Somatic TEK Mutation Identified in a Patient with Calvarial Venous Malformations

<b>Background</b>: Calvarial venous malformations (VMs) are rare and genetically understudied. While somatic <i>TEK receptor tyrosine kinase</i> (<i>TEK</i>) mutations drive sporadic VMs, their role in scalp-calvarial VMs is unknown. We report the first pediatric case of a calvarial VM with a pathogenic somatic <i>TEK</i> mutation and its molecular implications. <b>Methods</b>: A 16-year-old female with a symptomatic parietal scalp VM underwent neurosurgical resection. Exome sequencing was performed on both lesional and blood DNA. Single-cell RNA sequencing (scRNA-seq) data from normal brain vasculature were analyzed for <i>TEK</i> expression and pathway enrichment. <b>Results</b>: A novel somatic <i>TEK</i> L914F mutation (chr9:27212760-C-T [GRCh38]), absent in germline DNA and population databases, was identified and predicted to be deleterious (CADD: 24). scRNA-seq data analysis revealed <i>TEK</i> enrichment in endothelial cells, particularly in fetal and arterial subtypes, and implicated angiogenesis and PI3K/Rho signaling as potential downstream phenotypic and molecular consequences. <b>Conclusions</b>: This first pediatric scalp VM with a somatic <i>TEK</i> L914F mutation expands the phenotypes associated with <i>TEK</i>-related vascular anomalies. These findings emphasize the role of somatic <i>TEK</i> mutation in diverse VMs and support genetic testing in sporadic cases. Further studies are needed to define therapeutic targets.