Published online June 2, 2008
PEDIATRICS Vol. 121 No. 6 June 2008, pp. e1517-e1523 (doi:10.1542/peds.2007-2820)
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ARTICLE

Determinants of Height in Adolescent Girls With Anorexia Nervosa

Rajani Prabhakaran, MDa,b, Madhusmita Misra, MD, MPHa,b, Karen K. Miller, MDa, Kimberly Kruczek, BAa, Shankeertha Sundaralingam, MSa, David B. Herzog, MDc, Debra K. Katzman, MDd and Anne Klibanski, MDa

a Neuroendocrine Unit
c Harris Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
b Pediatric Endocrine Unit, MassGeneral Hospital for Children and Harvard Medical School, Boston, Massachusetts
d Division of Adolescent Medicine, Department of Pediatrics, Hospital for Sick Kids, Toronto, Ontario, Canada


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. Anorexia nervosa, a condition characterized by marked caloric restriction and low insulin like growth factor-1 levels, would be expected to cause short stature. However, this disorder is also associated with hypogonadotropic hypogonadism and high growth hormone levels. Delays in growth-plate closure from associated hypogonadism may result in a longer period of time available for statural growth with protective effects on stature. In addition, growth hormone may have direct effects on the growth plate independent of insulin-like growth factor 1 to increase statural growth.

OBJECTIVES AND METHODS. To determine the impact of undernutrition, hypogonadism, and acquired growth hormone resistance on height in adolescents with anorexia nervosa (aged 12–18 years), we examined 208 girls: 110 with anorexia nervosa and 98 controls of comparable chronological age. Sixty-three girls with anorexia nervosa and 79 controls were followed prospectively over 1 year. Mean duration of illness was 11.6 ± 13.2 months. In a subset, overnight growth hormone sampling was performed every 30 minutes for 12 hours, and fasting insulin-like growth factor 1 levels were obtained.

RESULTS. The difference between height and target height and between predicted adult height and target height did not differ between the groups, indicating preservation of height potential. The groups had comparable bone age, but bone age was lower than chronological age in girls with anorexia nervosa. Girls with anorexia nervosa had lower insulin-like growth factor 1 levels and higher nadir growth hormone levels than those of controls. Nadir growth hormone levels predicted height SD scores and predicted adult-height SD scores in controls but not in the girls with anorexia nervosa. In girls with anorexia nervosa, insulin-like growth factor 1 and duration of illness predicted height measures. Height SD scores of <0 were more likely after 32 months of illness and at insulin-like growth factor 1 levels of <134 ng/mL. Delayed baseline bone age predicted subsequent increases in height SD scores in immature girls with anorexia nervosa.

CONCLUSIONS. Our data suggest that preservation of height potential in this cohort of girls with anorexia nervosa may be a consequence of delayed bone age. Hypogonadism may negate the deleterious effects of undernutrition on stature by allowing for a longer duration of growth.

Key Words: height • anorexia nervosa • adolescents • bone age • hypogonadism • growth hormone

Abbreviations: AN—anorexia nervosa • IGF-1—insulin-like growth factor 1 • GH—growth hormone • BA—bone age • CA—chronological age • MGH—MassGeneral Hospital • SDS—standard deviation score • TH—target height • PAH—predicted adult height • AUC—area under the curve • Ht-0—baseline height • Ht-12—height at 12 months’ follow-up

Anorexia Nervosa (AN), a condition of severe undernutrition, is the third most common chronic condition in adolescent girls and affects 0.2% to 1.0% of this population. There have been few studies that have examined the effect of the severe nutritional deficiency characteristic of AN on adult height, particularly in comparison to healthy controls. Although there are some reports of short stature in girls with AN,1–4 our group and other investigators5,6 have reported a sparing of height potential or even greater-than-expected height in girls with this disorder. However, these studies have been small, and most have not compared girls with AN to a control group. It is important to note that the mechanism that underlies the sparing of height potential in girls with AN has not been investigated previously.

