ABSTRACT
Originally pioneered in adults, endoscopic endonasal approaches for skull base pathology are being increasingly applied as a minimally invasive alternative for young children. Intrinsic anatomic differences between these patient populations have sparked discussions on the feasibility, safety, and efficacy of these techniques in pediatric patients. This work aims to serve as a primer for clinicians engaged in the rapidly evolving field of pediatric endoscopic skull base surgery. A succinct overview of relevant embryology, sinonasal anatomy, and diagnostic workup is presented to emphasize key differences and unique technical considerations. Additional discussions regarding select skull base lesions, reconstructive paradigms, potential surgical complications, and postoperative care are also highlighted in the setting of multidisciplinary teams.
ABSTRACT
Cerebral cavernous malformations (CCMs) form following loss of the CCM protein complex in brain endothelial cells due to increased endothelial MEKK3 signaling and KLF2/4 transcription factor expression, but the downstream events that drive lesion formation remain undefined. Recent studies have revealed that CCM lesions expand by incorporating neighboring wild-type endothelial cells, indicative of a cell nonautonomous mechanism. Here we find that endothelial loss of ADAMTS5 reduced CCM formation in the neonatal mouse model. Conversely, endothelial gain of ADAMTS5 conferred early lesion genesis in the absence of increased KLF2/4 expression and synergized with KRIT1 loss of function to create large malformations. Lowering versican expression reduced CCM burden, indicating that versican is the relevant ADAMTS5 substrate and that lesion formation requires proteolysis but not loss of this extracellular matrix protein. These findings identify endothelial secretion of ADAMTS5 and cleavage of versican as downstream mechanisms of CCM pathogenesis and provide a basis for the participation of wild-type endothelial cells in lesion formation.