Eur J Pediatr (2011) 170:351358 DOI 10.

1007/s00431-010-1299-z

ORIGINAL PAPER

Health-related quality of life and cognitive functioning in pediatric short stature: comparison of growth-hormone-nave, growth-hormone-treated, and healthy samples
Matthew D. Stephen & James W. Varni & Christine A. Limbers & Michael Yafi & Rubina A. Heptulla & Venkat S. Renukuntla & Cynthia S. Bell & Patrick G. Brosnan

Received: 10 May 2010 / Accepted: 9 September 2010 / Published online: 1 October 2010 # Springer-Verlag 2010

Abstract The objective of this study was to evaluate the impact of short stature on generic health-related quality of life (HRQOL) and cognitive functioning in pediatric patients. Eighty-nine youth, 48 who were initially seen
M. D. Stephen (*) Department of Pediatrics, Division of Endocrinology, The Childrens Hospital at Scott & White and The University of Texas Health Science Center - Houston, 2401 S. 31st St., Temple, TX 76508, USA e-mail: mstephen@swmail.sw.org M. Yafi : P. G. Brosnan Department of Pediatrics, Division of Endocrinology, The University of Texas Health Science Center, Houston, TX, USA C. S. Bell Department of Pediatrics, Division of Nephrology, The University of Texas Health Science Center, Houston, TX, USA J. W. Varni Department of Pediatrics, College of Medicine, Texas A&M University, College Station, TX, USA J. W. Varni Department of Landscape Architecture and Urban Planning, College of Architecture, Texas A&M University, College Station, TX, USA C. A. Limbers Department of Psychology, Baylor University, Waco, TX, USA R. A. Heptulla : V. S. Renukuntla Department of Pediatrics, Division of Endocrinology & Metabolism, Baylor College of Medicine and Texas Childrens Hospital, Houston, TX, USA

with short stature (SS group) and 41 with a history of short stature being treated with growth hormone (GHT group) and one of their legal guardians participated in the study. HRQOL and cognitive functioning were assessed using the PedsQL 4.0 Generic Core Scales and PedsQL Cognitive Functioning Scale. Comparisons were made between the study groups and with a previously obtained matched healthy sample. For the GHT group, height Z score was found to be a positive predictor of overall HRQOL while duration of GHT was found to be a predictor of physical functioning. For the SS group, the difference between midparental height Z score and height Z score was found to be a negative predictor of overall HRQOL and cognitive functioning. Comparison with the healthy sample demonstrated significant negative impact on HRQOL for child self-report and on HRQOL and cognitive functioning for parent proxy-report in both study groups. The GHT group had a significantly higher child self-reported Physical Functioning score than the SS group (effect size (ES)= 0.52, p<0.05). In conclusion, the GHT group had slightly better HRQOL scores than the SS group, but the difference was not statistically significant. Both groups had significantly lower HRQOL and cognitive functioning scores than healthy sample. Predictors of HRQOL and cognitive functioning found in this study lend support to the use of the PedsQL 4.0 Generic Score Scales and PedsQL Cognitive Functioning Scale in routine assessment of children with short stature in order to identify children at increased risk for impaired HRQOL and cognitive functioning.

Keywords Quality of life . Short stature . PedsQL . Cognitive functioning . Growth hormone . Patient-reported outcomes

