Genetic Biomarkers to Identify the Risk of Osteonecrosis in Children with Acute Lymphoblastic Leukemia
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CURRENT OPINION
Genetic Biomarkers to Identify the Risk of Osteonecrosis in Children with Acute Lymphoblastic Leukemia Marissa A. H. den Hoed1,2 • Saskia M. F. Pluijm1,2 • Andre´ G. Uitterlinden3 Rob Pieters2 • Marry M. van den Heuvel-Eibrink1,2
•
Ó Springer International Publishing Switzerland 2016
Abstract Osteonecrosis is a disabling complication of treatment for pediatric acute lymphoblastic leukemia, and much effort has been made to predict which patients are prone to develop this disease. Multiple clinical and genetic factors have already been identified as being associated with osteonecrosis; however, a prediction model that combines pretreatment genetic biomarkers and clinical factors has not yet been designed. Such a prediction model can only be developed with continuing international collaborations and research efforts, including large genomewide association studies.
Key Points Many risk factors for osteonecrosis have been identified, however there is no model that uses these factors to predict and treat osteonecrosis. Genetic risk factors may contribute to such prediction models.
& Marry M. van den Heuvel-Eibrink [email protected] 1
Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital Rotterdam, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands
2
Princess Maxima Centre for Pediatric Oncology, Lundlaan 6, 3584 EA Utrecht, The Netherlands
3
Department of Internal Medicine, Erasmus University Medical Centre Rotterdam, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
1 Introduction: The Etiology of Osteonecrosis Osteonecrosis is a disabling complication of treatment for pediatric acute lymphoblastic leukemia (ALL). The general perception on the pathogenesis of osteonecrosis is that there is an altered coagulation profile, causing local microinfarction [1, 2]. In addition, altered lipid metabolism could increase local lipid deposition and adipocyte hypertrophy in the bone marrow. These factors lead to compromised subchondral blood flow in the joints [2]. As a consequence, the bone architecture deteriorates, which results in joint destruction, pain, and consequent longlasting serious handicaps and persistent symptoms [1, 3]. The weight-bearing joints are mainly affected, such as hips and knees. It is estimated that 38–70 % [3–5] of patients treated for ALL develop osteonecrosis, while only 0.9–17.6 % [3, 4, 6] develop osteonecrosis with symptoms of pain and disability. Bone tissue has regenerating qualities to overcome osteonecrosis, and many asymptomatic or symptomatic lesions resolve spontaneously; however, it is anticipated that a considerable subset of symptomatic osteonecrosis patients will still have to cope with the disabling consequences after cessation of therapy [3, 7].
2 Definition of Osteonecrosis To classify osteonecrosis, future studies should use the same symptom- and radiological-based definition. Recently, an international consensus has been obtained for the definition of osteonecrosis in pediatric ALL pa
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