AN is associated with a number of endocrine abnormalities that may impact growth, including low insulin-like growth factor 1 (IGF-1) levels and hypogonadism. Although IGF-1 deficiency causes delayed growth in children with hypothalamic and pituitary disorders, growth hormone (GH) levels in such states are also decreased. In contrast, we have reported increased GH levels coupled with low IGF-1 levels in AN, which suggests an acquired state of GH resistance.7 GH is known to have both direct and indirect effects on the growth plate; direct effects lead to increased proliferation of prechondrocytes, whereas indirect effects mediated by IGF-1 cause an increase in chondrocyte differentiation.8,9 It is unknown whether these direct effects of GH at the growth plate, in association with IGF-1 levels that are lower than those in healthy adolescents but higher than in those with GH deficiency, may prevent or override growth attenuation secondary to undernutrition. In addition, hypogonadism can cause a delay in epiphyseal maturation and growth-plate fusion, and hypothalamic amenorrhea is one of the defining features of AN. In fact, we have reported lower bone age (BA)/chronological age (CA) ratios in patients with AN compared with controls.5 It is not known whether estrogen deficiency leading to delayed growth-plate fusion contributes to sparing of height potential in patients with AN by allowing a longer period available for growth. Finally, the duration of illness may be a key factor in determining the effects of AN on height.

We hypothesized that height potential is preserved in girls with AN, mediated by (1) direct effects of GH on the growth plate, (2) a delay in BA, and (3) a short duration of illness.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Subject Selection
We studied 208 girls: 110 girls with AN (meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria) and 98 healthy controls with complete height, target-height (TH), and predicted adult-height (PAH) data at baseline and followed 63 girls with AN and 79 healthy subjects over 1 year. Baseline characteristics, but not detailed height data, for 38 girls with AN and 38 controls have been previously reported by Soyka et al10 and Misra et al.7 We also reviewed unpublished data from 72 girls with AN and 60 healthy controls. To our knowledge, this is the largest study published to date to examine height in girls with AN. To minimize bias during recruitment, subjects were recruited at Massachusetts General Hospital (MGH) through multiple sources including advertisements in area newspapers and referrals from pediatricians, adolescent medicine physicians, nutritionists, therapists, and psychiatrists. A subset (n = 18 girls with AN) was recruited at the Hospital for Sick Children.

Girls with AN ranged in age from 12.8 to 17.8 years, and healthy controls ranged from 12.2 to 18.0 years. The institutional review boards of Partners HealthCare and the Hospital for Sick Kids approved the study. Written consent or assent was obtained from study subjects, and consent from parents of subjects <18 years old.

Experimental Protocol
Eligibility of the subjects was determined during a screening visit at either the General Clinical Research Center at MGH or the Hospital for Sick Kids. A history and physical examination and screening laboratory tests were performed. Screening tests included obtaining levels of follicle-stimulating hormone, thyrotropin, hematocrit, blood glucose, and potassium. The resulting levels were within the reference ranges for all subjects. A detailed history, including age at menarche and duration of illness for subjects with AN, was obtained. A detailed physical examination that included anthropometric measurements was performed. Overnight sampling every 30 minutes for 12 hours was performed for GH analysis in 29 girls with AN and 51 healthy controls, and fasting IGF-1 levels were available for 38 girls with AN and 38 controls. Subjects returned for follow-up visits at the General Clinical Research Center at 6 and 12 months. These visits involved a history and physical examination, anthropometric measurements, and BA evaluation. No subject was receiving oral contraceptive pills.

Anthropometric Measurements
Weight was measured with the subject in a hospital gown on an electronic scale. Height was measured in triplicate with a Harpenden stadiometer, and the average of the 3 readings was used. BMI was calculated by using the formula weight in kg/(height in m)2, and BMI percentiles and SD scores (SDSs) were calculated by using published charts.11 A radiograph of the left hand and wrist was performed to assess BA, which was determined by using the methods of Greulich and Pyle.12 To minimize interobserver variation, a single investigator, a pediatric endocrinologist, read the BA films for study subjects from MGH and the Hospital for Sick Children. Predictions of adult height were based on the skeletal age and height measured at the visit.12 Parental heights were reported by the parent who accompanied the study subject. Midparental or target height (TH) was calculated by using the formula (maternal height in cm + paternal height in cm – 13 cm)/2. The height SDS for age and BMI SDS were obtained by using National Center for Health Statistics data from the 2000 Centers for Disease Control and Prevention age- and gender-specific growth data (www.cdc.gov/growthcharts).

