Clinical and Genetic Characteristics of Congenital Hyperinsulinism in Norway: A Nationwide Cohort Study

Abstract

Purpose: Congenital hyperinsulinism (CHI) is a rare, monogenic disease characterized by excessive insulin secretion. We aimed to evaluate all probands with suspected CHI in Norway registered over the past 2 decades.

Methods: The study included 98 probands. Clinical data were cumulated from medical records. All probands were screened for variants in the genes ABCC8 and KCNJ11. Other CHI-related genes were Sanger-sequenced as indicated by the patients' phenotype (n = 75) or analyzed by next-generation sequencing employing a panel of 30 CHI-related genes (n = 23).

Results: Twenty-one probands (21%) received a diagnosis other than CHI, the most common being idiopathic ketotic hypoglycemia (9%) or syndromic hyperinsulinism (4%). In the final cohort of 77 CHI probands, genetic findings were revealed in 46 (60%). ABCC8 variants were most common (n= 40), and 5 novel variants were identified. One proband harbored both the pathogenic GCK variant p.(Ala456Val) and the ABCC8 variant p.(Gly505Cys). Although most ABCC8 variants caused immediate disease onset with severe hypoglycemia and were diazoxide-unresponsive, 8 probands had a heterozygous, apparently dominant variant with milder phenotype. Two probands had pathogenic variants in GLUD1, whereas variants in HADH, HNF4A, KCNJ11, and HK1 were identified in 1 proband each, the latter being noncoding. Neurologic sequelae were reported in 53% of the CHI probands. Of nonsurgically treated probands, 43% had spontaneous resolution. The minimum birth prevalence of CHI in Norway is 1:19,400 live births.

Main conclusion: Individuals with disease-causing ABCC8 variants dominated our cohort. Patients with known genetic etiology had earlier and more severe disease onset than genetically unsolved patients.

Keywords: genetic testing; hyperinsulinemic hypoglycemia; insulin dysregulation; monogenic disease; neurologic sequela; persistent hypoglycemia.

Figure 1.

Flowchart of the study population consisting of 98 suspected CHI probands referred to Haukeland University Hospital between 2002 and 2023. Probands with idiopathic ketotic hypoglycemia, syndromic hyperinsulinism and other conditions were excluded from the study. “Genetic finding” includes probands with a mutation that justified the CHI diagnosis. “Clinically verified” probands had a phenotype that fulfilled diagnostic criteria for CHI but no pathogenic gene variant was identified. Patients with a clinical picture consistent with CHI but with insufficient clinical data to confirm the diagnosis and without genetic findings were classified as “Genetically and clinically uncertain.” Abbreviation: CHI, congenital hyperinsulinism.

Figure 2.

Age and glycemia at time of disease onset in 60 CHI probands. The x-axis indicates disease onset ascertained as age at first measured hypoglycemia. Glucose levels at first measured hypoglycemia are color-coded according to the legend. Squares correspond to males and circles to females. For some probands, the measured glucose value at disease onset was not available (grey color). Abbreviations: d, days; m, months; w, weeks.

Figure 3.

Localization of a novel noncoding HK1 variant (c.226 + 4909A > C) found in intron 2. On top of the sequences are binding motifs of transcription factor families according to Wakeling et al (33). DNA sequence is taken from nucleotide reference sequence NM_000188.3 (www.ncbi.nlm.nih.gov).