Pediatr Blood Cancer 2005;44:8–12

Epidemiology of Leukemia in Children With Down Syndrome

Julie A. Ross, PhD,1* Logan G. Spector, PhD,1 Leslie L. Robison, PhD,1

and Andrew F. Olshan, PhD2

DOWN SYNDROME: OVERVIEW

Down syndrome is the most common chromosomalabnormality in the United States with a prevalence ofapproximately 10 cases/10,000 births [1,2]. Rates amonglive-births have been shown to be about two-thirds of therates detected in fetuses at amniocentesis [3]. From 1983to 1990, analyses of state data show stable patterns forinfants of mothers younger than age 35 years [1]. In con-trast, significant declines have occurred for mothers aged35 years and older (36.6/10,000 in 1983 to 25.9/10,000in 1990), likely reflecting the increased use of prenataltesting.

In more than 90% of cases, Down syndrome is asso-ciated with full trisomy of chromosome 21, mainly due tomaternal meiotic non-disjunction [4]. Other chromosome21 abnormalities have been noted including Robertsoniantranslocations, partial trisomy of 21, in which only a smallbut critical portion of chromosome 21 is trisomic, iso-chromosomes, arising from the duplication of the long armof chromosome 21 and the deletion of the short arm, andring formations of chromosome 21 [4–8].

The only confirmed risk factor for Down syndrome isadvanced maternal age [9]. This observation has beendemonstrated in many populations regardless of race orgeography [10]. More recent data suggest that the riskmight level after 45 years of age [11]. Other risk factors forDown syndrome that have been explored include paternalage (age <20 and >50 years slightly elevated risk), oralcontraceptive use (inconsistent), preconceptional radia-tion (somewhat elevated risk, although not consistent),maternal smoking (slight decreased risk possibly due toincreased fetal loss), maternal immunity (inconsistent),and certain maternal and paternal occupations (incon-clusive) [12–30].

MALIGNANCY IN INDIVIDUALS WITHDOWN SYNDROME

The association between Down syndrome and leuke-mia was first reported over 65 years ago [31]. Follow-ing this initial observation, a series of case reports andcase series confirmed and described further this uniqueassociation (reviewed in [32]). Studies suggest a 10- to 20-fold increased risk of leukemia in children with Downsyndrome [33] with some reports suggesting as high asa 500-fold increased risk of a particular type of acutemyeloid leukemia (AML-M7) [34]. Recent studies havefurther characterized the risk of malignancy in individualswith Down syndrome.

Yang et al. [35], in an analysis from the Centers forDisease Control, reviewed 32 million death certificatesduring the period 1983–1997 including nearly 18,000individuals with Down syndrome. Over the 15-yearperiod, the median age at death for individuals with Downsyndrome increased from 25 to 49 years of age. The mostcommon causes of death in these individuals were con-genital heart defects, hypothyroidism, respiratory infec-tions, and malignancy (leukemia). For leukemia, the

Studies suggest nearly a 20-fold increased riskof leukemia in individuals with Down syndrome.Most of this increased risk appears in the first fewdecades of life, with the highest incidence inchildren less than5yearsofage. It isunknownwhychildren with Down syndrome are at such anincreased risk of leukemia. With respect toenvironmental exposures, it will be important toinvestigate risk factors associated with childhood

leukemia in general (including diagnostic x-rays,pesticides, and other occupational exposures) aswell as experiences common to children withDown syndrome (including routine medicalscreening tests, increased susceptibility to infec-tions, and increased vitamindeficiencies). PediatrBlood Cancer 2005;44:8–12.� 2004 Wiley-Liss, Inc.

Key words: Down syndrome; epidemiology; leukemia; risk factors

——————1Division of Pediatric Epidemiology and Clinical Research,

Department of Pediatrics, University of Minnesota, Minneapolis,

Minnesota

2Department of Epidemiology, University of North Carolina, Chapel

Hill, North Carolina

Grant sponsor: NCI; Grant numbers: R01-CA75169, U01-CA98543;

Grant sponsor: The Children’s Research Fund.

*Correspondence to: Julie A. Ross, University of Minnesota Cancer

Center, MMC 422, 420 Delaware St. S.E., Minneapolis, MN 55455.

E-mail: ross@epi.umn.edu

Received 19 April 2004; Accepted 10 June 2004

� 2004 Wiley-Liss, Inc.DOI 10.1002/pbc.20165

proportion of leukemia deaths in individuals significantlydecreased with advancing agewith standardized mortalityodds ratios (SMORs) of 3.31, 2.26, 2.11, 1.47, 0.52, 0.35,and 0.29 for ages<10, 10–19, 20–29, 30–39, 40–49, 50–59, and �60 years, respectively. Interestingly, with theexception of testicular cancer (SMOR¼ 3.23; 95%confidence interval (CI)¼ 2.19–4.78), there was a statis-tically significant lack of other solid tumors in individualswith Down syndrome.

