Ann Pediatr Endocrinol Metab.  2021 Mar;26(1):60-65. 10.6065/apem.2040042.021.

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

• Mouron-Hryciuk J
• Stoppa-Vaucher S
• Busiah K
• Bouthors T
• Antoniou MC
• Jacot E
• Brusgaard K
• Christesen HT
• Hussain K
• Dwyer A
• Roth-Kleiner M
• Hauschild M

• KMID: 2514154
• DOI: http://doi.org/10.6065/apem.2040042.021

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.

Keyword

ABCC8; Congenital hyperinsulinism; Hypoglycemia; Monogenic diabetes; Midgut volvulus

Figure

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  Fig. 1. Pedigrees showing inheritance of ABCC8 mutations in both families. Squares represent males and circles represent females. The arrow depicts the proband with CHI. The individual lVa of family B underwent genetic testing and was confirmed not to be a carrier of ABCC8 mutation. (A) Family A: parents (IIIa/b) are asymptomatic carriers. (B) Family B: variable presentation of individuals harboring the heterozygous ABCC8 mutation, including symptomatic hyperinsulinemic hypoglycemia (IIIb), monogenic diabetes (IIIc), and diabetes of unknown origin (IId).

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  Fig. 2. Axial fluorine-18L-3,4hydroxyphenylalanine positron emission tomography image. Diffuse uptake of F-fluoro-L-DOPA by the pancreas is visualized by the hot spot (white arrow). Physiological distribution of the radiotracer is observed with higher accumulation in the kidneys and lower accumulation in the liver.

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  Fig. 3. Three-dimensional modelled structure of a pancreatic ATP-sensitive potassium channel. (A) The KATP-channel is a hetero-octameric complex composed of 4 Kir6.2 subunits and 4 SUR1 units. The transmembrane domains are highlighted. (B) The genetic variants in our 2 cases are located on the same transmembrane domain (TMD1) of the SUR1 subunit.

Reference

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