Introduction 引言

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].
普拉德-威利综合症（PWS）是一种罕见的复杂神经发育障碍，因缺乏父源性 15q11.2-q13 染色体表达[1, 2]。父源性 15q11-13 区域的间质缺失和母源性单亲二倍体（mUPD）是 PWS 最常见的遗传亚型，印记缺陷约占 PWS 患者的 1%–3%[1]。这两种最大的遗传亚型之间存在一些表型差异。mUPD 患者似乎具有更高的语言智商和较轻的行为问题，而精神病和自闭症谱系障碍在该基因型中更为常见[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.
涉及各种下丘脑系统的功能障碍可能使患有普拉德-威利综合症（PWS）的患者易于出现多种症状[1]。PWS 的临床表现通常在生命早期就会出现，包括肌张力低下、生长迟缓、喂养困难、婴儿期生长不良、心理运动和语言发展延迟以及认知障碍[1]。从青少年到成年，认知障碍通常表现为轻度智力迟滞、过度进食和行为问题，这些是 PWS 的常见特征[1]。改善 PWS 患者心理运动发展的长期预后仍然难以解决，并且是当前研究的重点。

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 [2,3,4,5,6,7,8]. 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.
由于普拉德-威利综合症（PWS）的固有特性，患者通常在婴儿期或儿童期发展出生长激素（GH）缺乏，这导致了重组人类生长激素（rhGH）在 PWS 患者中的批准[2]。普遍认为，rhGH 替代治疗在改善生长、身体成分甚至健康相关生活质量方面具有许多好处[2, 3, 4, 5, 6, 7, 8]。然而，rhGH 治疗的一个重要方面涉及心理发展改善[1, 9]；尽管已有超过 20 篇手稿发表，但临床发现并不总是一致。

In infants, toddlers, and young children (aged 4–38 months in published studies), rhGH therapy could improve motor strength, mobility, and body composition [5, 10,11,12] 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.
在婴儿、幼儿和年轻儿童（在已发表的研究中，年龄为 4 至 38 个月）中，重组人类生长激素（rhGH）治疗可以通过对肌肉厚度的影响改善运动力量、活动能力和身体成分[5, 10, 11, 12][13]。几项研究显示，使用不同量表评估的心理和运动发展均有益处，包括贝利婴儿发展量表第二版（BSID-II）评估[14, 15]、幼儿和婴儿运动评估（TIME）以及卡普特婴儿语言和认知发展量表[6]，还有格里菲斯测试[16]。综合所有这些研究，目前关于普拉德-威利综合症（PWS）患者早期大脑发展的整体评估数据仍然稀缺。评估运动和心理发展的研究，包括对不同年龄患者的子发展商数的详细描述，仍在进行中。

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.
儿童相比成年人具有更强的脑可塑性。在早期发展阶段，大脑具有较高的可塑性，通过突触修剪和依赖活动的神经连接精细化来实现，许多儿科神经疾病对脑可塑性的基本机制产生影响[17]。神经可塑性使中枢神经系统能够学习技能和记忆信息，并在环境刺激的影响下重组神经网络[18]。研究表明，重组人生长激素（rhGH）在神经组织中具有显著的神经营养作用，包括促进生存的效果、神经保护、轴突生长、突触生成、神经发生和神经再生[19]，因此为早期 rhGH 治疗普拉德-威利综合症（PWS）儿童提供了合理性。然而，目前尚不清楚早期治疗应何时开始以及其安全性。

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.
为了研究重组人生长激素（rhGH）在其身体益处之外对心理运动发展的早期影响，我们在中国开展了一项三期研究，以评估日常 rhGH 治疗在患有普拉德-威利综合症（PWS）的婴幼儿中的运动和心理发展、身体改善及安全性方面的疗效。

Methods 方法

Subjects 受试者

A total of 45 genetically confirmed PWS subjects (42 tested using methylation-specific multiplex ligation-dependent probe amplification and three by methylation-specific polymerase chain reaction) were recruited, of whom 35 met the inclusion and exclusion criteria and received daily rhGH (Jintropin®, GeneScience Pharmaceuticals, Changchun, China) and 30 subjects completed treatment (Fig. 1). All participants fulfilled the following inclusion criteria: (1) genetically diagnosed with PWS; (2) informed consent obtained from the participant’s legal guardian; (3) agreed to complete the treatment and be assessed at scheduled visits; (4) aged between 1 month and 5 years; (5) male and female; (6) any one of the following: total motor quotient (TMQ), gross motor quotient (GMQ), or fine motor quotient (FMQ) calculated using Peabody Developmental Motor Scales-second edition (PDMS-2) less than 90 points, which corresponds to a below average score or worse [20]; (7) thyroid function is normal or maintained normal by replacement therapy; and (8) no history of GH therapy.
共招募了 45 名基因确认的普拉德-威利综合症（PWS）患者（42 名通过甲基化特异性多重连接依赖探针扩增检测，3 名通过甲基化特异性聚合酶链反应检测），其中 35 名符合纳入和排除标准并接受了每日重组人生长激素（rhGH，金特罗品®，基因科学制药，长春，中国），30 名患者完成了治疗（见图 1）。所有参与者均满足以下纳入标准：（1）基因诊断为 PWS；（2）获得参与者法定监护人的知情同意；（3）同意完成治疗并在预定访视时接受评估；（4）年龄在 1 个月至 5 岁之间；（5）男女均可；（6）以下任一项：使用皮博迪发展运动量表第二版（PDMS-2）计算的总运动商（TMQ）、粗大运动商（GMQ）或精细运动商（FMQ）低于 90 分，属于低于平均水平或更差的评分[20]；（7）甲状腺功能正常或通过替代治疗维持正常；（8）无生长激素治疗史。

