Pediatr Blood Cancer 2011;56:767–770

Western Australian Children With Acute Lymphoblastic Leukemia Are Tallerat Diagnosis Than Unaffected Children of the Same Age and Sex

Esther Davis, MBBS,1 Peter Jacoby, BA, MSc,2 Nicholas H. de Klerk, MSc, PhD,2 Catherine Cole, MBBS, FRACP, FRCPA,3*and Elizabeth Milne, MPH, PhD

2

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common

childhood malignancy, accounting for approximately 30% of

childhood cancer disease burden in Australia [1]. The etiology of

acute childhood leukemia remains incompletely understood [2], but

recently there has been a growing interest in the role of growth

factors in the etiology of childhood and adult malignancies.

Many studies have investigated the relationship between birth

weight and the risk of childhood leukemia. A recently published

meta-analysis of 32 studies [3] reported a positive association

between high birth weight (defined as >4,000 g) and childhood

leukemia, with a pooled odds ratio (OR) of 1.35 (95% confidence

interval (CI): 1.24, 1.48) for all leukemia, and 1.23 (95% CI: 1.15,

1.32) for ALL. For ALL, they also reported an OR of 1.18 (95% CI:

1.12, 1.23) per 1,000 g increase in birth weight.

Recently published data from Western Australia suggested a link

between proportion of optimal birth weight (POBW) (an estimate of

the appropriateness of intrauterine growth) and the risk of ALL [4].

This study found that a one standard deviation increase in POBW

was associated with a 25% (95% CI: 7, 47%) increase in risk. This

increased risk was also observed among children who did not have a

high birth weight, suggesting that accelerated fetal growth, rather

than high birth weight alone, is associated with a risk of childhood

ALL. The authors suggested that this association might be related to

increased levels of insulin-like growth factors (IGFs) in utero, as

birth weight has been positively associated with levels of IGF-I [5]

and implicated in the promotion of growth of leukemic blast

cells [6].

Few studies have investigated the relationship between growth

during infancy and early childhood and risk of leukemia, and they

have yielded inconsistent results. While two studies found little

difference in height between childhood and adolescent cancer cases,

including ALL and other leukemias, and population norms [7,8],

another study reported that children with leukemia were taller at

diagnosis than children from the general population [9].

The aim of this study was to determine whether children

diagnosed with ALL in Western Australia were taller at the time of

diagnosis than children of the same age and sex in the general

population.

MATERIALS AND METHODS

Children with ALL were identified through the database of the

Department of Oncology and Haematology at Princess Margaret

Hospital (PMH). PMH is the sole pediatric tertiary referral center in

Western Australia, so its database includes virtually all children

diagnosed with acute leukemia in Western Australia. Patients

eligible for inclusion in this study were those diagnosed with ALL

who underwent induction chemotherapy at PMH between January

1984 and June 2008. Eligible patients were aged <15 years at

diagnosis and had biometric parameters (height and weight)

recorded immediately prior to the commencement of the chemo-

therapeutic treatment. Height had been measured by trained

professionals using a stadiometer, with the child standing unless

they were too young to stand, in which case their length was

measured.

Of the 375 cases of ALL identified in the database, 32 (8.53%)

were excluded because they had been diagnosed and had initial

treatment outside Western Australia; biometric parameters prior to

induction chemotherapy were not available for these patients. Ten

cases were excluded due to lack of biometric data in the patient file

Background. Acute lymphoblastic leukemia (ALL) is the com-monest childhood malignancy in Australian children. Recentlypublished data from Western Australia suggest a link betweenproportion of optimal birth weight and the risk of ALL, but few studieshave investigated the relationship between growth during infancyand early childhood and risk of leukemia. The aim of this study wasto determine whether children diagnosed with ALL in WesternAustralia were taller at the time of diagnosis than children of thesame age and sex in the general population. Methods. Records ofchildren diagnosed with ALL between January 1984 and June 2008were accessed. Height before the commencement of chemotherapywas recorded and compared to the height of population norms

derived from the Longitudinal Study of Australian Children. Results.On average, male cases were 0.67 cm (95% CI�0.21, 1.54 cm) tallerand female cases were 0.30 cm (95% CI �0.68, 1.28 cm) taller thanpopulation controls. Conclusions. Our results suggest that childrendiagnosed with ALL in Western Australia are slightly taller than theircounterparts in the general population. These findings are consistentwith at least one previous study. While this increase in height may betoo small to be recognizable clinically, it is consistent with thenotion that growth factors play a role in the pathogenesis of ALLbeyond infancy. Pediatr Blood Cancer. Pediatr Blood Cancer2011;56:767–770. � 2010 Wiley-Liss, Inc.

