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The influence of genotype makeup on the effectiveness of growth hormone therapy in children with Prader-Willi syndrome

BMC Pediatrics volume 24, Article number: 627 (2024) Cite this article

Abstract

Background

Prader-Willi syndrome (PWS) is a rare multisystemic hereditary illness. Recombinant human growth hormone (rhGH) therapy is widely recognized as the primary treatment for PWS. This study aimed to examine how different PWS genotypes influence the outcome of rhGH treatment in children with PWS.

Methods

A review was conducted on 146 Chinese children with PWS, genetically classified and monitored from 2017 to 2022. Unaltered and modified generalized estimating equations (GEE) were employed to examine the long-term patterns in primary outcomes (growth metrics) and secondary outcomes (glucose metabolism metrics and insulin-like growth factor-1 (IGF-1)) during rhGH therapy. The study also evaluated the prevalence of hypothyroidism, hip dysplasia, and scoliosis before and after rhGH treatment.

Results

Children with PWS experienced an increase in height/length standard deviation scores (SDS) following rhGH administration. The impact of rhGH therapy on growth measurements was similar in both the deletion and maternal uniparental diploidy (mUPD) cohorts. Nevertheless, the deletion group was more prone to insulin resistance (IR) compared to the mUPD group. No significant variations in growth metrics were noted between the two groups (P > 0.05). At year 2.25, the mUPD group showed a reduction in fasting insulin (FINS) levels of 2.14 uIU/ml (95% CI, -4.26, -0.02; P = 0.048) and a decrease in homeostasis model assessment of insulin resistance (HOMA-IR) of 0.85 (95% CI, -1.52, -0.17; P = 0.014) compared to the deletion group. Furthermore, there was a decrease in the IGF standard deviation scores (SDS) by 2.84 (95% CI, -4.84, -0.84; P = 0.005) in the mUPD group during the second year. The frequency of hip dysplasia was higher in the mUPD group compared to the deletion group (P < 0.05).

Conclusions

rhGH treatment effectively increased height/length SDS in children with PWS, with similar effects observed in both deletion and mUPD genotypes. Children with mUPD genetype receiving rhGH treatment may experience enhanced therapeutic effects in managing PWS.

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Background

Prader-Willi syndrome (PWS) is a multifaceted genetic disorder affecting various systems [1, 2]. The condition arises from the absence of gene expression from the maternally imprinted genes located on chromosome 15q11.2-q13.1. According to an Australia screening study, the birth incidence rate is approximately 1 in 8,290 [3], aligning with the estimated range of 1 in 10,000 to 1 in 30,000 [4, 5]. PWS is characterized by paternal deletions of chromosome 15q11.2-q13 (65–75%), maternal uniparental diploidy (20–30%), imprinting center defects (1–3%), and other infrequent conditions such as balanced translocation on 15q (< 1%). The symptoms of PWS include neonatal low muscle tone [6], difficulties with sucking and feeding in the early stages of infancy [7], increased food consumption in late infancy or toddlerhood, and the gradual development of severe obesity [7]. Delays are observed in the progression of motor skills and language abilities [8], along with varying levels of cognitive impairment [9]. Certain growth abnormalities may arise as a consequence of diminished secretion of growth hormone (GH) [10,11,12,13], hypogonadotropic hypogonadism leading to underdeveloped genitals and delayed puberty [14,15,16], and central hypothyroidism [17, 18]. Despite the general tendency for patients with PWS to develop significant insulin resistance (IR) and type 2 diabetes mellitus as they age and gain weight [19], several studies have indicated that these patients may actually have higher insulin sensitivity compared to those with simple obesity [20, 21]. This phenomenon highlights the unique metabolic characteristics of PWS. Typical characteristics of PWS include distinct facial characteristics [1, 22], eye abnormalities [23], spinal curvature, and hip malformation [24]. Clinical presentation can vary based on the underlying genotypes; for example, patients with deletions tend to have higher body weight compared to those with mUPD. This is due to the fact that patients with the deletion tend to exhibit more severe overeating, resulting in increased intake. Patients with mUPD, on the other hand, tend to have lower levels of heavy binge eating, resulting in better controlled weight gain and a lower body mass index (BMI) [25]. These genotype-specific differences underline the importance of tailored therapeutic approaches in managing PWS.

Currently, regardless of GH deficiency, PWS patients seem to benefit from rhGH therapy in different ways [26]. The use of rhGH effectively addresses the issue of limited height in children with PWS and significantly enhances metabolic well-being, physical composition, muscle strength, and psychomotor development [27,28,29,30]. Moreover, studies based on observation and experience have demonstrated the beneficial effects of rhGH on the cognitive abilities of infants and toddlers with PWS [31,32,33,34,35].

