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Longitudinal Study on Growth and Body Mass Index before and after Diagnosis of Childhood Craniopharyngioma

Department of Pediatrics, Zentrum für Kinder- und Jugendmedizin, Klinikum Oldenburg GmbH (H.L.M., G.B., N.E.-G., U.G., R.O., R.K.), Oldenburg, Germany; Institute for Medical Biostatistics, Epidemiology and Informatics, University of Mainz (A.E., A.F.), Mainz, Germany; and Department of Pediatric Neurosurgery, University Hospital (N.S.), Wurzburg, Germany

Address all correspondence and requests for reprints to: Hermann L. Müller, M.D., Department of Pediatrics, Zentrum für Kinder- und Jugendmedizin, Klinikum Oldenburg GmbH, Dr. Eden Strasse 10, 26133 Oldenburg, Germany. E-mail: mueller.hermann{at}klinikum-oldenburg.de.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We analyzed whether childhood craniopharyngioma predisposes to obesity and growth impairment. Height/length, body mass index (BMI), and hypothalamic involvement were evaluated in 90 patients at standardized ages and time points before, after, and at the time of diagnosis. Relevant decreases in height SD score (SDS) started at 10–12 months of age and persisted until diagnosis of childhood craniopharyngioma. Relevant increases in BMI SDS were detectable between 4 and 5 yr of age. Postoperative BMI SDS (yr 1–6) had a weak positive correlation with BMI SDS at the time of diagnosis. In linear regression analysis, hypothalamic tumor involvement (P < 0.001), ponderal index at birth (P = 0.014), and BMI SDS at age 6–7 months (P = 0.029) and at age 5 yr (P < 0.001) had relevant and independent impacts on the development of obesity. Patients with hypothalamic involvement (n = 48) presented lower ponderal index and BMI SDS at birth and higher BMI SDS at the time of diagnosis (P < 0.001) as well as during annual follow-up (P < 0.001) compared with patients without hypothalamic involvement (n = 42). From childhood (3.5–4 yr) to the time of diagnosis, growth rates were reduced for patients with hypothalamic tumor involvement. Patients without hypothalamic involvement presented reduced growth rates in early infancy (age 10–12 months) that persisted until diagnosis. We conclude that reduced growth rates occur quite early in history; BMI SDS increases occur later and are predictive of obesity. Hypothalamic involvement is the major risk factor for obesity in patients with childhood craniopharyngioma.

	Introduction

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CRANIOPHARYNGIOMAS ARE BENIGN embryogenic malformations that arise from ectoblastic remnants of Rathke’s pouch and can be found anywhere along the development path of Rathke’s pouch in hypothalamic and pituitary regions, both of which are important in endocrine regulation and satiety modulation (1, 2). Craniopharyngiomas are the most common intracranial tumors of nonglial origin in the pediatric population, constituting between 6–9% of pediatric brain tumors. Overall there are 0.5–2 new cases/million population occurring each year, 30–50% of which are children and adolescents (3). The peak incidence is at age 5–10 yr, but they can occur at any age, including infancy and during the pre- and neonatal periods (4). Although the tumor itself is benign, and the overall survival rate of patients is high (5), there is considerable morbidity and impaired quality of life even when the tumor can be completely resected. Obesity is present postoperatively in up to 52% of patients, with at least half of these patients having severe difficulty controlling their desire to eat (5, 6, 7, 8).

