the recognition and treatment of growth disorders – a 50-year retrospective
TRANSCRIPT
REVIEW ARTICLE
The recognition and treatment of growth disorders � A50-year retrospective
BABETTE ZEMEL
Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of
Philadelphia, Department of Pediatrics, The University of Pennsylvania School of
Medicine, Philadelphia, PA 19104, USA
(Received 23 March 2009; accepted 26 March 2009)
AbstractThe past 50 years have seen great progress in the understanding and treatment of classic growthdisorders. Advances such as the recognition of hormone receptor defects, the development ofrecombinant growth hormone, and the expanding awareness of epigenetic phenomena affectinggrowth are among these great achievements. Yet growth failure remains a pervasive problem amongchildren with complex health conditions, such as survivors of childhood cancers, premature infants,organ transplant recipients, and children with cystic fibrosis. The significant increases in lifeexpectancy among these groups underscores the potential consequences of poor growth, whetherdue to the underlying conditions or medical treatments, as they may have long-lasting effects intoadulthood. The ongoing contributions of human biologists to the study of human growth remainessential in the recognition and treatment of growth disorders, by defining normal patterns of growthand body composition, the interplay of growth and maturation, the role of environmental, behavioraland genetic factors, and the long-term consequences of growth patterns. Examples will be given basedon two common genetic disorders, cystic fibrosis and sickle-cell anemia, to highlight the relationshipsbetween growth failure, survival, and malnutrition. Also, a study of bone mineral accretion in childrenwith cystic fibrosis will illustrate the importance of understanding patterns of growth in healthychildren, and their application in the diagnosis and management of children with chronic disease.These examples accentuate the need for continued participation of human biologists in the study ofgrowth and development and the care of children.
Keywords: Growth, children, sickle-cell disease, cystic fibrosis
Introduction
In the past 50 years there has been phenomenal progress in the basic and clinical science of
growth and its disorders. Witness the expansion and refinement in understanding the
Correspondence: Babette Zemel, Division of Gastroenterology, Hepatology and Nutrition, The Children’s Hospital of
Philadelphia, Department of Pediatrics, The University of Pennsylvania School of Medicine, 3535 Market Street, Room 1560,
Philadelphia, PA 19104, USA. E-mail: [email protected]
ISSN 0301-4460 print/ISSN 1464-5033 online # 2009 Informa UK Ltd.
DOI: 10.1080/03014460902980303
Annals of Human Biology, September�October 2009; 36(5): 496�510
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mechanisms of growth, particularly with respect to the growth hormone axis and insulin-
like growth factors, the role of receptors, carrier proteins and transcription factors (Le Roith
et al. 2001; Mullis 2005; Daughaday 2006), and the treatment of growth disturbances
through innovations such as recombinant growth hormone (Zucchini 2008) and insulin-like
growth factor-I (IGF-I) (Rosenbloom 2008).
In parallel, the human biology of growth has flourished. Most notably, there has been
extensive documentation of worldwide variation in human growth (Eveleth and Tanner
1991) and the factors that influence growth including nutrition (e.g. see Norgan 1995;
Panter-Brick 1997; Shoff 2006; Stein et al. 2003; Zemel et al. 2002), ethnicity/population
ancestry (racial differences) (Rona and Chinn 1986; Denham et al. 2001; Komlos and
Breitfelder 2008), social and economic forces (Norgan 1995; Laska-Mierzejewska
and Olszewska 2007), the physical environment (Cameron et al. 1992; Panter-Brick
1997), and pre-natal (Adair 2007), perinatal (Luke et al. 2004) and intergenerational effects
(Alberman et al. 1991; Stein et al. 2003). In addition, the assessment of growth has
advanced significantly, particularly with respect to large, well-designed surveys to establish
reference data for growth and nutritional assessment (Cole et al. 1995; Leung et al. 1998;
Ogden et al. 2002; de Onis et al. 2007), new statistical techniques for creating growth
curves (Cole and Green 1992) and interpreting growth (such as mid-parental height
adjustment (Himes et al. 1985) and malnutrition screening (Cole et al. 2007)), and the
assessment of skeletal (Tanner et al. 2001) and sexual maturation (Tanner 1962; Morris and
Udry 1980; Schall et al. 2002; Sun et al. 2002).