The decision to administer rhGH treatment and the development of dosing plans for PWS patients should not depend on the genotype of PWS [36]. Although there has been some research on the topic, comprehensive studies examining the relationship between genotype and the outcomes of rhGH therapy in large, diverse populations of PWS patients remain limited. The main objective of our study was to investigate how genotype affects the outcome of rhGH therapy in children diagnosed with PWS.

Materials and methods

Study population

Since 2016, this study has been examining the clinical features of Chinese children with PWS as a component of a broader analysis. In 2024, we presented a study on the impact of age at rhGH treatment initiation on treatment outcomes in children with PWS [37]. The study concluded that earlier initiation of rhGH therapy significantly improved growth metrics and metabolic outcomes in children with PWS. Additionally, the Pediatric Rare Disease Platform (https://pws.xun-qi.cn/index) was developed in 2019 to assist children with rare medical conditions. By the end of 2022, a total of 584 genetically confirmed and registered children with PWS were accounted for. From the 570 cases collected between the start of 2017 and the end of 2022, 357 individuals were excluded due to unknown rhGH treatment status, 17 were excluded due to interrupted rhGH treatment, and 29 were excluded as they had not received rhGH treatment. After further clarification on genetic categorization, 146 participants with PWS were selected for this research (Fig. 1).

Fig. 1
figure 1

Cohort Design

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The research sample consisted of 81 boys (55.48%) and 65 girls (44.52%). Medical and familial background details were gathered through interviews with all children and their families, using a standardized questionnaire. The research plan was approved by the Ethics Committee at the Children’s Hospital of Zhejiang University School of Medicine (2019-IRB-025). Moreover, informed written consent was acquired from every parent or guardian enrolled in the Pediatric Rare Disease Platform.

Children with PWS in the study underwent initial diagnosis using methylation analysis techniques, specifically methylation-specific polymerase chain reaction (MS-PCR) and methylation-specific multiplex ligation probe amplification (MS-MLPA). Subsequently, typing was conducted using chromosomal microarray analysis (CMA) or short tandem repeat (STR) methods. The statistical analysis focused on two distinct groups: 106 cases (72.60%) characterized by deletion and 40 cases (27.40%) characterized by mUPD.

A total of 146 children were followed up for more than one year, 107 children for more than two years, and 71 children for more than three years. Data collection occurred at three-month intervals, serving as follow-up time points. Annual data were used as reference points for evaluation and subsequent statistical analysis due to the occurrence of missed visits.

Dosage and modification of rhGH

Because of the wide age range for which rhGH therapy is indicated, the dose of rhGH used in adolescent PWS would be large at the start of PWS, whereas the starting dose of rhGH would be small in 3-month-old PWS [38]. Thus, in the deletion group, children with PWS were administered rhGH doses ranging from 0.05 to 0.20 IU/kg/day, with an average and median value of 0.10 IU/kg/day. In the mUPD group, the range of rhGH doses to PWS was also 0.05–0.2 IU/kg/day, with an average dose of 0.09 IU/kg/day. At baseline, no significant difference in the dose of rhGH between the two groups was observed (p > 0.05). Specialized pediatric endocrinologists made slight modifications to the rhGH dosage, considering factors such as height/length, weight, and IGF-1 levels [27, 29, 39], to maintain IGF-1 levels within a range of 2 standard deviation scores (SDS).

Anthropological measurement

Measurements of height/length were obtained in both upright and reclining positions, with an accuracy of 0.1 cm. Measurements of weight were taken while fasting and rounded to the nearest 0.1 kg. The standard deviation scores (SDS) for height/length, weight, and body mass index (BMI) were adjusted based on age and gender, using the growth criteria set by the National Health and Wellness Commission of the People’s Republic of China (http://www.nhc.gov.cn/wjw/index.shtml) and the standardized growth chart for children and adolescents aged 0–18 in China [40].

Laboratory inspection

Chemiluminescent immunoassay was used to evaluate the levels of fasting glucose (FGLU) and fasting insulin (FINS), IGF-1, and thyroid function. Insulin resistance (IR) was assessed using the homeostasis model (HOMA-IR). Age-matched reference values provided by the test instrument manufacturer were used to standardize IGF-1 treatment. Secondary hypothyroidism is diagnosed when there are two consecutive decreases in free thyroxine (fT4); while elevated thyroid-stimulating hormone (TSH) is also observed in primary hypothyroidism.