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Introduction Understanding the stature-exclusive effects of short stature is important [10, 18, 22]. The predominant focus of psychological research in children with short stature has been on performance and functioning as outcomes [3]. Children with short stature report more teasing, lower academic achievement test scores, and greater likelihood of grade repetition than their normal height peers [3335]. Adults with short stature have shown more difficulties in education, employment, relationships, and friendships, as compared to those of normal height [34]. While these studies point to profound psychosocial disadvantages, it is not clear how large these disadvantages are, nor whether they are due only to societal bias or to biological or functional consequences of growth hormone deficiency [6]. In addition, study of normal short stature patients (defined as height less than 5% for age and gender not attributable to illness, hormonal deficiency, or syndrome) has not always supported these deficits [11, 24]. Comparison of these studies is complicated by variation in diagnoses represented, age at inquiry, use of different psychosocial measurement instruments, and degree of short stature. A number of authors have argued that improving quality of life is the ultimate goal of healthcare. Health-related quality of life (HRQOL) is a multidimensional construct, consisting at minimum of the physical, psychological (including emotional and cognitive), and social health dimensions delineated by the World Health Organization [37]. HRQOL, which assesses a patients subjective perception of the impact of disease and treatment on health and well-being, has been increasingly acknowledged as an important outcome in children with short stature [2, 3]. Overall, generic HRQOL scales used among growth-hormone (HGH)-treated subjects with short stature have failed to demonstrate a significant difference as compared to healthy subjects [3, 35]. However, there remains a relative dearth of studies that have assessed generic HRQOL in pediatric short stature using well-validated HRQOL measures [2]. In addition, the existing studies have a number of methodological limitations including small sample size and an absence of data on parentchild agreement [2, 3]. Thus, further studies are needed to assess the impact of actual height, perceived height, and psychological adaptation on HRQOL among children with short stature [2, 3]. The primary objective of the present study was to better define the impact of actual height on HRQOL in children and adolescents being seen for short stature and to assess whether there were differences in HRQOL between those initially being evaluated for short stature and those currently being treated with growth hormone for short stature. Further, we sought to compare these two groups to a previously obtained healthy sample and examine intercorrelations between child self-report and parent proxyreport. We administered the internationally widely used

Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales and PedsQL Cognitive Functioning Scale to evaluate the generic HRQOL and cognitive functioning of those with stature concerns. The PedsQL Measurement Model integrates both generic and diseasespecific instruments [17, 25]. A growing number of disease-specific instruments have been developed from this model [8, 9, 16, 27, 28]. Advantages of using a generic instrument include the ability to make comparisons between multiple medical conditions and healthy population norms [31]. Though there are short-stature-specific and treatmentspecific questionnaires, this limits the ability for comparison between groups and healthy samples [2]. The central hypothesis of this study was that generic HRQOL in children and adolescents initially seen with untreated short stature would be impaired when compared to both patients with a history of short stature who had been treated with HGH for at least 1 year and a previously obtained healthy sample. We also explored the impact of short stature and treatment status on cognitive functioning.

Methods Population We performed a cross-sectional multidimensional analysis of study participants and their consenting parent/legal guardian who were seen in the pediatric endocrinology clinics at the University of Texas Health Science Center at Houston and at Texas Childrens Hospital/Baylor College of Medicine with confirmed, untreated short stature (SS group) and those with a history of short stature currently being treated with HGH for at least 1 year (GHT group). Youth aged 5 to 18 years were included in the study with their consenting parent/legal guardian. Exclusion criteria included failure to thrive (defined as weight Z score less than height Z score), multiple pituitary hormone deficiencies, untreated metabolic disturbance (i.e., inadequately treated primary endocrine disorder such as thyroid disease), syndromic short stature (i.e., Turner Syndrome, Noonan Syndrome), and an inability to complete the questionnaires. Short stature was defined as height more than the two standard deviations (SDs) below the mean for age and gender. Participants had to meet this criterion either at enrollment for the untreated SS group or prior to beginning HGH for the GHT group. We evaluated our short stature participants on HGH at least 1 year into therapy in order to allow participants to witness some stature effects of HGH. This study was approved by the institutional review boards at each participating center. Informed consent and assent were obtained from all participants.