Fig. 1 图 1
figure 1

Patient enrollment flow chart of this study
本研究的患者入组流程图

Full size image 完整图像

Exclusion criteria were: (1) abnormal liver or kidney function; (2) obvious central sleep apnea (central apnea index ≥ 5 events/hour sleep) and/or moderate or severe obstructive sleep apnea (obstructive apnea index > 5 events/hour sleep, or apnea–hypopnea index > 10 events/hour sleep), assessed by polysomnography, acute lung infection; (3) chronic diseases with long-term effects on bone metabolism and body composition; (4) congenital skeletal dysplasia, or spine scoliosis with moderate and above degree requiring treatment or claudication; (5) congenital heart disease, or an echocardiogram showing that the structural abnormalities require surgery or interventional therapy or that the left ventricular ejection fraction is < 40%, or an abnormal electrocardiogram requiring intervention; (6) history of convulsions or epilepsy; (7) other systemic chronic diseases; (8) with diagnosed tumors; (9) family history of cancers (two or more immediate family members within three generations who have had cancer), a previous history of cancer, or considered to be at a high risk of cancer after assessing other information; (10) psychosis; (11) diabetes, or abnormal fasting glucose that may affect the safety of the participant; (12) severe obesity [body mass index (BMI) above 95th percentile for the same gender and age] [21]; (13) known to be allergic to the investigational product or its excipient; (14) took part in other clinical trials within three months; (15) received drug treatment that may interfere with GH secretion or GH action within three months; and (16) other conditions that the investigator considers not suitable for enrollment into the study.
排除标准为：(1) 肝脏或肾脏功能异常；(2) 明显的中枢性睡眠呼吸暂停（中枢性呼吸暂停指数 ≥ 5 次/小时睡眠）和/或中度或重度阻塞性睡眠呼吸暂停（阻塞性呼吸暂停指数 > 5 次/小时睡眠，或呼吸暂停-低通气指数 > 10 次/小时睡眠），通过多导睡眠监测评估，急性肺部感染；(3) 对骨代谢和身体成分有长期影响的慢性疾病；(4) 先天性骨骼发育不良，或需要治疗的中度及以上程度脊柱侧弯或跛行；(5) 先天性心脏病，或超声心动图显示结构异常需要手术或介入治疗，或左心室射血分数 < 40%，或需要干预的异常心电图；(6) 癫痫或抽搐病史；(7) 其他系统性慢性疾病；(8) 诊断为肿瘤；(9) 家族癌症史（在三代内有两个或更多直系亲属患癌症）、癌症既往史，或在评估其他信息后被认为有高风险癌症；(10) 精神病；(11) 糖尿病，或可能影响的异常空腹血糖参与者的安全；（12）严重肥胖[同年龄和性别的体重指数（BMI）超过第 95 百分位] [21]；（13）已知对研究产品或其辅料过敏；（14）在三个月内参加过其他临床试验；（15）在三个月内接受过可能干扰生长激素分泌或生长激素作用的药物治疗；以及（16）研究者认为不适合入组的其他情况。

Study design 研究设计

This was a phase 3, single-arm, multicenter, self-controlled study conducted in six clinical sites in China. There was no positive control due to a lack of approved indication for rhGH treatment in PWS patients in China. A negative control was also not included due to ethical reasons. All eligible subjects were given a low dose of daily subcutaneous injection of rhGH 0.5 mg/m2/day for the first four weeks, then increased to 1 mg/m2/day thereafter for up to 52 weeks. All subjects were followed up at baseline and weeks 4, 13, 26, 39, and 52. The sample size was determined to be 30 after considering the rarity of PWS in China and a dropout rate of 20%. Before the start of the study, the study protocol, informed consent form, case report form, investigator’s manual, and other related documents were approved by the Medical Ethics Committee of the Children's Hospital of Fudan University. The study was conducted in compliance with the ethical guidelines of the Declaration of Helsinki and Good Clinical Practices and was approved by the institutional review board of each study site. The study was registered at ClinicalTrials.gov, identifier NCT03554031.
这是一项在中国六个临床中心进行的三期单臂多中心自我对照研究。由于在中国缺乏对 PWS 患者使用 rhGH 治疗的批准适应症，因此没有阳性对照。出于伦理原因，也未包含阴性对照。所有符合条件的受试者在前四周接受每日 0.5 mg/m2 的 rhGH 皮下注射，随后增加至每日 1 mg/m2，持续至 52 周。所有受试者在基线及第 4、13、26、39 和 52 周进行随访。考虑到 PWS 在中国的稀有性和 20%的脱落率，样本量确定为 30。在研究开始之前，复旦大学附属儿童医院的医学伦理委员会批准了研究方案、知情同意书、病例报告表、研究者手册及其他相关文件。该研究遵循《赫尔辛基宣言》和良好临床实践的伦理指南，并获得了每个研究中心的机构审查委员会的批准。该研究已在 ClinicalTrials.gov 注册，标识符为 NCT03554031。

Outcomes and assessments 结果与评估

The primary objective of the study was to evaluate the effectiveness of rhGH treatment on motor development. The secondary objectives were to assess the effectiveness of rhGH treatment in terms of mental development, growth, and BMI.
本研究的主要目标是评估重组人生长激素（rhGH）治疗对运动发展的有效性。次要目标是评估 rhGH 治疗在心理发展、成长和体重指数（BMI）方面的有效性。