Other advances include the new techniques for the assessment of growth and body
composition, such as the knemometer (Hermanussen 1988; Michaelsen 1994) and knee
height measuring device (Cronk et al. 1989), total body electrical conductivity (Van Loan
and Koehler 1990; Bell et al. 1994; de Bruin et al. 1995) and bioelectrical impedance
analysis (Fuller et al. 2002; Wells et al. 2007), air displacement plethysmography (Wells
et al. 2003; Fields et al. 2004a,b; Ittenbach et al. 2006), dual energy X-ray
absorptiometry (Koo et al. 2004; Margulies et al. 2005; Buison et al. 2006; Wosje
et al. 2006), magnetic resonance imaging (Pietrobelli et al. 2007), infrared interactance
(Brooke-Wavell et al. 1995), and ultrasound techniques for assessment of prenatal growth
(Salomon et al. 2006; Verburg et al. 2008), bone density (Lappe et al. 2000; Magkos et
al. 2005; Micklesfield et al. 2006; Jones and Boon 2008) and body composition
(Guagnano et al. 1997).
While growth assessment has undergone major improvements, the improvements in
medical care have increased survival of children with health conditions that challenge
overall well-being and survival, such as premature birth, childhood cancer, genetic disorders
and congenital anomalies, and organ transplantation. For many of these groups of children,
survival to adulthood is now common albeit with long-term consequences of their disease or
its treatment. Childhood growth and body composition are general indicators of well-being
and disease effects in childhood; poor growth and compromised body composition
represent threats to well-being in adulthood.
To illustrate this partnership between human biology and clinical care of children with
growth disorders, two case studies are presented; one of children with sickle-cell disease
(SCD) and the other of children with cystic fibrosis (CF). While both these diseases are
common potentially lethal genetic disorders, one is common among children of African
ancestry while the other is common among children of European ancestry.
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Case study: Sickle-cell disease
SCD occurs in one of every 500 African-American births (1 in 12 African Americans carries
the SCD trait) and one in every 1000�1400 Hispanic�American births (Ashley-Koch et al.
2000). The symptoms of SCD include severe chronic anemia, acute chest syndrome,
stroke, splenic sequestration, renal dysfunction, pain crises, bacterial infections and
pulmonary hypertension, but the severity of these symptoms is highly variable (Yanni
et al. 2009). The disease is caused by a point mutation whereby glutamic acid is replaced by
valine in the b-globin chain located on the short arm of chromosome 11 (Mehanna 2001).
Altered hemoglobin polymerizes under altered conditions, and the red blood cells become
sickled in shape and fragile. Sickled cells cause vasoocclusion, microvascular damage and
tissue necrosis (Serjeant and Serjeant 2001). People who are heterozygotes for SCD are
protected from the harmful effects of malaria infection, whereas those who are homozygotic
for normal hemoglobin or sickled hemoglobin have an increased risk of mortality from
malaria when living in malaria endemic zones (Serjeant 1989; Nagel and Fleming 1992).
Over the past 50 years, the treatment of SCD has been transformed. In 1956, Ingram and
Hunt sequenced hemoglobin and discovered the single amino acid change in the protein
sequence that caused SCD (Hunt and Ingram 1958, 1960, 1961). Five years later, the first
major report of growth failure in children with SCD was published by Whitten (1961), yet
the cause of the growth failure was not discovered. Up until 1970, death in childhood was
not uncommon, often of overwhelming infection, and approximately 10% of children
suffered fatal or debilitating strokes (Sarnaik et al. 1979; Sarnaik and Lusher 1982). In 1986
profound changes in treatment of children with SCD were instituted as a result of a clinical
trial of oral penicillin therapy (Gaston et al. 1986). Within 8 months, this trial demonstrated
an 84% reduction in the incidence of infection, and the trial was terminated early because of
its success. In 1995, a clinical trial of hydroxyurea therapy in adults was stopped early due to
significant reduction in hospitalizations for painful crises (Charache et al. 1995). Today,
newborn screening programs for SCD are operating in most states, and all children with
SCD are prescribed daily penicillin to prevent fatal infections. In addition, the transcranial
doppler ultrasound technique has proven to be a successful screening measure to identify
those who might be at-risk of stroke so that they can be given regular blood transfusions for
stroke prevention (Adams 2000). Hydroxyurea therapy is another treatment innovation that
has increased life expectancy and reduced emergency department visits and hospitalizations
in adults and children, 5�15 years of age (Brawley et al. 2008; Mehanna 2001; Wang et al.