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Measures and procedures Patients being treated with growth hormone were screened prior to their appointment to determine if they met inclusion criteria. Patients initially being seen for evaluation of short stature were screened at check-in, once anthropometric data was available. Those meeting criteria were approached and respective consent/assent was obtained if the parent and patient agreed to participate. Each participant and consenting parent/legal guardian was provided the PedsQL 4.0 Generic Core Scales and the PedsQL Cognitive Functioning Scale. The PedsQL 4.0 Generic Core Scales (23 questions) evaluates Physical Functioning (eight questions), Emotional Functioning (five questions), Social Functioning (five questions), and School Functioning (five questions) and has been validated in numerous pediatric medical conditions and in healthy youth [31, 32]. The PedsQL Cognitive Functioning Scale (six questions) asks questions regarding memory and attention. Additionally, the consenting parent/legal guardian completed the PedsQL Family Information Form which requests extensive sociodemographic data [30]. The PedsQL scales are answered using a five-point Likert scale, except for participants less than 8 years who use a three-point Likert scale. Age appropriate scales were used (ages 57 years, 812 years, and 1318 years). Likert scale scores are converted to a score ranging from 0 to 100 (100 indicating better HRQOL). Permission to use the questionnaires was provided by MAPI Research Trust (http://www.mapi-trust.org) through the PedsQL domain (http://www.pedsql.org). Participants were requested not to discuss questions or share answers among themselves. For younger children who needed help reading, the questions were read aloud by a research assistant or parent (with a research assistant in room). Careful attention was made to limit distractions. During the consent/assent process, care was taken not to introduce concerns about short stature with the participants. It was stressed to all participants to leave questions blank that they felt uncomfortable answering. Sample size and statistical analysis Sample estimations were difficult to determine secondary to lack of data using the PedsQL in either patients with short stature or those being treated with growth hormone. Previous studies using the PedsQL suggest the need for at least 50 subjects per group and preferably 100 subjects to reach satisfactory statistical power [31]. Though many patients are referred for short stature, relatively few screened were more than the 2 SDs below the mean for age and gender at initial consult (for SS group) or prior to initiating HGH (for GHT group). Consequently, we include

effect size (ES) calculations in order to identify trends in the data. Statistical analyses were performed using SPSS 17 (SPSS, Chicago, IL) [21]. Means and standard deviations were calculated to compare study groups. T tests and Fishers exact tests were performed to evaluate for differences between groups. The healthy sample HRQOL data was taken from previously reported data [26, 29] and matched for age, gender, and race/ethnicity using SPSS random sample case selection command [21]. The healthy cognitive functioning data were not able to be matched secondary to inadequate sample size [13]. Comparison of scale score means between groups was performed using effect sizes [4]. ES was calculated by dividing the difference between the group means by the pooled standard deviation of the study population. ES less than 15 is considered to represent a negligible difference. Further, ES can be defined as small (0.2), medium (0.5), and large (0.8) [4]. ES is a way of demonstrating the magnitude of differences between means with a higher score signifying a greater difference. Intraclass Correlation Coefficients (ICC) were utilized to evaluate agreement between child self-report and parent proxy-report [14]. The ICC provides an index of absolute agreement given that it takes into account the ratio between subject variability and total variability [5, 14]. Correlation coefficients are designated as 0.40 poor to fair agreement, 0.410.6 moderate agreement, 0.610.8 good agreement, and 0.811 excellent agreement [1, 36]. Linear regression analysis was performed to predict the effect(s) of multiple factors on scale scores. Specifically, we used linear regression analyses to predict the effect(s) of age, gender, race/ethnicity, diagnosis, enrollment height Z score, difference between midparental height Z score and baseline height Z score, current growth velocity, and duration of growth hormone therapy on scale scores.

Results Baseline characteristics Over 16 months, we recruited a total of 89 patients. Of these, 48 had short stature initially being evaluated (SS group), while 41 had a history of short stature currently being treated with HGH (GHT group). The characteristics of each group were similar including gender, race/ethnicity, and parents educational level and are summarized in Table 1. Not surprisingly, the GHT group was slightly older than those being initially evaluated with short stature. The maximal parental education of the families was quite high with over 90% having at least a high school degree and >65% having at least a college degree. Baseline anthropometric data is provided in Table 2. Though