Hasle et al. [36] described the incidence of malignancyin 2,814 individualswithDown syndrome registered in theDanish Cytogenetic Registry during the period 1968–1995. A total of 60 cancers were found compared to about50 expected (standardized incidence ratio (SIR)¼ 1.20,95% CI¼ 0.92–1.55). When site-specific malignancieswere examined, leukemias accounted for 60% of cancersoverall and 97% of cancers in children under the age of15 years. The rate of leukemia was highest in childrenunder 5 years of age (SIR¼ 56, 95% CI¼ 37.8–81.0) butdeclined notably thereafter. Overall, the cumulative in-cidence by the age of 5 years was 2.1% and by the age of30 years, 2.7%. There was almost a fourfold higherincidence ofAML to acute lymphoblastic leukemia (ALL)before the age of 5. In fact, for children under the age of20 years, all AML cases occurred in the first 3 years oflife. Finally, with the exception of germ cell tumors andretinoblastoma, there was a conspicuous lack of othermalignancies in both children and adults (e.g., no breastcancers were reported where seven would have beenexpected).

Figures 1 and 2 provide recent data from the Children’sOncology Group registrations of children with Down syn-drome and leukemia. While some caution is needed ininterpreting these graphs (i.e., we are providing estimatesof total case numbers by age against published incidencedata), it is apparent that the distribution by age at diagnosisof childrenwith Down syndrome andALL closely follows

what would be expected in the general population, whilethe distribution of children with Down syndrome andAML is skewed toward the first few years of life. Thispattern follows what has been noted above by Hasleet al. [36].

WHY DO CHILDREN WITH DOWN SYNDROMEDEVELOP LEUKEMIA?

There is considerable speculation as to why childrenwith Down syndrome are at such an increased risk ofleukemia and some of these genetic and molecular hypo-theses are presented elsewhere in this series. Below, wepresent some hypotheses with respect to environmentalexposures.

First, it would be important to determine whether riskfactors for childhood acute leukemia (both AML andALL) are associated with leukemia in Down syndrome. Inutero exposure to diagnostic X-rays is one of the onlyknown causes of childhood leukemia; although, due to theextremely low number of individuals exposed, the popu-lation attributable risk is quite small [37]. Other factorsthat have been associated with childhood leukemia in-clude maternal history of fetal loss (ALL and AML),maternal alcohol consumption during pregnancy (parti-cularly, AML), infant birth weight (high) (particularly,ALL), parental and child pesticide exposure, and certainparental occupational exposures (both AML and ALL).There are several less well-documented associationsincluding maternal age and birth order [37]. By and large,the only potentially shared risk factor for both Downsyndrome and childhood leukemia is advanced maternalage. However, it is unknown if any of these risk factorsplay a role in leukemia development in Down syndrome.Moreover, investigation of these potential risk factors inthe etiology of leukemia in Down syndrome might lead toa better understanding of these leukemia risk factors forchildren without Down syndrome.

Fig. 1. Distribution of COG Down syndrome patients with ALL

(1997–2002) by age compared to age-specific SEER ALL incidence

rates, 1986–1994.

Fig. 2. Distribution of COG Down syndrome patients with AML

(1997–2002) by age compared to age-specific SEER AML incidence

rates, 1986–1994.

Epidemiology of Leukemia in Children 9

Second, it may be useful to investigate medical teststhat children with Down syndrome receive. According tothe general pediatric guidelines for preventive health care[38], it is recommended that Down syndrome childrenroutinely undergo several medical procedures in the firstfewyears of life, including radiographs, thyroid screening,karyotyping, echocardiograms, etc. Moreover, many ofthese screening procedures are recommended at specifiedintervals throughout childhood. However, it is unknownwhether the administration and/or number of these pro-cedures could be associated with leukemia in Downsyndrome.