Radiographic examination

A professional pediatric orthopedic surgeon is accountable for diagnosing and evaluating scoliosis and hip abnormalities. Scoliosis is identified by a sideways curvature of the spine, diagnosed via an upright X-ray showing a Cobb angle greater than 10 degrees. The Cobb angle is determined by measuring the tilt between two lines parallel to the upper and lower surfaces of the vertebrae. The severity of hip dysplasia is assessed using the Crowe method [41], which includes comparing the degree of upward displacement of the femoral head, usually ranging from 50 to 100%.

Statistical analysis

To evaluate the distribution’s normality, the Shapiro-Wilk test was utilized. Data that conformed to a normal distribution were represented as mean ± standard deviation, whereas non-normally distributed measurements were indicated by median (interquartile range, IQR). To analyze the data, ANOVA was employed for quantitative variables that followed a normal distribution, parametric tests for those that did not follow a normal distribution, and either the χ2 test or Fisher’s exact test for qualitative data.

The study utilized generalized estimating equation (GEE) modeling to analyze data and explore patterns in primary outcomes (growth metrics), secondary outcomes (glucose metabolism metrics and IGF-1), and the influence of genotype on these patterns in individuals with PWS who were receiving rhGH treatment. GEE analyses were conducted to consider within-subject correlations by utilizing a working correlation matrix. The unadjusted and adjusted GEE models were used to assess temporal patterns for each indicator. The modified models took into consideration different variables such as gender, age when treated, duration of pregnancy, age of mother and father at childbirth, height of mother and father, weight of mother and father before pregnancy, education of mother and father, presence of chronic illness in mother during pregnancy, and income of the household.

The data were examined utilizing SPSS software (version 26.0) and R software version 3.5.3. Statistically significant was defined as P values below 0.05.

Results

Population characteristics and baseline

No notable disparities were observed between the two cohorts in terms of gender, age at diagnosis, age at treatment, and duration of treatment (P > 0.05). Nevertheless, analysis of overall demographic data revealed that the mUPD group had a significantly higher percentage of older parents at the time of birth compared to the deletion group (P < 0.001). In contrast, no statistically significant disparities were found in the other demographic variables (P > 0.05). Furthermore, the baseline growth metrics, glucose metabolism metrics, and IGF-1 levels were comparable between the two groups (P > 0.05) (Table 1).

Table 1 Population characteristics and baseline
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Results of Height SDS, Weight SDS, and BMI SDS for the deletion group and mUPD group

Over the course of three years, growth metrics in both groups, except BMI SDS, exhibited a notable positive correlation with time (P < 0.05). After two years of rhGH treatment, children with PWS in both groups reached the mean height/length SDS of normal children of the same age and sex. However, no statistically significant difference was observed between the two groups (P > 0.05). In the third year after rhGH treatment, the average weight and BMI SDS remained more than 1 standard deviation higher in the deletion group compared to the mUPD group, but this difference was not statistically significant (P > 0.05) (Fig. 2 and Table 2).

Table 2 Primary and secondary outcomes
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Fig. 2
figure 2

Changes in height SDS (A), weight SDS (B), and BMI SDS (C) from baseline to three years of treatment in children with both genotypes. Error lines indicate means with 95% confidence intervals

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Glucose metabolism measurement results in the deletion group and mUPD group

Regarding glucose metabolism measurements, it was noted that FGLU consistently remained within the normal range for both cohorts, and there was no notable association discovered between group and time (P > 0.05). In year 3, a significant correlation between group and time was observed for FINS and HOMA-IR, with HOMA-IR frequently surpassing the normal range in both groups (P < 0.001). In year 3, the mUPD group exhibited a decrease in FGLU values of 0.17 mmol/L (95% CI, -0.35, 0.02; P = 0.081) compared to the deletion group, as indicated by the adjusted modeling. At 2.25 years, the mUPD group experienced a decrease of 2.14 uIU/ml (95% CI, -4.26, -0.02; P = 0.048) in FINS values and a decrease of 0.85 (95% CI, -1.52, -0.17; P = 0.014) in HOMA-IR compared to the deletion group. Nevertheless, there were no notable disparities detected at the remaining time intervals (P > 0.05) (Fig. 3and Table 2).

Fig. 3
figure 3

Changes in fasting insulin (A), and HOMA-IR (B) from baseline to three years of treatment in children with both genotypes

The lower and upper limits are the 25th and 75th percentile. The horizontal line in the box shows the median. The dashed line is the upper limit of the normal reference range. #, mUPD group vs. Deletion group. P < 0.05

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During the treatment period, the deletion group exhibited a higher mean IGF-1 SDS compared to the mUPD group. Adjusted modeling revealed a significant reduction of 2.84 (95% CI, -4.84, -0.84; P = 0.005) in the mUPD group at year 2 when compared to the deletion group. Nevertheless, by year 3, this distinction did not have any statistical significance (P > 0.05). Both groups exceeded 2SD at 1.75 years (Tables 2 and Fig. 4).