In a recent study (5) we analyzed risk factors for the development of obesity in patients with childhood craniopharyngioma. Patients who remained at normal weight during follow-up after diagnosis of childhood craniopharyngioma presented a lower body mass index (BMI) SD score (SDS) at the time of diagnosis. Furthermore, patients with childhood craniopharyngioma frequently had a long history of reduced growth rate and weight gain at the time of diagnosis (9), confirming an earlier report by Sorva (10). These observations led to the hypothesis that pathogenic factors in the development of obesity influence BMI before diagnosis and treatment of craniopharyngioma. Accordingly, we analyzed data on height and weight collected from patients with childhood craniopharyngioma before diagnosis in the context of a standardized German health care survey. The aim of our study was to analyze whether an embryogenic malformation such as craniopharyngioma predisposes obesity and impaired growth in patients, and what role hypothalamic involvement plays in this risk for development of obesity.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The height and weight of 90 patients (50 females and 40 males) before and after diagnosis of childhood craniopharyngioma were retrospectively analyzed based on patient records. As historic data were essential to this study, only patients tracked with the standardized German health survey qualified for inclusion in this study, eliminating a sizable percentage (over half) of the reported pediatric craniopharyngioma patient base in Germany (5). Tumor diagnosis was confirmed by histology. Hypothalamic involvement was assessed by intraoperative microscopic inspection and/or imaging. All patients were treated at Department of Pediatric Neurosurgery, University of Wurzburg (Wurzburg, Germany). Informed consent was obtained from parents, and the study was approved by the local standing committee on ethical practice. Childhood craniopharyngioma was diagnosed at a median age 8.3 yr (ranging from 2 wk to 20.5 yr). A gross total resection was achieved in 42 patients (47%) at first neurosurgical intervention. Relapses after complete resection occurred in nine of 42 patients (21%). A progression of residual tumor was found in 34 of 48 patients (71%) after incomplete resection. Forty-eight patients (53%) presented with craniopharyngioma involving hypothalamic structures. Focal irradiation was performed in 22 patients with a cumulative dose of 54 Gray units and single daily doses of 1.8 Gray units. The median follow-up period was 6.2 yr, ranging from 0.1–21.5 yr. The median age at latest follow-up was 14.6 yr (range, 4.0–29.5 yr).

Weight and height/length data were acquired from patient child health records, standardized and financed by German health authorities and conducted by local physicians and pediatricians (11, 12). Health supervision visits are recommended at standardized ages: at the time of birth (U1) and at eight additional standardized ages (U2, 3–10 d; U3, 3–4 wk; U4, 3–4 months; U5, 6–7 months; U6, 10–12 months; U7, 21–24 months; U8, 3.5–4-yr; U9, 5 yr). Furthermore, BMI SDS and height SDS at the time of diagnosis and annually (yr 1–9) after diagnosis and at the latest follow-up visit were analyzed. Height or length was measured using a stadiometer and expressed as the SDS according to the references of Prader et al. (13). The degree of obesity was evaluated by calculating BMI [BMI = weight (kilograms) ÷ height² (square meters)] and ponderal index [PI = weight (grams) ÷ birth length³ (cubic centimeters) x 100] for newborns. BMI was expressed as an SDS using the method described by Rolland-Cachera et al. (14). Hormonal status and endocrine substitution therapy at the time of latest visit were evaluated based on patient records.

Statistical analysis was performed by the Institute for Medical Biostatistics, Epidemiology and Informatics, University of Mainz (Mainz, Germany), using SPSS 10.0 (SPSS, Inc., Chicago, IL). To analyze the correlation between a categorical variable and the development of obesity or hypothalamic tumor involvement, Fisher’s exact test was applied. To analyze the correlation between a continuous variable and the two group categories, the t test was applied. Continuous variables are depicted by box plots (Figs. 1–4). The horizontal line in the middle of the box depicts the median. The edges of the box mark the 25th and 75th percentiles. Whiskers indicate the range of values that fall within 1.5 box-lengths. Categorical variables are depicted by absolute and relative frequencies.