354 Table 1 Sociodemographic characteristics of patients (by Group) SS groupa Standard Mean Age (in months) Gender 136.25 SD 34.24 Count 48 34 14 29 12 2 5 1 15 30 70.80 29.20 60.40 25.00 4.20 10.40 2.20 32.60 65.20 % GHT groupb Standard Mean 156.56 SD 26.13

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Count 41 34 7 26 11 1 3 2 7 31

p 0.003 NS

Male Female Race/ethnicity White, non-Hispanic White, Hispanic Black, non-Hispanic Other Highest level of education (by either parent) Less than high school High school/some college College or above NS not significant
a b

82.90 17.10 NS 63.40 26.80 2.40 7.30 NS 5 17.50 77.50

Short stature group Growth-hormone-treated group

statistically different when comparing height and weight data, children in both groups clearly met the definition of short stature (all height Z scores less than 2). For the SS group baseline and enrollment height data are the same, while for the GHT group baseline height data are prior to HGH. Enrollment data including diagnoses for the GHT group are included in Table 3. Diagnoses were not included for the SS group because many patients did not have a diagnosis assigned yet and commonly the diagnosis may
Table 2 Baseline anthropometric data SS groupa Height (cm) Height Z score Weight (kg) Weight Z score Growth velocity (cm/year)c Midparental height (cm)c Midparental height Z score NS not significant
The height and weight data for the short stature group (SS group) is from enrollment/baseline
b The data for the growth-hormone-treated group (GHT group) is from baseline (prior to starting growth hormone therapy) a

GHT groupb 123.15 4.55 26.63 4.45 8.76 170.38 0.53

p 0.05 <0.0001 <0.0001 <0.0001 <0.0001 NS NS

129.16 2.56 28.97 2.1 5.43 168.27 0.65

change with longer follow-up. Nine patients refused participation in the study. Linear regression analysis was performed to evaluate for predictors of HRQOL (including individual components) and cognitive functioning for the child self-report by group. The mean total HRQOL score at enrollment was 5.34 (SD=2.12) points higher for every one height SD taller in the GHT group (p=0.016) while it trended toward a positive correlation in the SS group (p=0.072). Mean total HRQOL score was 3.29 (SD=1.49) points lower for every one height SD greater difference between baseline height Z score and midparental height Z score in the SS group (p=0.034) while it trended toward a negative correlation in the GHT group (p=0.076). For the SS group, the cognitive functioning mean was 8.05 (SD=3.58) points higher for every one height SD higher at baseline/enrollment (p=0.029). The mean Physical Func-

Table 3 Enrollment data for growth-hormone-treated group (GHT group) Height (cm) Height Z score Weight (kg) Weight Z score Diagnosis Growth hormone deficiency Idiopathic short stature 144.25 1.62 38.28 1.34 23 (56.1%) 18 (43.9%)

The midparental height and growth velocity data at enrollment for both groups is provided

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tioning score in the GHT group was found to be 4.1(SD= 1.59) points higher for every 1 SD taller (p=0.014) and 0.32 (SD=0.12) points higher for every month longer of HGH (p=0.011). The average duration of HGH was 36.55 months (SD=18.67). For the regression analyses, no significant differences were demonstrated based on age, gender, race/ethnicity, or diagnosis (for the GHT group). Short stature group (not treated with HGH) compared to healthy sample Table 4 presents PedsQL Generic Core Scales and PedsQL Cognitive Functioning Scale comparisons between the short stature (not treated with HGH) and healthy sample. Child self-report revealed significant impairment on the total HRQOL score (p<0.001) including the physical (p<0.001), psychosocial (p<0.001), emotional (p<0.05), and social (p<0.001) domains in the SS group compared to the healthy sample. There was no significant difference between school and cognitive functioning scores. Parent proxy-report did not demonstrate the significant physical function impairment seen in the child self-report, but did suggest a lower cognitive functioning (p<0.001) as compared to the healthy sample. Though the difference in

