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Growth hormone treatment for children with mucopolysaccharidosis I or II
Journal of Genetic Medicine 2023;20:60-69
Published online December 31, 2023;  https://doi.org/10.5734/JGM.2023.20.2.60
© 2023 Korean Society of Medical Genetics and Genomics.

Minji Im1, Chiwoo Kim2, Juyoung Sung3, Insung Kim3, Ji-Hoon Hwang3, Min-Sun Kim3, and Sung Yoon Cho3*

1Department of Pediatrics, CHA Gangnam Medical Center, CHA University, Seoul, Korea
2Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
3Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Sung Yoon Cho, M.D., Ph.D. https://orcid.org/0000-0003-2913-059X
Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul 06351, Korea.
Tel: +82-2-3410-3539, Fax: +82-2-3410-0043, E-mail: nadri1217@naver.com
Received December 10, 2023; Revised December 19, 2023; Accepted December 20, 2023.
cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Purpose: Despite enzyme replacement therapy (ERT) and/or allogeneic hematopoietic stem cell transplantation, individuals with mucopolysaccharidosis (MPS) I or II often experience significant growth deficiencies. This study aimed to assess the safety and efficacy of recombinant human growth hormone (hGH) treatment in children diagnosed with MPS I or II.
Materials and Methods: A total of nine pediatric patients—four with MPS I and five with MPS II—underwent treatment with ERT and hGH at Samsung Medical Center.
Results: The mean hGH dose administered was 0.26±0.03 mg/kg/week. In the MPS I group, three patients showed an increase in height Z-score from –4.09±0.83 to –3.68±0.43 after 1 year of hGH treatment, and to –3.10±0.72 by the end of the hGH regimen. In the MPS II group, while the height Z-score of four patients decreased according to standard growth charts, it improved from 1.61±1.79 to 2.71±1.68 based on the disease-specific growth chart through hGH treatment. Two patients discontinued hGH treatment due to lack of efficacy after 22 and 6 months each of treatment, respectively. No new-onset neurological symptoms or necessity for prosthetic or orthopedic surgery were reported during hGH treatment.
Conclusion: This study provides insights into the impact of hGH on MPS patients, demonstrating its potential to reverse growth deceleration in some cases. Further research is needed to explore the long-term effects of hGH on changes in body composition, muscle strength, and bone health in this population.
Keywords : Mucopolysaccharidoses, Growth hormone, Dwarfism.
Introduction

Mucopolysaccharidosis (MPS) are characterized by progressive growth retardation resulting in significant short stature [1]. This disorder stems from defective lysosomal enzyme activity, constituting inherited lysosomal storage disorders. MPS I (Hurler syndrome [MPS IH], Hurler-Sheie syndrome [MPS IH/S]) and MPS II (Hunter syndrome) arise from deficiencies in alpha-L-iduronidase and iduronate-2-sulfatase, respectively. Both enzymes are crucial for glycosaminoglycan (GAG) breakdown. The absence of these enzymes leads to multisystemic disease impacting bone, skeletal muscle, heart, lungs, liver, and mental development [1].

Most individuals diagnosed with MPS experience varying degrees of growth retardation and short stature. The exact pathogenesis of short stature in MPS remains unclear. Despite treatments such as hematopoietic cell transplantation (HCT) for MPS I or enzyme replacement therapy (ERT) for MPS II, moderate to severe short state persists in both syndromes, with unsatisfactory effects on the musculoskeletal system and growth [2]. In clinical practice, some children diagnosed with Hurler or Hunter syndrome and exhibiting short stature undergo recombinant human growth hormone (hGH) treatment, despite a lack of substantial evidence [3,4]. These treatment decisions rely on extensive literature demonstrating safety and successful use of hGH to enhance growth in children with short stature and to increase adult height, including growth hormone deficiency (GHD) and non-deficiency conditions (e.g., Turner syndrome, small for gestational age [SGA], idiopathic short stature) [5].

Studies on hGH treatment in MPS are notably scarce, with the efficacy and safety of hGH treatment remaining unclear in MPS. Therefore, this study aims to investigate the effectiveness and safety of hGH in children diagnosed with MPS I and II.

Materials and Methods

This retrospective observational cohort study included individuals under 19 years of age with confirmed diagnoses of MPS I or II through clinical findings, biochemical tests, and genetic testing. Approval for this study was obtained from the Institutional Review Board of Samsung Medical Center (IRB file number: SMC 2020-10-133-001). This study was conducted according to the Declaration of Helsinki ethical principles. Written informed consent for publication of this case report details was obtained from the parents who are the legal guardians of the patients who participated in the study.

