Risk factors for symptomatic osteonecrosis in childhood ALL: A retrospective study of a Slovenian pediatric ALL population between 1970 and 2004

Treatment induced non-traumatic osteonecrosis (ON) has been reported increasingly in children treated for acute lymphoblastic leukemia (ALL). Several risk factors for ON have been identified in childhood cancer patients; however, their diagnostic and prognostic power is limited and the etiology of the disease remains unclear. Therefore, a continuous effort is focused on the identification of additional ON risk factors. We performed a retrospective study of 313 childhood ALL patients to test the association between the ON occurrence in children receiving ALL therapy and common polymorphisms in potential target genes: Thiopurine S-methyltransferase (TPMT; 460G> A, 719A> G), 5,10-methylenetetrahydrofolate reductase (MTHFR; 677C> T, 1298A> C), estrogen receptor alpha 1 (ESR1; XbaI) and collagen type I, alpha 1 (COL1A1; Sp1). In the present cohort, higher age and more recently developed treatment protocols were independent risk factors for ON. In children > 14.5 years old, TPMT genotype modulated the risk of ON. Additionally, in children < 12.9 years old ESR1 genotypes were also implicated in the pathogenesis of ON. Besides greater age and more recent treatment protocols, genetic factors (polymorphisms in ESR1 and TPMT genes) were suggested to be implicated in the pathogenesis of ON and could be potentially used as genetic prognostic markers for ON.