parent proxy-report of the total HRQOL score (p<0.05) was not as large as for child self-report, parents did recognize similar concerns to their children with regards to psychosocial health (p< 0.01), emotional functioning (p <0.001), and social functioning (p <0.001). Growth-hormone-treated group compared to healthy sample Table 4 contains PedsQL Generic Core Scales and PedsQL Cognitive Functioning Scale comparisons between the short stature growth-hormone-treated group and healthy sample. Child self-report in the GHT group showed differences between the GHT group and healthy sample, smaller but similar to the differences between the SS group and the healthy sample, except that there was not a significant difference in the physical functioning domain. There was lesser, yet still significant, difference in the total HRQOL score (p<0.05) and the emotional (p<0.05), and social domains (p<0.05). Parent proxy-report scores for the GHT group showed significantly lower scores in psychosocial (p < 0.05) and emotional domains (p < 0.05) as compared to the healthy sample as well as an impairment in cognitive functioning (p<0.001) comparable to that in the SS group.

Table 4 PedsQL 4.0 generic core scales and PedsQLTM cognitive functioning scale comparisons between Short Stature (SS Group), GrowthHormone-Treated (GHT), and healthy samples for child self-report and parent proxy-report PedsQL scale SS group (a) Mean Child self-report Total score Physical Psychosocial Emotional Social School Cognitivea Parent proxy-report Total score Physical Psychosocial Emotional Social School Cognitivea (n=48) 79.28 83.92 76.74 76.04 76.92 77.60 78.11 (n=48) 78.39 86.87 75.00 71.91 73.10 77.29 78.59 SD GHT group (b) Mean (n=41) 82.56 89.55 78.54 76.83 81.86 77.68 82.00 (n=41) 80.97 89.10 77.14 75.91 80.37 72.84 76.07 SD Healthy (c) Mean (n=1,259) 86.19 90.28 84.03 82.17 87.98 81.96 82.78 (n=1535) 83.67 86.86 81.94 81.78 85.39 78.57 86.62 SD Comparisons Effect sizes a vs. c b vs. c a vs. b

11.17 11.97 12.32 17.35 20.20 13.64 15.49 13.86 14.37 15.43 18.95 18.90 20.73 23.08

12.16 9.15 15.37 18.70 18.02 16.47 16.35 11.67 13.68 13.62 17.78 17.08 16.96 20.20

11.57 11.62 13.25 16.97 14.96 16.28 16.26 14.41 17.86 14.78 16.87 17.76 18.95 16.36

c>a***;c>b* c>a***;b>a* c>a***;c>b* c>a,b* c>a***;c>b* c>a* c>a**;c>b* c>a***;c>b* c>a*** c>a,b***

0.60 0.55 0.55 0.36 0.73 0.37 0.29 0.37 0.00 0.47 0.58 0.69 0.07 0.49

0.31 0.06 0.41 0.31 0.41 0.26 0.05 0.19 0.13 0.33 0.35 0.28 0.30 0.64

0.29 0.52 0.13 0.04 0.26 0.01 0.24 0.20 0.16 0.15 0.22 0.40 0.23 0.12

Healthy Sample Data from references 30, 31, and 32 indicates no statiscally significant differences *p<0.05, **p<0.01, ***p<0.001 based on independent sample t test. Effects sizes are designated as an all (0.20), medium (0.50), and large (0.80)
a

Sample are for the PedsQL Cognitive Functioning Scale for child self-report and parent proxy-report for the healthy sample equals 157