2002). The combined effect of these changes in the treatment of SCD is evident in the
significantly reduced mortality of children with SCD over the past two decades, as
illustrated in Figure 1 (Yanni et al. 2009).
Although growth failure was recognized over 40 years ago, and documented by numerous
reports in the following decades (Whitten 1961; Kramer et al. 1980; Platt et al. 1984),
growth failure remains a significant problem and its causes and consequences remain
elusive. We conducted a longitudinal growth study of children with SS-type SCD (Zemel
et al. 2007) receiving care at the Comprehensive Sickle Cell Center at The Children’s
Hospital of Philadelphia. Figure 2a compares the growth of children (males and females
combined) from this recent study with the children described by Whitten in the 1960s
(Whitten 1961). Although height status was significantly greater in the children evaluated in
the 1990s, there was still considerable overlap in height status. An important feature in
growth data from both time periods was that height status declined with age. This feature of
growth status of children with SCD was further demonstrated using the longitudinal results
illustrated in Figure 2b (Zemel et al. 2007). Nearly all children (�80%), including those
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whose initial growth status was excellent, declined in their height z-score over time. Girls
demonstrated some recovery of growth status with the onset and progression through
puberty, but for boys, height status declined through age 19�20. Growth failure defined as a
height, weight or body mass index (BMI) value below the 5th percentile at any time during
the 4-year observation period occurred in 28% of girls and 49% of boys (Zemel et al. 2007).
Hemoglobin concentrations were significant predictors of height status for girls, but acute
SCD-related illnesses were not related to growth failure in girls or boys. These findings
suggest that growth failure is more strongly associated with the chronic anemia associated
with SCD, rather than acute effects of the disease.
Sexual maturation was delayed among children with SCD. Figure 3 illustrates the older
ages at entry into each Tanner stage of pubertal development for boy and girls with SCD
compared to US national survey results for healthy African�American children. Compar-
ison to data published in the 1980s on the timing of puberty in children with SCD (Platt
et al. 1984) suggested that there was no improvement in the timing of puberty over that
time period (Zemel et al. 2007).
The degree to which growth failure and delayed maturation is inherent in SCD is still a
matter of much debate. The presence of nutrient deficiencies and poor dietary intake,
suggests that nutritional factors likely contribute to the growth failure of children with SCD.
As part of the longitudinal growth survey of children with SCD, dietary intake and
nutritional biochemistry data were collected. The biochemical indices indicated a high
prevalence of nutritional insufficiency for folate (Kennedy et al. 2001), iron (Stettler et al.
2001), zinc (Leonard et al. 1998; Zemel et al. 2002), and vitamins A (Schall et al. 2004), B6
(Nelson et al. 2002), and D (Buison et al. 2004; Rovner et al. 2008). The dietary data were
in good agreement with this, showing suboptimal intake of energy and vitamins D and E,
folate, calcium, magnesium, zinc, and fiber (Kawchak et al. 2007). A zinc supplementation
study demonstrated improved linear growth in children receiving the zinc supplement
compared to a placebo (Zemel et al. 2002). The nutritional factors contributing to growth
failure are multifactorial and likely include increased energy requirements. Using stable
isotopes (doubly labeled water method) to measure total energy expenditure, and indirect
calorimetry to measure resting energy expenditure, we observed significantly increased
resting energy requirements and reduced total energy expenditure in children with SCD
1983-1986 1991-1994 1999-2002
4 to 9 yrs
-39%
0.00
0.50
1.00
1.50
2.00
2.50
1983-1986 1991-1994 1999-2002
0 to 3 yrs
-68%
1983-1986 1991-1994 1999-2002
10 to 14 yrs
-25%
SCD related deaths per 100,000 black children 1983 to 2002
Age Group
Figure 1. Decline in age-specific mortality rates in children with sickle-cell disease (SCD) from 1983to 2002. Adapted from Yanni et al. (2009).
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(Barden et al. 2000). Reduced lean and fat mass stores accompanied these patterns of
energy expenditure (Barden et al. 2002), suggesting that improved nutritional intake might
alleviate some of the growth failure and delayed maturation of children with SCD. Increased
protein turnover may also impact nutrient requirements and body composition (Borel et al.
1998a,b).
