Genetics and Natural History of Non-pancreatectomized Patients With Congenital Hyperinsulinism Due to Variants in ABCC8

Abstract

Introduction Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycaemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomised patients. This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomised patients with congenital hyperinsulinism due to variants in the ABCC8 gene. Subjects and Methods Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were non-pancreatectomised. Continuous Glucose Monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test (OGTT) was performed if hyperglycemia was detected in the CGM. Results Eighteen non-pancreatectomised patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, eight (44.4%) compound heterozygous, two (11.1%) homozygous, and one patient carried two variants with incomplete familial segregation studies. Seventeen patients were followed-up and twelve (70.6%) of them evolved to spontaneous resolution (median age 6.0±4years; range:1-14). Five out of these twelve patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. Conclusion The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

Clinical management of diazoxide-unresponsive congenital hyperinsulinism: A single-center experience

“…Despite the remaining challenges, including discrepancies and time lags with self-monitoring of BG (SMBG), CGM in conjunction with SMBG has been reported in several studies as useful for preventing hypoglycemia in infants and children with CHI ( 33 , 34 , 35 , 36 , 37 ); however, it has not been approved for use in CHI management. Owing to the possibility of gradual improvement and spontaneous remission ( 17 , 38 ), CGM may also be useful when determining safe feeding intervals and tapering or discontinuing OCT in patients with DZX-unresponsive CHI. The time in and below this range could be new parameters for evaluating blood glucose control in patients with CHI.…”

“…Even in the absence of neurodevelopmental difficulties or brain imaging features, as in our patient, periodic developmental follow-up is required to facilitate early referral to community services. Additionally, some cases of KATP-associated CHI that develop diabetes despite absence of pancreatic surgery have been reported ( 38 , 46 , 47 ), indicating the need for long-term follow-up and transition to adult care, regardless of whether continuing treatment for CHI is warranted. Therefore, the establishment of comprehensive continuous support systems with careful follow-up and individualized approaches for each child and family is required to ensure optimal patient experiences and outcomes.…”