Third, several studies have investigated the increasedsusceptibility of Down syndrome children to infections[38–43]. In particular, defects in cell-to-cell communica-tion and decreasedwhite cell counts have been observed insome children with Down syndrome [40,41]. This impair-ment in immune function could make a Down syndromechildmore at risk of developing leukemia. Importantly, theage peak for children with Down syndrome and ALLappears to closely follow the age peak for childhood ALL(Fig. 1). This age peak is also found in other industrializedcountries [37]. Greaves proposed that the age peak inchildhood ALL may represent the result of at least twoindependent genetic mutations [44,45]. The first mutationoccurs during the expansion of B-cell precursors in utero,giving rise to a population of preleukemic clone cells[44,46]; the second mutation occurs in a mutant cloneduring postnatal proliferation of B-cells. Greaves hypo-thesized that exposure to common infections in earlychildhoodmayprotect a child againstALLby contributingto normal maturation of the immune system, whereaschildren whose exposure is delayed will be at compara-tively higher risk [44,47,48]. Some studies have supportedthe possible role of delayed infection in the etiology ofchildhood leukemia [49–53]. It will be of interest todetermine whether delayed exposure to infections mightbe more relevant for ALL than AML in children withDown syndrome.

Fourth, Down syndrome children are more prone tovitamin and mineral deficiencies than children withoutDown syndrome [54–61]. In particular, children withDown syndrome tend to be zinc deficient, which has beenassociated with impaired immune function. Severalclinical studies have been conducted that have exploredthe benefits of zinc supplementation in Down syndrome.Thus, vitamin supplementation provided to the childpostnatally, as well as maternal diet during pregnancy,could be explored.

Finally, in addition to the differences described abovein the epidemiology of AML and ALL in children withoutDown syndrome, it will be important to consider uniqueaspects of AML in childrenwithDown syndrome. Besidesan early age at onset, AML in children with Down syn-drome is often preceded by a transient myeloproliferative

disorder (TMD) that appears in infancy [62]. About 30%of infants with Down syndrome and TMD develop AMLwithin 3 years [63]. Importantly, acquired mutations inGATA-1, a gene important in the development of certaincell lineages of the hematopoietic system, are common inpatients with Down syndrome and AML as well as Downsyndrome and TMD [62]. Thus, given the short latency ofAML in Down syndrome, a focus on maternal exposuresduring pregnancy would be appropriate, similar to epi-demiological studies investigating infant leukemias withMLL gene translocations [64]. We are currently exploringthese relationships in a case-control study conductedin the Children’s Oncology Group, which included158 children with leukemia and Down syndrome (97ALL and 61 AML), 173 children with Down syndrome,and 178 children that had neither condition. Initial resultsof this study should be available by the end of 2004.

REFERENCES

1. Centers for Disease Control. Down syndrome prevalence at birth in

the United States, 1983–1990. MMWR 1994;43:617–622.

2. Edmonds LD, James LM. Temporal trends in the birth prevalence

of selected congenital malformations in the Birth Defects

Monitoring Program/Commission on Professional and Hospital

Activities, 1979–1989. Teratology 1993;48:647–649.

3. Hook EB, Cross PK, Jackson L, et al.Maternal age-specific rates of

47,þ21, and other cytogenetic abnormalities diagnosed in the first

trimester of pregnancy in chorionic villus biopsy specimens:

Comparison with rates expected from observations at amniocent-

esis. Am J Hum Genet 1988;42:797–807.

4. Yoon PW, Freeman SB, Sherman SL, et al. Advanced maternal age

and the risk of Down syndrome characterized by the meiotic stage

of chromosomal error: A population-based study. Am JHumGenet

1996;58:628–633.

5. Korenberg JR, Kawashima H, Pulst SM, et al. Molecular de-

finition of a region of chromosome 21 that causes features of

the Down syndrome phenotype. Am J Hum Genet 1990;47:236–

246.

6. Janerich DT, Bracken MB. Epidemiology of trisomy 21: A

review and theoretical analysis. J Chronic Dis 1986;39:1079–

1093.

7. Wolff DJ, Schwartz S. The effect of Robertsonian translocation on

recombination on chromosome 21. Hum Mol Genet 1993;2:693–

699.

8. Shaffer LG, McCaskill C, Haller V, et al. Further characterization

of 19 cases of rea(21q21q) and delineation as isochromosomes or

Robertsonian translocations in Down syndrome. Am J Med Genet

1993;47:1218–1222.

9. Hook EB, Cross PK, Schreinemachers DM. Chromosomal

abnormality rates at amniocentesis and in live-born infants. Jama

1983;249:2034–2038.

10. Benn PA. Advances in prenatal screening for Down syndrome: I.

General principles and second trimester testing. Clin Chim Acta

2002;323:1–16.

11. Morris JK, Mutton DE, Alberman E. Revised estimates of the

maternal age specific live birth prevalence of Down’s syndrome.

J Med Screen 2002;9:2–6.

12. McIntosh GC, Olshan AF, Baird PA. Paternal age and the risk of

birth defects in offspring. Epidemiology 1995;6:282–288.

13. Kline J, Levin B, Stein Z, et al. Cigarette smoking and trisomy 21 at

amniocentesis. Genet Epidemiol 1993;10:35–42.