Biochemical Measurements
Measurements of plasma glucose and serum follicle-stimulating hormone, thyrotropin, hematocrit, and potassium were obtained in the hospital laboratory by using standard assays. Serum IGF-I levels were measured with an acid-alcohol extraction and radioimmunoassay kit (Nichols Institute Diagnostics, San Juan Capistrano, CA) with a detection limit of 0.06 µg/L and an intraassay coefficient of variation of 2.4% to 3.0%. An immunoradiometric assay (Nichols Institute Diagnostics) was used to measure GH (detection limit: 0.05 ng/mL; coefficient of variation: 2.4%–9.4%). All samples were stored at –80°C until analysis. GH data obtained from frequent sampling were analyzed by cluster (1 x 2) analysis using methods previously described,7,13 and area under the curve (AUC) and nadir GH are reported here. Descriptive GH and IGF-I data have been reported previously for a subset of subjects7 but not in relation to height measures.

Statistical Analysis
The JMP 5.0.1 program (JMP Statistical Data Software [SAS Institute, Inc, Cary, NC]) was used for statistical analysis. All results are expressed as mean ± SD. Significance was assumed for a P value of <.05 for all comparisons. Student's t test was used to calculate differences between means. Logarithmic transformations were performed for GH data to approximate a normal distribution. We used Pearson's correlation to determine associations between height measures (height, height SDS, predicted adult height [PAH] and its SDS, and the difference in height and TH [height – TH]) and the difference between corresponding SDSs (height SDS – TH SDS), the difference between PAH and TH (PAH – TH) and between corresponding SDSs (PAH SDS – TH SDS)] and covariates such as GH and IGF-I measures, the degree by which BA lagged behind CA (BA–CA), and duration of illness. We first compared all girls with AN with all controls; then, we examined subjects with a BA of ≥15 years (mature AN versus mature controls) and subjects who had a BA of <15 years (immature AN versus immature controls). A BA of 15 years was chosen because only 1% of growth remains at this level of skeletal maturity, and the individual's height at this BA represents near adult height.12 Temporal effects of AN on height would be expected to be more evident in girls who still have growth potential (BA < 15 years).


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Baseline Characteristics
Table 1 details the baseline characteristics of all subjects with AN and controls, of mature AN and controls, and immature AN and controls. Girls with AN and controls did not differ for CA or BA. As expected, girls with AN had significantly lower BMIs than those of controls in the group as a whole and in the subgroups. Although the 2 groups had comparable BAs, the difference between BA and CA was lower in girls with AN than in controls, which indicates relative skeletal immaturity in girls with AN. Compared with controls, girls with AN had significantly lower IGF-1 and higher nadir GH levels, more marked in mature than in immature girls. GH AUC trended higher for girls with AN than for controls and was significantly higher than for the controls in the mature subset. Although only 15.8% of the girls with AN had IGF-I levels below the reference range expected for pubertal stage, girls with AN had a relative IGF-I deficiency such that 52.6% of the girls with AN versus 18.4% of controls had levels in the lowest IGF-I quartile for pubertal stage. The duration of illness for girls with AN was 11.6 ± 13.2 months. Twenty-five girls with AN and 10 controls were premenarcheal at baseline.


