. Seventy-four percent of patients experienced at least one adverse drug reaction. Tremendously increased focal lesions (32%) were detected and 75% of them were cured through surgery. Thirty-one nucleotide sequence changes were identified in 48% patients. Four novel variants (Q608X, Q1347X, Q289X, F1489S) in ABCC8 gene and 2 novel variants (G132A, V138E) in KCNJ11 gene were detected. Of the variants, 87.1% harbored in ABCC and KCNJ11 genes. T1042Qfs*75 in ABCC8 gene was the most common mutation. Conclusion : Highly increased portion of focal lesion was presented in Chinese CHI patients compared with that of the previous reports. Intolerance to diazoxide was much more evident in Chinese or East Asian than other populations. Certain hotspot mutations harbored in Chinese CHI patients. What is Known: • 18 F DOPA-PET CT scanning can provide informative guidance for surgical procedure when medical therapy is not well responded in CHI patients . What is New: • Intolerance to diazoxide is much more evident in Chinese and East Asian CHI patients compared with the other ethnic populations . • Novel mutations were detected in ABCC8 and KCNJ11 gene. Hotspot mutations such as T1042Qfs*75, I1511K, E501K, G111R in ABCC8 gene, and R34H in KCNJ11 gene are predominantly responsible for Chinese CHI patients .

Case Report: Two Distinct Focal Congenital Hyperinsulinism Lesions Resulting From Separate Genetic Events

“…Limited histopathological data is provided, and this report predated our understanding of the genetic and molecular mechanisms responsible for congenital HI. Since then, Ni et al described a patient with a KCNJ11 mutation found to have one focal lesion in the pancreatic head and another in the pancreatic body (11). Our group previously reported two separate cases, one suspected and one confirmed, of focal HI in which there were both pancreatic and ectopic intestinal focal lesions (10,12).…”

“…Owing to the mechanism of focal lesion development, the occurrence of multiple focal lesions is exceedingly rare. Few cases of HI with multiple focal lesions have been reported to date (8)(9)(10)(11)(12). Of these reports, only one included molecular genetic information confirming that the two lesions, one pancreatic and one ectopic, arose from independent somatic events (8).…”

Marked clinical heterogeneity in congenital hyperinsulinism due to a novel homozygous ABCC8 mutation

“…Even if nonsense-mediated mRNA decay was involved in the variant, it would not directly explain the cause of the clinical heterogeneity among the three cases. 17,19,20 Moreover, methylation analysis using the patients' lymphocytes, not pancreatic cells, would be complicated, because it has been reported that tissue-specific regulatory elements are strongly associated with tissue-specific differentially methylated regions. 21 To decipher the precise mechanisms underlying the heterogeneity of CHI, accumulating cases and further robust approaches, such as generating pancreatic beta cells from iPS cells of the patients, are necessary.…”

“…Although those experiments could add some information to our study, we presume that their impact would be limited, because the purpose of our analyses was to elucidate the clinical pathophysiology, especially heterogeneity, among the three cases. Even if nonsense‐mediated mRNA decay was involved in the variant, it would not directly explain the cause of the clinical heterogeneity among the three cases 17,19,20 . Moreover, methylation analysis using the patients’ lymphocytes, not pancreatic cells, would be complicated, because it has been reported that tissue‐specific regulatory elements are strongly associated with tissue‐specific differentially methylated regions 21 .…”

Altered Serum Amino Acid and Acylcarnitine Profiles in Hyperinsulinemic Hypoglycemia and Ketotic Hypoglycemia

“…The following parameters were used to validate the diagnosis: elevated serum concentrations of insulin and C-peptide when blood glucose levels were <2.6 mmol/L; reduced serum levels of β-hydroxybutyrate, acetoacetic acid and FFAs; a glucose infusion rate >8 mg/kg/min to maintain euglycemia; a blood glucose increase >1.5 mmol/L after an injection of glucagon; and positive 18 F-DOPA PET scan results ( 17 ). Due to domestic technical unavailability, 50 of the 74 HH patients received 18 F-DOPA PET scan to confirm pancreas lesions starting in 2017 ( 18 – 20 ). For KH cases, we also examined charts for evidence of elevated urine ketones or serum β-hydroxybutyrate at the time of hypoglycemia to validate the diagnosis.…”