MON-210 - Opposite Ends of the Glycemic Spectrum: Two Pediatric Presentations of Kabuki Syndrome with Hyperinsulinemic Hypoglycemia and Type 2 Diabetes

Background: Kabuki syndrome (KS) is a rare multisystem neurodevelopmental disorder caused by pathogenic variants in KMT2D or KDM6A. These genes encode histone modifying enzymes that regulate transcriptional programs crucial for pancreatic development, insulin secretion, adipogenesis, and hepatic glucose metabolism. Consequently, single gene defects can generate strikingly divergent glycemic phenotypes.

Methods: We report two unrelated children with KS who presented at opposite ends of the glycemic spectrum. Detailed clinical, biochemical, radiological, and endocrine evaluation was performed, including critical sample analysis during hypoglycemia, measures of insulin resistance, and targeted or exome based next generation sequencing. Variants were classified using ACMG criteria and correlated with phenotype.

Results: Case 1, a 2 month old male, presented with recurrent, symptomatic hypoglycemia requiring high glucose infusion rates and diazoxide. Laboratories showed inappropriately detectable insulin and C-peptide, suppressed ketones and free fatty acids, and glycemic response to glucagon, consistent with congenital hyperinsulinism. Syndromic facies, growth faltering, and mild hydrocephalus were present. A hemizygous ~0.85 kb deletion of exons 11–12 in KDM6A confirmed KS type 2. Loss of the H3K27 demethylase KDM6A can disturb β-cell epigenetic programming, leading to excessive basal insulin gene expression, impaired fasting suppression of insulin release, and dysregulated KATP channel dependent stimulus secretion coupling.
Case 2, a 12.5 year old female, presented with obesity, acanthosis nigricans, hypertension, and fasting hyperglycemia. She had elevated C-peptide and HOMA IR 3.2, indicating insulin resistance. Whole Exome Sequencing identified a heterozygous nonsense KMT2D variant (c.11578C>T; p.Gln3860*), confirming KS type 1. KMT2D haploinsufficiency, via reduced H3K4 methylation, is implicated in abnormal adipocyte differentiation, ectopic lipid deposition, hepatic insulin resistance, and impaired skeletal muscle glucose uptake, predisposing to pubertal onset Type 2 Diabetes despite preserved β cell mass.

Conclusions: These cases illustrate how disruption of a shared epigenetic axis can yield diametrically opposite disturbances in glucose homeostasis, from neonatal hyperinsulinemic hypoglycemia to adolescent-onset insulin resistant diabetes. Developmental stage, gene specific chromatin targets, and tissue selective vulnerability likely shape this metabolic polarity. Integrating mechanistic epigenetic insights with bedside glycemic phenotyping may refine risk stratification, guide diazoxide use, and support early lifestyle or pharmacologic interventions for emerging insulin resistance.

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