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Short stature group (not treated with HGH) compared to growth-hormone-treated group Table 4 presents PedsQL Generic Core Scales and PedsQL Cognitive Functioning Scale comparisons between the short stature (not treated with HGH) and growth-hormonetreated group. Comparison of child self-report between the two groups indicated a small non-significant difference in total HRQOL score (ES=0.29, p>0.05), social functioning (ES=0.26, p>0.05), and cognitive functioning (ES=0.24, p >0.05) and a moderately better significant physical functioning score in the treated group (ES=0.52, p<0.05). Parent proxy-report revealed a small non-significant difference in total HRQOL score (ES=0.2, p>0.05), emotional (ES=0.22, p>0.05), and social functioning (ES=0.4, p>0.05). Interestingly, there was a small non-significant negative effect on school functioning (ES=0.23, p>0.05) between the groups. There were no significant differences found between the groups on either the child self-report or parent proxyreport based on age, gender, or race/ethnicity. Additionally, among the GHT group, there were no significant differences in HRQOL or cognitive functioning scores between those with growth hormone deficiency or idiopathic short stature. Parent/child agreement ICCs between pediatric patient self-report and parent proxyreport for the SS group (not treated with HGH) across the PedsQL 4.0 Generic Core Scales and Cognitive Functioning Scale are as follows: Total Score=0.45 (p<0.001), Physical Health = 0.38 (p < 0.01), Psychosocial Health = 0.44 (p<0.001), Emotional Functioning=0.45 (p<0.0001), Social Functioning=0.56 (p<0.0001), School Functioning=0.37 (p<0.01), Cognitive Functioning=0.21 (p>0.05). These ICCs are in the poor to moderate agreement range. For the GHT group, ICCs between pediatric patient selfreport and parent proxy-report across the PedsQL 4.0 Generic Core Scales and Cognitive Functioning Scale are as follows: Total Score = 0.69 (p < 0.0001), Physical Health = 0.61 (p < 0.0001), Psychosocial Health = 0.64 (p<0.0001), Emotional Functioning=0.54 (p<0.0001), Social Functioning=0.55 (p<0.0001), School Functioning= 0.51 (p<0.0001), Cognitive Functioning=0.65 (p<0.0001). These ICCs are in the moderate to good agreement range.

Discussion Our study demonstrates HRQOL deficits in youth with marked short stature either untreated (SS group) or treated with HGH (GHT group), as perceived by pediatric patients themselves and their caregivers, and lends support for the routine assessment of HRQOL in children with short stature.

Children in the GHT group and SS group self-reported significantly lower emotional functioning and social functioning than healthy peers, with greater deficits reported in the SS group. Similarly, parents in both the SS group and GHT group reported significantly lower psychosocial health and emotional functioning for their children compared to parents of healthy children, with greater impairments reported in the SS group. Parents in the SS group also reported significantly lower social functioning for their children compared to parents of healthy children. Overall, findings from other empirical studies have been mixed with regard to social and emotional problems in children with short stature [12, 15, 19, 20, 23, 34]. A recent population based study of 712 sixth graders (28 with height less than 10 percentile for age and gender) demonstrated no differences in social, emotional, or behavioral outcomes compared to non-short peers. However, this study only included 11 children with height less than 5 percentile for age and gender. Theunissen et al. reported impairments in social functioning in a sample of 36 children with ISS when compared to a normative population [23]. The present study supports some deficits in emotional and social functioning from the perspective of children and parents in youth with marked short stature untreated and treated with HGH for at least 1 year, with greater deficits in the untreated group. This highlights the need for parents and clinicians alike to look for opportunities to support the emotional and social needs of children seeking care for short stature. We found that children in the GHT group who had been treated for at least 1 year self-reported significantly better physical functioning than subjects with short stature initially presenting at the pediatric endocrinology clinics. This finding is consistent with what we observe clinically in terms of patients and their families remarking that the childs physical abilities have improved since starting HGH. Specifically, the GHT group self-reported statistically better ability to lift something heavy and keeping up with their peers when playing than the SS group (p<0.05). Results of our linear regression analyses indicated that duration of HGH was a positive predictor of physical functioning in the GHT group. A prospective cohort study of subjects from their initial visit through their treatment with HGH would be needed to determine if the physical functioning differences that we found result from therapy and if there is lasting effect of HGH on HRQOL. For both the GHT group and SS group, children and parents reported similar school functioning to healthy peers. However, while children in the SS group and GHT group reported similar cognitive functioning to healthy peers, their parents rated their cognitive functioning to be significantly lower than healthy peers. These conflicting findings may represent expectation bias, but should not be trivialized. Investigation of intercorrelations between child self-report

