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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2762
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 6 2081-2086
Copyright © 2006 by The Endocrine Society

Evidence for Hypermetabolism in Boys with Constitutional Delay of Growth and Maturation

Joan C. Han, Prabharakan Balagopal, Shawn Sweeten, Dominique Darmaun and Nelly Mauras

Division of Pediatric Endocrinology (J.C.H., D.D., N.M.) and Biomedical Analysis Laboratory (P.B., S.S.), Nemours Children’s Clinic, Jacksonville, Florida 32207; Developmental Endocrinology Branch (J.C.H.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Human Nutrition Research Center (D.D.), Institut National de la Santé et de la Recherche Médicale, 44093 Nantes, France

Address all correspondence and requests for reprints to: Nelly Mauras, M.D., Chief, Division of Endocrinology, Nemours Children’s Clinic— Jacksonville, 807 Children’s Way, Jacksonville, Florida 32207. E-mail: nmauras{at}nemours.org.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Children with constitutional delay of growth and maturation (CDGM) tend to be thin and have a growth pattern reminiscent of nutritional insufficiency.

Objective: Our objective was to compare differences in nutrition, body composition, bone mineral density, and resting and total energy expenditure (REE/TEE) in boys with CDGM and controls. We hypothesized that an imbalance between energy intake and expenditure may contribute to the pathogenesis of CDGM.

Design and Setting: We conducted an observational, cross-sectional study at an outpatient clinical research center.

Patients: Patients included 36 boys (8–17 yr): 12 with CDGM (short stature, delayed bone age and puberty, and no other pathology) and 12 height-matched (pre- or early-pubertal) and 12 age-matched (pubertal) healthy controls.

Main Outcome Measures: Outcome measures included doubly labeled water studies (TEE), serum nutritional/hormonal markers, dual-energy x-ray absorptiometry, dietary analysis, and indirect calorimetry (REE).

Results: Nutritional markers were comparable among the groups. CDGM subjects had bone mineral density lower than age-matched controls (P < 0.01) but comparable with height-matched controls. Even though REE did not differ between groups, CDGM subjects had 25% higher caloric intake adjusted for fat-free mass (FFM) than height-matched controls (P < 0.05) and 78% higher caloric intake per kilogram FFM compared with age-matched controls (P < 0.00001). CDGM subjects had 46% (P < 0.05) and 91% (P < 0.001) higher TEE per kilogram FFM than height- and age-matched controls, respectively. CDGM subjects had lower IGF-I and testosterone than age-matched controls (P < 0.001) but levels were comparable with height-matched controls.

Conclusions: Boys with CDGM have higher rates of overall energy expenditure compared with age- and size-matched controls. This increased metabolism may result in impaired tempo of growth. Additional studies are needed to determine whether augmenting nutrition to match their energy needs (with or without hormonal therapy) can improve linear and ponderal growth in patients with CDGM.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONSTITUTIONAL DELAY OF growth and maturation (CDGM) is a term commonly used to describe youngsters with short stature and delayed onset of puberty but no evidence for systemic disease or hormonal dysfunction. Children with CDGM usually attain normal adult height, but often within the lower part of their midparental target height zone (1, 2). Negative psychosocial effects, such as low self-esteem, depression, and school difficulties, have been associated with CDGM, particularly among boys (3). From a physiological standpoint, the delayed growth and tempo of puberty can result in reduced peak bone mass (4, 5, 6) and, depending on the severity of the growth delay, adult short stature. Various treatment modalities, such as testosterone, oxandrolone, and GH, have been used to manage CDGM, but these do not necessarily address the underlying mechanisms for the poor linear and ponderal growth (7, 8, 9).

