Anorexia nervosa (AN), which affects about 1% of adolescent females, is characterized by an intense fear of gaining weight, self-imposed semi-starvation, weight loss, and amenorrhea [6]. The disease provides an attractive model for studying the effect of caloric restriction during adolescence on growth and final height, since in AN patients undernutrition occurs in the absence of other physical illness, and weight rehabilitation is planned and controlled.

Several studies reported growth failure or short stature in patients with AN [7]–[14] (Table 1) or other forms of voluntary caloric restriction [15]–[17]. Possible contributors to growth retardation in these patients include hypothyroxinemia, hypercortisolemia, hypogonadism [18]–[20], and growth hormone resistance [21]–[23]. However, despite the relatively high prevalence of AN in adolescent females [24]–[25], data regarding final height of AN patients are scarce and inconclusive [2], [10], [13]. Reports describing catch-up growth in AN range from failure to gain any height [7] to complete catch-up growth [2], [7], [12], [15] (Table 1). This apparent discrepancy reflects small patient series, heterogeneous patient populations, variable duration of follow-up, and absence of pre-morbid growth data.

We have previously shown that linear growth retardation was common in male adolescent AN patients [11]. Weight restoration was associated with significant catch-up growth, but complete catch up growth was achieved only in a minority of the patients; Although the mean adult final height standard deviation score (SDS) was higher than the admission height SDS, it was lower than both the pre-morbid and the mid-parental target height SDSs [11].

The mean height SDS on admission for all 211 patients was −0.285±1.02, significantly lower than expected in a normal population. In the subgroup of patients with complete growth data, the mean pre-morbid height SDS was not significantly different from the expected in a normal population, whereas mean height SDS on admission was significantly lower. These results are in agreement with Swenne et. al. and Nielsen [12], [31] (Table 1), and suggest that the decreased height SDS observed on admission reflects actual growth retardation, rather than an increased predilection to AN in females with short stature as suggested elsewhere [13]. Furthermore, our findings imply that early signs of AN may not be detected in a significant number of patients, and that the diagnosis of the disorder is often delayed.

Patients admitted at age 13 years or younger, and patients admitted less than one year after menarche presented with more severe growth-impairment compared to patients admitted at an older age. A possible explanation of this finding is that some of the older patients may have already accomplished most of their linear growth prior to the onset of AN.

Weight restoration resulted in accelerated linear growth and improvement in height SDS during hospitalization. Still, complete catch-up growth was not achieved, and the mean final height SDS of our patients was significantly lower than expected in a normal population, and not significantly different from height SDS on admission. Considering the pre-morbid records, our data suggest that compromised final adult height was the result of prolonged malnutrition and not related to pre-morbid short stature. This notion is further supported by the finding that BMI-SDS upon admission was negatively correlated with the difference between height-SDS on admission and at final height, implying that patients with a greater degree of malnutrition upon admission had a lesser degree of catch-up growth.

Several hormonal changes may contribute to growth retardation in AN. These include low thyroxine and triiodothyronine, elevated cortisol, and low sex hormone levels. Growth hormone (GH) resistance - characterized by GH hypersecretion, and low serum levels of growth hormone binding protein, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding-protein 3 (IGF-BP3) - has also been related to growth failure in AN patients. These changes are reversible with weight gain, with a gradual increase in thyroid hormone levels, gonadotropins and IGF-I, and a decrease in GH and cortisol levels (19, 32). In addition, it has been suggested that leptin may act as a skeletal growth factor and induce longitudinal growth (33). Since leptin levels are low in underweight AN patients and increase with re-feeding (32), it is possible that hypoleptinemia may contribute to growth retardation in AN, whereas the increase in leptin levels with weight restoration may contribute to catch-up.

Several smaller studies [7]–[9], [11], [12] (Table 1) described the occurrence of growth retardation in AN. However, whether growth retardation seen at the time of diagnosis of AN affects final adult height has not yet been established. Two studies suggested that adolescents with AN can realize their height potential. Pfeiffer et al [2] assessed final adult height in 13 males and 58 female AN patients, claiming that most patients reached their expected heights. However, final height percentile was compared with height percentile at diagnosis, with no reference to pre-morbid height. Thus, height deceleration prior to admission could have been missed. Moreover, since only limited information was given regarding the patients' age distribution, it is possible that at least some of them reached final height prior to the onset of AN. Prabbhakaran et al [14] followed 63 female AN adolescents for one year. They found that height at study entry, as well as the difference between target height and both follow-up height and predicted adult height did not differ between patients and controls, suggesting the preservation of height potential in female AN adolescents. However, no information was given regarding the premorbid height of the AN patients, and final height was not assessed. Furthermore, this study included patients treated as outpatients that might have had a milder disease course compared to the inpatients included in our study. In keeping with this assumption, the investigators reported that girls with longer duration of illness had lower height SDSs and lower predicted height SDSs [14].