Motor and mental development assessments
运动和心理发展评估

Motor and mental development of the subjects were measured using PDMS-2 [20, 22] and the Griffiths Development Scales-Chinese (GDS-C) [23], respectively, at baseline and weeks 26 and 52. These assessments were conducted by professionally trained and qualified assessors. The primary outcome measure was change in (Δ) TMQ calculated according to PDMS-2 with treatment; ΔGMQ and ΔFMQ were also assessed as secondary outcome measures. The general quotient (GQ) of the GDS-C contains six sub-quotients: locomotor quotient (AQ), personal-social quotient (BQ), language quotient (CQ), eye and hand co-ordination quotient (DQ), performance quotient (EQ), and practical reasoning quotient (FQ). Other exploratory outcome measures were changes in the PDMS-2 subtests for stationary, locomotion, grasping, and visual–motor integration expressed using the standard score.
受试者的运动和心理发展分别使用 PDMS-2 [20, 22]和格里菲斯发展量表-中文(GDS-C) [23]在基线及第 26 周和第 52 周进行测量。这些评估由经过专业培训和资格认证的评估员进行。主要结果指标是根据 PDMS-2 计算的治疗后 TMQ 的变化(Δ)；ΔGMQ 和ΔFMQ 也作为次要结果指标进行评估。GDS-C 的一般商数(GQ)包含六个子商数：运动商数(AQ)、个人-社会商数(BQ)、语言商数(CQ)、眼手协调商数(DQ)、表现商数(EQ)和实际推理商数(FQ)。其他探索性结果指标是 PDMS-2 的静态、运动、抓握和视觉-运动整合子测试的变化，以标准分数表示。

Anthropometric assessments
人类测量评估

Throughout the study, height and weight were measured by a designated assessor at each clinical site using a designated weighing scale and height-measuring device. The average height, weight, and BMI data were converted to height standard deviation score (HT-SDS), body weight SDS (BW SDS), and BMI SDS according to the 2009 edition of Chinese growth standards adjusting for age and gender [21]. Bone age radiography was performed at baseline and week 52 at each center and these were collated and analyzed at the Children's Hospital of Fudan University by a qualified radiologist using the Tanner-Whitehouse 3 method. ΔHT-SDS, ΔBW SDS, ΔBMI SDS, and bone maturation (bone age/chronological age) were included as secondary outcome measures.
在整个研究过程中，身高和体重由指定评估员在每个临床现场使用指定的称重秤和身高测量设备进行测量。根据 2009 年版的中国生长标准，调整年龄和性别，平均身高、体重和 BMI 数据被转换为身高标准差分数（HT-SDS）、体重标准差分数（BW SDS）和 BMI 标准差分数（BMI SDS）[21]。在每个中心的基线和第 52 周进行了骨龄 X 光检查，这些数据由复旦大学附属儿童医院的合格放射科医师使用 Tanner-Whitehouse 3 方法进行汇总和分析。ΔHT-SDS、ΔBW SDS、ΔBMI SDS 和骨成熟（骨龄/生理年龄）被纳入次要结果指标。

Biochemical growth marker assessments
生化生长标志物评估

At each follow-up, blood samples were collected and measured for serum insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) levels at a central laboratory. Both serum IGF-1 and IGFBP-3 were measured by enzyme-labeled chemiluminescent immunometric assays (IMMULITE 2000; Siemens Healthcare Diagnostics Products Limited). IGF-1 SDS was calculated after adjusting for age and gender according to the reference published by Isojima et al. [24]. The IGF-1/IGFBP-3 molar ratio was calculated according to the formula described by Friedrich et al.: [IGF-1 (ng/mL) × 0.13]/[IGFBP-3 (ng/mL) × 0.03478] [25].
在每次随访中，血样被收集并在一个中心实验室测量血清胰岛素样生长因子 1（IGF-1）和 IGF 结合蛋白 3（IGFBP-3）水平。血清 IGF-1 和 IGFBP-3 均通过酶标记化学发光免疫测定法（IMMULITE 2000；西门子医疗诊断产品有限公司）进行测量。根据 Isojima 等人发布的参考文献[24]，在调整年龄和性别后计算 IGF-1 标准差分数（SDS）。IGF-1/IGFBP-3 摩尔比根据 Friedrich 等人描述的公式计算：[IGF-1（ng/mL）× 0.13]/[IGFBP-3（ng/mL）× 0.03478][25]。

Safety assessments 安全评估

Safety was monitored and assessed throughout the study duration. Adverse events (AEs) were evaluated based on clinical symptoms, vital signs, physical examination, and laboratory examination and, thereafter, coded using the Medical Dictionary for Regulatory Activities Chinese version 23.1. Antidrug and neutralizing antibodies at baseline, week 26, and week 52 were monitored.
在整个研究期间，安全性得到了监测和评估。不良事件（AEs）根据临床症状、生命体征、体格检查和实验室检查进行评估，并随后使用医学术语监管活动中文版本 23.1 进行编码。基线、26 周和 52 周时的抗药物和中和抗体进行了监测。

Statistical analysis 统计分析

All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). P < 0.05 was considered statistically significant. All quantitative variables were expressed as mean ± SD unless otherwise stated. All qualitative variables (e.g., safety parameters) were presented in frequency and percentage based on the total number of people in the analysis set. Within-group comparisons were assessed using the paired t test and Wilcoxon signed-rank test.
所有统计分析均使用 SAS 9.4 版（SAS Institute, Cary, NC, USA）进行。P < 0.05 被认为具有统计学意义。除非另有说明，所有定量变量均以均值 ± 标准差表示。所有定性变量（例如，安全参数）根据分析集中的总人数以频率和百分比呈现。组内比较使用配对 t 检验和 Wilcoxon 符号秩检验进行评估。