Children with CDGM are typically underweight for height and often have a family history of CDGM, suggestive of an underlying, intrinsic problem in energy intake and energy utilization (10, 11, 12). Most children with CDGM begin to deviate from the normal growth curve before age 2 yr, subsequently grow at a relatively normal velocity, and then have a delayed pubertal growth spurt (10). This pattern of growth is strikingly similar to that of malnourished children (13, 14, 15), suggesting that CDGM may lie in the spectrum of nutritional dwarfing because of an imbalance in caloric intake and energy expenditure. Total energy expenditure (TEE) in children with short stature compared with normal-stature children has been reported to not be statistically different (16); however, TEE was highly variable in those children, and CDGM as a subset was not specifically examined. Moreover, although previous studies have assessed TEE in children with CDGM in the context of treatment with testosterone or GH (17, 18), direct comparison of TEE in children with CDGM vs. normal children has not, to our knowledge, been previously reported. We therefore conducted a study to examine the differences in body composition, nutrition, and energy expenditure in boys with CDGM compared with height-matched (pre- or early-pubertal) and age-matched (pubertal) controls to test the hypothesis that children with CDGM have a mismatch between energy intake and energy utilization, resulting in poor growth.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The protocol was approved by the Nemours Clinical Research Review Committee and the Institutional Review Board of Baptist Medical Center/Wolfson Children’s Hospital. Informed written consent from the parents/guardians and assent from each boy were obtained. A total of 36 boys with either CDGM or normal growth were recruited for these studies through the Nemours pediatric endocrine clinics and through local advertising.

Boys were considered as having CDGM (n = 12) if they were 11–17 yr-old, with a height of less than the fifth percentile for age, a bone age delay of at least 1 yr below chronological age, genital Tanner stage more than 2 SD delayed for age (19), and normal physical exam. All other forms of organic and hormonal pathology had been excluded before study participation. Subjects were not taking any medication during the study, which was conducted before any hormonal treatment in the CDGM group. Two groups of 12 healthy boys, either height matched (pre- or early-pubertal, n = 12) or age matched (pubertal, n = 12), were recruited as controls.

Protocol design

After an initial screening visit, including a physical exam to determine eligibility, each subject was admitted to the Clinical Research Center at Wolfson Children’s Hospital by 0800 h after an overnight fast. Height was measured using a Harpenden stadiometer and weight by a beam balance in subjects wearing light clothing. Blood was sampled for IGF-I, testosterone, insulin, leptin, prealbumin, albumin, transferrin, alkaline phosphatase, iron, and zinc concentrations. Indirect calorimetry was performed in the postabsorptive state over three 10-min steady-state periods using a CPX/D calorimeter (Medical Graphics Corp., St. Paul, MN) to determine substrate oxidation as well as carbon dioxide production and oxygen consumption using a mouth piece. Body composition was assessed with dual-energy x-ray absorptiometry (DEXA) using a Hologic 4500QDR instrument (Hologic, Waltham, MA). Urine was collected over a 4-h period while the subjects remained fasting to determine urine nitrogen excretion.

Doubly labeled water for TEE assessment

After a baseline urine sample was obtained, each subject received an oral dose of 0.15 g/kg body weight of H218O, containing 10% atoms percent excess of 18O, and 0.3 g/kg of 2H2O (99.9% enriched), followed by 120 ml of natural water used to rinse the cup and ensure full consumption of the tracers. Subjects were sent home and were asked to provide two urine samples on the day after tracer administration, one sample daily for the following 9 d, and two samples on the 10th day after tracer administration for the measurement of the dual isotopic enrichment. The samples were stored at –20 C in sealed Vacutainer tubes until later analysis. During the urine collection period for TEE assessment, all subjects were asked to complete a 3-d dietary log while maintaining their typical diet and a log of all sports and exercise activities.

Isotopes. H218O and 2H2O were purchased through Cambridge Isotope Laboratories (Andover, MA) and verified to be sterile and pyrogen free, as previously described (6).

