High-dose radiation to the head and neck for treatment of cancer or other conditions is an established risk factor for childhood brain tumors (Kleinerman 2006). Cranial radiation therapy for acute lymphoblastic leukemia is associated with a particularly high risk for developing (Ohgaki and Kleihues 2005) brain tumors (gliomas, PNETs) in children who received prophylactic CNS irradiation (usually a cumulative dose of 25 Gy, which is no longer part of contemporary therapy). Additionally, childhood exposure to low-dose ionizing radiation for tinea capitis has been associated with benign meningiomas and malignant brain tumors (Sadetzki et al. 2005). The latency between radiation therapy and subsequent brain tumor development has been estimated at 7–9 years with a higher risk for children diagnosed earlier in life (Ohgaki and Kleihues 2005). It has also been broadly accepted for several decades that in utero diagnostic radiation exposure is associated with a small to moderate dose-dependent increase in childhood cancer risk, including brain tumors (Streffer et al. 2003).

While there have been several epidemiologic studies of childhood brain tumors, few risk factors have been confirmed and established. Additionally, very few of these have led to prevention strategies. A recent review concluded that the strongest evidence for childhood brain tumor risk factors was for hereditary cancer predisposition syndromes and therapeutic ionizing radiation (Johnson et al. 2014). While some risk factors including parental age, birth defects, and pesticides have suggestive evidence, other factors including maternal medications and parental occupational exposure during pregnancy have only weak or insufficient evidence (Johnson et al. 2014).

Up to 10% of pediatric cancers occur in the context of a set of well-described hereditary cancer predisposition syndromes (HCPSs) (Strahm and Malkin 2006). Individuals affected by these rare conditions are at greatly increased risk of developing malignancies at levels 10–100 fold above those seen in the general population. Several clues may raise suspicion for the presence of one of these conditions. An individual may have a specific tumor (or subtype) which is commonly associated with genetic susceptibility (e.g., optic pathway glioma with Neurofibromatosis Type 1) (Listernick et al. 2007). A tumor may occur at a significantly younger age than seen in the general population (e.g., childhood meningioma and Neurofibromatosis Type 2) (Evans et al. 1999, 2005; Thuijs et al. 2012). Family history, clinical features, certain laboratory values, or imaging abnormalities may indicate the presence of HCPS. Multiple primary tumors may occur in the same individual. A comprehensive family history may also trigger a genetic evaluation either due to a relative who has been diagnosed with a hereditary cancer predisposition syndrome or suggestive clinical history evident in the pedigree.

HCPSs are associated with increased risk of pediatric brain tumors (Table 1.3) may be categorized by their pattern of inheritance: autosomal dominant or autosomal recessive. The autosomal dominant syndromes can be further subdivided into neurocutaneous disorders, familial colon cancer syndromes involving elevated risks of brain tumors (i.e., Turcot Syndrome), and conditions exclusively having oncologic features. The autosomal recessive syndromes associated with increased childhood brain tumor susceptibility share impaired DNA repair as their underlying defect. Select examples for each of these syndrome groupings will be presented (extended listing in Table 1.3).