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  		TABLE 1 Baseline and Hormonal Characteristics of Girls With AN and Controls

 
Height data are shown in Table 2. TH and TH SDSs were minimally greater in girls with AN than in controls (for the group as a whole and in mature AN). Initial height (Ht-0) was greater in girls with AN than in controls for the group as a whole but not for the subgroups, and there was no significant difference in the Ht-0 SDS of girls with AN compared with healthy controls. PAH and PAH SDSs trended higher in girls with AN than in controls for the group as a whole but not the subgroups. It is worth noting that there was no significant difference between girls with AN and healthy controls with regard to the difference between height and TH (Ht-0 – TH), the difference between PAH and TH (PAH – TH), or corresponding SDSs. The proportion of girls with AN versus controls who had a deficit in height SDS or PAH SDS in comparison to TH SDS did not differ. Height at 12 months’ follow-up (Ht-12) was available for 79 healthy adolescents and 63 girls with AN (14 of whom were in the immature group with a BA of <15 years). Between the girls with AN and healthy controls, there was no difference in Ht-12, Ht-12 SDSs, Ht-12 – TH, or Ht-12 SDS–TH SDS. Change in height over 12 months trended lower in girls with AN than controls for the group as a whole, despite significant increases in BMI and BMI SDSs over the follow-up period for girls with AN.


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  		TABLE 2 Height Characteristics of Girls With AN and Controls

 
Associations of Height Measures With GH and IGF-I
For all subjects, height parameters were positively associated with GH parameters (Table 3) such that girls with higher nadir GH levels had greater height and PAH SDSs. The associations between nadir GH and height measures were stronger in immature subjects than in mature subjects. Overall, the association between nadir GH levels and height measures was driven not by girls with AN but by controls (r = 0.29, P = .04 [for height SDS]; r = 0.30, P = .03 [for PAH SDS in controls]) (Fig 1A). In girls with AN, IGF-I levels, rather than GH levels, correlated with height SDS and PAH SDS (r = 0.33, P = .04 and r = 0.31, P = .05, respectively) (Fig 1B). A negative value for height SDS and PAH SDS was likely with IGF-I levels of <134 and 115 ng/mL, respectively.


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  		TABLE 3 Associations Between GH, IGF-I, and Height Measures in All Subjects, Immature Subjects, and Mature Subjects

 

Figure 1
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  		FIGURE 1 Associations of height SDS with nadir GH in controls (gray) and girls with AN (black) (A) and IGF-I levels in girls with AN (B). There was a positive association between height SDS and GH concentrations in healthy adolescent girls (r = 0.29, P = .04) but not in girls with AN (r = 0.03, P not significant). In girls with AN, IGF-I levels were associated with height SDSs (r = 0.33, P = .04).

 
Associations of Height Measures With BA and Duration of Illness
A baseline delay in BA in relation to CA (BA–CA) was a strong inverse predictor of changes in height SDSs over time in immature AN (r = –0.76, P = .003) (Fig 2) and, to a lesser extent, for all girls with AN (r = –0.30, P = .02). However, we found no association of baseline height measures with the difference between BA and CA. As expected, BA correlated negatively with logGH – AUC (r = –0.34, P = .002) and log nadir GH (r = –0.27, P = .02), reflecting higher GH levels in younger subjects and indicating that girls with AN were likely to be delayed for BA in comparison to CA and to have higher GH levels.


Figure 2
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  		FIGURE 2 Association between change in height over a 1-year follow-up period and the difference between BA and CA in girls with AN whose baseline BA was <15 years (immature AN). An inverse association was observed between changes in height and the delay in BA (r = –0.76, P = .003).

 
For girls with AN, duration of illness predicted height measures such that girls with longer duration of illness had lower height SDSs and PAH SDSs (r = –0.24, P = .02 for both). A negative value for height SDS and PAH SDS was more likely with a duration of illness of longer than 32.0 and 29.5 months, respectively. Duration of amenorrhea in girls with AN did not predict height measures.

Effect of Weight Gain
We examined changes in height over the follow-up period of immature subjects, given that they still had growth potential. In immature AN, follow-up data were available for 14 subjects, and within this group, girls who had a ≥10% increase in BMI (n = 8) had a trend toward greater increases in height than in those who did not gain weight (n = 6) (2.5 ± 1.0 vs 1.4 ± 0.9 cm; P = .08). Similarly, change in height SDS was higher for girls with AN who gained weight. However, this did not reach statistical significance (0.25 ± 0.29 for those who gained weight versus 0.07 ± 0.20 for those who did not gain weight). These trends were not observed when immature girls with AN were analyzed on the basis of menstrual recovery. On regression analysis, change in BMI or BMI SDS of girls with AN did not predict changes in height or height SDS over the follow-up period.