Assays

General chemistries, including all substrate analyses, were performed using automated chemical analyzers. IGF-I, testosterone, insulin, and leptin concentrations were measured by standard RIA using commercial kits. Urinary nitrogen excretion was measured using the Paramax urea nitrogen method (Baxter, Deerfield, IL). Urine samples were analyzed for H218O and 2H2O by isotope ratio mass spectrometry (IRMS). For measurement of 18O enrichment, we used the CO2 equilibration technique as previously described (20, 21). Briefly, duplicate 1-ml aliquots of urine samples were isotopically equilibrated with CO2 placed in septum-capped Vacutainers by overnight gentle shaking at room temperature. The 18O isotopic enrichment in the CO2 was then measured directly by IRMS (Micromass, Manchester, UK) (21, 22). Measurement of the enrichment of 2H was performed by direct pyrolysis of samples (21) using a Europa Scientific 20–20 IRMS instrument upgraded to HD by adding a single Faraday collector and high-gain amplifier for m/z 3 on the hydrogen spur as described (21, 23).

Calculations

TEE. TEE assessment using the doubly labeled water technique is based on the general principle that 18O administered in a dose of H218O will be eliminated from the body as both CO2 and H2O, whereas the deuterium administered as 2H2O will be eliminated solely as a function of water turnover. Hence, the difference between the elimination rates of the two tracers is a measure of CO2 flux, which in turn can be used to calculate TEE (22, 24). In brief, total body water (TBW) was calculated first as the mean of the zero time isotope dilution spaces for H218O (VO) and 2H2O (VH) after dividing by correction factors: TBW = (VO /1.01 + VH /1.04)/2. In turn, TEE can be calculated as previously described (25): rCO2 (liters/day) = 0.4554 x TBW x (1.01 KO– 1.04 KH) x 22.4 and TEE (kcal/day) = 3.9 rCO2/RQ + 1.11 rCO2, where rCO2 is the total daily production of CO2 and KO and KH are the fractional turnover rates of H218O and 2H2O, respectively, calculated by regression analysis of the rate of decrease in isotope enrichment in the urine samples. A respiratory quotient (RQ) of 0.85 was used for all calculations after it was determined that the RQ from indirect calorimetry and the food quotient (FQ) from dietary logs yielded consistent values for the three groups of subjects.

Nutritional intake. Nutritional intake was assessed using 3-d dietary logs (26). The diaries were analyzed by a research dietician using Nutritionist Pro (version 2.3.1; First Data Bank, copyright 2005). The average of all 3 d of the dietary log was used for calculations. FQ, an estimate for RQ, was calculated as follows (22): FQ = 0.81P + 0.71F + 1.0C, where P, F, and C represent the percentage of calories of total energy intake derived from protein, fat, and carbohydrates, respectively.

Resting energy expenditure (REE). Resting energy expenditure (REE) was calculated as previously described (27), using values for carbon dioxide production and oxygen consumption obtained from indirect calorimetry and measurement of urinary nitrogen excretion.

Body composition. Analysis was performed using the body composition software of the DEXA Hologic 4500A instrument.

Statistical analysis. Single-factor ANOVA was performed to assess the differences among the groups and significance determined by post hoc Tukey’s honestly significant difference test. Mann-Whitney U test was used for categorical variables (Tanner stage). Significance was established at P < 0.05. TEE, REE, and caloric intake were compared in three ways: 1) total values, 2) values per kilogram fat-free mass (FFM), and 3) values adjusted for FFM using covariate analysis and Bonferroni correction for multiple comparisons. We acknowledge that each of these forms of expressing energy expenditure has inherent flaws. Unadjusted values fail to take into consideration the size of the subjects. Energy expenditure adjusted for FFM corrects for the size of the metabolically active body compartment of the subjects but does so at the expense of decreased statistical power. Energy expenditure per kilogram FFM preserves statistical power but tends to yield disproportionately lower values for larger subjects, particularly if the relationship between energy expenditure and FFM is not linear at the extremes. Because no single form is ideal, for completeness, we analyzed our data using all three formats.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical characteristics of subjects (Table 1Go)

Thirty-six subjects were enrolled, and all completed the full protocol. CDGM subjects were well matched with height controls for height (P = 0.68), weight (P = 0.98), and body mass index (BMI) (P = 0.76) and were well matched with age controls for age (P = 0.96). The CDGM subjects were pre- or early-pubertal (genital Tanner stage 1–2) except for one subject who was genital Tanner stage 3 at age 15.9 yr (+2 SD for stage 3 = 14.9 yr) (19). The height controls were pre- or early-pubertal (genital Tanner stages 1–2), and Tanner staging as a group was not clinically different from that of the CDGM subjects. The age controls were genital Tanner stages 2–5. The CDGM group had a mean bone age delay of 1.9 yr, mean bone age Z-score of –2.0 SD, and 10 of 12 had a family history of CDGM.


