Focal Congenital Hyperinsulinism (CHI) Due To Paternally Inherited Variant in ABCC8 Gene: Importance of Genetic Testing & PET Imaging in Stratification & Management of Diazoxide Unresponsive CHI

Case Report

J Pediatri Endocrinol. 2023; 8(2): 1062.

Focal Congenital Hyperinsulinism (CHI) Due To Paternally Inherited Variant in ABCC8 Gene: Importance of Genetic Testing & PET Imaging in Stratification & Management of Diazoxide Unresponsive CHI

Abhishek Kulkarni¹*; Joewin Monteiro²; Devika Desai³

1Senior Consultant Paediatric and Adolescent Endocrinologist, SRCC Children’s Hospital, Mumbai & Sir HN Reliance Foundation Hospital, Mumbai, India

2Clinical and Research Fellow, Department of Pediatric and Adolescent Endocrinology, SRCC Children’s Hospital, Haji Ali, Mumbai, India

3Clinical Associate, Department of Paediatric Endocrinology, SRCC Children’s Hospital, Mumbai, India

*Corresponding author: Abhishek Kulkarni Senior Consultant Paediatric and Adolescent Endocrinologist, SRCC Children’s Hospital, Mumbai & Sir HN Reliance Foundation Hospital, Mumbai, India. Email: cpedndc@gmail.com

Received: October 30, 2023 Accepted: November 25, 2023 Published: December02, 2023

Abstract

Congenital Hyperinsulinism (CHI) may be transient or permanent and inherited either in autosomal recessive or dominant forms. Variants in ABCC8 and KCNJ11 genes coding for Sulphonyl Urea Receptor (SUR1) and potassium channel subunit (Kir6.2) respectively, account for 82% cases of diazoxide-unresponsive patients and 45% of all cases of CHI. The histology of CHI is classified into focal and diffuse. Approximately half of all cases can be classified as diffuse, 40 % as focal, and 10% of cases are considered atypical. We report a 1 month old male with recurrent hypoglycemia detected with focal congenital hyperinsulinism secondary to a paternally inherited heterozygous ABCC8 gene mutation. Focal disease results due to inheritance of a monoallelic recessive paternal ABCC8 or KCNJ11 variant together with somatic Loss of Heterozygosity (LOH) of the maternal allele at 11p15 within a pancreatic progenitor cell. Infants & children with focal disease may be cured by resection of their hyperplastic lesion and the risk for postoperative diabetes is significantly lower as compared to that following pancreatectomy for diffuse CHI. The report describes molecular mechanisms underlying CHI & emphasises the need of genetic testing and diagnostic functional imaging modalities in diazoxide unresponsive CHI to guide management and improve clinical outcomes.

Keywords: Focal congenital hyperinsulinism; CHI; Recessively inherited monoallelic mutation; 18F-DOPA PET

Introduction

Congenital Hyperinsulinism (CHI) is a rare, clinically heterogenous disorder and the most frequent cause of persistent hypoglycaemia in neonates, infants, and children. The incidence of CHI varies between 1 in 50,000 live births to as high as 1 in 2500 live births in countries with high degree of consanguinity. The etiology of CHI is largely genetic. Mutations in at least 12 genes that play a role in regulating beta-cell insulin secretion are implicated in the pathogenesis of HI. Approximately 50% of diazoxide-responsive cases and 10% of diazoxide-unresponsive cases of CHI have unknown etiology, suggesting that additional genes & genetic mechanisms may need elucidation [1].

The histology of CHI is classified into focal and diffuse. Approximately half of all cases can be classified as diffuse, 40 % as focal, and 10% of cases are considered atypical [2]. Genetic mutation testing is well established as standard of care to define best approaches to treatment of CHI especially in diazoxide unresponsive patients. Fluorine-18L-3,4-hydroxyphenylalanine positron emission tomography (18F-DOPA-PET) is considered the gold standard for preoperative differentiation of focal from diffuse disease and localization of the focal lesion [2]. We report a 1 month old male with recurrent hypoglycemia detected with focal congenital hyperinsulinism secondary to a paternally inherited heterozygous ABCC8 gene mutation.

Case Report

A 1 month old male, born at term by LSCS of a non-consanguineous union was referred with history of multiple episodes of hypoglycaemic seizures since day 4 of life. A critical sample was sent on presentation at capillary blood glucose value of 40 mg/dl which depicted an insulin level of 5.7 mIU/ml for a corresponding laboratory RBS value of 35 mg/dl. The values of cortisol, GH, ammonia, lactate as sent from the critical sample were within permissible limits & beta hydroxybutyrate was undetectable. Screening for sepsis & IEMs were negative. Inability to wean the baby off a Glucose Infusion Rate of >6mg/kg/min inspite of use of threshold doses of diazoxide & hydrochlorothiazide suggested unresponsiveness to diazoxide. The baby was initiated on subcutaneous octreotide therapy & was weaned off IV fluids over the next 48 hours. Euglycemia was maintained with a subcutaneous dose of 5 mcg/kg octreotide administered 8 hourly & timely breast feeds.

Citation: Kulkarni A, Monteiro J, Desai D. Focal Congenital Hyperinsulinism (CHI) Due To Paternally Inherited Variant in ABCC8 Gene: Importance of Genetic Testing & PET Imaging in Stratification & Management of Diazoxide Unresponsive CHI. J Pediatri Endocrinol. 2023; 8(2): 1062.