Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms “Li-Fraumeni” AND “pediatric high-grade glioma (HGG)”, identifying six cases of HGGs in pediatric patients with LFS. We added a further case with peculiar features such as no familiar history of LFS, association of embryonal rhabdomyosarcoma and bithalamic HGG, whose immunohistochemical profile was accurately defined by Next Generation Sequencing. Knowledge synthesis and case analysis grounded the discussion about challenges in the management of this pathology in pediatric age.