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  		TABLE 1. Clinical characteristics of study subjects

 
Hormonal and nutritional assessments (Table 2Go)

CDGM subjects had lower levels of IGF-I (290 vs. 716 ng/ml; P < 0.001) and testosterone (93 vs. 542 ng/dl; P < 0.001) compared with age controls but comparable to height controls. CDGM subjects had similar fasting insulin levels compared with height controls (2.8 ± 0.6 vs. 2.2 ± 0.4 µU/ml; P = 0.77) but lower, although not statistically different, when compared with age controls (4.9 ± 0.9 µ/ml, P = 0.067). All the nutritional markers tested (leptin, prealbumin, albumin, transferrin, alkaline phosphatase, iron, and zinc) were comparable between the CDGM subjects and both control groups.


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  		TABLE 2. Hormonal and nutritional laboratory analysis

 
Body composition and bone mineral density (BMD) (Table 3Go)

The FFM of CDGM subjects was comparable to that measured in much younger height controls (27.5 vs. 26.0 kg; P = 0.82) but was much lower than in age controls (27.5 vs. 45.1 kg; P < 0.001). CDGM subjects and age controls had comparable percent body fat (18.9 vs. 16.4%; P = 0.37), whereas height controls had the greatest percent body fat (23.5%; P = 0.0016); the latter difference vs. the CDGM group approached significance (P = 0.05). Although the CDGM subjects had lower lumbar and whole-body BMD Z-scores than both control groups (P < 0.01), actual BMD values were comparable with the height controls.


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  		TABLE 3. Body composition and BMD analysis by DEXA

 
Nutritional intake (Table 4Go)

Total daily caloric intake and intake adjusted for FFM were comparable between CDGM subjects and age controls but were both 25% higher in CDGM subjects compared with height controls (P < 0.05). Caloric intake per kilogram FFM was 78% higher for CDGM subjects than age controls (P < 0.00001) and was 20% higher but not statistically different from height controls (P = 0.086). Average daily intake of vitamins A and D, iron, zinc, and calcium was comparable among the three groups.


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  		TABLE 4. Nutritional intake

 
Energy expenditure (Fig. 1Go)

REE, REE per kilogram FFM, and REE adjusted for FFM were comparable (P = 0.96, 1.0, and 0.88 respectively) between the CDGM subjects (1195 ± 67 kcal/d, 43.8 ± 2.6 kcal/d·kg, and 1217 ± 68 kcal/d, respectively) and height controls (1172 ± 55 kcal/d, 45.5 ± 2.5 kcal/d·kg, and 1200 ± 72 kcal/d, respectively). When compared with the age controls (1552 ± 56 kcal/d, 35.9 ± 2.6 kcal/d·kg, and 1502 ± 93 kcal/d), CDGM subjects had lower REE (P < 0.001) but not statistically different REE adjusted for FFM (P = 0.12) and REE per kilogram FFM (P = 0.084).


Figure 1
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  		FIG. 1. Energy expenditure per kilogram FFM: comparison of TEE (kcal/ d·kg FFM) in the boys with CDGM vs. height-matched (younger, prepubertal) and age-matched (taller, pubertal) controls (n = 12 per group). Data are expressed as mean ± SEM. Solid bar represents the REE contribution to TEE. *, P < 0.05 vs. CDGM; **, P < 0.001 vs. CDGM.