Participants included individuals regularly visiting Samsung Medical Center over a 28-year period from 1994 to 2021. Exclusion criteria comprised pregnancy and prior HCT. Discontinuation of hGH was based on several factors: ineffective treatment (<1 cm growth in 6 months), severe musculoskeletal complications after treatment initiation, bone maturation with epiphyseal plate closure, or withdrawal of consent for the study.

All participants concurrently received ERT throughout the study observation period. Pretreatment growth velocity data were determined based on measurements taken at least 24 months before the initiation of hGH treatment. A single experienced pediatric endocrinologist conducted baseline and ongoing endocrine evaluations during hGH treatment. GHD was defined as a peak growth hormone (GH) level of <10 ng/mL during glucagon and levodopa GH stimulation testing. Standing heights were measured using a wall-mounted stadiometer to the nearest 0.1 cm, with the average of three measurements taken. Standard deviation scores (SDS or height-for-age Z-scores) were calculated based on age- and sex-adjusted population data. All participating patients underwent radiological assessment for scoliosis before commencing hGH treatment. Those diagnosed with GHD underwent sella magnetic resonance imaging (MRI) to identify pituitary lesions. Only patients treated with hGH for a minimum of 6 months within this cohort were included.

Descriptive statistics present means±standard deviation for continuous variables and numbers and percentages for nominal variables. Statistical analyses were conducted using IBM SPSS Statistics ver. 26.0 (IBM Corp.). Student’s t-test was employed to analyze cross-sectional differences between groups at the last evaluation (Table 1).

Results

1. Participants

A total of nine participants diagnosed with MPS I or II were enrolled in this study, with a median follow-up duration of 14.0 years (range, 4.6-17.1 years). Among them, four patients had MPS I, and the remaining five had MPS II. All the patients with MPS II were male. The median age at diagnosis for MPS I and II were 2.8 years (range, 2.3-7.0 years) and 4.1 years (range, 1.9-5.3 years), respectively. Throughout the study period, all participants received ERT, with all but one initiating this treatment before commencing hGH treatment. The median ages at the start of ERT were 2.7 years (range, 2.5-10.1 years) for MPS I and 10.0 years (range, 5.3-19.5 years) for MPS II. Among those receiving hGH treatment, two participants were diagnosed with GHD (one with MPS I and one with MPS II). The mean age at the initiation of hGH treatment was 11.5±3.03 years (range, 5.1-14.6 years), with a mean bone age of 7.8±4.07 years (range, 2.1-13.3 years). The prescribed hGH dose averaged 0.26±0.03 mg/kg/week (range, 0.20-0.30 mg/kg/week), and the mean duration of hGH treatment was 3.4±1.75 years (range, 0.5-4.8 years) (Table 2).

2. Effect on Growth

Participant growth data, presented as Z-scores in Appendix 1 and 2, illustrate the changes in annual growth outcomes among those treated with hGH by MPS type, as detailed in Fig. 1. However, growth velocity showed considerable variability, ranging from 1.9 to 11.5 cm per year among individuals treated with hGH. The participant with MPS II diagnosed with GHD exhibited a tendency toward higher annualized growth velocity compared with those without GHD, reaching a peak growth velocity of 11.2 cm/year in the first year of treatment (Fig. 2). The change in height SDS for all participants ranged from –0.48 to 1.225 SDS at the median. Of the individuals, two with MPS I and four with MPS II showed positive responses to hGH treatment. In the MPS I group, three patients, excluding one who discontinued hGH early, displayed an increase in height Z-score from –4.09±0.83 to –3.68±0.43 after 1 year of hGH treatment, with their final height Z-score reaching –3.10±0.72. One patient diagnosed with MPS I exhibited significantly improved linear growth upon initiation of recombinant GH, with the height Z-score changing from –4.98 to –2.992). Regarding the MPS II group, the height Z-scores of four patients decreased from –3.53±1.54 to –3.64±1.92 after 1 year of hGH treatment and dropped further to –4.43±3.20 at discontinuation. However, as per the disease-specific growth chart (Appendix 2), their height Z-scores improved from 1.61±2.07 to 2.71±1.68 due to hGH treatment. Two participants, one with MPS I and one with MPS II, discontinued hGH treatment after 22 and 6 months, respectively, due to its lack of efficacy [6]. No statistically significant differences were observed between MPS groups concerning age, duration of hGH treatment, or hGH dose (P>0.05).

