Epigenetic Insights into Tuberous Sclerosis Complex, Von Hippel-Lindau Syndrome, and Ataxia-Telangiectasia

Neurocutaneous syndromes represent a clinically and genetically heterogeneous group of disorders, with tuberous sclerosis complex (TSC), von Hippel-Lindau syndrome (VHL), and ataxia-telangiectasia (A-T) exemplifying some of the most complex entities within this category. These syndromes have traditionally been considered monogenic disorders, caused by germline mutations in tumor suppressor or regulatory genes. However, they exhibit a striking degree of phenotypic variability and divergent clinical trajectories that cannot be fully explained by their underlying genetic alterations alone. Increasingly, epigenetic regulatory mechanisms, such as DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA (ncRNA) activity, are recognized as key modulators of gene expression, cellular differentiation, and tissue-specific function. Disruption of these mechanisms has been implicated in disease pathogenesis, tumorigenesis, and neurodegeneration associated with TSC, VHL, and A-T. Aberrant epigenetic profiles may underlie the observed variability in clinical outcomes, even among individuals with identical mutations. This review consolidates current evidence on the epigenetic landscape of these syndromes, elucidating how these modifications may influence disease behavior and contribute to incomplete genotype-phenotype correlations. By integrating epigenetic insights with known molecular pathways, a more nuanced understanding of disease biology emerges, with potential implications for diagnostic stratification, prognostic assessment, and therapeutic innovation.