Since the first well-documented case of malignant rhabdoid tumor of the CNS published in 1986, atypical teratoid/rhabdoid tumor (AT/RT) has been recognized as a distinct pathological entity. AT/RT commonly affects very young children under 2 years of age at diagnosis. They are most commonly located in the posterior fossa (60 %), but also present supratentorially and often metastasize throughout the CNS at presentation (27 %). In the past AT/RT was often misdiagnosed as medulloblastoma or PNET. The first diagnostic clue came from the identification of deletion of chromosome 22q in these tumors. In 1999, Biegel et al. have reported germline and somatic mutations of SMARCB1 gene, a tumor suppressor gene, which maps to 22q11.2 in children with CNS AT/RT [28]. Most mutations result in loss of function of the gene and therefore lack of immunostaining of the corresponding antibody BAF47 is diagnostic for AT/RT. In 2008, the fourth edition of WHO classification of tumors of CNS included the newly described entity of AT/RT. AT/RT still confers poor outcome. However, the use of aggressive multimodality treatment combining extensive surgical excision with intensive systemic chemotherapy using myeloablative chemotherapy with autologous stem cell rescue, with or without brain irradiation has recently improved the prognosis [29–31]. Whether intrathecal chemotherapy can replace irradiation for young children is still unclear. The outcome of CNS AT/RT in the setting of rhabdoid predisposition syndrome has not yet been reported.

Malignant gliomas are the most frequent brain tumors affecting individuals with LFS. However, they tend to occur during late childhood and adult life. In the setting of LFS, both de novo glioblastoma and diffuse astrocytomas with secondary transformation are reported. The prognosis for LFS-associated gliomas is just as poor as in sporadic cases.

The fact that brain tumors seem to cluster in certain families with LFS suggests that mutations in specific regions of TP53, such as those binding the minor groove of DNA, may exert some degree of organ-specific carcinogenesis. Mutations in IDH1, ubiquitous in secondary sporadic GBM, are also present in astrocytomas from LFS patients [34]. However, in all reported cases the acquired mutation was R132C, a rare occurrence in the setting of sporadic tumors (<5 %).

TP53 alterations play a significant role in CPC tumorigenesis. Somatic TP53 mutations were observed in 50 % of CPC and germline mutations in 16–36 % of patients. Therefore, the new LFS guidelines include CPC as a part of the diagnostic criteria for LFS. P53 dysfunction is associated with poor outcome in CPC; however, the significance of germline TP53 mutations on survival is still unknown.

Medulloblastomas account for 11 % of reported LFS-associated brain tumors. TP53 mutations are found in 5–10 % of medulloblastomas. Most LFS-associated medulloblastomas belong to the SHH group and are associated with the large cell type, anaplastic type, high degree of genomic instability, and poor outcome [35]. In contrast to CPC which occur at young age, most LFS-associated medulloblastomas occur in the second decade at older age than sporadic medulloblastomas.

Hemangioblastomas of the CNS are the most common tumor in VHL disease, affecting 60–80 % of all patients at an average age of 33 years. The earliest case reported was at 11 years of age. In a recent series of 6 children with solitary cerebellar hemangioblastoma, only those with other suggestive features of VHL had a germline mutation [38]. Although of benign nature, these tumors are a major cause of morbidity. Symptoms related to hemangioblastomas depend on tumor location and size, the presence of associated cysts (30–80 %), and/or edema. They arise anywhere along the craniospinal: spinal cord (13–50 %), the cerebellum (44–72 %), the brainstem (10–25 %), the lumbosacral nerve roots (<1 %), and the supratentorial region (<1 %). Hemangioblastomas of the CNS often grow at several sites simultaneously with an irregular and unpredictable growth pattern. They are best assessed by gadolinium-enhanced MRI. Preoperative embolization is done at some centers to reduce tumor vascularity before resection. Most of them can be safely and completely resected by surgery. Stereotactic radiation therapy is used in case of multiple craniospinal hemangioblastomas, especially those not associated with cysts. Erythrocytosis occurs in 5–20 % of cerebral hemangioblastomas and can necessitate periodic phlebotomies, but it responds to surgical resection [39].