View larger version (32K): [in this window] [in a new window]   FIG. 1. Height in patients with childhood craniopharyngioma. A, SDS (13 ) of body height in 90 patients with childhood craniopharyngioma before, after, and at the time of diagnosis (dgx). The height SDS before dgx is shown at the time of birth (U1) and at eight standardized ages before dgx (U2 to U9). Height SDS after dgx is depicted at annual intervals (yr 1 to 9) after dgx. B, Changes in height SDS before dgx compared with height SDS at birth [change in height SDS = (height SDS at U2 to U9, dgx) minus (height SDS at birth)] and after dgx compared with height SDS at dgx [change in height SDS = (height SDS at yr 1–9 after dgx) minus (height SDS at dgx)]. The horizontal line in the middle of the box depicts the median. The edges of the box mark the 25th and 75th percentiles. Whiskers indicate the range of values that fall within 1.5 box-lengths.

View larger version (35K): [in this window] [in a new window]   FIG. 2. BMI in patients with childhood craniopharyngioma. A, SDS (14 ) of BMI in 90 patients with childhood craniopharyngioma before, after, and at the time of diagnosis (dgx). The BMI SDS before dgx is shown at the time of birth (U1) and at eight standardized ages before dgx (U2 to U9). The BMI SDS after dgx is depicted at annual intervals (yr 1–9) after dgx. B, Changes in BMI SDS before dgx compared with BMI SDS at birth ([change in BMI SDS = (BMI SDS at U2 to U9, dgx) minus (BMI SDS at birth)] and after dgx compared with BMI SDS at dgx [change in BMI SDS = (BMI SDS at yr 1–9 after dgx) minus (BMI SDS at dgx)]. The horizontal line in the middle of the box depicts the median. The edges of the box mark the 25th and 75th percentiles. Whiskers indicate the range of values that fall within 1.5 box-lengths.

View larger version (47K): [in this window] [in a new window]   FIG. 3. Height before and after diagnosis and hypothalamic involvement. A and B, SDS (13 ) of body height in patients with childhood craniopharyngioma before, at the time of diagnosis (dgx), and at annual intervals (yr 1–9) after dgx. The height SDS before dgx is shown at the time of birth (U1) and at eight standardized ages before dgx (U2 to U9; ). The height SDS at the time of dgx () and those at annual intervals after dgx () are shown. C and D, Changes in height SDS before dgx compared with height SDS at birth [change in height SDS = (height SDS at U2 to U9) minus (height SDS at birth)] and after dgx compared with height SDS at dgx [change in height SDS = (height SDS at yr 1–9 after dgx) minus (height SDS at dgx)]. Data are shown as box plots for patients who presented with (B and D) and without (A and C) hypothalamic involvement of craniopharyngioma. The horizontal line in the middle of the box depicts the median. The edges of the box mark the 25th and 75th percentiles. Whiskers indicate the range of values that fall within 1.5 box-lengths.

View larger version (45K): [in this window] [in a new window]   FIG. 4. BMI before and after diagnosis and hypothalamic involvement. A and B, SDS (14 ) of BMI in patients with childhood craniopharyngioma before, at the time of diagnosis (dgx), and at annual intervals (yr 1–9) after dgx. BMI SDS before dgx is shown at the time of birth (U1) and at eight standardized ages before dgx (U2 to U9; ). The BMI SDS at the time of dgx () and those at annual intervals after dgx () are shown. C and D, Changes in BMI SDS before dgx in comparison with BMI SDS at birth (change in BMI SDS = [BMI SDS at U2 to U9] minus [BMI SDS at birth]) and after dgx in comparison with BMI SDS at dgx (change in BMI SDS = [BMI SDS at yr 1 to 9 after dgx] minus [BMI SDS at dgx]). Data are shown as box plots for patients who presented with (B and D) and without (A and C) hypothalamic involvement of craniopharyngioma. The horizontal line in the middle of the box depicts the median. The edges of the box mark the 25th and 75th percentiles. Whiskers indicate the range of values that fall within 1.5 box-lengths.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Weight and height/length before and after diagnosis of childhood craniopharyngioma

