A contemporary treatment regimen normalizes muscle mass and adult height in children with Prader-Willi syndrome - a longitudinal analysis

INTRODUCTION

Prader-Labhart-Willi syndrome (PWS) is a rare genetic disorder resulting from the lack of expression of the paternally derived chromosome 15q11-q13. PWS is characterized by intellectual disability, behavioral problems, and hypothalamic dysfunction combined with specific dysmorphisms^[1,2]. Over the past three decades, the phenotype of children with PWS has changed significantly. Early growth hormone therapy, rigorous nutritional restriction, appropriate substitution of sex steroids, and enhanced physical activity have contributed to improvements in stature, body composition, and motor strength^[3-5]. Among these, improvements in body composition and motor strength are the main reasons for initiating growth hormone therapy in children with PWS^[4]. In contrast, untreated children with PWS exhibit increased fat mass and reduced lean mass compared to peers with non-syndromic obesity^[6].

Thus, improving body composition is the main goal of growth hormone therapy in PWS. Reports on the development of body composition mostly do not account for changes in body size and are, therefore, not reliable. Of particular interest are changes in muscle mass, as peak lean body mass and peak bone mass are typically achieved during growth. Achieving normal levels of these parameters is important to help prevent osteoporosis and promote cardiovascular health^[7,8]. Therefore, reliable data on the development of lean body mass, fat mass and bone mass during growth hormone treatment - up to adult height - are needed, along with an understanding of the factors that influence these outcomes. The presumed factors influencing adult height and body composition, e.g., premature adrenarche, puberty, obesity, and accelerated bone maturation, have not been studied systematically. Mean (near) adult height has been reported between -0.3 and -1.13 SD^[5,9-11]. Mean BMI SDS was in the upper normal range and fat-free mass in the lower normal range^[5,9,10]. Gaston^[12] reported on the acceleration of growth and mid-childhood bone maturation in children with PWS and found an association of these phenomena with premature adrenarche but no effect of BMI. Very recently, Griffing reported on the effect of premature pubarche on adult height^[11]. There was no difference in adult height between children with or without premature pubarche. They also found that obesity was not related to premature pubarche. Based on these existing data, it seems that with growth hormone therapy, adult height is in the normal range, fat-free mass in the lower normal range, and fat mass in the upper range. It seems that premature adrenarche does not have a negative effect on adult height.

Our investigated cohort contributes to the understanding of the effects of long-term growth hormone therapy on adult height and body composition with a longitudinal analysis of the data, as study data are limited. In particular, the influence of premature pubarche on adult height and body composition has only been seldom investigated. Due to the standardized procedure in our center, a uniform approach can be assumed, which certainly contributes to the quality of the analysis. This study, therefore, contributes to improving patient care management and optimizing treatment in PWS.

METHODS

RESULTS

In our center, 27 boys and 28 girls were eligible for the study. In 1 boy and 3 girls, the treatment duration in our institution was less than 5 years and they were excluded from the study. In 2 boys and 5 girls, adult height data were missing because they moved and were lost to follow-up. Thus, 44 children (24 boys and 20 girls) were included in the study. Patient characteristics are summarized in Table 1. Genetic findings: deletion was found in 28 children and uniparental disomy in 16 children. Eight out of 44 children were born small for gestational age. Growth hormone therapy was started at a mean age of 3.9 years and continued for a mean duration of 13.5 years. Premature pubarche was noted in 57 % of the children (52% in boys and 63% in girls). We compared the characteristics of the children with and without premature pubarche. Of the different variables, only the age of the start of growth hormone therapy was significantly lower in the girls who developed premature pubarche. In these girls, growth hormone therapy was started at a mean age of 2.2 years, compared to 5.75 years in girls without premature pubarche (P = 0.004). Results at adult height are shown in Tables 2 and 3 for boys and girls separately. Mean adult height was 172.4 cm (-0.87 SD) in boys and 160 cm (-0.90 SD) in girls. The difference between men and women is about 13 cm, like in the general population. The mean difference of adult height expressed as SDS to target height SDS was small - nonsignificant in boys and just significantly different from zero in girls. Adult height did not differ significantly between the children with or without premature pubarche.