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and parent proxy-report in the present study revealed better overall agreement between parents and children in the GHT group compared to the SS group. Agreement between parents and children in the SS group was particularly low on cognitive functioning as compared to the other domains of functioning. Taken together, these data suggests that evaluating both childrens and parents perspectives regarding HRQOL and cognitive functioning should be the standard for routine assessment in clinical practice and clinical trials for children with short stature since their different perspectives potentially provide unique information. Unpublished data from our center suggested an increased prevalence of attention-deficit hyperactivity disorder (ADHD) in our growth-hormone-deficient patients (personal communication, Vanasse, L and PGB). Other research reports an increased use of ADHD medications among those being treated with HGH [7]. Further study of the factors contributing to cognitive functioning among youth with short stature and those being treated with HGH are warranted. Strengths of our study included efforts to limit bias and inclusion of only those with true short stature (either at enrollment for the SS group or prior to HGH for the GHT group). The study was sponsored through an institutional grant without industry sponsorship. Care was made not to introduce concern about short stature to the child or parent. Patients already on HGH were generally much more receptive of the study, while those initially seeking attention for short stature were often more hesitant. In fact, a few parents voiced significant concerns about the potential that by asking questions to their child about their quality of life and cognitive function we might invoke concerns that were not already there. This attests to the strong societal bias surrounding short stature as well as the potential parental contribution to this bias. We included only children who met the definition of short stature at enrollment for the SS group or prior to HGH for the GHT group. Some parents noted concerns that the questions being asked did not allow them to fully express their concerns. As discussed, the questionnaires used were not designed specifically for children with short stature. Though parents of short children expressed anxiety about immediate and long-term effects of short stature, many parents of children already on HGH voiced concerns about the balance between numerous injections and uncertain increase in stature. They worried that treatment might hurt their childs self-perceptions more than improved stature helped. Limitations of our study included the lack of prospective follow-up of patients. Secondly, our limited sample size reduced the statistical power of the study and might have increased the Type II error rate between the treated (GHT group) and untreated (SS group) groups. Setting height entry requirement of at least minus 2 standard deviations may have provided more interpretable results but reduced

the number of subjects despite inclusion of two highvolume centers. Excluding these patients improved validity, but limited numbers. Baseline height differences between the GHT and SS groups may indicate a difference in underlying diagnosis. For those in the SS group, a firm diagnosis was often not apparent and not uncommonly may change as the patient is followed over time. The duration of this study did not allow for final diagnoses to be made in the SS group. Further, our primary end point was comparison of HRQOL among those in the GHT and SS groups with regards to their current height and not a specific diagnosis or treatment. Finally, we cannot make any conclusions about the effect(s) of treatment (i.e., growth hormone) on HRQOL. However, we can make inferences about the differences between groups (GHT and SS) and as compared to a healthy sample given our primary interest was investigating the impact of stature on HRQOL, irrespective of diagnosis. In summary, we found slight differences in HRQOL, particularly physical functioning, between youth being initially seen with short stature and those with a history of short stature being treated with HGH. Our findings lend support to the clinical usefulness of the PedsQL 4.0 Generic Core Scales and PedsQL Cognitive Functioning Scale in the routine assessment of children with short stature.
Acknowledgments Appreciation is expressed to our patients and their families who made this study possible, and to the various medical providers who allowed us to enroll their patients in this study. Special thanks to Kyrie Collins RN, Nunilo Rubio MD, Robyn Klenk RN, FNP-C, MSN and Parvin Yazdani MD who assisted with enrolling patients when the primary investigator was not available and William Risser MD, PhD for editorial contributions. Competing Interest Dr. Varni holds the copyright and the trademark for the PedsQL and receives financial compensation from the MAPI Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality of Life Inventory.

Funding Funding was provided through an intradepartmental grant from the University of Texas Health Science Center at Houston.

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