Fig. 4
figure 4

Changes in IGF-1 SDS from baseline to three years of treatment in children with both genotypes. Error lines indicate means with 95% confidence intervals. #, mUPD group vs. Deletion group. P < 0.05

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Adverse reactions

In the entire group of individuals prior to rhGH treatment, hypothyroidism was observed in 17 cases (11.64%), hip dysplasia in 54 instances (40.00%), and scoliosis in 51 instances (38.93%). Among them, 15 cases of primary hypothyroidism (9 with deletion type and 6 with mUPD type) (7 patients were negative for Thyroid peroxidase (TPO) Ab, thyroglobulin (Tg) Ab and 8 cases had no data) and 2 cases (deletion type) of secondary hypothyroidism. After rhGH treatment, hypothyroidism was found in 32 cases (21.92%), hip dysplasia in 45 cases (33.33%), and scoliosis in 61 cases (46.56%). Of these, 30 were primary hypothyroidism (22 with deletion type and 8 with mUPD type) (11 patients were negative for TPO Ab, Tg Ab and 19 had no data.) and 2 (deletion type) were secondary hypothyroidism.

The occurrence of hypothyroidism increased significantly after rhGH treatment in the deletion groups (χ2 = 5.783, P = 0.016). Regardless of rhGH treatment, the mUPD group exhibited a significantly higher occurrence of hip dysplasia compared to the deletion group (χ2 = 9.116, P = 0.003; χ2 = 6.136, P = 0.013). In addition, there was no significant difference in the incidence of scoliosis between the two groups before and after rhGH treatment (P > 0.05)(Table 3).

Table 3 Other abnormalities found
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Discussion

While the exact age to initiate rhGH treatment remains uncertain, an increasing number of studies [27, 36, 42] have confirmed significant advantages of early rhGH therapy for children diagnosed with PWS. The average and median age of receiving rhGH treatment in this group was during early childhood. Nevertheless, there is an inadequate amount of research examining the influence of the PWS genotype on individual growth metrics, blood examinations, and changes in x-ray imaging resulting from rhGH treatment.

No variations in height/length, weight, or BMI SDS were observed among children with different PWS genotypes during rhGH treatment. These findings partially align with previous research [25]. Their study differs from ours in that the average age of individuals starting GH treatment was 4 ± 0.4 years (ranging from birth to 49 years). This age was comparatively higher and failed to consider the potential influence of confounding variables, such as parental height and weight.

During the follow-up period, the analysis revealed that the levels of FGLU in both groups of PWS were predominantly sustained within the standard range, and no significant disparity was observed between the two groups. This is comparable to prior research [28, 43, 44]. Hyperinsulinemia was present initially but resolved by the end of the follow-up period. Both cohorts exhibited a rise in HOMA-IR levels surpassing the established norms towards the end of the observation period [45]. Nevertheless, the alterations in FINS and HOMA-IR indicated that the deletion group was more prone to IR compared to the mUPD group.

During GH therapy, both groups experienced IGF-1 SDS at levels exceeding 2 SD. Studies have examined and documented the safety of elevated IGF-1 levels, indicating the existence of increased IGF-1 bioactivity in children with PWS who have undergone rhGH treatment [46]. Despite the PWS group having higher levels of IGF-1 SDS than normal, there was no alteration in the molar ratio of IGF-1 to IGF binding proteins-3 (IGFBP-3) [47]. This indicates a consistent biological effect, and the monitoring process included improvements in IGF-BP3. In this specific group, it was noticed that the IGF-1 SDS showed a greater value in the deletion group in comparison to the mUPD group. This difference was statistically significant during the second year of treatment. Nevertheless, there were no notable differences noted regarding the age of rhGH treatment, dosage, and height SDS between the two groups. Further investigation is warranted as this observation suggests that the mUPD group exhibited greater sensitivity to GH or higher IGF-1 bioactivity compared to the deletion group.