10 Ross et al.

14. Khoury MJ, Flanders WD, James LM, et al. Human teratogens,

prenatal mortality, and selection bias. Am J Epidemiol 1989;130:

361–370.

15. Rothman KJ. Spermicide use and Down’s syndrome. Am J Public

Health 1982;72:399–401.

16. Warburton D, Neugut RH, Lustenberger A, et al. Lack of asso-

ciation between spermicide use and trisomy. N Engl J Med 1987;

317:478–482.

17. Strobino B, Kline J, Lai A, et al. Vaginal spermicides and spon-

taneous abortion of known karyotype. Am J Epidemiol 1986;123:

431–443.

18. Polednak AP, Janerich DT. Uses of available record systems in

epidemiologic studies of reproductive toxicology. Am J Ind Med

1983;4:329–348.

19. Olshan AF, Baird PA, Teschke K. Paternal occupational exposures

and the risk of Down syndrome. Am J Hum Genet 1989;44:646–

651.

20. Schnitzer PG, Olshan AF, Erickson JD. Paternal occupation and

risk of birth defects in offspring. Epidemiology 1995;6:577–583.

21. Silverman J, Kline J, Hutzler M, et al. Maternal employment and

the chromosomal characteristics of spontaneously aborted con-

ceptions. J Occup Med 1985;27:427–438.

22. Matte TD, Mulinare J, Erickson JD. Case-control study of con-

genital defects and parental employment in health care. Am J Ind

Med 1993;24:11–23.

23. McDonald AD, McDonald JC, Armstrong B, et al. Congenital

defects and work in pregnancy. Br J Ind Med 1988;45:581–588.

24. Boue J, Bou A, Lazar P. Retrospective and prospective epidemio-

logical studies of 1,500 karyotyped spontaneous human abortions.

Teratology 1975;12:11–26.

25. Strigini P, Pierluigi M, Forni GL, et al. Effect of X-rays on chromo-

some 21 non-disjunction. Am J Med Genet 1990;7:155–159.

26. Alberman E, Polani PE, Roberts JA, et al. Parental exposure to

X-irradiation and Down’s syndrome. Ann Hum Genet 1972;36:

195–208.

27. Fialkow PJ. Thyroid antibodies, Down’s syndrome, and maternal

age. Nature 1967;214:1253–1254.

28. Fialkow PJ, Hecht F, Uchida IA, et al. Increased frequency of

thyroid autoantibodies in mothers of patients with Down’s

syndrome. Lancet 1965;2:868–870.

29. Cuckle H, Wald N, Stone R, et al. Maternal serum thyroid

antibodies in early pregnancy and fetal Down’s syndrome. Prenat

Diagn 1988;8:439–445.

30. Khoury MJ, Becerra JE, d’Almada PJ. Maternal thyroid disease

and risk of birth defects in offspring: A population-based case-

control study. Paediatr Perinat Epidemiol 1989;3:402–420.

31. Brewster HF, Cannon HE. Acute lymphatic leukemia: Report of a

case in eleventh month mongolian idiot. New Orleans Med Surg J

1930;82:872–873.

32. Satge D, Sommelet D, Geneix A, et al. A tumor profile in Down

syndrome. Am J Med Genet 1998;78:207–216.

33. Robison LL. Down syndrome and leukemia. Leukemia 1992;1

5–7.

34. Zipursky A, Peeters M, Poon A. Megakaryoblastic leukemia and

Down’s syndrome: A review. Pediatr Hematol Oncol 1987;4:211–

230.

35. Yang Q, Rasmussen SA, Friedman JM. Mortality associated with

Down’s syndrome in the USA from 1983 to 1997: A population-

based study. Lancet 2002;359:1019–1025.

36. Hasle H, Clemmensen IH, Mikkelsen M. Risks of leukaemia and

solid tumours in individuals with Down’s syndrome. Lancet 2000;

355:165–169.

37. Ross JA, Davies SM, Potter JD, et al. Epidemiology of childhood

leukemia, with a focus on infants. Epidemiol Rev 1994;16:243–

272.

38. Hayes A, Batshaw ML. Down syndrome. Pediatr Clin North Am

1993;40:523–535.

39. Adams MM, Erickson JD, Layde PM, et al. Down’s syndrome.

Recent trends in the United States. Jama 1981;246:758–760.

40. Cuadrado E, Barrena MJ. Immune dysfunction in Down’s

syndrome: Primary immune deficiency or early senescence of the

immune system? Clin Immunol Immunopathol 1996;78:209–214.