Mean DHEAS levels were 1.3 μmol/L higher in boys with premature pubarche than in those without (not significantly different, P = 0.06). In girls, mean DHEAS levels were 1.4 μmol/L higher in those with premature pubarche compared to those without (not significantly different, P > 0.10).

The best model to predict adult height included target height, age, sex, and bone age, but excluded DHEAS, FM, or FMI. The model explains 87% of the variance. Compared to the boys without premature pubarche, the boys with premature pubarche were taller when they were between 5 and 13-14 years old. From the pubertal age, this changed, and at adult height, there was no difference anymore [Figure 1A and B]. In girls, no height difference was observed between those with and without premature pubarche [Figure 1C and D]. Body composition did not differ significantly between children with or without premature pubarche [Tables 4 and 5]. Lean mass increased with age and lean mass Z-scores for age and corrected for height were normal compared to European standards [Tables 4 and 5, Figure 2]. Median Lean mass Z-scores for age were -0.42 SD and -0.13 SD in boys and girls, respectively. LMI Z-scores for age were +0.06 SD and +0.64 SD in boys and girls, respectively. Fat mass Z-scores for age and corrected for height were above normal compared to European standards [Table 4 and 5, Figure 3]. Fat mass Z-scores were +1.58 SD and +2.08 SD in boys and girls, respectively. FMI Z-scores for age were +0.64 SD and +1.67 SD in boys and girls, respectively. FM development was associated with age, LM, and DHEAS in boys, but in girls with age and LM only. LM development was associated with age, FM, and DHEAS in boys. The model explains 91% of the variance. The relation was non-linear: at low FM, there was little effect on LM development; with increasing FM, there was a clearly positive effect on LM development; and with high FM, the effect on LM development diminished. DHEAS had a (small) linear positive effect on LM. In girls, we found the same variables, and the model explained 93 % of the variance. The effects of age and FM were similar as in boys. The effect of DHEAS was linear but negative with increasing DHEAS levels.

Figure 1. Height standard deviation score (SDS) for chronological age in boys with (A) and without (B) premature pubarche and in girls with (C) and without (D) premature pubarche. Colored dotted lines: growth without growth hormone therapy; colored solid lines: growth with growth hormone therapy.

Figure 2. Lean mass standard deviation score (SDS) corrected for height longitudinal in Boys (A) and Girls (B). Smooth solid line: average trend SDS with standard error in grey (LOESS smoothing).

Figure 3. Fat mass standard deviation score (SDs) corrected for height longitudinal in boys (A) and girls (B). Smooth solid line: average trend SDS with standard error in grey (LOESS smoothing).

DISCUSSION

The most important findings of our study are: (1) normal linear growth with normal adult height can be achieved with moderate doses of GH; (2) premature pubarche has no influence on adult height; (3) under our current treatment regimen with growth hormone therapy, substitution of sex steroids at a normal age and measures to influence eating behavior and exercise, LM (muscle mass) develops normally; and (4) the FM (fat mass) develops on higher levels up to a certain degree of maturity and then increases significantly.