Moreover, it is important to mention that the occurrence of hypothyroidism among the group showed an increase from 10.38 to 11.64% to 21.92–22.64% throughout the observation period. Prior research has consistently indicated a significant prevalence of hypothyroidism in children who have been diagnosed with PWS, with a rate of occurrence of 25% and an average age of diagnosis of around two years [17, 18, 48, 49]. Since the average and median age of the individuals in this specific group were in the early stages of life, it is uncertain if the observed rise in hypothyroidism occurrence can be linked to GH therapy. The occurrence of hip dysplasia was also significantly higher in the mUPD group than in the deletion group both before and after the rhGH treatment, contrary to the results of prior research [24]. In addition, of the 32 patients who developed hypothyroidism after treatment, 30 were primary hypothyroidism (22 with deletion type and 8 with mUPD type) and 2 were secondary hypothyroidism (both deletion type). This significant rise in primary hypothyroidism raises questions about its potential autoimmune background. Typically, secondary hypothyroidism is more common in PWS patients due to hypothalamic dysfunction [50]. However, the observed increase in primary hypothyroidism, especially of the autoimmune type, warrants further investigation to understand its etiology and possible link to rhGH therapy.

This study has several limitations. Firstly, its retrospective nature may introduce bias and affect the generalizability of the results. Secondly, the number of laboratory samples was limited, which could impact on the robustness of the findings related to biochemical and metabolic markers. Third, data collected throughout all follow-up time points for the most extensive group of participants was incomplete. However, the research is still ongoing, and there are anticipated upcoming data additions that will be more extensive, covering longer periods of follow-up.

Conclusion

To summarize, current research established that administering rhGH can effectively increase the height/length SDS in children with PWS. Significantly, there were no notable differences in growth metrics between the two groups when they underwent rhGH therapy. Nevertheless, the deletion group displayed a more pronounced tendency towards IR compared to the mUPD group. This observation suggests the possibility that the mUPD group may possess superior sensitivity to GH or exhibit higher IGF-1 bioactivity than the deletion group. To better understand the relationship between PWS genotype and hip dysplasia, future studies with larger sample sizes and longer follow-up periods are necessary.

Data availability

The data and materials utilized in this study are available for sharing upon the request of any qualified investigator.

Abbreviations

PWS:

Prader-Willi syndrome

rhGH:

Recombinant human growth hormone

GEE:

generalized estimating equations

IGF-1:

Insulin-like growth factor-1

mUPD:

Maternal uniparental diploidy

HOMA-IR:

Homeostasis model assessment of insulin resistance

SDS:

Standard deviation scores

IR:

Insulin resistance

MS-PCR:

Methylation-specific polymerase chain reaction

CMA:

Chromosomal microarray analysis

STR:

Short tandem repeat

BMI:

Body mass index

FGLU:

Fasting glucose

FINS:

Fasting insulin

fT4:

Free thyroxine

TSH:

Thyroid stimulating hormone

IQR:

Interquartile range

IGFBP-3:

IGF binding proteins-3

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Acknowledgements

We would like to extend our appreciation to all the children diagnosed with PWS and their families who took part in this research.

Funding

The National Natural Science Foundation of China (81670786), Key R&D Projects of Zhejiang Provincial Science and Technology Agency (2021C03094), Public Technology Project of Zhejiang Provincial Science and Technology Agency (LGF22H090006), and Medical and Health Science and Technology Project of Zhejiang Province (2020KY230) provided funding for this research.

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Authors and Affiliations

  1. Department of Endocrinology and Metabolism, Hangzhou Children’s Hospital, Hangzhou, Zhejiang, 310014, China

    Qiong Zhou

  2. Department of Endocrinology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No. 3333 Binsheng Road, Hangzhou, Zhejiang, 310052, China

    Yun-qi Chao, Yang-li Dai, Ying Gao, Zheng Shen, Guan-ping Dong & Chao-Chun Zou

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  1. Qiong Zhou
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Contributions

QZ and CCZ were responsible for designing the study. QZ, YG, and YQC gathered and obtained the information. QZ, YLD, and ZS analyzed and interpreted the data. The paper’s initial draft was written by QZ, CCZ and GPD thoroughly reviewed and made significant revisions to the paper. Every writer took part in the crucial editing of the document and gave their consent to the final version for submission.

Corresponding author

Correspondence to Chao-Chun Zou.

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Ethics approval and consent to participate

Approval for the study protocol was granted by the Ethics Committee of the Children’s Hospital of Zhejiang University School of Medicine (Ethics number 2019-IRB-025). Informed consent was obtained from all subjects.

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Not applicable.

Competing interests

The authors declare no competing interests.

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Zhou, Q., Chao, Yq., Dai, Yl. et al. The influence of genotype makeup on the effectiveness of growth hormone therapy in children with Prader-Willi syndrome. BMC Pediatr 24, 627 (2024). https://doi.org/10.1186/s12887-024-05109-y

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Keywords

BMC Pediatrics

ISSN: 1471-2431

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