Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li–Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

Wilms tumors are commonly associated with predisposition syndromes, many but not all of which include overgrowth. Several of these syndromes also include a risk of other embryonal malignancies—particularly hepatoblastoma. Guidelines for surveillance in this population were published in 2017, and recently, members of the American Association for Cancer Research Pediatric Cancer Working Group met to update those guidelines with a review of more recently published evidence and risk estimates. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors, and other health care professionals on revised diagnostic criteria; review previously published surveillance guidelines; and harmonize updated surveillance recommendations in the North American and Australian contexts for patients with overgrowth syndromes and other syndromes associated with Wilms tumor predisposition.

Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.

Neurofibromatosis type 1 (NF1), Noonan syndrome, and related syndromes, grouped as RASopathies, result from dysregulation of the RAS-MAPK pathway and demonstrate varied multisystemic clinical phenotypes. Together, RASopathies are among the more prevalent genetic cancer predisposition syndromes and require nuanced clinical management. When compared with the general population, children with RASopathies are at significantly increased risk of benign and malignant neoplasms. In the past decade, clinical trials have shown that targeted therapies can improve outcomes for low-grade and benign neoplastic lesions but have their own challenges, highlighting the multidisciplinary care needed for such individuals, specifically those with NF1. This perspective, which originated from the 2023 American Association for Cancer Research Childhood Cancer Predisposition Workshop, serves to update pediatric oncologists, neurologists, geneticists, counselors, and other health care professionals on revised diagnostic criteria, review previously published surveillance guidelines, and harmonize updated surveillance recommendations for patients with NF1 or RASopathies.

Hereditary retinoblastoma is a classic cancer predisposition syndrome with risks beginning in early infancy. About 45% of children with retinoblastoma (RB) have hereditary disease. These children are at risk for both intraocular disease and additional neoplasms throughout their lifetime. Germline pathogenic/likely pathogenic variants in RB1 typically lead to bilateral intraocular disease, elevated risks of trilateral RB, and risks of non-ocular subsequent malignant neoplasms (SMN), especially sarcomas and melanomas. There is further increased risk of SMNs if radiation treatment is used. In this report, with a reconvening of the American Association for Cancer Research (AACR) Childhood Cancer Predisposition Workshop, we expand on strategies for identifying individuals with hereditary RB, with a focus on testing strategies for children with RB. We also provide updates from previous recommendations. Given the high penetrance of retinal tumors, we review the importance of close intraocular surveillance and consider recent data on surveillance for SMNs. Finally, we discuss the importance of counseling for survivors of intraocular disease to address risks of adult-onset tumors as well as to consider reproductive risks.

Schwannomatosis (SWN) is a distinct cancer predisposition syndrome caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is a significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal, and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma. SMARCB1-related SWN is a familial SWN syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence of radiation. These individuals do not develop bilateral vestibular schwannomas. Finally, patients with LZTR1-related SWN typically present with peripheral schwannomas, and unilateral vestibular schwannomas have been reported. The following perspective is intended to highlight the clinical presentation and international tumor surveillance recommendations across these SWN syndromes.