Introduction
Prader–Willi syndrome (PWS) is a rare, complex, neurodevelopmental disorder due to lack of paternal chromosome 15q11.2-q13 expression [
1,
2]. Paternal interstitial deletion of the 15q11-13 region and maternal uniparental disomy (mUPD) of chromosome 15 are the most common genetic subtypes of PWS, with imprinting defects accounting for around 1%–3% of PWS patients [
1]. There are some phenotypic differences between the two largest classes of genetic subtypes. Those with mUPD appear to have a higher verbal intelligence quotient and milder behavioral problems, while psychosis and autism spectrum disorders are more common in this genotype [
1].
Dysfunction involving various hypothalamic systems may predispose patients with PWS to a number of symptoms [
1]. The clinical presentation of PWS occurs very early in life and this includes hypotonia, growth retardation, feeding difficulties, failure to thrive in infancy, delayed psychomotor and language development, and cognitive impairment [
1]. From adolescent to adulthood, cognitive impairment usually in the form of mild mental retardation, excessive eating, and behavior problems are common features of PWS [
1]. Improving the long-term prognosis of PWS patients' psychomotor development remains difficult to address and is the focus of current research.
Due to the innate nature of PWS, patients usually develop growth hormone (GH) deficiency at infancy or during the childhood period, which led to the approval of recombinant human GH (rhGH) in PWS patients [
2]. It is widely accepted that rhGH replacement therapy has many benefits in terms of improving growth, body composition, and even health-related quality of life [
2‐
8]. However, an important aspect of rhGH treatment pertains to improvement in mental development [
1,
9]; although more than 20 manuscripts have been published, the clinical findings are not always consistent.
In infants, toddlers, and young children (aged 4–38 months in published studies), rhGH therapy could improve motor strength, mobility, and body composition [
5,
10‐
12] through the effect on muscle thickness [
13]. Several studies showed benefits both for mental and motor development assessed with different scales, including the Bayley Scales of Infant Development II (BSID-II) assessment [
14,
15], Toddler and Infant Motor Evaluation (TIME) and the Capute Scales of Infant Language and Cognitive Development [
6], and the Griffith test [
16]. Taking all of these studies together, there is a paucity of data on the complete evaluation of the whole picture on early brain development in PWS patients. Studies that assessed both motor and mental developments including detailed descriptions of sub-development quotients for patients of different ages are still ongoing.
Children have an enhanced capacity for brain plasticity compared with adults. The brain has high plasticity during its early development through pruning of the synapses and activity-dependent refinement of neuronal connections, and many pediatric neurologic disorders have an impact on the fundamental mechanisms of brain plasticity [
17]. Neuronal plasticity allows the central nervous system to learn skills and remember information and to reorganize neuronal networks in response to environmental stimulation [
18]. Studies have shown that rhGH has significant neurotrophic actions in neural tissues including prosurvival effects, neuroprotection, axonal growth, synaptogenesis, neurogenesis, and neuro-re-generation [
19], thus providing the rationality for early rhGH therapy in children with PWS. However, it is not clear when early treatment should commence nor its safety.
To investigate the early use of rhGH on psychomotor development beyond its physical benefits, we conducted a phase 3 study to evaluate the efficacy in terms of motor and mental development, physical improvement, and safety of daily rhGH therapy in infants and young children with PWS in China.
Discussion
To our knowledge, this is the first study in China to describe the time effect of early rhGH treatment in infants and young children with PWS. After 52 weeks of treatment, besides significant improvement in anthropometric parameters, we found that PWS patients’ motor development quotients were negatively correlated with age when analyzed by linear regression models, and rhGH treatment slowed down the rate of deterioration in TMQ and GMQ. Mental development assessed by the GDS-C showed significant improvement both in GQ and AQ–EQ after treatment especially in subjects aged < 9 months.
We found that TMQ, GMQ, and FMQ were negatively correlated with age in pediatric patients with PWS in a linear regression analysis. However, treatment alleviated the deterioration of TMQ and GMQ. Several studies reported improvement in motor development scores assessed using various motor scales with rhGH treatment among PWS patients [
5‐
7,
9,
13,
14]. In one study, rhGH treatment in infants and toddlers aged 4–37 months resulted in a positive trend of mobility and stability when assessed using TIME [
6]. The age of independent walking was also earlier than typical for this condition [
6]. Another study assessing motor changes in infants with a mean age of 15.5 months using TIME also reported an improvement in mobility and stability by 40.8% ± 31.0% and 48.5% ± 43.3% following six months of rhGH treatment, respectively [
5]. Reus et al. also noticed a positive effect of rhGH on motor development in infants with PWS when assessed using the Alberta Infant Motor Scale (AIMS) and the Gross Motor Function Measure (GMFM) but not with BSID-II [
12]. The authors explained that both AIMS and GMFM focus on gross motor function while BSID-II, which also includes fine motor skills, may be less sensitive at detecting the effects of treatment. In contrast, Festen et al. reported an improvement in motor development by + 11.2% in infants and toddlers assessed using BSID-II with one year of rhGH treatment compared with – 18.5% in the untreated control group [
14]. Donze et al. showed that three years of rhGH treatment assessed using BSID-II improved both mental and motor development in infants, reducing the developmental gap between PWS and healthy peers [
15], and eight years of continuous treatment with rhGH starting from infancy improved cognitive functioning in terms of vocabulary and total intelligence quotient [
27]. Assessment using the PDMS-2 and the BSID-II scale may yield dissimilar findings in motor development [
28]. In our study, PDMS-2 was utilized to assess motor development. PDMS-2 is often used in the clinical setting (e.g., in early childhood) to assess gross and fine motor skills along the developmental trajectory, identify delays in motor skills, establish individual goals and objectives for therapy or intervention, and monitor progress [
22,
29]. We found positive, but less evident, effects of rhGH therapy in our cohort; the reasons may be due to the difference in the evaluation scales used.
