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

Abstract

Focal hyperinsulinism (HI) comprises nearly 50% of all surgically treated HI cases and is cured if the focal lesion can be completely resected. Pre-operative localization of the lesion is thus critical. Few cases of hyperinsulinism with multiple focal lesions have been reported, and assessment of the molecular mechanisms driving this rare occurrence has been limited. We present two cases of multifocal HI, each resulting from two independent, pancreatic focal lesions. 18Fluoro-dihydroxyphenylalanine positron emission tomography/computed tomography detected both lesions preoperatively in one patient, whereas identification of the second lesion was an incidental finding during surgical exploration in the other. Complete resection of the focal lesions resulted in cure of the HI in both cases. In each patient, genetic testing of the individual focal lesions revealed different regions of loss of heterozygosity for the maternal 11p15 allele, confirming that each lesion arose from independent somatic events in the setting of a paternally inherited germline ABCC8 mutation. These cases highlight the importance of a multidisciplinary and personalized approach to the management of infants with HI.

Correlation of PET-MRI, Pathology, LOH, and Surgical Success in a Case of CHI With Atypical Large Pancreatic Focus

“…Few patients with separate bifocal lesions have been described before. Giurgea et al [ 10 ] and Rosenfeld et al [ 11 ] each reported 2 cases with bifocal lesions based on genetic examinations demonstrating differently sized regions of LOH in the foci from the same patient. Both authors postulated independent somatic events being causative for the separated focal pathologies.…”

Functional Regulation of KATP Channels and Mutant Insight Into Clinical Therapeutic Strategies in Cardiovascular Diseases

“…Cantú syndrome (CS) is an ultrarare autosomal dominant inherited disorder caused by dominant gain-of-function mutations in both the SUR2A and Kir6.1 subunits of the K ATP channel, which is also characterized by multiple cardiovascular abnormalities, including edema, pericardial effusion, pulmonary hypertension, dilated and tortuous blood vessels with decreased systemic vascular resistance, cerebrovascular defects, patent ductus arteriosus, and marked cardiac hypertrophy ( Chen et al, 2019 ; Chihara et al, 2020 ; McClenaghan et al, 2020 ; Zhang et al, 2021a ) ( Table 3 ). CHI is a rare genetically heterogeneous disorder caused by inactivating mutations in the SUR1 and Kir6.2 subunits of the K ATP channel and it is characterized by persistent hypoglycemia in infants and children, which may increase the risk of permanent brain damage ( Boodhansingh et al, 2019 ; Rosenfeld et al, 2019 ; Männistö et al, 2020 ; Rosenfeld et al, 2021 ). NDM is characterized by the development of hyperglycemia within the first 6 months of life, beta-cell destruction, pancreatic hypoplasia or aplasia, impaired beta-cell function or severe insulin resistance resulting from impaired insulin secretion caused by gain-of-function mutations in KCNJ11 and/or ABCC8 subunits of the K ATP channel, which can be divided into two transient diabetes mellitus (TNDM) and perma-nent diabetes mellitus (PNDM) clinical subtypes, depending on the length of the disease course ( Cao et al, 2020 ; Dahl and Kumar, 2020 ; Pipatpolkai et al, 2020 ; Horita et al, 2021 ).…”

Genetic Heterogeneity Correlated with Phenotypic Variability in Congenital Hyperinsulinism Caused by Mutation in ABCC8 Gene Associated with Early‐Onset Persistent Neonatal Hypoglycemia

“…Another possible mechanism would be paternal uniparental isodisomy of chromosome 11p15.5 and the absence of the same region of maternal origin in focal lesions [5,9]. Mutations with loss of heterozygosity (LOH) in pancreatic somatic cells will determine the unbalanced expression of the imprinted genes (paternal IGF2, maternal H19 and CDKN1C) from the chromosomal 11p15.5 region, which regulates cell growth, with the appearance of focal adenomatous hyperplasia [10,11].The presence of the paternally inherited heterozygous KATP mutations has a predictive value for focal CHI in 94% of cases [10,12]. In the focal form of CHI, the lesions are unique.…”