Key words: acute lymphoblastic leukemia, epidemiology, height

� 2011 Wiley-Liss, Inc.DOI 10.1002/pbc.22832Published online 18 January 2011 in Wiley Online Library(wileyonlinelibrary.com).

——————1Royal Perth Hospital, Perth, WA, Australia; 2Centre for Child Health

Research, Telethon Institute for Child Health Research, University of

Western Australia, Perth, WA, Australia; 3School of Paediatrics and

Child Health, University of Western Australia, Subiaco, WA, Australia

Conflict of interest: Nothing to declare.

Resident Medical Officer.

*Correspondence to: Catherine Cole, Director of Paediatric

Haematology and Oncology, Princess Margaret Hospital for

Children, GPO Box D184, Perth, WA 6840, Australia.

E-mail: catherine.cole@health.wa.gov.au

Received 18 March 2010; Accepted 17 August 2010

and eight were excluded because they had pre-morbid constitutional

trisomy 21. The medical records for a further four cases were not

available for review during the period of data collection. The

remaining 321 cases of ALL were eligible for inclusion in this study.

Cases were then restricted to those aged between 27 and 94 months

at the time of diagnosis to match the age distribution of controls (see

below). Following this restriction, 207 ALL cases were available for

inclusion.

The following data were extracted from the records of all eligible

cases: sex, month and year of birth, date of diagnosis, age at

diagnosis, and height at the time of induction chemotherapy.

Immunophenotype and cytogenetic class of ALL were also recorded

where available.

Data on the height of Australian children were derived from the

Longitudinal Survey of Australian Children (LSAC) [10]. LSAC is a

multidisciplinary study which aims to follow up two cohorts of

children for a minimum of 7 years. The first cohort comprised of

children aged<12 months who have been followed up every 2 years

to age 6–7 years, while the second cohort is made up of children

aged 4–5 years followed to age 11–12 years [10]. Initial measure-

ments in both cohorts were undertaken by trained personnel in 2003/

2004 with first follow-up measurements undertaken in 2005/2006.

Objectively measured height was therefore available for children

between the ages of 27 and 94 months.

As our ALL cases were all from Western Australia, we used

LSAC data for Western Australian children only. This study was

approved by the Princess Margaret Hospital Human Research Ethics

Committee.

STATISTICAL METHODS

Age-specific mean heights were estimated for the Western

Australian population by fitting fractional polynomial functions to

the LSAC height data for males and females separately and the

uncertainty in population means was estimated via standard errors

of mean prediction. Each ALL case’s expected height was then

calculated using the age-interpolated value from the appropriate

fitted function, and paired t-tests were used to calculate means and

confidence intervals for the differences between actual and expected

height. We used STATA to perform the curve fitting and EXCEL to

analyze height differences.

Results

Measurements were available for 207 ALL cases: 120 males and

87 females. Controls were derived from LSAC measurements of

Western Australian children only. Height measurements were

available for a total of 1,481 children: 466 children aged 27–

46 months, 553 children aged 51–67 months, and 462 children aged

75–94 months. Heights of ALL cases and the fitted population mean

height versus age curves are plotted in Figures 1 and 2 for males and

females, respectively. The standard errors for the fitted population

means averaged 0.28 cm for males and 0.29 cm for females. On

average, male cases were 0.67 cm (95% CI �0.21, 1.54 cm) taller

and female cases were 0.30 cm (95% CI�0.68, 1.28 cm) taller than

population controls.

Discussion

This study of Western Australian children diagnosed with ALL

between 1984 and 2008 showed that male cases were, on average,

slightly taller than other Western Australian males. The difference in

height between female cases and controls was smaller again.

Pui et al. [8] concluded that there was no difference in height

between the ALL cases and healthy children of the same age and

sex. However, the authors reported a mean of standard deviation

score for height of 0.082 in males with ALL (P¼ 0.02), suggesting

male ALL cases were 0.082 standard deviations taller than the

population mean for the same age. Standard deviations of height

vary by age, but are approximately 6 cm. Therefore, 0.082 of a

standard deviation equates to approximately 0.5 cm, consistent with

our finding that male cases were, on average, 0.67 cm taller than

male controls. Broomhall et al. [9] also reported a relationship

between increased height and diagnosis of ALL, reporting a mean

standard deviation score of 0.492 suggesting a difference in height in

the vicinity of 3 cm. However, these results should be interpreted

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Age (m)

Hei

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Fig. 1. Measured height versus age for male cases and fitted population mean height curve. [Color figure can be viewed in the online issue, which is

available at wileyonlinelibrary.com.]