Our analysis of adult height clearly shows normalization of height outcomes. Gamage et al. recently reported long-term adult height results in individuals with PWS, comparing those with and without growth hormone therapy^[19]. They found that the adult or near-adult height SDS was -1.04 for boys and -1.58 for girls. In contrast, our cohort achieved heights closer to the normal range, with mean adult height SDS values of -0.87 for boys and -0.90 for girls. This corresponded to an average adult height of 172.4 cm for boys and 160.0 cm for girls in our study. A likely key factor for this difference is the shorter duration of treatment in the Gamage cohort, which ranged from 3.32 to 6.61 years, depending on the year group. In comparison, our participants began GH therapy at an average age of 3.58 years and received treatment for a significantly longer duration of 13.84 years. In our study, the age at adult height was about the same for boys and girls, although typically girls achieve adult height at a younger age. Additionally, the age range at adult height was wider in girls, which may reflect greater variability in the timing of puberty induction. This is consistent with the fact that hypogonadism is less frequent and more difficult to diagnose in girls with PWS than in boys^[20]. As reported in literature and observed in our patients, hypogonadism manifested as hypogonadotropic, hypergonadotropic, or a combination of both forms. Furthermore, there is generally less urgency among families to start puberty induction in girls, partly because estrogens, produced through the aromatization of androgens, often lead to some degree of spontaneous breast development.

Angulo et al. were the first to show the results of long-term treatment (average treatment duration of 7.9 years) of PWS with GH and found a near-adult height SDS of -0.3 SDS on average in treated children with PWS^[9]. Bakker et al. showed a mean adult height of -1.19 SDS with a larger group from the KIGS register, which is comparable to the results in our study^[5]. In a smaller cohort of children from the KIGS register, Lindgren and Lindberg^[10] showed an average midparental height median of -0.5 SDS and 0.9 SDS for girls and boys, respectively. However, in our cohort, the adult height minus target height SD was -0.74 SDS and -0.12 SDS for girls and boys, respectively.

Adult height in our cohort could be predicted by factors that are well known to experts in the field: target height, age, and bone age. Growth hormone dosage and therapy duration were not included in the model, which is unsurprising given that both were relatively uniform across the cohort. However, it can be concluded that the growth hormone dosage was sufficient to reach normal height. Since the dosage used in PWS is approximately equivalent to the replacement dose for growth hormone deficiency, this suggests normal growth hormone sensitivity in individuals with PWS. Therefore, our data also support the approach with a rather low growth hormone dose, as this appears sufficient to normalize growth.

As premature pubarche is frequent in children with PWS, the relationship between premature androgen production/adrenarche and adult height warrants further investigation. In our cohort, more than half of the children had premature pubarche - a proportion higher than previously reported^[21-24], but consistent with the findings of Griffing^[11]. One possible explanation is the earlier start of growth hormone therapy over the years. Supporting this hypothesis, our data show that girls with premature pubarche began GH therapy earlier than those without. In PWS, elevated DHEAS and androgen levels could be detected from an early age, indicating premature adrenal cortex maturation^[12,23]. However, unlike in children with obesity^[12,22], no direct correlation was observed between increased fat mass and androgen levels in our cohort. Similarly, children with premature pubarche did not have higher fat mass compared to those without. This indicates that factors other than fat mass likely contribute to the early maturation of the adrenal cortex. We found no difference in adult height between children with and without premature pubarche, confirming Griffing’s findings^[11]. Thus, premature pubarche does not appear to affect adult height. Nevertheless, boys with premature pubarche exhibited accelerated growth during childhood followed by reduced growth during puberty [Figure 1A and B]. These boys also showed accelerated bone maturation during childhood, presumably due to increased androgen levels (data not shown). Interestingly, this pattern was not observed in girls, and differences in androgen levels between girls with and without premature pubarche were less pronounced. The finding that premature pubarche does not impact adult height is reassuring. In the absence of central precocious puberty, there is no indication for therapeutical interventions aimed at slowing bone maturation. This approach is not standard practice and has not been systematically investigated.

Apart from promoting normal height, GH therapy in PWS is also aimed at improving body composition. Untreated individuals with PWS typically exhibit greater fat mass and lower muscle mass compared to non-syndromic individuals with obesity^[6,25-27]. The positive influence of GH therapy - especially when combined with adjunctive treatment - on body composition has been well demonstrated^[3-5,28,29]. However, most of these studies are limited by relatively short follow-up periods. Our Dutch colleagues^[5,30], reporting on 8 years of GH treatment, demonstrated stabilization of percent fat SDS and BMI SDS in children with PWS. Nevertheless, full normalization was not achieved, and LM remained in the lower normal range.