The full analysis set (FAS) comprised all cases enrolled in the study who received the experimental drug at least once and had at least one post-drug assessment evaluated according to the intention-to-treat principle. All missing TMQ data in the FAS were imputed using the last-observation-carried forward method. The per-protocol set (PPS) was a subset of the FAS excluding subjects with major protocol violations. Safety data analyses were performed on a safety set (SS) that included all subjects who had received the study drug at least once and had post-drug safety evaluation data. Week 52 was the main evaluation time point, and all effects were compared before and after treatment within the group. Study results were further stratified by genetic subtype and age of rhGH initiation. The 9-month distinction for age of rhGH initiation was selected as it corresponds to the median age where children with PWS enter another nutritional phase [26]. All exploratory analyses were carried out on the FAS. The number of subjects included in the FAS, PPS, and SS was 35 (100.0%), 29 (82.9%), and 35 (100.0%), respectively. Trends of TMQ, GMQ, and FMQ with age were calculated using PDMS-2. A linear regression model was established to explore the relationship between TMQ, GMQ, or FMQ and age, without (baseline scores) and with treatment.
完整分析集（FAS）包括所有在研究中注册的病例，这些病例至少接受过一次实验药物，并且至少有一次根据意向治疗原则评估的药物后评估。FAS 中所有缺失的 TMQ 数据均采用最后观察值前推法进行填补。按方案集（PPS）是 FAS 的一个子集，排除了有重大方案违反的受试者。安全性数据分析是在安全集（SS）上进行的，该安全集包括所有至少接受过一次研究药物并且有药物后安全性评估数据的受试者。第 52 周是主要评估时间点，所有效果在组内治疗前后进行比较。研究结果进一步按遗传亚型和 rhGH 启动年龄进行分层。选择 9 个月的 rhGH 启动年龄区分，因为它对应于 PWS 儿童进入另一个营养阶段的中位年龄[26]。所有探索性分析均在 FAS 上进行。FAS、PPS 和 SS 中包含的受试者数量分别为 35（100.0%）、29（82.9%）和 35（100.0%）。TMQ、GMQ 和 FMQ 随年龄的趋势是使用 PDMS-2 计算的。 建立了线性回归模型，以探讨 TMQ、GMQ 或 FMQ 与年龄之间的关系，分别在无治疗（基线评分）和有治疗的情况下。

Results 结果

Subject baseline characteristics and demographics
受试者基线特征和人口统计学信息

A total of 16 (45.7%) male and 19 (54.3%) female subjects received treatment; 22 (63.9%) had paternal deletion, 10 (28.6%) had aberrant methylation (mUPD and imprinting defect), and three with unknown genotype. The three patients with unknown genotype were diagnosed with PWS using methylation-specific polymerase chain reaction; however, specific genetic aberrations were not distinguishable with this method. There were 20 (57.1%) and 15 (42.9%) subjects in the < 9 months and ≥ 9 months groups, respectively; statistical significances between the < 9 months and ≥ 9 months groups were observed in chronological age at baseline, chronological age at rhGH initiation, height, weight, head circumference, BMI, TMQ, FMQ, and GMQ (Table 1).
共 16 名（45.7%）男性和 19 名（54.3%）女性受试者接受了治疗；22 名（63.9%）有父源缺失，10 名（28.6%）有异常甲基化（mUPD 和印记缺陷），3 名基因型未知。三名基因型未知的患者通过甲基化特异性聚合酶链反应被诊断为普拉德威利综合征（PWS）；然而，使用该方法无法区分特定的遗传异常。在< 9 个月和≥ 9 个月组中分别有 20 名（57.1%）和 15 名（42.9%）受试者；在基线时的年龄、rhGH 启动时的年龄、身高、体重、头围、BMI、TMQ、FMQ 和 GMQ 等方面观察到< 9 个月组和≥ 9 个月组之间的统计学显著性（见表 1）。

Table 1 Patient demographics and baseline characteristics of the full analysis set
表 1 全部分析集的患者人口统计学和基线特征
Full size table 完整表格

Effect of rhGH treatment on motor and mental development
重组人生长激素治疗对运动和智力发展的影响

The mean TMQ decreased across 52 weeks of treatment (Fig. 2a), the ΔTMQ from baseline to week 52 was – 5.20 ± 6.88 (P < 0.001) (Table 2). Similarly, both mean GMQ and FMQ declined despite rhGH treatment over time (Fig. 2b, c). At week 52, statistically significant differences in ΔGMQ (− 3.90 ± 7.90, P = 0.015) and ΔFMQ (− 6.60 ± 8.57, P < 0.001) from baseline were observed (Table 2). The linear regression analysis showed that TMQ, GMQ, and FMQ were negatively correlated with age (Fig. 2d–f), meaning that these motor scores declined and the gap when compared with normal children widened as age increased (average motor quotient standard score 100). However, the linear regression slopes of TMQ and GMQ were flatter with treatment compared with those without treatment (baseline scores), indicating that the rates of decline were slower after rhGH treatment (Fig. 2d, e), narrowing the gap with normal children.
在 52 周的治疗过程中，平均 TMQ 下降（图 2a），从基线到第 52 周的ΔTMQ 为–5.20 ± 6.88（P < 0.001）（表 2）。同样，尽管接受 rhGH 治疗，平均 GMQ 和 FMQ 也随时间下降（图 2b，c）。在第 52 周，从基线观察到ΔGMQ（−3.90 ± 7.90，P = 0.015）和ΔFMQ（−6.60 ± 8.57，P < 0.001）具有统计学显著差异（表 2）。线性回归分析显示 TMQ、GMQ 和 FMQ 与年龄呈负相关（图 2d–f），这意味着这些运动评分随着年龄的增长而下降，与正常儿童的差距加大（平均运动商标准分为 100）。然而，与未治疗（基线评分）相比，治疗后的 TMQ 和 GMQ 的线性回归斜率较平坦，表明在 rhGH 治疗后，下降速率较慢（图 2d，e），缩小了与正常儿童的差距。