The changes in BMI SDS and height/length SDS before diagnosis were analyzed at nine standardized ages, beginning at birth (U1) and throughout infancy and childhood until age 5 yr (U2 to U9). Relevant decreases in height/length SDS were observed at an early age of 10–12 months (U6) and persisted until diagnosis of childhood craniopharyngioma (Fig. 1). It was also observed that BMI SDS decreased during the first 10 d of life (U1–U2). After this U1–U2 period, BMI SDS increased until age 6–7 months (U5). Further relevant increases in BMI SDS occurred during age 21–24 months (U7) and persisted until diagnosis (Fig. 2). BMI SDS at annual postoperative intervals (yr 1–6 after diagnosis) and at the time of latest evaluation were slightly positively correlated with BMI SDS at the time of diagnosis (correlation coefficient, 0.36–0.58; data not shown).

Multivariate analysis on preoperative risk factors for postoperative obesity

The data for 90 patients were evaluated to assess the relationship between PI at birth, BMI SDS before and at the time of diagnosis, and the sequela of obesity (BMI SDS at latest follow-up visit). Furthermore, hypothalamic involvement of childhood craniopharyngioma, irradiation, gender, age at diagnosis, and follow-up interval between diagnosis and latest evaluation were included in the multivariate analysis. Not all measurements of BMI SDS at all specified time points were available for all 90 patients.

Hypothalamic tumor involvement, PI at birth (U1), and BMI SDS at age 6–7 months (U5) and at age 5 yr (U9) had relevant impact on the development of obesity, specified by the BMI SDS at latest evaluation. The final general linear model was built using the complete datasets of 40 patients. Hypothalamic tumor involvement caused a mean increase in BMI SDS at last evaluation of 3.51 SD (95% CI, 2.10–4.93; P < 0.001). The BMI SDS at last evaluation increased, on the average, 0.76 SD (95% CI, 0.36–1.16; P < 0.001) per 1 BMI SDS at age 5 yr and 0.71 SD (95% CI, 0.08–1.34; P = 0.029) per BMI SDS at age 6–7 months. Per unit of PI at birth, the BMI SDS at last evaluation decreased –3.31 (95% CI, –5.92 to –0.71; P = 0.014). The intercept was 8.77 (95% CI, 2.26–15.29; P = 0.010). The adjusted r² for the model was 0.61.

Hypothalamic involvement and pre- and postoperative BMI and height

As hypothalamic involvement was shown to be a major risk factor for the sequela of obesity, we compared two groups of childhood craniopharyngioma patients: those with (n = 48) and those without (n = 42) hypothalamic involvement with regard to weight and height/length before and after diagnosis. Patients with hypothalamic involvement had higher BMI SDS (difference in means, 1.28 SD; P = 0.002) at the time of diagnosis and at annual follow-up intervals (Fig. 4 and Table 1). Sixty-nine percent of the patient group without hypothalamic involvement maintained their normal weight (BMI, <2 SD), whereas only 10% of patients with hypothalamic tumor involvement maintained their normal weight (Fig. 4 and Table 1). BMI variances before diagnosis between the two groups were found at birth (U1) and at checkpoint ages 6–7 months (U5) and 5 yr (U9). Patients with hypothalamic involvement had lower PI (P = 0.044) and lower BMI SDS at birth (difference in means, –0.47 SD; P = 0.025; Table 1). The BMI SDS in patients with hypothalamic involvement was also lower at U5 age 6–7 months (difference in means, –0.56 SD; P = 0.042), but was slightly higher at U9 age 5 yr (difference in means, 0.97 SD; P = 0.089; Fig. 4, A and B, and Table 1).