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
To date, this is the largest study to our knowledge to examine the association of AN with height, particularly in relation to normative data from a control group. Possible mechanisms that underlie height alterations for subjects with AN compared with controls have also not been investigated previously. AN, being a condition of severe undernutrition, has traditionally been thought to be associated with short stature.1–4 However, our earlier work, as well as reports by other investigators, have indicated that girls with AN are not shorter than healthy controls, and they may even be taller than controls of comparable maturity.5,6 Height potential, therefore, seems to be preserved in this condition of undernutrition. However, the physiology underlying this phenomenon has not been investigated. In this study, we examined near adult height and PAH and corresponding SDSs in a large group of subjects with AN and controls, particularly in relation to TH, as well as changes in height and height SDS over a 1-year period in girls with AN. We demonstrate here that height potential is preserved with AN despite underlying undernutrition, and this may be related to hypogonadism in AN, leading to a delay in skeletal maturity and a longer period available for growth. In addition, IGF-I levels in subjects with AN, although significantly lower than in controls, may not be low enough to affect height measures.

In contrast to previous reports of short stature in AN,1–4 our study found no significant differences in height measures in relation to TH between subjects with AN and controls. Statural growth is mediated by many hormones, and, particularly during the pubertal years, the GH–IGF-I axis and the gonadal steroids are key determinants of stature. Puberty is associated with rising levels of GH and IGF-I, which bring about the pubertal growth spurt, followed by a slowing and ultimate cessation of growth from epiphyseal fusion caused by rising levels of estrogen. Effects of GH on statural growth are mediated by both IGF-I and direct effects of GH on the growth plate.8,9

In AN, both the hypothalamic–pituitary–gonadal axis and the GH–IGF-I axis are affected by the underlying state of undernutrition. Girls with AN have hypogonadotropic hypogonadism and lower estrogen levels than controls,14,15 which can cause a delay in epiphyseal fusion in relation to CA. Our current data indicate a nutritionally acquired resistance to GH effects with AN, associated with low IGF-I but high GH levels, which confirms a previous report.7 Other conditions of acquired GH resistance, such as chronic renal failure16 and cystic fibrosis,17 are associated with short stature,16,18 likely related to low IGF-I levels. We hypothesized that the preservation of stature with AN may be related to the direct (IGF-I-independent) effects of GH and a commensurate delay in BA from associated hypogonadism.

We observed a positive association between GH levels and height measures for the group as a whole; however, this association was driven by the controls rather than the girls with AN. In healthy adolescents, girls with higher GH levels were likely to be taller with higher height SDSs and PAH SDSs. However, for girls with AN, GH levels were not a predictor of height measures, which is suggestive of a resistance to GH effects at the growth plate, similar to the resistance to GH of bone-formation markers demonstrated by our group in girls with AN.7 Effects of GH at the growth plate are mediated both directly by GH and indirectly by IGF-I.8,9 The girls in our study with AN had a relative IGF-I deficiency. For girls with AN, IGF-I levels, which are also a marker of nutritional status, predicted height measures, as did duration of illness, such that girls with the lowest IGF-I levels and the longest duration of illness had the lowest height measures. These data indicate that direct effects of GH at the growth plate may not explain the preservation of height potential with AN. The associations of height measures in girls with AN with IGF-I and duration of illness indicate that extent and duration of undernutrition contribute significantly to stature in this condition. We noted that girls with a duration of illness of >32 months and IGF-I levels of <134 ng/mL were more likely to have a negative height SDS. Similarly, a duration of illness of >29.5 months and IGF-I levels of <115 ng/mL were associated with a negative PAH SDS. Thus, on the basis of our data, height deficits appear ~2.5 years after the onset of AN in growing children. It should be noted that IGF-I levels in girls with AN, although significantly lower than those in controls, were not below the reference range for the most part, and greater severity of AN with lower IGF-I levels may be associated with greater height deficits than those observed in this study.