Fig. 2 图 2
figure 2

Assessment of motor development with Peabody Developmental Motor Scale-2. TMQ (a), GMQ (b), FMQ (c), and scatter plot and linear regression model of TMQ (d), GMQ (e), and FMQ (f) with and without treatment. Linear regression equation for TMQ is y =  − 0.3636x + 78.78 for baseline, and y =  − 0.29376x + 76.73 for treatment, respectively. Linear regression equation for GMQ is y =  − 0.3668x + 77.40 for baseline, and y =  − 0.2435x + 74.69 for treatment, respectively. Linear regression equation for FMQ is y =  − 0.2923x + 85.39 for baseline, and y =  − 0.2939x + 84.25 for treatment, respectively. FMQ fine motor quotient, GMQ gross motor quotient, TMQ total motor quotient, SD standard deviation
使用皮博迪发展运动量表-2 评估运动发展。TMQ (a)、GMQ (b)、FMQ (c)以及 TMQ (d)、GMQ (e)和 FMQ (f)的散点图和线性回归模型，分别有和没有治疗。TMQ 的线性回归方程为基线时 y = − 0.3636x + 78.78，治疗时 y = − 0.29376x + 76.73。GMQ 的线性回归方程为基线时 y = − 0.3668x + 77.40，治疗时 y = − 0.2435x + 74.69。FMQ 的线性回归方程为基线时 y = − 0.2923x + 85.39，治疗时 y = − 0.2939x + 84.25。FMQ 为精细运动商，GMQ 为粗大运动商，TMQ 为总运动商，SD 为标准差。

Full size image 完整图像
Table 2 Changes in motor and mental development at week 52 from baseline
表 2 基线至第 52 周运动和心理发展变化
Full size table 完整表格

Among the PDMS-2 subtest standard scores, there was significant improvement in stationary subtest standard score at week 52 from baseline (1.90 ± 3.09, P = 0.003). Significant declines in locomotion subtest standard score (− 1.90 ± 2.93, P = 0.001) and visual–motor integration score (− 1.30 ± 1.70, P < 0.001) were observed from baseline at week 52. Grasping score also decreased from baseline to week 52, albeit not significant (− 0.90 ± 2.68, P = 0.080).
在 PDMS-2 子测试标准分数中，静态子测试标准分数在第 52 周相比基线有显著改善（1.90 ± 3.09，P = 0.003）。在第 52 周，运动子测试标准分数（− 1.90 ± 2.93，P = 0.001）和视觉-运动整合分数（− 1.30 ± 1.70，P < 0.001）相比基线均显著下降。抓握分数也从基线下降到第 52 周，尽管不显著（− 0.90 ± 2.68，P = 0.080）。

GQ and all sub-quotients of the GDS-C showed increments from baseline to week 52 (Fig. 3a–f). At week 52, significant ΔGQ (14.10 ± 16.80, P < 0.001), ΔAQ (26.60 ± 20.94, P < 0.001), ΔBQ (10.90 ± 22.73, P = 0.014), ΔCQ (8.90 ± 22.40, P = 0.039), ΔDQ (8.70 ± 22.56, P = 0.043), and ΔEQ (17.20 ± 22.04, P < 0.001) from baseline were reported (Table 2). Statistical analyses were not computed for FQ and ΔFQ, as data were only available for one subject.
GQ 及 GDS-C 的所有子量表在基线到第 52 周期间均显示出增量（图 3a-f）。在第 52 周，报告了显著的ΔGQ（14.10 ± 16.80，P < 0.001）、ΔAQ（26.60 ± 20.94，P < 0.001）、ΔBQ（10.90 ± 22.73，P = 0.014）、ΔCQ（8.90 ± 22.40，P = 0.039）、ΔDQ（8.70 ± 22.56，P = 0.043）和ΔEQ（17.20 ± 22.04，P < 0.001）相对于基线的变化（表 2）。由于仅有一名受试者的数据可用，因此未对 FQ 和ΔFQ 进行统计分析。

Fig. 3 图 3
figure 3

Changes in the general and sub-quotients of the Griffiths Mental Development Scale-Chinese (GDS-C). GQ (a), AQ (b), BQ (c), CQ (d), DQ (e), and EQ (f) calculated by GDS-C of the FAS. AQ locomotion quotient, BQ personal-social quotient, CQ language quotient, DQ eye and hand co-ordination quotient, EQ performance quotient, GQ general quotient, FAS full analysis set, SD standard deviation
格里菲斯心理发展量表-中文（GDS-C）的一般和子商数的变化。GQ（a），AQ（b），BQ（c），CQ（d），DQ（e）和 EQ（f）由 FAS 的 GDS-C 计算得出。AQ 运动商，BQ 个人-社会商，CQ 语言商，DQ 眼手协调商，EQ 表现商，GQ 一般商，FAS 完整分析集，SD 标准差。