By contrast, the results of Lantzouni et al [10] in 16 females with early onset AN, and of Lanes and Soros [17] in healthy children after prolonged period of inadequate caloric intake, were similar to ours. Both groups reported decreased height SDS at presentation. Despite accelerated growth following nutritional rehabilitation, the patients did not achieve their predicted final height [17] or their target height [10], [17].

As emphasized earlier, the occurrence of growth impairment in our patients well before hospitalization suggests a considerable delay in the diagnosis of AN. We hypothesize that weight loss in our patients may have been masked by their reduced height: once growth retardation occurs, the severity of malnutrition may be underestimated because weight is related to the “stunted” height rather than to the pre-morbid projected height, resulting in a weight-per-height/BMI SDS that may seem reasonable. In addition, growth impairment may have not been recognized in adolescents whose heights were in the upper percentiles. This is illustrated in figure 4 - the patient depicted in this figure shifted from the 90^th to the 50^th height percentile well before AN has been noticed, perhaps because she still appeared normal relative to her peers (Fig. 4). Irrespective of the reason, a delay in the diagnosis of AN in adolescent, and perhaps even more so in pre-adolescent females, may result in severe malnutrition and compromised final height. Furthermore, since AN may be associated with irreversible multi-organ damage including brain atrophy [34], [35], osteoporosis [36], and major adverse obstetric outcomes [37], we postulate that stunting of growth may be viewed as a measurable marker of covert tissue injury. Thus, we believe that early diagnosis of AN and early aggressive nutritional rehabilitation are of utmost importance in order to prevent not only growth failure but also irreversible tissue damage with long-term implications.

It has been suggested that the hypogonadism found in AN may lead to delay in growth-plate closure [14], allowing, in turn, for compensatory growth with the potential for catch-up during later adolescence. Hence, we hypothesized that patients admitted at a younger age, with seemingly significant growth potential, will show the greatest degree of catch-up growth. However, in contrast to our hypothesis, and similar to the findings of Favaro et al [13], these patients actually had the worst outcome regarding final height. Thus, it seems that prolonged undernutrition, arising (albeit not diagnosed) during early adolescence and continuing around the critical time of peak height velocity, may interfere with growth and result in irreversible stunting despite the delay in skeletal maturity.

Our series is one of the largest series describing growth in female AN patients. It provides important pre-morbid, follow-up and final-height data not previously available in other series. Nevertheless, several limitations should be considered. Our study included only inpatient AN female adolescents, so that our findings cannot be generalized to less severe forms of the disorder. Secondly, we did not include matched controls. Thirdly, only a third of the original cohort had final height data, and premorbid height was reported in only a minority, although no difference was shown between patients with and without final height data in any of the demographic and clinical parameters evaluated. Although we made an attempt to contact all former patients, many refused to come for a final assessment, or have not been located. This was likely the result of our department being a tertiary care center that hospitalizes patients from all over Israel, reducing the likelihood of continuation of treatment in our center following discharge. Finally, Tanner stages of sexual development, bone age studies, parental heights, and results of laboratory tests were not recorded in most of the charts. Therefore, we were unable to calculate the pre-morbid predicted adult height and the mid-parental target height, or to investigate the relationships between pubertal stages and adult height.

Despite these limitations, our study provides strong evidence to support our hypothesis. In particular, the strength of our study relies on the data obtained from the subgroup of patients with pre-morbid and final height measurements (figure 3), showing normal pre-morbid height followed by growth deceleration and almost no catch-up growth. These patients present an unusual growth pattern that cannot be explained based on genetic height potential or timing of puberty.

It could be argued that growth deceleration and the subsequent catch-up growth observed in our patients may actually represent the effects of delayed puberty per-se. However, inspection of the growth data makes this unlikely. First, the severity of growth failure observed in some of our patients far exceeds the pre-pubertal growth deceleration observed in children with delayed puberty, which is in the range of 4.0–4.5 cm/year [38], [39]. For instance, the patient depicted in figure 4 had virtually no linear growth for the 2 years preceding her hospitalization (figure 4). Secondly, whereas patients with delayed puberty may not reach their parental target height [40], [41], they typically regain or even exceed their own childhood growth percentile [42]. In contrast, in our patients, catch-up growth was incomplete, and their pre-morbid height percentile was not reached.