56 Chapter 2 When looking into treatment related risk factors, it is important to realize that not only steroids can cause APRs or sleep problems. Other ALL treatment components, such as methotrexate, might cause synergistic toxicity.8 Also, a higher steroid dose and dexamethasone, both risk factors for sleep problems, are commonly used in treatment protocols for children with higher risk ALL. These children are treated with more chemotherapy compared to lower risk groups, which could explain a higher occurrence of sleep problems as well. Furthermore, the distress associated with being confronted with ALL and subsequent treatment regimen can cause both APRs and sleep problems on its own.66,67. We hypothesized that a (family) history of psychiatric or sleep problems might predispose for steroid-induced adverse events, since in the general or adult oncology population this factor increases the risk of developing APRs or sleep problems.64,68 However, no studies assessed this risk factor for steroid-induced APR or sleep problems. Only case reports describing steroid-induced APRs in patients with a (family) history of psychiatric symptoms were found. However, case reports of patients with psychiatric deterioration without such histories were described as well. See Supplemental Tables 7 and 8 for an overview of these case reports. No case reports regarding steroid-induced sleep problems were found. Larger studies focusing on (medical) history and the occurrence of both APR and sleep problems are warranted. Besides a history of psychiatric or sleep problems, it is conceivable that certain family risk factors (e.g., family background, premorbid functioning), parenting stress, but also received psychosocial support can influence the coping strategies of parents and may thereby influence their perceptions of problems during steroid treatment.27,66,69,70 None of these possible risk factors have been studied in steroid-induced APRs or sleep problems. Genetic predisposition may contribute to the inter-individual differences in developing steroid-induced APRs or sleep problems. Several studies have identified relevant SNPs in the GR gene, which could contribute to differences in increased glucocorticoid sensitivity as well as APRs such as depression.71,72 Only one of our included studies found a significant association between a SNP and APR: Kaymak Cihan et al. described that carriers of the Bcl1 polymorphism were more susceptible for depression symptoms.44 However, this result was not replicated, nor did the other included studies find this association.4,39,45 No other SNPs were found to be associated with APRs. Genetic predisposition for sleep problems is complex and correlations depend on the definition of sleep outcome.73,74 Vallance et al. studied several polymorphisms that may contribute to inter-patient variability of steroid-induced sleep problems, using a candidate gene approach.56 Only one polymorphism (rs4918, AHSG gene) was associated with impaired sleep both on and off dexamethasone treatment in children with ALL.56 AHSG is a hepatic protein, associated with type 2 diabetes.75 During dexamethasone treatment, the rs4918 polymorphism may
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