Full size image 完整图像

Effect of rhGH treatment on anthropometric parameters of growth
重组人类生长激素治疗对生长的人体测量参数的影响

Growth parameters are shown in Table 3. HT-SDS increased with treatment from − 1.23 ± 1.02 at baseline to 0.24 ± 0.99 at week 52 and the ΔHT-SDS was 1.50 ± 0.71 after 52 weeks of treatment (P < 0.001). Mean BW SDS increased from − 1.52 ± 1.46 at baseline to 0.21 ± 1.48 at week 52 and ΔBW SDS was 1.68 ± 1.45 after 52 weeks of treatment (P < 0.001). BMI SDS increased from − 1.20 ± 2.00 at baseline to − 0.14 ± 1.62 at week 52 and a statistically significant increment in ΔBMI SDS was observed after 52 weeks of treatment (0.95 ± 1.62, P = 0.003). Bone age/chronological age at week 52 was 0.98 ± 0.24, with marginal difference in bone maturity at week 52 compared with baseline (0.34 ± 0.05, P = 0.060).
生长参数见表 3。HT-SDS 在治疗后从基线的−1.23 ± 1.02 增加到第 52 周的 0.24 ± 0.99，ΔHT-SDS 在 52 周治疗后为 1.50 ± 0.71（P < 0.001）。平均体重 SDS 从基线的−1.52 ± 1.46 增加到第 52 周的 0.21 ± 1.48，ΔBW SDS 在 52 周治疗后为 1.68 ± 1.45（P < 0.001）。BMI SDS 从基线的−1.20 ± 2.00 增加到第 52 周的−0.14 ± 1.62，经过 52 周治疗后观察到ΔBMI SDS 的统计学显著增量（0.95 ± 1.62，P = 0.003）。第 52 周的骨龄/生理年龄为 0.98 ± 0.24，与基线相比，第 52 周的骨成熟度差异微弱（0.34 ± 0.05，P = 0.060）。

Table 3 Growth parameters stratified by genetic subtype and age at rhGH start of the full analysis set
表 3 按遗传亚型和重组人生长激素（rhGH）开始时年龄分层的生长参数（完整分析集）
Full size table 完整表格

Effect of rhGH treatment on biochemical growth markers
重组人类生长激素治疗对生化生长标志物的影响

IGF-1 SDS, IGF-1/IGFBP-3 molar ratio, and serum IGFBP-3 increased from baseline to week 39 and remained stable until the end of the study. At week 52, ΔIGF-1 SDS (3.52 ± 1.64, P < 0.001), ΔIGF-1/IGFBP-3 molar ratio (0.11 ± 0.07, P < 0.001), and ΔIGFBP-3 (2211.70 ± 1012.51 ng/mL, P < 0.001) were statistically significant from baseline.
IGF-1 SDS、IGF-1/IGFBP-3 摩尔比和血清 IGFBP-3 从基线到第 39 周增加，并在研究结束前保持稳定。在第 52 周，ΔIGF-1 SDS（3.52 ± 1.64，P < 0.001）、ΔIGF-1/IGFBP-3 摩尔比（0.11 ± 0.07，P < 0.001）和ΔIGFBP-3（2211.70 ± 1012.51 ng/mL，P < 0.001）与基线相比具有统计学意义。

Effect of rhGH treatment on mental, motor, and growth outcomes stratified by genetic subtype and age of rhGH initiation
重组人类生长激素治疗对心理、运动和生长结果的影响，按遗传亚型和重组人类生长激素开始治疗的年龄分层分析

GMQ did not decline significantly from baseline for subjects with aberrant methylation genotype. ΔGQ and all sub-quotients of the GDS-C achieved significant or non-significant increments at week 52 apart from ΔBQ in subjects with aberrant methylation genotype (Table 2). In terms of growth outcomes, only the paternal deletion group had a significant increase in BMI SDS after 52 weeks of treatment (Table 3). When stratified according to the age at which rhGH treatment was initiated, TMQ and GMQ in the ≥ 9-month group did not decline significantly at week 52 from baseline. It was only in the < 9-month group that GQ and all sub-quotients of the GDS-C increased significantly (Table 2). BMI SDS increased significantly only in the < 9-month group after 52 weeks of treatment (Table 3). After adjusting for baseline measurements and age of rhGH treatment initiation, there were no significant differences in all the motor, mental, and growth indicators between genotype subgroups. After adjusting for baseline measurements, ΔGQ and ΔAQ in the < 9-month group were significantly higher than the ≥ 9-month group after 52 weeks of treatment. The least squares mean difference between the < 9-month and ≥ 9-month groups for ΔGQ and ΔAQ was 11.08 [95% confidence interval (CI) = 3.32–18.83] and 27.95 (95% CI = 11.07–44.84), respectively.
对于具有异常甲基化基因型的受试者，GMQ 从基线未显著下降。除了具有异常甲基化基因型的受试者的ΔBQ 外，ΔGQ 和 GDS-C 的所有子商在第 52 周均实现了显著或非显著的增量（表 2）。在生长结果方面，只有父系缺失组在治疗 52 周后 BMI SDS 有显著增加（表 3）。根据 rhGH 治疗开始的年龄进行分层时，≥ 9 个月组的 TMQ 和 GMQ 在第 52 周与基线相比未显著下降。只有在< 9 个月组中，GQ 和 GDS-C 的所有子商显著增加（表 2）。在治疗 52 周后，BMI SDS 在< 9 个月组中显著增加（表 3）。在调整基线测量和 rhGH 治疗开始年龄后，各基因型亚组之间的所有运动、心理和生长指标没有显著差异。在调整基线测量后，< 9 个月组的ΔGQ 和ΔAQ 在治疗 52 周后显著高于≥ 9 个月组。 <9 个月组和≥9 个月组在ΔGQ 和ΔAQ 上的最小二乘均值差分别为 11.08 [95%置信区间(CI) = 3.32–18.83]和 27.95 (95% CI = 11.07–44.84)。