 
CDGM subjects had daily TEE (4190 ± 363 kcal/d), TEE adjusted for FFM (4326 ± 384 kcal/d), and TEE per kilogram FFM (156.3 ± 15.3 kcal/d·kg) that were significantly higher by 52% (P = 0.013), 48% (P = 0.020), and 46% (P = 0.014), respectively, than height controls (2749 ± 223 kcal/d, 2923 ± 410 kcal/d, and 107.0 ± 9.0 kcal/d·kg, respectively). TEE and TEE adjusted for FFM were comparable between CDGM subjects and age controls (3632 ± 403 kcal/d, 3312 ± 530 kcal/d adjusted FFM), but TEE per kilogram FFM was 91% higher in CDGM subjects compared with age controls (156.3 ± 15.3 vs. 81.9 ± 9.6 kcal/d·kg; P < 0.001).

Daily caloric intake as a percentage of TEE was not statistically different (P = 0.25) among the three groups: CDGM, 65 ± 5%; height controls, 83 ± 11%; and age controls, 71 ± 7%. The subjects’ exercise logs showed similar volitional activity during the 10-d study period among the three groups: CDGM, 12.4 ± 2.2 h; height controls, 8.8 ± 1.7 h; and age controls, 9.2 ± 1.9 h. Although the CDGM subjects had higher mean self-reported exercise activity, the difference was not statistically significant when compared with the control subjects (P = 0.40). Participation on sports teams, enrollment in physical education class at school, and distribution of enrollment during the seasons of the year were similar among the three groups.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
To the best of our knowledge this is the first study to methodically examine differences in metabolic rates in boys with CDGM carefully matched for size and age with healthy controls. We observed marked differences in TEE among the groups with significantly higher rates among those with CDGM compared with those controls matched for size (younger) and age (taller). These comparisons allowed for an independent assessment for both height and age contributions to changes in TEE. All other measures of nutritional health, including serum levels of leptin, prealbumin, albumin, transferrin, alkaline phosphatase, iron, and zinc, as well dietary intake of micronutrients were comparable among the groups, suggesting an intrinsic increase in the energy expenditure of these youngsters, which, we hypothesize, may explain, in part, the poor growth pattern in this condition. CDGM subjects were clinically healthy and essentially physically and biochemically indistinguishable from size-matched healthy controls. Thus, the condition of CDGM itself does not appear to induce a state of illness that would lead to hypermetabolism, as is seen in cardiac, pulmonary, or renal disease. Therefore, the observation of greater energy expenditure in the CDGM subjects when compared with size-matched controls suggests that this phenomenon may be one of the underlying causes of CDGM itself.

TEE comprises REE, activity (exercise/nonexercise), and dietary-induced thermogenesis (22). REE per kilogram FFM and REE adjusted for FFM were comparable between CDGM subjects and both control groups. Dietary-induced thermogenesis was not measured but is presumably fairly constant even over a wide range of body weights (28, 29, 30). Thus, it would appear that increased activity expenditure could account for the significantly higher TEE observed in the CDGM subjects. Use of accelerometers or direct subject observation would be necessary to confirm this, but our data provide indirect evidence for increased activity energy expenditure in the CDGM subjects. Whether this is because of increased volitional exercise and/or increased nonexercise-activity thermogenesis (NEAT) remains to be determined. Although the CDGM group did report a higher average amount of time spent exercising, this difference was not statistically significant compared with both control groups. NEAT comprises fidgeting, muscle tone, posture maintenance, and other low-level daily physical activities; it is difficult to quantitate, but we hypothesize that increased NEAT may be an important component of the significantly higher TEE observed in the CDGM subjects. Just as decreased NEAT may contribute to obesity (31, 32), we speculate that increased NEAT could contribute to the decreased total body weight, lower percent body fat, and lower FFM observed in CDGM. A higher prevalence of attention deficit hyperactivity disorder, a condition associated with increased NEAT (and lower caloric intake if treated with stimulant medication), has been observed in CDGM patients (10). In our CDGM group, 25% had a diagnosis of attention deficit with hyperactivity disorder (none on medication), but with the sample size used, any subanalysis in this condition could not be performed.

The net negative caloric balance observed across all three groups suggests an underreporting of food consumption on the dietary logs, which reflects a common shortcoming with this method (33). However, because the discrepancy appeared to be consistent across all three groups, some general comparisons may still be considered. The higher daily caloric intake observed in the CDGM group supports the finding of higher TEE as well, suggesting that increased metabolic need drives greater caloric consumption in these children.