We also found that younger pediatric patients had a greater improvement in mental development using the GDS-C. When stratified according to age of rhGH initiation, those in the < 9-month group performed significantly better with rhGH treatment than baseline in GQ and the other sub-quotients. General and locomotor development were significantly improved in the < 9-month group compared with the ≥ 9-month group. Our results were in line with other studies that demonstrated the positive impact of GH treatment on mental functioning in children with PWS [
6,
14]. Meyers et al. reported a significant improvement in language and cognitive quotients combined with improvement in head circumference after two years of rhGH treatment [
6], while Festen et al. observed significant mental development using BSID-II, noting that treatment increased mental development by 9.3% compared with – 2.9% in the untreated group after one year of follow-up among children with a median age of two years [
14]. A recent meta-analysis of 10 randomized controlled trials performed by Luo et al. did not find significant improvement in cognitive development with rhGH treatment in PWS children [
30]. However, the authors cautioned that the assessment of cognitive function in the randomized controlled studies included in that meta-analysis was not well represented [
30]. Most studies focused on general cognition and intelligence quotients, leaving out important cognitive domains, such as language, vocabulary, and memory abilities [
30]. The GDS-C used in our study provided a comprehensive developmental profile across different domains from motor function to cognitive skills [
22]. Thus, the findings in our cohort can be credible.
Our results were consistent with other studies showing improvements in and normalization of anthropometric parameters [
6,
7,
9]. Scheermeyer et al. reported normalization of HT-SDS and weight SDS after just one year of rhGH treatment in infants and toddlers with PWS, with continued improvement in the second year [
31]. In our study, we observed normalization of HT-SDS and BW SDS after 52 weeks of GH treatment regardless of genetic subtype or age of GH initiation. Depending on the age and nutritional phase, BMI SDS increases or decreases could be considered an improvement [
32]. Younger patients typically start off with hypotonia and feeding difficulties up to age nine months according to their nutritional phases. This is followed by normal feeding and growth until approximately two years of age. Therefore, in our study, BMI SDS significantly increased with treatment only in the < 9-month group, whereas the change in the ≥ 9-month group was not significant, which suggested a positive effect on improving malnutrition in these younger patients. This was consistent with the age-dependent BMI SDS trends in Festen et al., which showed increasing BMI SDS with treatment despite not being statistically significant [
14]. Lecka-Ambroziak et al. also showed rhGH therapy to be most effective in improving anthropometric parameters in the youngest patients before the nutritional phase of increased appetite [
33]. Overall, rhGH treatment restored physical growth, and the growth-promoting effect seemed to be more obvious among those with a more severe growth deficit at baseline or who started treatment early.
Children with PWS are sensitive to GH and have high levels of IGF-1 during rhGH treatment, increasing beyond + 2 SDS. This raises concerns about the safety issues related to high IGF-1 levels, as high levels of IGF-1 have been associated with lymphoid hyperplasia and this might increase the risk of sleep apnea [
2]. As such, IGF-1 levels should be monitored regularly during treatment. IGF-1/IGFBP-3 molar ratio is another useful clinical tool to monitor the rhGH dose. In the present study, the IGF-1/IGFBP-3 ratio remained stable at 0.19 ± 0.06 with rhGH treatment, similar to the study by Gaddas et al. that reported a molar ratio of 0.19 ± 0.09 in children with PWS—well within the normal range [
34].
In general, daily rhGH was well tolerated in pediatric patients with PWS throughout the 52-week treatment. Safety concerns about the potential AEs of rhGH treatment in this study were mainly focused on tonsillar hypertrophy, adenoidal hypertrophy, and upper airway obstruction, which are well documented in children with PWS [
1]. Previous literature also suggests that rhGH treatment may increase adenoids and enlarge tonsils, potentially resulting in airway obstruction and aggravating sleep apnea [
35]. Therefore, infants or children with PWS should be assessed for any signs of upper airway obstruction and sleep apnea before commencing treatment. In our present study, only one patient withdrew from the study due to sleep apnea, which was mild in severity and deemed related to the treatment. The majority of the TEAEs in this study were mild to moderate in severity and all adverse drug reactions did not require further intervention, suggesting that the potential benefits of rhGH outweigh its risks in infants and young children with PWS.
The merit of our study was the simultaneous use of PDMS-2 and the GDS-C to comprehensively evaluate, monitor, and accurately capture the development of different motor skills and the overall development of pediatric patients with PWS, and this study enrolled younger patients with a median age of 7.0 months, in line with increasing evidence supporting the benefit of early intervention with rhGH [
1,
2,
6,
9,
14,
16,
36]. However, the short duration and small number of patients may not be able to reveal the full spectrum of rhGH potency, so future studies should recruit larger sample sizes and have longer study periods to elucidate the effect of rhGH treatment on motor and mental outcomes.
In conclusion, treatment with rhGH for 52 weeks in infants and young children with PWS improved growth (height and weight), BMI, and mental development. In addition, the results of this study support the premise that initiation of treatment at early infancy (before age nine months) yielded better mental outcomes than those who started treatment later. The impact on motor development remains inconclusive, although our linear regression analysis suggested a positive effect by alleviating the deterioration of motor function in infants and young children with PWS. The present findings of this study add to the growing evidence that rhGH administration in infants and young children with PWS is well tolerated and effective, providing benefits that extend beyond physical growth when initiated early. No rhGH was approved for the treatment of PWS in China at the time of study commencement. Therefore, the results of our study will provide more evidence to guide the clinical practice of rhGH therapy in Chinese PWS patients.
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