Safety 安全

A total of 34 (97.1%) subjects experienced treatment-emergent AEs (TEAEs). Serious AEs (SAEs) were reported in seven (20.0%) subjects including infectious pneumonia, sepsis, hypoglycemia, seizures, and respiratory failure. No severe TEAEs or SAEs were related to the use of the study drug (Table 4). SAEs resulted in the death of one (2.9%) subject due to sepsis and was deemed unrelated to treatment; all the other SAEs were resolved. Treatment-related AEs of mild-to-moderate severity were reported in six (17.1%) subjects; one subject who experienced sleep apnea withdrew from the study. No significant changes were found in the clinical laboratory safety parameters with treatment.
共有 34 名（97.1%）受试者经历了治疗出现的不良事件（TEAEs）。七名（20.0%）受试者报告了严重不良事件（SAEs），包括感染性肺炎、脓毒症、低血糖、癫痫发作和呼吸衰竭。没有严重的 TEAEs 或 SAEs 与研究药物的使用相关（见表 4）。SAEs 导致一名（2.9%）受试者因脓毒症死亡，且被认为与治疗无关；其他所有 SAEs 均已解决。六名（17.1%）受试者报告了轻度至中度严重的治疗相关不良事件；一名经历睡眠呼吸暂停的受试者退出了研究。治疗过程中临床实验室安全参数未发现显著变化。

Table 4 Adverse events of the safety set
表 4 安全组的不良事件
Full size table 完整表格

Discussion 讨论

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.
据我们所知，这是中国首次研究早期重组人生长激素（rhGH）治疗对患有普拉德-威利综合症（PWS）婴幼儿时间效应的研究。在 52 周的治疗后，除了在人体测量参数上有显著改善外，我们发现 PWS 患者的运动发育商与年龄在通过线性回归模型分析时呈负相关，且 rhGH 治疗减缓了 TMQ 和 GMQ 的恶化速度。通过 GDS-C 评估的心理发展在治疗后，尤其是在 9 个月以下的受试者中，GQ 和 AQ–EQ 均显著改善。

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 [5,6,7, 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.
我们发现，在进行线性回归分析时，PWS 儿童患者的 TMQ、GMQ 和 FMQ 与年龄呈负相关。然而，治疗减轻了 TMQ 和 GMQ 的恶化。一些研究报告显示，接受 rhGH 治疗的 PWS 患者在使用各种运动量表评估的运动发展评分上有所改善[5, 6, 7, 9, 13, 14]。在一项研究中，对 4 至 37 个月大的婴幼儿进行 rhGH 治疗时，使用 TIME 评估的移动性和稳定性呈现出积极趋势[6]。独立行走的年龄也早于该病症的典型情况[6]。另一项对平均年龄为 15.5 个月的婴儿进行的研究，使用 TIME 评估运动变化，报告在接受六个月的 rhGH 治疗后，移动性和稳定性分别改善了 40.8% ± 31.0%和 48.5% ± 43.3%[5]。Reus 等人也注意到，使用阿尔伯塔婴儿运动量表（AIMS）和粗大运动功能测量（GMFM）评估时，rhGH 对 PWS 婴儿的运动发展有积极影响，但在 BSID-II 评估中未见此效果[12]。 作者解释道，AIMS 和 GMFM 都关注粗大运动功能，而 BSID-II 则包括精细运动技能，可能在检测治疗效果方面敏感性较低。相比之下，Festen 等人报告称，在接受一年 rhGH 治疗的婴幼儿中，使用 BSID-II 评估的运动发展改善了 11.2%，而未治疗的对照组则为-18.5% [14]。Donze 等人显示，经过三年的 rhGH 治疗，使用 BSID-II 评估的婴儿在心理和运动发展方面都有所改善，缩小了 PWS 与健康同龄人之间的发展差距 [15]，而从婴儿期开始的八年连续 rhGH 治疗在词汇和总智商方面改善了认知功能 [27]。使用 PDMS-2 和 BSID-II 量表进行评估可能会在运动发展方面得出不同的结果 [28]。在我们的研究中，使用 PDMS-2 评估运动发展。PDMS-2 通常在临床环境中使用（例如。在早期儿童阶段）评估粗大和精细运动技能的发展轨迹，识别运动技能的延迟，为治疗或干预设定个人目标和目的，并监测进展[22, 29]。我们在我们的队列中发现了 rhGH 治疗的积极但不明显的效果；原因可能是由于所使用的评估量表的差异。

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.
我们还发现，较年轻的儿科患者在使用 GDS-C 进行心理发展评估时有更大的改善。当根据 rhGH 治疗开始的年龄进行分层时，< 9 个月组在 GQ 和其他子商数方面的表现明显优于基线。与≥ 9 个月组相比，< 9 个月组的整体和运动发展显著改善。我们的结果与其他研究一致，这些研究表明 GH 治疗对 PWS 儿童的心理功能有积极影响[6, 14]。Meyers 等人报告称，在经过两年的 rhGH 治疗后，语言和认知商数显著改善，同时头围也有所增加[6]，而 Festen 等人则观察到使用 BSID-II 进行的显著心理发展，指出治疗后心理发展提高了 9.3%，而未治疗组为-2.9%，在中位年龄为两岁的儿童中经过一年的随访[14]。Luo 等人最近进行的一项包含 10 个随机对照试验的荟萃分析未发现 rhGH 治疗对 PWS 儿童的认知发展有显著改善[30]。 然而，作者警告说，在该荟萃分析中纳入的随机对照研究中，认知功能的评估并未得到很好的体现[30]。大多数研究集中于一般认知和智商，忽略了重要的认知领域，如语言、词汇和记忆能力[30]。我们研究中使用的 GDS-C 提供了一个涵盖从运动功能到认知技能的不同领域的综合发展概况[22]。因此，我们队列中的发现是可信的。