In our cohort, LM [Figure 2] developed normally from age 6 until attainment of adult height, while FM [Figure 3] began to increase after the onset of puberty and remained clearly above normal thereafter. Starting with the positive findings: under our current treatment regimen, LM appears to develop normally, and peak lean body mass - reflecting muscle mass - seems to reach normal levels by adult height. LM, measured in kilograms, was higher in boys than in girls, consistent with known sex differences in muscle development due to higher testosterone levels in males^[31]. When normalized for height and sex, LM SDS was similar in boys and girls. However, the interpretation of lean mass measurements requires caution, especially in cases of catch-up growth and obesity. To account for body size at adult height, we measured LM using DXA and corrected for height using the LMI. SDS of both LM and LMI at adult height expressed as Z-score were within a similar range, which was expected, as our patients’ adult height was comparable to that of the reference population. It remains unclear whether LM should be even higher in individuals with PWS at adult height, given their elevated FM. In our study, we observed the known positive correlation between increased FM and LM. FM, and to a lesser extent DHEAS, were positively associated with LM. Accordingly, LM tended to be higher in boys with premature pubarche compared to those without, although the difference did not reach statistical significance. With further increases in FM, the positive effect on LM diminished, probably because of a more sedentary lifestyle associated with higher FM. Currently, there is no international consensus on the optimal amount of LM in individuals with obesity^[32]. When LM is disproportionately low relative to FM, the condition is referred to as sarcopenic obesity, which is associated with an unfavorable metabolic profile^[33]. This phenotype is common in people with obesity and a sedentary lifestyle, as is typical in PWS. Our treatment regimen consists of growth hormone therapy, a structured living environment, caloric restriction, daily physical exercise, and when necessary, induction of puberty at the appropriate age. Although we cannot determine which component of the regimen is most responsible for normal LM development, our approach complies with international guidelines. The only aspect lacking broad consensus is the optimal timing for pubertal induction^[34]. Among our interventions, the early and consistent emphasis on physical exercise - beginning at diagnosis - may be a key factor. We have previously shown that even limited daily exercise can increase muscle mass in children with PWS^[35]. We strongly advocate for continued emphasis on physical activity beyond the attainment of adult height to prevent sarcopenic obesity.

Nevertheless, challenges remain. FM remained within the upper normal range until around age 12, after which it increased to levels indicative of overweight. No clear sex differences were observed. A likely contributing factor is increased autonomy and reduced external control after this age, leading to higher caloric intake. Evidently, pharmacological intervention with growth hormone and the current treatment regimen are insufficient to normalize FM. Hypothalamic dysregulation seems to play a central role in the pathogenesis of obesity in PWS, and pharmacological interventions such as GLP-1 agonists have not yet been proven effective^[36,37]. A multimodal, multidisciplinary approach remains essential in the treatment of PWS^[38]. Recent studies have confirmed that care provided in specialized residential facilities, as opposed to living with parents or in non-specialized homes, yields better outcomes in weight development and prevention of morbid obesity^[39,40].

The main limitations of our study include its single-center, retrospective design, and the relatively small cohort size. However, the standardized treatment approach enhances its relevance to current clinical practice in the Western world. A key strength is the longitudinal follow-up through to adult height in a consistently treated cohort.

In summary, our study demonstrated normalization of adult height following long-term growth hormone therapy in children with PWS. Premature pubarche did not negatively influence adult height. LM, and thus muscle mass, developed normally compared to the general population, although it may ideally need to be higher given the elevated FM. FM did not normalize. Future research should focus on optimizing the ratio of muscle mass to fat mass and investigating how this ratio affects long-term cardiovascular health.