Several studies have suggested various micronutrient deficiencies, including vitamins A and D, iron, and zinc in patients with CDGM (11, 34, 35, 36). We did not observe any difference among the groups in serum iron and zinc levels or in micronutrient intake. Furthermore, all serum nutritional markers were comparable among the three groups. Thus, our CDGM subjects are not malnourished, based on conventional definitions, but they may still be lacking the additional energy reserves required to achieve normal tempo of growth and puberty. Boys with CDGM have been previously reported to have lower leptin concentrations than expected for age and BMI (37). We observed that the mean percent body fat and mean serum leptin level were lower in the CDGM group compared with size-matched controls, but these differences were not statistically significant. IGF-I, which can be lower in the setting of malnutrition, was lower in the CDGM subjects compared with the age controls. However, IGF-I levels were within the normal range for Tanner stage and were comparable with that of the height controls, suggesting that the lower levels reflect the delayed puberty and lower testosterone levels of the CDGM subjects. Similarly, insulin levels were comparable in the CDGM subjects and height controls, and both were lower than the age controls, a finding consistent with the relatively greater insulin resistance associated with puberty.

BMD was comparable for the CDGM subjects and height controls, which we had anticipated, given their similar size and pre-/early-pubertal status. The pubertal age controls had higher BMD, as expected. Whether peak bone mass in adulthood will be affected in our CDGM subjects, as reported previously (4, 5), cannot be predicted and would require long-term follow-up.

The underlying mechanisms involved in this increased rate of energy expenditure, and NEAT in particular, are presently unknown. Because of the common tendency for delayed growth and puberty to occur in several members in the same family (of note, 83% of our CDGM subjects had a first-degree relative with a history of CDGM), it is possible that a given abnormal set-point in energy utilization is inherited. Polymorphisms in the gene for uncoupling protein 1 (UCP1), a carrier protein located in the mitochondrial inner membrane of brown adipose tissue, have been associated with differences in weight changes in response to dietary restriction and exercise, mediated presumably through alterations in thermogenic proton leakage (38, 39). More recently, other UCP1 homologs have been identified in skeletal muscle and other organs and are thought to play roles in insulin secretion and lipid oxidation (40, 41). Given that the CDGM subjects in our study did not have significantly higher REE compared with the control groups, increased basal metabolism is unlikely the etiology; however, increased thermogenesis in skeletal muscle or adipose tissue during exercise and activities of daily living could lead to greater relative energy dissipation.

In conclusion, the substantially higher TEE observed in the CDGM subjects compared with height- and age-matched controls suggests that boys with CDGM have markedly greater metabolic needs. Despite increased caloric intake, there still appears to be a deficit in the balance between caloric intake and expenditure, thus resulting in a growth pattern reminiscent of nutritional insufficiency. Additional studies are needed to elucidate the potential role of nutritional supplementation, alone and in combination with hormonal supplementation, in meeting the increased energy needs of these children and improving their linear and ponderal growth.


   Acknowledgments
 
We are grateful to Brenda Hartman and the Nemours biomedical analysis laboratory for the measurement of hormonal and substrate assays, to Darlise DiMatteo at the Dupont Hospital for Children for the measurement of leptin concentrations, to Kristen Farnham for analysis of dietary records, and to Suzanne Murphy for assistance with statistical analysis.


   Footnotes
 
This work was supported by the Nemours Research Programs.

J.C.H. is a Commissioned Officer of the United States Public Health Service.

First Published Online March 21, 2006

Abbreviations: BMD, Bone mineral density; BMI, body mass index; CDGM, constitutional delay of growth and maturation; DEXA, dual-energy x-ray absorptiometry; FFM, fat-free mass; FQ, food quotient; IRMS, isotope ratio mass spectrometry; NEAT, nonexercise-activity thermogenesis; REE, resting energy expenditure; RQ, respiratory quotient; TBW, total body water; TEE, total energy expenditure.

Received December 19, 2005.

Accepted March 13, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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