Girls with AN had lesser increases in height over a 1-year follow-up period compared with controls, and we observed trends toward greater increases in height in immature girls with AN who gained weight over the follow-up period compared with those who did not.

In immature girls with AN, an inverse association was noted between change in height SDS over a 1-year period of follow-up and the delay in BA in relation to CA (BA/CA), and these data indicate that girls with AN who have a delay in BA are more likely to catch up for height SDS than those without a delay in BA. This argues in favor of a delay in BA contributing to the preservation of height potential with AN. A delay in BA likely reflects a prolonged period of hypogonadism, and the preservation of height potential in girls with a delay in BA is reminiscent of the preservation and/or improvement of height potential in girls with a history of early puberty, in whom puberty and advancement of BA are suppressed by use of the long-acting form of a gonadotropin-releasing hormone analog.19,20 After a BA of 15 years (mature AN), growth is almost complete, with only ~1% of growth potential still remaining.12 Therefore, a delay in BA would not be expected to be associated with a preservation of height potential in girls with AN who develop the disorder late in puberty (mature AN) but may be anticipated in girls with AN who develop the condition before they achieve a BA of 15 years (immature AN).

The severity of growth deficits before weight rehabilitation may determine whether height is preserved in girls with AN. The subjects in our study had been diagnosed with AN for only a short period of time. It is possible that previous reports of short stature with AN1,21,22 were from studies in children with a prolonged duration of AN and delayed diagnosis. In such situations, a delay in BA may not be sufficient to protect against statural deficits that arise from very low and sustained IGF-I levels consequent to severe and prolonged undernutrition. In addition, Lantzouni et al22 reported that after nutritional rehabilitation for girls with AN, an acceleration in growth velocity was not sufficient to prevent the girls from falling short of the TH, which is in contrast to the data from our study and may reflect a greater severity of illness in subjects with AN.

Limitations of this study include the fact that associations do not prove causation. In addition, the TH for our subjects was based on reported parental heights because both parents were usually not able to accompany our subjects to the study visits and have their heights measured on our stadiometer. However, reported heights tend to be greater than true heights,23,24 and the fact that our subjects did not fall short of genetic target on the basis of reported heights indicates that actual measurements of parental heights would likely not have changed the direction of our results. Finally, a larger number of younger subjects would be useful for prospective data collection. However, we report a larger number of subjects than reported by the 1 other prospective study that examined height of girls with AN,22 and that study did not examine predictors of height changes over time.


   CONCLUSIONS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
On the basis of our data, we speculate that hypogonadism and a delay in BA in subjects with AN may protect against the deleterious effects of undernutrition on stature, at least in the short term. In addition, although there is a relative state of IGF-I deficiency in our AN cohort, the fact that few girls had levels below the reference range for pubertal stage was likely also protective. However, it is possible that girls who are particularly severely affected with AN and for a long period of time may fall short of TH, and longitudinal studies with larger numbers of younger girls with AN are necessary to explore this issue.


   ACKNOWLEDGMENTS
 
This work was supported in part by National Institutes of Health grants M01-RR-01066, DK 062249, and K23 RR018851.

We thank the skilled nursing and bionutrition staff of the General Clinical Research Center and our study volunteers, without whose participation this study would not have been possible.


   FOOTNOTES
 
Accepted Dec 14, 2007.

Address correspondence to Madhusmita Misra, MD, MPH, BUL 457, MassGeneral Hospital, Neuroendocrine Unit, 55 Fruit St, Boston, MA 02114. E-mail: mmisra{at}partners.org

The authors have indicated they have no financial relationships relevant to this article to disclose.

Drs Prabhakaran and Misra contributed equally to this work.


What's Known on This Subject

Few articles have described height outcome in adolescents with AN; available studies have reported both short stature and greater-than-expected stature in this population.

 

What This Study Adds

In this study we describe height outcome in a large cohort of girls with AN and the determinants of stature in this population. We demonstrate that a delay in bone age preserves height potential, whereas low IGF-1 levels and prolonged duration of illness predict shorter stature.

 


   REFERENCES
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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