3. Safety Concerns

No significant differences in adverse events were observed between the treatment groups. The estimated median annual change in bone age showed a variance of 1.8 years (range, 0.9-2.9 years). Musculoskeletal manifestations were observed, encompassing various degrees of genu valgum, kyphosis/scoliosis, and cervical spinal stenosis. Among the six patients, varying degrees of kyphosis, scoliosis, and spinal stenosis were detected without myelopathy. One patient required a prosthesis for lumbar scoliosis during the hGH treatment period. Throughout hGH treatment, there were no reports of new-onset neurological symptoms or the necessity for prostheses or orthopedic surgeries. No serious complications were observed during the hGH treatment.

Discussion

In this retrospective observational study, our findings suggest that hGH treatment holds promise for addressing growth retardation in patients exhibiting a mild-skeletal phenotype of MPS, without adverse effects. In a reported study, GH deficiency appears to be relatively prevalent in MPS cases, particularly after HCT, possibly linked to GAG deposition in the pituitary [7]. One study reported a significantly higher prevalence of GH deficiency (1:4,000-1:8,000) within the MPS patient population compared with the general population [8]. The observed lack of response in growth velocity for children with MPS I or II undergoing hGH treatment may stem from various factors. Abnormalities within the growth plate, such as chondrocyte and osteoblast abnormalities, including GAG accumulation, may hinder the efficacy of hGH treatment by disrupting epiphyseal elongation and mineralization [9]. Moreover, children with MPS I subjected to total body irradiation after HCT displayed limited responsiveness to hGH treatment, possibly due to radiation-induced damage to the growth plate [7]. To mitigate the impact of HCT on growth restriction, we selectively enrolled MPS patients without prior HCT history. All participants in this study had no previous HCT history.

The growth-promoting effect of hGH treatment is indeed widely acknowledged. Beyond its role in height augmentation, hGH treatment in children with conditions such as Prader–Willi syndrome, Turner syndrome, those born SGA, and individuals with GHD has demonstrated benefits such as increasing lean body mass, boosting bone mineral density and exercise performance, and decreasing percentage body fat [10]. A study by Cattoni et al. [8] suggests the effectiveness of hGH treatment in increasing height velocity and reversing the progressive loss of height SDS in MPS patients with GHD, particularly within the first 2 years. The study noted a significant increase in height velocity SDS at 6 and 12 months after the initiation of hGH treatment (average Δ height velocity SDS: +4.23±2.9 at the 6-month follow-up, +4.55±0.96 at the 12-month follow-up), effectively counteracting the previous trend of declining height SDS among all patients. Additionally, there is a case series documenting attempts at hGH treatment in patients diagnosed with MPS IVA and mucolipidosis who had GHD. However, the treatment proved ineffective in these cases. Furthermore, in the case of MPS IV, hGH was reported to be ineffective as well.

Meanwhile, studies have reported on the efficacy of ERT in addressing growth patterns seen in MPS. Chen et al. [11] conducted a review focusing on the growth trajectories of patients with MPS. Their findings indicated that while ERT was ineffective in improving growth, HCT demonstrated more promising results in mitigating growth retardation among MPS patients. However, even among HCT-treated patients, there remained a tendency to fall below 1 to 2 standard deviations compared with age-matched controls. For MPS II, ERT showed a growth-improving effect, suggesting that initiating ERT before the age of 10 years could potentially maintain the growth of MPS II patients within the normal range. As for MPS IVA, further follow-up studies are warranted, but currently, there is insufficient evidence supporting the notion that ongoing ERT improves growth rate or addresses bone lesions in patients with MPS IVA and VI. Limited evidence exists regarding the growth effectiveness of ERT in other types of MPS. In our study, one of the MPS II patients had not undergone ERT before commencing hGH treatment. While the height SDS of the other four MPS II patients improved after hGH treatment, this patient’s hGH treatment was discontinued early due to its ineffectiveness. Evaluating the efficacy of hGH treatment in patients who have not received ERT appears to necessitate longer-term, controlled follow-up studies.

