Clinical and Molecular Characterization of Hyperinsulinism in Kabuki Syndrome

Abstract

Abstract Context Kabuki syndrome (KS) is associated with congenital hyperinsulinism (HI). Objective To characterize the clinical and molecular features of HI in children with KS. Design Retrospective cohort study of children with KS and HI evaluated between 1998 and 2023. Setting The Congenital Hyperinsulinism Center of the Children’s Hospital of Philadelphia. Patients Thirty-three children with KS and HI. Main Outcome Measure(s) HI presentation, treatment, course, genotype Results Hypoglycemia was recognized on the first day of life in 25 children (76%). Median age at HI diagnosis was 1.8 months (IQR 0.6-6.1 months). Median age at KS diagnosis was 5 months (IQR 2-14 months). Diagnosis of HI preceded KS diagnosis in 20 children (61%). Twenty-four children (73%) had a pathogenic variant in KMT2D, 5 children (15%) had a pathogenic variant in KDM6A, and 4 children (12%) had a clinical diagnosis of KS. Diazoxide trial was conducted in 25 children, 92% of whom were responsive. HI treatment was discontinued in 46% of the cohort at median age 2.8 years (IQR 1.3-5.7 years). Conclusions Hypoglycemia was recognized at birth in most children with KS and HI, but HI diagnosis was often delayed. HI was effectively managed with diazoxide in most children. In contrast to prior reports, the frequency of variants in KMT2D and KDM6A were similar to their overall prevalence in individuals with KS. Children diagnosed with KS should undergo evaluation for HI, and, as KS features may not be recognized in infancy, KMT2D and KDM6A should be included in the genetic evaluation of HI.