41. Novo E, Garcia MI, Lavergne J. Non-specific immunity in Down

syndrome: A study of chemotaxis, phagocytosis, oxidative meta-

bolism, and cell surface marker expression of polymorphonuclear

cells. Am J Med Genet 1993;46:384–491.

42. Roizen NJ, Amarose AP. Hematologic abnormalities in children

with Down syndrome. Am J Med Genet 1993;46:510–512.

43. LockitchG, SinghVK, PutermanML, et al. Age-related changes in

humoral and cell-mediated immunity in Down syndrome children

living at home. Pediatr Res 1987;22:536–540.

44. Greaves MF. Speculations on the cause of childhood acute

lymphoblastic leukemia. Leukemia 1988;2:120–125.

45. Greaves MF, Pegram SM, Chan LC. Collaborative group study of

the epidemiology of acute lymphoblastic leukaemia subtypes:

Background and first report. Leuk Res 1985;9:715–733.

46. Greaves MF, Maia AT, Wiemels JL, et al. Leukemia in twins:

Lessons in natural history. Blood 2003;102:2321–2333.

47. Greaves MF, Alexander FE. An infectious etiology for common

acute lymphoblastic leukemia in childhood? Leukemia 1993;7:

349–360.

48. GreavesMF.Aetiology of acute leukaemia. Lancet 1997;349:344–

349.

49. McKinney PA, Juszczak E, Findlay E, et al. Pre- and perinatal risk

factors for childhood leukaemia and othermalignancies: AScottish

case control study. Br J Cancer 1999;80:1844–1851.

50. Jourdan-DaSilvaN, PerelY,MechinaudF, et al. Infectious diseases

in the first year of life, perinatal characteristics, and childhood acute

leukaemia. Br J Cancer 2004;90:139–145.

51. Schuz J, Kaletsch U, Meinert R, et al. Association of childhood

leukaemia with factors related to the immune system. Br J Cancer

1999;80:585–590.

52. van Steensel-Moll HA, Valkenburg HA, van Zanen GE. Childhood

leukemia and infectious diseases in the first year of life: A register-

based case-control study. Am J Epidemiol 1986;124:590–594.

53. Neglia JP, Linet MS, Shu XO, et al. Patterns of infection and day

care utilization and risk of childhood acute lymphoblastic

leukaemia. Br J Cancer 2000;82:234–240.

54. Chiricolo M, Musa AR, Monti D, et al. Enhanced DNA repair in

lymphocytes of Down syndrome patients: The influence of zinc

nutritional supplementation. Mutat Res 1993;295:105–111.

55. Licastro F, Mocchegiani E, Zannotti M, et al. Zinc affects the

metabolism of thyroid hormones in children with Down’s syn-

drome: Normalization of thyroid stimulating hormone and of

reversal triiodothyronine plasmic levels by dietary zinc supple-

mentation. Int J Neurosci 1992;65:259–268.

56. Licastro F, Chiricolo M, Mocchegiani E, et al. Oral zinc supple-

mentation in Down’s syndrome subjects decreased infections

and normalized some humoral and cellular immune parameters.

J Intellect Disabil Res 1994;38:149–162.

57. Napolitano G, Palka G, Lio S, et al. Is zinc deficiency a cause of

subclinical hypothyroidism in Down syndrome? Ann Genet 1990;

33:9–15.

58. Colombo ML, Givrardo E, Ricci BM, et al. [Blood zinc in patients

with Down’s syndrome and its relations with their immune status].

Minerva Pediatr 1989;41:71–75.

59. ColomboML, Girardo E, Incarbone E, et al. [Vitamin C in children

with trisomy 21]. Minerva Pediatr 1989;41:189–192.

60. Cartlidge PH, Curnock DA. Specificmalabsorption of vitamin B12

in Down’s syndrome. Arch Dis Child 1986;61:514–515.

Epidemiology of Leukemia in Children 11

61. Purice M, Maximilian C, Dumitriu I, et al. Zinc and copper in

plasma and erythrocytes of Down’s syndrome children. Endocri-

nologie 1988;26:113–117.

62. Gurbuxani S, Vyas P, Crispino JD. Recent insights into the

mechanisms of myeloid leukemogenesis in Down syndrome.

Blood 2004;103:399–406.

63. Zipursky A, Poon A, Doyle J. Leukemia in Down syndrome:

A review. Pediatr Hematol Oncol 1992;9:139–149.

64. Ross JA, Potter JD, Reaman GH, et al. Maternal exposure to

potential inhibitors of DNA topoisomerase II and infant leukemia

(United States): A report from the Children’s Cancer Group.

Cancer Causes Control 1996;7:581–590.

12 Ross et al.