To some degree, the growth failure of children with SCD may be due to their chronic
hemolytic anemia and its direct and indirect effects on growth. Longitudinal analyses
showed that Hgb was significantly associated with growth status over time in children with
SCD (Zemel et al. 2007). Moreover, children who began hydroxyurea therapy had an
increase in fetal hemoglobin production and a decline in their resting energy requirements
over a 3-month period as shown in Figure 4 (Fung et al. 2001). These findings bring
promise that the growth failure and delayed maturation of children with SCD are not
disease characteristics, but are secondary effects of the severe anemia that may improve with
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0 5 10 15 20 0 5 10 15 20
Female Male
Hei
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-Sco
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Age, y
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-4
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Age, y
1993 to 1998 1960
1960’s Mean Ht Z-1.11990’s Mean Ht Z-0.4
(b)
(a)
Figure 2. Growth status of children with sickle-cell disease. (a) illustrates the growth status of childrenreported by Whitten et al. (1961) compared to children measured in the 1990s. The growth status ofchildren measured in the 1960s was significantly worse than the more recent cohort, although for bothgroups, growth status was worse in older children. (b) illustrates the longitudinal growth of childrenwith SCD from 1993 to 1998, showing the decline with age. Even among children who are tall for ageinitially, their growth declines as shown by the circled points of an individuals growth measurements.Girls have some recovery with the onset and progression through puberty, but boys do not. Adaptedfrom Zemel et al. (2007).
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advances in clinical care. The role of nutrition in promoting improved overall health
remains to be determined.
In sum, despite decades of advances in the understanding of SCD and its treatment,
growth failure and malnutrition are common. Sickle cell ‘crises’, or acute, life-threatening
episodes of sickle cell related symptoms have virtually no relationship to growth failure, yet
a measure like hemoglobin level, representing the usual state of chronic anemia, was
associated with growth status of children with SCD. In the context of the multiple
0
5
10
15
Age
, y
20
2 3 4 5
Females
Breast Stage2 3 4 5
Males
Genital Stage
SCD 1990's* SCD 1980's NHANESIII**
Figure 3. Delayed sexual maturation in children with sickle-cell disease. Children evaluated in 1993�1998 were compared to earlier published data on children with SCD (Platt et al. 1984), and to USNational Reference data (Sun et al. 2002). The comparison illustrates the delay in breast developmentin girls and genital development in boys. * refers to the reference Platt et al. 1984 and ** refers to Sunet al. 2002.
60
70
80
90
100
110
120
130
140
150
0 5 10 15 20 25Hb F, %
%W
HO
p=0.015
REE %Predictedfor age & gender
Figure 4. Resting energy expenditure (REE) of children with sickle-cell disease on hydroxyureatherapy. Resting energy expenditure was measured by indirect calorimetry in children prior to therapyand at 3 months after initiating therapy. Fetal hemoglobin increased, and resting energy decreased innearly all children. Hydroxyurea therapy may improve energy balance in children with sickle-celldisease, and ultimately results in improved growth status. Figure reproduced with permission fromFung et al. (2001).
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nutritional deficits, it is likely that nutritional factors contribute significantly to the growth
failure of children with SCD. However, the SCD patient, advocate and clinical care
communities have not yet galvanized to address these problems.
Case study: Cystic fibrosis
CF is an autosomal recessive disorder affecting mucus and sweat glands. It is caused by a
defect in the cystic fibrosis trans-membrane conductance regulator (CFTR) gene which
functions as a chloride channel and controls the regulation of other transport pathways
(Davies et al. 2007). CF is most common in people of European ancestry; the incidence is
one in every 2500 births. It is less common in South Asian and African�American children
for whom the incidence is one in 10 000 (Mei-Zahav et al. 2005) and 15 000 births
(Friedman et al. 1998), respectively, and quite rare among East Asians. Given these
incidence rates, about one in every 31 Americans are carriers and approximately 30 000
people in the United States have CF and 70 000 people worldwide (Cystic Fibrosis
Foundation 2008a). Clinical symptoms include progressive lung disease, and adverse
effects in the pancreas, liver, intestines, sinuses, and sex organs. Approximately 90% of
people with CF are pancreatic insufficient and have significant fat malabsorption, so
maintaining good growth and adequate nutritional status is a challenge (Littlewood et al.
2006).
