A de novo HK1 Variant in a Boy Fulfilling the Diagnostic Criteria for Tuberous Sclerosis Complex: Expanding the Phenotypic Spectrum of NEDVIBA.

Hexokinase 1 (HK1) catalyzes the first step of glycolysis by phosphorylating glucose to glucose-6-phosphate. Recently, de novo heterozygous missense variants in the N-terminal regulatory domain of HK1 have been associated with neurodevelopmental disorders with visual defects and brain anomalies (NEDVIBA), likely through gain-of-function mechanisms causing excessive glucose phosphorylation. Tuberous sclerosis complex (TSC), a neurocutaneous syndrome characterized by hamartoma formation in multiple organs, results from TSC1/TSC2 complex dysfunction and mTOR pathway dysregulation. To date, no association between NEDVIBA and TSC has been reported. Here, we present a 4-year-old boy with developmental delay meeting clinical diagnostic criteria for TSC, including hypopigmented skin patches and radial migration lines on brain MRI. Genetic analysis revealed the recurrent de novo HK1 variant c.1334C>T (p.Ser445Leu) associated with NEDVIBA, while no pathogenic variants in TSC1/TSC2 were detected. Notably, our patient lacked hamartomas, a hallmark of TSC. This case expands the phenotypic spectrum of NEDVIBA and suggests that HK1 variants should be considered in the differential diagnosis of TSC-like presentations, particularly in cases without hamartomas or identifiable TSC1/TSC2 variants.