Down syndrome and leukemia: new insights into the epidemiology, pathogenesis, and treatment.

Down syndrome is the most common autosomal chromosomal disorder with incidence ranging from 1 in 700 to 1:1,000 live births [1]. The protean manifestation are mental retardation, congenital heart disease, and risk for early death. The predominant cause of death is related to the congenital heart defects followed by hypothyroidism, respiratory infections, and malignancy (particularly, leukemia) [2,3]. Death from leukemia in Down syndrome children is predominately in the younger ages [2]. Down syndrome children account for approximately 3% of children with acute lymphoblastic leukemia (ALL) and 5–8% of children with acute myeloid leukemia (AML) diagnosed in the United States. Despite the fact that the association of increased risk for leukemia with Down syndrome have now been recognized for nearly 50 years, it is this relatively low frequency of the total number of cases and the reluctance to give aggressive chemotherapy in a developmentally challenged youngster hindered the systematic evaluation of the pathogenesis and treatment of leukemia in children with Down syndrome. Within the last two decades, several important developments in the understanding of the biology and treatment of leukemias in Down syndrome children have occurred. These developments in general define the pivotal role played by chromosome 21, both in childhood ALL and AML. The serendipitous discovery of the unique drug sensitivity of AML in Down syndrome [4] provided additional impetus for these studies. What emerges is a fascinating story for increased risk for leukemia on the one hand and the increased sensitivity to chemotherapy on the other [5]. In this issue of the journal, six articles describe some of these developments and provide new insights on the biology and treatment of leukemia in Down syndrome [3,6–10]. It is a privilege to write this overview. The articles will be reviewed in the context of epidemiology, pathogenesis, and treatment/drug sensitivity. Some of the remaining challenges will be identified in the summation.