Like SCD, there have been dramatic changes in the understanding and treatment of CF
in the past 50 years. In 1962, the estimated median survival of children with CF increased
to about 10 years of age (Cystic Fibrosis Foundation 2008b). In 1989, the gene defect that
caused the CF gene and its protein product were identified (Kerem et al. 1989). Since then,
about 1300 variants of the CFTR gene have been identified (Kammesheidt et al. 2006). By
1993, the first gene therapy trial began for people with CF (Wilson 1993). Gene therapy is
still very much at an experimental stage, but other changes in treatment and prevention of
Figure 5. Median predicted survival age for people with cystic fibrosis has been increasing over thepast four decades. Reproduced with permission from the Cystic Fibrosis Foundation Registry Report(Cystic Fibrosis Foundation 2006).
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lung infections, earlier diagnosis and aggressive nutritional care have produced dramatic
improvements in life expectancy (see Figure 5), with especially rapid improvements in the
last decade. In 2005, the predicted median age of survival increased to nearly 37 years
(Cystic Fibrosis Foundation 2006). Corresponding changes are evident in the slower
progression of lung disease (see Figure 6a), and improved nutritional status relative to age
(see Figure 6b). Typically, low weight status recovers in early childhood once the CF
diagnosis is made and aggressive nutritional and medical therapy is instituted (Shoff et al.
2006). Thus from birth to about age 5 years, there is an increase in relative weight status.
Subsequent declines in weight status are due, in part to delayed puberty, and also due to
declining health status. Based on the relationship between nutritional status (BMI) and lung
function, one of the major goals of CF care is to maintain BMI at the 50th percentile
throughout life to optimize lung function and survival (Stallings et al. 2008).
Now that patients with CF are surviving to adulthood, long term complications of CF are
increasingly common (Cystic Fibrosis Foundation 2006) as shown in Figure 7. Among the
frequently reported complications of CF in adulthood is bone disease, primarily
osteoporosis or bone fragility. Osteoporosis is affected by many of the complications of
CF, such as physical inactivity, inflammation, malabsorption, and gonadal insufficiency. It
is widely believed that osteoporosis is a disease that begins in childhood, and that
Figure 6. Improvements in pulmonary function and nutritional status in children with cystic fibrosis.(a) shows the improvements age-related pulmonary function as indicated by forced expiratory volumeat 1 s (FEV1) between the 1990 cohort and 2004 cohort. (b) shows the corresponding improvementsin the median age-specific BMI percentile. Reproduced with permission from the Cystic FibrosisFoundation Registry Report (Cystic Fibrosis Foundation 2006).
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inadequate bone accretion during the growing years is a risk factor for osteoporosis later in
life (Bachrach 2001).
To address this problem, we conducted a study of children with CF in order to determine
whether bone deficits are widespread in childhood and adolescence (Kelly et al. 2008).
Assessment of bone health in a population with poor growth and delayed maturation is a
classic problem for human biologists, since growth and maturation are major determinants
of bone density. Bone density measures by dual energy X-ray absorptiometry (DXA) were
obtained. DXA measures are based on a two-dimensional image of a three-dimensional
object. Because the third dimension is not measured, DXA bone density measurements are
influenced by bone size, such that smaller individuals appear to have lower bone density
(Leonard and Zemel 2002). Accordingly, assessment of bone deficits in CF requires that
their smaller body size be considered. The CF subjects were enrolled in an IRB approved
study (with written informed consent) to measure bone density and related factors. A group
of healthy volunteers from the same institution were used for comparison so the effects of
short stature and altered body composition could be assessed. The CF sample had low
weight-for-age, height-for-age and BMI-for-age z-scores compared to the healthy group.
Bone density was also significantly lower (see Figure 8). However, when we adjusted for
their short stature and/or lean body mass deficits, the deficits in bone density were no longer
clinically or statistically significant. These findings are important because they demonstrate
that small body size is the primary determinant of the bone deficits in children and
adolescents with CF.
In summary, in the past 50 years, there have been profound improvements in the care of
children with CF resulting in significant improvements in life expectancy, pulmonary
function, growth and nutritional status. These gains have increased the need in this patient
population to attend to diseases of adulthood that may have antecedents in childhood.
Osteoporosis is one such concern, but our recent study in children demonstrated that the
low bone density in children with CF is related to their mild growth failure. Thus there is an
ongoing need for improved growth status as it may have long-term benefits for the
complications of osteoporosis in adulthood.