For patients with hypothalamic tumor involvement, growth rates [change in height SDS = height SDS (at U2 to U9) minus birth length SDS (U1)] were observed to be reduced starting at early childhood age 3.5–4 yr (U8) and persisted at a reduced rate until the time of diagnosis. For patients without hypothalamic involvement, growth rates were additionally reduced beginning in early infancy (10–12 months; U6; Fig. 3, C and D). However, the comparison of height SDS before and after diagnosis between patients with and without hypothalamic involvement did not reach statistical significance (Fig. 3, A and B, and Table 1). Normal height at latest visit (height, –2 SD) was achieved in 86% of patients without hypothalamic involvement and in 90% of patients with hypothalamic involvement. The rate of GH therapy was similar in both groups (Table 1). Differences in terms of hormonal status (hypocortisolism, hypothyroidism, diabetes insipidus, and GH deficiency) did not reach statistical significance. Doses of endocrine substitution were comparable between the groups of patients with and without hypothalamic involvement (Table 1). Sixty-four of 70 adult (age, 18 yr) patients (34 females and 30 males) presented with hypogonadism at the latest evaluation. Rate and doses of sex steroid substitution (n = 64) were comparable in patients with and without hypothalamic involvement (data not shown).

The groups of patients presenting with and without hypothalamic involvement were comparable in terms of sex distribution, age at diagnosis, irradiation, and progression rates of residual tumor after incomplete resections (Table 1). Differences in the degree of resection reached statistical significance. In patients with hypothalamic involvement, gross total resection was achieved in 15%. Craniopharyngiomas without hypothalamic involvement could be completely resected in 83% of all patients (P < 0.001; Table 1).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have previously reported that obesity due to hypothalamic eating disorders is a major adverse side-effect in children and adolescents with craniopharyngioma, occurring in up to 50% of survivors, and that early and rapid postoperative weight gain seems to be a significant predictive factor for severe long-term obesity in patients with childhood craniopharyngioma (5, 15, 16). It is important to note that childhood craniopharyngioma patients at risk of obesity had a higher BMI SDS at the time of diagnosis (5, 15). Analyzing their history before diagnosis, we found complaints of reduced growth rates in 35% and reports of weight gain in 15% (9). These observations lead to the hypothesis of the present study that pathogenic mechanisms influence growth and BMI and are predisposed before diagnosis of childhood craniopharyngioma. In our present study we observed that childhood craniopharyngioma patients at risk for severe postoperative obesity had a higher BMI SDS before diagnosis and that decreased growth rates and increased BMI can occur in patients before diagnosis. Whereas persistently impaired growth rates were observed in patients as early as the end of the first year of life, increased BMI occurred in these same patients at an older age. Accordingly, we speculate that persistent growth impairment during early infancy can be consistent with childhood craniopharyngioma. Obesity, on the other hand, occurred relatively late in the history of the analyzed patients, i.e. shortly before diagnosis of childhood craniopharyngioma.

We were also able to confirm a relevant relationship between the degree of obesity before diagnosis (PI at birth, BMI SDS at 6–7 months, and at 5 yr), hypothalamic tumor involvement, and the sequela of obesity and that higher BMI SDS at checkpoint ages 6–7 months and 5 yr can increase the risk for long-term obesity. There was some indication that a lower PI at birth might suggest relative intrauterine growth retardation (IUGR) and could be a relevant risk factor for obesity after diagnosis of childhood craniopharyngioma. This is consistent with British studies performed 15 yr ago showing that people who had low birth weight were at increased risk of coronary heart disease and related disorders of stroke, noninsulin-dependent diabetes, elevated blood pressure, and metabolic syndrome (17, 18). However, given the definition of IUGR [birth weight less than 2500 g (<–2 SD) for full-term infants], only 12 patients (13%) met the criteria for IUGR. Accordingly, a relation between relative IUGR and obesity remains highly speculative in our cohort.