768 Davis et al.

with caution due to the 20-year gap between collection of case and

control data.

Cases for our Western Australian study were diagnosed over a

period of 24 years between 1984 and 2008, while controls were all

assessed in 2003/2004 and 2005/2006, towards the end of the 24-

year interval. Anecdotal reports suggest that children may be

becoming progressively taller over time and these reports have been

supported by a recent review of growth studies in Australian

children [11] which found that Australian children were increasing

in height at a rate of approximately 1.02 cm per decade. This is

consistent with findings from other countries around the world [11].

Because of this, the measurement of controls towards the end of the

period during which our cases were diagnosed would lead to our

controls tending to be taller, and thus to an underestimation of the

association between height and risk of ALL. On the other hand,

Broomhall et al. may have overestimated the association between

height and risk of leukemia, as the controls were measured up to

25 years before the cases were diagnosed.

The potential for error in the measurement of height among the

subjects in this study was minimal. Height measurement for ALL

cases was undertaken by trained professionals at a single center

using standard techniques. The main purpose of these height (and

weight) measurements was to determine the appropriate dose of

chemotherapy for the treatment of the child’s disease, so the need for

accurate recording is clear. Height measurements among controls

were made by trained research staff using standardized instruments

as part of the LSAC protocol. This study, as in previous studies, has

no available information on parental height, and is therefore not able

to determine whether these children were taller than might be

predicted based on genetic factors. However, with such a large

control group, this is unlikely to have influenced the results. Our

assumption of no uncertainty in the fitted means from the population

is likely to have led to an overestimation of the precision of the

height differences between ALL cases and controls.

Data on birth weight were not available, so we were unable to

assess whether adjusting for it would alter the weak association we

observed between childhood height and risk of ALL. The

appropriateness of adjusting for birth weight would depend on the

likely underlying biological pathways. For example, if height in

childhood is related directly to childhood growth factors (i.e.,

independent of fetal growth factors), then adjustment for birth

weight would not be necessary to determine whether there is a

relationship between childhood height and risk of ALL. It is widely

accepted that IGFs and GHs are important in both pre- and post-natal

growth, but evidence suggests that IGF levels in childhood are not

necessarily related to IGF levels in utero. A study of 497 healthy

5 years old found that IGF-I levels at age 5 were positively related to

current weight and height, but unrelated to cord blood IGF-I levels at

birth [12]. On the other hand, IGF-II levels at age 5 were positively

related to IGF-II levels at birth, suggesting that childhood IGF-II

levels may be determined to some extent by antenatal or genetic

factors. IGF-I is the most commonly implicated growth factor in

both high birth weight [5] and the promotion of leukemic cells [6].

As evidence suggests that there is no positive association between

IGF-I levels in utero and in childhood, childhood height may be

associated with risk of ALL, mediated through IGFs in childhood,

irrespective of birth weight. However, as little is known about the

possible role played by other growth factors in the etiology of

childhood ALL, there is a possibility that the association may be

influenced to some extent by fetal growth factors. As indicated

above, we were unable to investigate this possibility in this study.

Our study has only considered the height of children aged

between 2 and 7 years because of a lack of availability of control

data for older and younger children. This is a limitation of our

present study in that the results cannot be applied to children outside

this age range. However, our results include the peak age at

incidence of childhood ALL (2–5 years). Further studies consid-

ering a broader patient group may allow for further generalization of

these results.

In conclusion, the results of this small study are consistent with

young male children diagnosed with ALL being slightly taller than

their counterparts in the general population. The absolute magnitude

of the height difference we observed is unlikely to be clinically

apparent in an individual. However, such an increase in height, if

consistently established, may suggest an ongoing effect of growth

factors in the pathogenesis of ALL beyond infancy. Future studies in

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Fig. 2. Measured height versus age for female cases and fitted population mean height curve. [Color figure can be viewed in the online issue, which

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Height of Children With Acute Lymphoblastic Leukemia 769

this area would benefit from consideration of parental heights in

order to determine whether children with leukemia are taller than

predicted within their family, as well as slightly taller than unrelated

children. Establishing such relationships would lend weight to the

case for further investigation into the role of growth factors during

childhood in relation to the risk of ALL.

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