Figure 7. Changing profile of health complications in patients with cystic fibrosis. Now that manypeople with cystic fibrosis survive well into adulthood, the rate of other related health complications,such as bone disease, diabetes and depression, increases sharply with age. Reproduced withpermission from the Cystic Fibrosis Foundation Registry Report (Cystic Fibrosis Foundation 2006).
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Discussion
The study of growth and its disorders is a trans-disciplinary effort to which the field of
human biology has made a significant contribution over the past 50 years. It is a challenging
and engaging area of study encompassing central themes of human biology, such as the
unique characteristics of human growth, the responses of the human organism to the stress
of adverse conditions (including disease), the consequences of early exposures and
developmental adaptations to function and well-being later in life, and the relevance of
body size differences to overall health and survival.
The case studies presented on the growth of children with SCD and CF illustrate many of
these important themes. Growth failure is recognized as a common complication of these
genetic disorders, and was originally thought to be a primary disease characteristic. The
improvements in growth over the past five decades, and the studies demonstrating the role
of nutrition, improved medical therapies and other modifiable factors that contribute to
growth have two important implications. First, growth is still a very basic indicator of a
child’s overall health status. Although growth has improved for children with chronic
diseases such as SCD and CF, in parallel with improvements in treatments and survival, the
growth of these children still lags behind that of their peers. Secondly, growth failure is not
encoded in these genetic defects but is a consequence of disease stresses on the organism.
The goal of normal growth in children with chronic diseases represents an achievement of
well-being that will someday be attained for the majority of these children. Meanwhile,
growth studies of children with chronic diseases provide insights into developmental
plasticity, nutrient requirements, and the relationship between growth and other physio-
logical processes in the human body.
There are still important areas where the expertise of human biologists and other growth
experts is desperately needed to impact the clinical care of children with chronic diseases
and growth disorders. The advances in the collection of national and international reference
data on height, weight and BMI, and construction of growth curves provide essential tools
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BMI Z Ht Z Spine BMC Z WB BMC ZCF Control CF Control CF Control CF Control
Figure 8. Growth and bone mineral status of children with cystic fibrosis (CF) compared to healthycontrols. Children and adolescents with cystic fibrosis were short-for-age, had lower BMI and lowerbone mineral content (BMC) of the spine and whole body (WB). However, when bone measures wereadjusted for stature and/or lean body mass, the differences were no longer statistical significant.Adapted from Kelly et al. (2008).
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for growth assessment. But there is still a paucity of reference data for other aspects of
growth which are needed for clinical care, such as growth velocity and sexual maturity
indicators (e.g. Tanner stages).
Population differences in growth, maturation and body composition have been identified
primarily by human biologists, but the relevance of these differences in clinical care is
uncertain. For example, there are known differences in bone density such that people of
African ancestry have higher bone mass and density than those of European ancestry. For
adults, it is recommended that reference data for Caucasians should be used, since there is
an established association between bone density status (i.e. the Z-score from the bone
density distribution) and hip fracture (Leib et al. 2004). For children, ethnic-specific
reference curves are recommended to assist in the determination of whether the genetic
potential for bone density during the growth period is being attained when evaluating a
child (Gordon et al. 2008). The clinical implications in the choice of population-specific
curves needs to be carefully considered in each case, along with a consideration of ‘optimal’
vs ‘normal’ patterns of growth and development.
The timing of physical maturation is another area that brings the contributions of human
biologists to the front of clinical growth assessment. The continual improvements to the
reference data for skeletal maturation using the Tanner�Whitehouse system provide robust
estimates of biological maturation and the magnitude of bone age delay or advancement for
an individual child as well as groups of patients. There has been considerably less progress
in characterizing normal patterns of sexual maturation; presently there is no adequate way
to define delayed (or advanced) sexual maturation or the magnitude of delay either for an
individual or a population unless it is quite pronounced. Similarly, the nature of ‘catch-up’
growth in the context of delayed sexual and skeletal maturation requires further study.
As a final point, the perspective and experience of human biologists in examining
environmental, cultural and behavioral influences on human health are highly relevant in
understanding growth disorders associated with chronic diseases. Identifying the modifiable
and non-modifiable influences on growth provides a basis for intervention strategies to
improve growth and prevent the long-term sequelae of altered growth, maturation and body
composition.
Declaration of interest: The author reports no conflicts of interest. The author alone is
responsible for the content and writing of the paper.
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