Unexpectedly high risk of childhood leukemia associated with Down syndrome

29 Jun 2021

Children with Down syndrome are at an elevated risk of multiple malignancies and hematological disorders such as different types of leukemia.1,2 To better reflect the current risk association between Down syndrome and childhood leukemia, investigators from the United States had conducted a large, contemporary cohort following up around 4 million children born between 1996-2016 to evaluate their leukemia risk in relation to Down syndrome.3 The results were recently published in The Journal of Pediatrics to show that although Down syndrome remains as a strong risk factor for childhood leukemia consistent with previous findings, the association between Down syndrome and acute myeloid leukemia (AML) in particular was much more significant than previously recognized.3

Caused by trisomy 21, a condition of a supernumerary at chromosome 21, Down syndrome is clinically characterized by a collection of musculoskeletal, neurological and cardiovascular features such as short stature, intellectual disability and congenital heart defects.4 As the most common genomic disorder of intellectual disability, Down syndrome continues to have an increasing lifetime prevalence worldwide with an estimated local average rate of 8.0 per 10,000 live births.4,5 In addition to intellectual impairment, people with Down syndrome are also susceptible to various hematological malignancies.1,2 In view of the scarcity of data in this aspect as well as the increased use of radiating imaging techniques such as computed tomography (CT) in recent decades, which has exposed children to an elevated level of radiation and has been reportedly associated with leukemia risk, a group of investigators from the United States had conducted a large-scale study to explore the potential association between Down syndrome and childhood leukemia.3

The study was a retrospective cohort study that followed 3,905,399 children born between 1996-2016 in the United States from their birth until either cancer diagnosis, death, the age of 15-years-old, disenrollment or the end of the study.3 The primary outcome was an incident diagnosis of primary leukemia with no previous diagnosis of any cancer.3

 “One main strength of this study is its large cohort with more leukemia cases in children with Down syndrome than most previous studies.” Dr. Emily Marlow, first author of the study from the UC Davis Department of Public Health Sciences, reflected, “This allowed more precise risk estimation, especially for rare leukemia types such as AML-7, previously estimated from small case reports.”

Among the enrolled subjects, leukemia was diagnosed in 124 out of 4,401 children with Down syndrome and in 1,941 out of 3,900,998 other children.3 Compared with other children, children with Down syndrome had a greater risk of AML before the age of 5-years-old (HR=399; 95% CI: 281-566), as well as a greater risk of acute lymphoid leukemia (ALL) regardless of age (<5 years: HR=28, 95% CI: 20-40; ≥5 years: HR=21, 95% CI: 12-38).3 Yet, children with Down syndrome were found to be at a greater risk of megakaryoblastic leukemia only before the age of 5-years-old (HR=1,500, 95% CI: 555-4,070).3

At the age of 4-years-old, the cumulative incidence for AML was 1,405/100,000 (95% CI: 1,076-1,806) which remained unchanged at the age of 14-years-old.3 For ALL, the cumulative incidence was 1,059/100,000 (95% CI: 755-1,451) at the age of 4-years-old which climbed to 1,714/100,000 (95% CI: 1,264-2,276) at the age of 14-years-old.3

Given the unexpectedly elevated leukemia risks in children with Down syndrome, the investigators deduced that this association might be attributed to the surge of using ionizing radiation imaging in children over the past decades.3 Co-senior author, Prof. Rebecca Smith-Bindman, UC Davis Department of Public Health Sciences, thus suggested, “Other non-ionizing radiation modes of imaging, such as ultrasound and magnetic resonance imaging (MRI), should be used as the first-line image tests.”

Overall, this study is one of the very few large cohorts that presented more updated and yet generalizable results on the risk association between Down syndrome and childhood leukemia. Based on study findings, Down syndrome remains largely a strong risk factor for this hematological condition, of which the leukemia subtype, AML, is subjected to a much stronger association than previously reported.3 It is therefore imperative to conduct further researches to affirm these alarming findings.3

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