Congenital hyperinsulinism: 2 case reports with different rare variants in ABCC8

Abstract

Congenital hyperinsulinism (CHI) is a rare glucose metabolism disorder characterized by unregulated secretion of insulin that leads to hyperinsulinemic hypoglycemia (HH). Most cases are caused by mutations in the K ATP -channel genes ABCC8 and KCNJ11 . We report 2 patients that experienced severe HH from the first day of life. Patient 1 developed midgut volvulus after initiating diazoxide and required intestinal resection. He was subsequently managed with a high-dose octreotide and glucose-enriched diet. Consistent with diffuse type CHI by 18F-dihydroxyphenylalanine positron emission tomography-computed tomography, genetic testing revealed a homozygous ABCC8 variant, c.1801G>A, p.(Val601Ile). The rare variant was previously reported to be diazoxide-responsive, and the patient responded well to diazoxide monotherapy, with clinical remission at 2 years of age. Patient 2 responded to diazoxide with spontaneous clinical remission at 15 months of age. However, an oral glucose tolerance test at 7 years of age revealed hyperinsulinism. Genetic testing revealed that the proband and several seemingly healthy family members harbored a novel, heterozygous ABCC8 variant, c.1780T>C, p.(Ser594Pro). Genetic findings identified previously unrecognized HH in the proband’s mother. The proband’s uncle had been diagnosed with monogenic ABCC8 -diabetes and was successfully transitioned from insulin to glibenclamide therapy. We report findings of intestinal malrotation and volvulus occurring 2 days after initiation of diazoxide treatment. We also report a novel, heterozygous ABCC8 variant in a family that exhibited cases of CHI in infancy and HH and monogenic diabetes in adult members. The cases demonstrate the importance and clinical utility of genetic analyses for informing and guiding treatment and care.

Congenital Hyperinsulinaemic Hypoglycaemia—A Review and Case Presentation

“…There are reports that heterozygous patients with an inactivating mutation in the ABCC8 gene responsible for the mild form of HH (even those with no history of pancreatectomy) occasionally develop diabetes later in life, and that their family members often have diabetes, which can be successfully treated with sulphonylurea [ 62 , 68 , 69 , 70 , 71 , 72 , 73 ]. One study performed on transgenic mice with inactivating K ATP channel mutations showed that unresponsiveness to glucose, increased apoptosis and/or decreased insulin gene expression in the pancreatic β-cells might be associated with the development of diabetes caused by the inactivating mutations [ 68 ].…”

Monogenic diabetes: recent updates on diagnosis and precision treatment: A narrative review

“…Before the availability of genetic screening, NDM was classified based on the clinical course of transient NDM (TNDM), permanent NDM (PNDM), or a specific syndrome. The development of targeted sequencing has allowed for rapid diagnosis of all known genetic etiologies and subsequent precision treatment for NDM [7][8][9][10].…”

“…The most frequent causes of PNDM are heterozygous gain-of function mutations in KCNJ11 and ABCC8, while homozygous or some heterozygous loss-of-function mutations in KCNJ11 and ABCC8 develop congenital hyperinsulinism [9,14]. These K ATP mutations impede K ATP channel closure in multiple ways in both TNDM and PNDM [15].…”