We also found that hypothalamic involvement seems to have a major impact on the development of obesity in patients with childhood craniopharyngioma, whereas endocrine deficiencies and hormonal substitution therapy did not seem to have a relevant influence. Another risk factor associated with hypothalamic involvement was a lower rate of gross total resection. Hypothalamic involvement predisposing multiple pathologies, including obesity, has been implicated in other studies. Hypothalamic lesions, especially in ventromedial areas, are postulated as pathogenic factors for hyperphagia and obesity (19). The regulative influence of the ventromedial and lateral hypothalamus on eating behavior has been confirmed in animal models (20). Additionally, deficient modulation of hunger due to a lack of feedback in areas of satiety regulation in lateral hypothalamus has been postulated as a mechanism for hypothalamic obesity (21). The neuroanatomical model of hypothalamic obesity has been successively modified by observations regarding the effects of neurochemical factors, such as neurotransmitters, neuromodulators, and peripheral hormones, on eating behavior. Roth et al. (22) reported an up-regulation of leptin levels due to an impaired hypothalamic responsiveness caused by craniopharyngiomas with extension to the suprasellar area. Brabant et al. (23) observed that leptin concentrations in serum of patients with craniopharyngioma increased over proportionally when patients developed obesity. De Vile et al. (24) categorized the degree of hypothalamic damage in patients with craniopharyngioma based on magnetic resonance imaging and showed that obesity in craniopharyngioma patients relates to the degree of hypothalamic damage. Comparable with other reports in the literature (6, 7), the rate of long-term obesity was about 50% in our study group.

Weight control is important for the prognosis, because obesity has a negative impact on quality of life in patients with childhood craniopharyngioma (5, 25, 26, 27). Unfortunately, weight control for these patients is made more difficult by further complications of the disease. Harz et al. (28) recently reported reduced physical activity in patients with childhood craniopharyngioma, quantified by accelerometric analysis. Notably, nutritional caloric intake in obese patients with childhood craniopharyngioma was similar to that in weight- and age-matched controls. Reports (29) of increased daytime sleepiness and reduced nocturnal melatonin levels in patients with childhood craniopharyngioma support the hypothesis that physical activity might be decreased in these patients due to as yet unknown neuroendocrine disorders. Lustig et al. (30, 31, 32) hypothesized that obesity in patients with hypothalamic lesions is caused by insulin hypersecretion due to ß-cell dysfunction. In a recently published, double-blind, placebo-controlled study of treatment with the somatostatin analog octreotide, a significant effect on BMI in patients with childhood craniopharyngioma was reported (33). Despite these encouraging results, specific treatment of obesity and eating disorders due to hypothalamic lesions remains difficult, and the difficulty is exacerbated by the previously mentioned sequelae of increased daytime sleepiness, reduced nocturnal melatonin levels, and decreased physical activity. We recommend that prophylactic and therapeutic intervention should be initiated early in the course of the disease for patients at risk for obesity. Anthropometrical parameters, such as height and weight, are compromised early in children with craniopharyngioma and are certainly valuable in assessing their follow-up.

The results of our study are limited due to retrospective analysis, and as indicated, some observations are speculative at this point. To our knowledge, there is only one other report in the literature (10) on growth and weight development before diagnosis of childhood craniopharyngioma to offer confirmatory validation of our hypothesis that pathogenic factors relevant to the development of obesity have a predispositional influence before diagnosis and treatment of craniopharyngioma. Accordingly, the multicenter surveillance study KRANIOPHARYNGEOM 2000 (www.kraniopharyngeom.com) was initiated to confirm our results by prospective evaluation (34). This multicenter study is designed to improve both the size and standardization of data for the patient cohort of childhood craniopharyngioma so that the results both of this study and others can be confirmed.

	Acknowledgments

 
We are grateful to Ms. M. Neff-Heinrich (Gottingen, Germany) for her help in editing the manuscript.

	Footnotes

 
This work was supported by Deutsche Kinderkrebsstiftung (Bonn, Germany; www.kinderkrebsstiftung.de) Grant DKS 2001.04.

Results of this study were presented in part at the 85th Annual Meeting of The Endocrine Society, Philadelphia, Pennsylvania, 2003.

Abbreviations: BMI, Body mass index; CI, confidence interval; IUGR, intrauterine growth retardation; PI, ponderal index; SDS, SD score.

Received October 10, 2003.

Accepted March 18, 2004.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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