Hyperinsulinemic Hypoglycemia Diagnosed in Childhood Can Be Monogenic

Abstract

Context: Congenital hyperinsulinism (HI) is characterized by inappropriate insulin secretion despite low blood glucose. Persistent HI is often monogenic, with the majority of cases diagnosed in infancy. Less is known about the contribution of monogenic forms of disease in those presenting in childhood.

Objective: We investigated the likelihood of finding a genetic cause in childhood-onset HI and explored potential factors leading to later age at presentation of disease.

Methods: We screened known disease-causing genes in 1848 individuals with HI, referred for genetic testing as part of routine clinical care. Individuals were classified as infancy-onset (diagnosed with HI < 12 months of age) or childhood-onset (diagnosed at age 1-16 years). We assessed clinical characteristics and the genotypes of individuals with monogenic HI diagnosed in childhood to gain insights into the later age at diagnosis of HI in these children.

Results: We identified the monogenic cause in 24% (n = 42/173) of the childhood-onset HI cohort; this was significantly lower than the proportion of genetic diagnoses in infancy-onset cases (74.5% [n = 1248/1675], P < 0.00001). Most (75%) individuals with genetically confirmed childhood-onset HI were diagnosed before 2.7 years, suggesting these cases represent the tail end of the normal distribution in age at diagnosis. This is supported by the finding that 81% of the variants identified in the childhood-onset cohort were detected in those diagnosed in infancy.

Conclusion: We have shown that monogenic HI is an important cause of hyperinsulinism presenting outside of infancy. Genetic testing should be considered in children with persistent hyperinsulinism, regardless of age at diagnosis.

Keywords: childhood; genetic testing; hyperinsulinism; hypoglycemia; monogenic disease.

Figure 1.

Distribution of age at clinical diagnosis of hyperinsulinism (HI) in probands referred for genetic testing. Gray bars indicate total number of probands, black bars indicate number of probands with a confirmed monogenic etiology. The y-axis is split to include all values. (A) Age at diagnosis of HI in years of the whole cohort (n = 1848). (B) Age at diagnosis of HI in months for those diagnosed in infancy (n = 1675). For those individuals with a genetic diagnosis, 83% (n = 1036/1248) were diagnosed within the first month of life.

Figure 2.

Comparison of genetic causes of hyperinsulinism identified in individuals diagnosed in infancy (< 12 months of age) or in childhood (between 1 and 16 years). Genes with variants in fewer than 1% of patients in the overall cohort were grouped in the “Other” category (KMT2D, PMM2, KDM6A, HNF1A, INSR, CACNA1D, and TRMT10A).

Figure 3.

Comparison of birth weight z-score for infancy (< 12 months) and childhood (between 1 and 16 years) diagnosed hyperinsulinism. The middle line depicts the median birth weight Z-score, the length of the box shows the interquartile range, and the whiskers extend to a maximum of 1.5 × IQR from the edge of the box, outliers are plotted individually. P values were calculated using Mann-Whitney. Birthweight Z-scores for all genetic causes are shown in panel (A). Data was then separated by gene where there were more than 5 individuals in both the infancy- and childhood-onset cohorts. Data for ABCC8 is shown in panel (B) GCK is shown in panel (C) and GLUD1 is shown in panel (D).