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.
我们的结果与其他研究一致，显示出人体测量参数的改善和正常化[6, 7, 9]。Scheermeyer 等人报告称，在接受 rhGH 治疗的一岁以下 PWS 婴儿和幼儿中，HT-SDS 和体重 SDS 在仅一年后实现了正常化，并在第二年继续改善[31]。在我们的研究中，我们观察到在 52 周的 GH 治疗后，无论遗传亚型或 GH 启动年龄如何，HT-SDS 和 BW SDS 均实现了正常化。根据年龄和营养阶段，BMI SDS 的增加或减少可以被视为一种改善[32]。根据他们的营养阶段，年轻患者通常在九个月大之前会出现肌张力低下和喂养困难。此后，直到大约两岁，喂养和生长正常。因此，在我们的研究中，BMI SDS 在<9 个月组中随着治疗显著增加，而≥9 个月组的变化则不显著，这表明对这些年轻患者改善营养不良有积极的影响。这与 Festen 等人的年龄依赖性 BMI SDS 趋势一致。尽管没有统计学意义，但研究显示治疗后 BMI SDS 逐渐增加[14]。Lecka-Ambroziak 等人还表明，rhGH 治疗在最年轻患者中改善人体测量参数的效果最佳，尤其是在营养阶段食欲增加之前[33]。总体而言，rhGH 治疗恢复了身体生长，生长促进效果在基线时生长缺陷更严重或早期开始治疗的患者中似乎更为明显。

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].
患有普拉德-威利综合症（PWS）的儿童对生长激素（GH）敏感，并且在重组人类生长激素（rhGH）治疗期间，IGF-1 水平较高，超过+2 标准差（SDS）。这引发了对高 IGF-1 水平相关安全问题的担忧，因为高 IGF-1 水平与淋巴组织增生相关，这可能增加睡眠呼吸暂停的风险。因此，在治疗期间应定期监测 IGF-1 水平。IGF-1/IGFBP-3 摩尔比是监测 rhGH 剂量的另一个有用临床工具。在本研究中，IGF-1/IGFBP-3 比率在 rhGH 治疗期间保持稳定，为 0.19 ± 0.06，类似于 Gaddas 等人的研究，该研究报告 PWS 儿童的摩尔比为 0.19 ± 0.09，均在正常范围内。

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.
总体而言，日常使用重组人生长激素（rhGH）在患有普拉德-威利综合症（PWS）的儿童患者中在 52 周的治疗期间耐受良好。本研究中关于 rhGH 治疗潜在不良事件的安全性关注主要集中在扁桃体肥大、腺样体肥大和上呼吸道阻塞，这些在 PWS 儿童中已有充分文献记录[1]。先前的文献还表明，rhGH 治疗可能会导致腺样体增大和扁桃体肥大，可能导致气道阻塞并加重睡眠呼吸暂停[35]。因此，在开始治疗之前，应评估患有 PWS 的婴儿或儿童是否有上呼吸道阻塞和睡眠呼吸暂停的迹象。在我们目前的研究中，仅有一名患者因轻度睡眠呼吸暂停退出研究，且该情况被认为与治疗相关。本研究中的大多数治疗相关不良事件（TEAEs）为轻度至中度，所有不良药物反应均不需要进一步干预，表明在患有 PWS 的婴儿和幼儿中，rhGH 的潜在益处超过其风险。

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.
我们研究的优点在于同时使用 PDMS-2 和 GDS-C 来全面评估、监测并准确捕捉患有普拉德-威利综合症（PWS）的小儿患者不同运动技能的发展及整体发展。本研究招募了中位年龄为 7.0 个月的年轻患者，这与越来越多的证据支持早期干预使用重组生长激素（rhGH）的益处相一致[1, 2, 6, 9, 14, 16, 36]。然而，短期的研究持续时间和小样本量可能无法揭示 rhGH 效力的全貌，因此未来的研究应招募更大样本量并延长研究周期，以阐明 rhGH 治疗对运动和心理结果的影响。

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.
总之，对患有普拉德-威利综合症（PWS）的婴儿和幼儿进行 52 周的重组人生长激素（rhGH）治疗改善了生长（身高和体重）、身体质量指数（BMI）和心理发展。此外，本研究的结果支持在早期婴儿期（九个月之前）开始治疗的前提，这样的治疗比晚些时候开始治疗的患者获得更好的心理结果。尽管我们的线性回归分析表明，通过减轻患有 PWS 的婴儿和幼儿的运动功能恶化，治疗对运动发展产生了积极影响，但其影响仍不确定。本研究的当前发现增加了越来越多的证据，表明在患有 PWS 的婴儿和幼儿中，rhGH 的使用耐受性良好且有效，且在早期开始治疗时提供的益处超出了身体生长的范围。在本研究开始时，中国尚未批准使用 rhGH 治疗 PWS。因此，我们的研究结果将为指导中国 PWS 患者的 rhGH 治疗临床实践提供更多证据。