Reports on achondroplasia have raised concerns about the potential exacerbation of skeletal imbalances in children with MPS treated with hGH [12]. Conversely, another study on hGH treatment for achondroplasia did not indicate worsening of skeletal imbalances [13,14]. However, it is worth noting the possibility that hip dysplasia observed in MPS could increase the risk of a rare complication associated with hGH treatment—slipped capital femoral epiphysis—as a study previously reported in a small cohort of children with Hurler syndrome treated with hGH following HCT [15]. In our study, the observed spinal abnormalities were relatively mild, and hip dysplasia was absent. Even when hGH was administered, the spinal abnormalities did not significantly deviate from the typical course of MPS. At present, establishing a correlation between the progression of orthopedic abnormalities and hGH treatment remains elusive. Further data, especially from larger sample sizes and comparisons with untreated groups, are imperative to assess any potential correlation.

hGH has demonstrated positive skeletal effects. Although we could not evaluate bone mineral density, research indicates that hGH treatment increases bone mineral density and enhances peak bone mass accrual in children with GHD, cerebral palsy, and those born SGA [16,17]. The elevation in bone mineral density is likely attributed to the heightened production of insulin-like growth factor-1, fostering increased bone turnover favoring bone formation [16,17].

It is important to note the limitations of the study, particularly its retrospective observational design and relatively small sample size. The small sample size restricted our ability to determine statistical significance. However, all participants underwent annual monitoring for known disease complications, which typically included X-rays for kyphoscoliosis and hip dysplasia, echocardiograms for cardiac function and valvular disease, and brain MRIs for ventricular size. Consequently, it is improbable that significant adverse events linked to hGH treatment went unnoticed. In addition, we lack long-term data on the effects of hGH in this specific population.

In conclusion, this study offers detailed insights into the response to hGH treatment among MPS patients. Notably, hGH treatment exhibits potential effectiveness in addressing growth retardation in individuals with a mild-skeletal phenotype of MPS, without adverse effects. However, the specific impact of hGH on final height in MPS patients, along with its role in hGH-induced bone maturation, remains unexplored and necessitates further analysis. Moreover, it is crucial to investigate the long-term safety implications and the benefits regarding changes in body composition, muscle strength, and bone health stemming from hGH treatment within this population.

Acknowledgements

We wish to thank all the individuals who are living with rare diseases, their families, and the clinical and research laboratory staff.

Funding

No fundings to declare.

Authors' Contributions

Conception and design: MI, MSK, SYC. Acquisition of data: MI, CK, JS, IK, JHH. Analysis and interpretation of data: MI, CK, JS, IK, JHH, MSK, SYC. Drafting the article: MI, CK, MSK, SYC. Critical revision of the article: MI, MSK, SYC. Final approval of the version to be published: MI, CK, JS, IK, JHH, MSK, SYC.

Figures
Fig. 1. The growth curve of three patients with mucopolysaccharidosis (MPS) I (A) and four patients with MPS II on disease-specific growth chart (B). (A) This is the growth curve of three patients with MPS I, excluding one who terminated the hGH treatment early because of ineffectiveness. In patient 1 (black), who was diagnosed with Hurler-Sheie syndrome, height SDS showed an increase every year after starting the hGH treatment. Patient 2 (red) was diagnosed with GHD. In patient 4 (blue), who had mild type MPS I, height SDS tended to decrease every year before starting hGH treatment. However, after starting the hGH treatment, the annual height SDS of the patient increased relatively continuously.(B) This is the growth curve of four patients with MPS II, excluding one who terminated the hGH treatment early because of ineffectiveness. In this MPS II disease-specific growth curve, height SDS shows a relatively sustained increase in four MPS II patients after starting growth hormone treatment. The height SDS at the end of treatment increased in all four patients compared to the height SDS at the start of treatment. Patient 3 (red) was diagnosed with GHD. H/S, Hurler/Scheie syndrome; hGH, human growth hormone; SDS, standard deviation score; GHD, growth hormone deficiency.
Fig. 2. Growth curves of the three patients with mucopolysaccharidosis (MPS) I (A) and four patients with MPS II (B). (A) Growth patterns for three patients with MPS I on the 2017 Korean national growth charts. The red dots represent height for age and the blue dots represent weight for age. The black triangles indicates when enzyme replacement therapy was started for each patient. The transparent triangles indicates when human growth hormone (hGH) treatment was started for each patient. The asterisk indicates when hGH treatment ended for each patient. (B) Growth patterns for four patients with MPS II on the 2017 Korean national growth charts. The red dots represent height for age and the blue dots represent weight for age. The black triangles indicates when enzyme replacement therapy was started for each patient. The transparent triangles indicates when hGH treatment was started for each patient. The asterisk indicates when hGH treatment ended for each patient. 1, MPS I patient number 1; 2, MPS I patient number 2; 3, MPS II patient number 3; 4, MPS I patient number 4; 5, MPS II patient number 5.
TABLES

Growth values according to growth hormone treatment for all MPS participants

MPS type Age (yr) Duration of hGH (yr) hGH dose (mg) Ht (cm) End Ht (cm) GV (cm/year) Ht-SDS End Ht-SDS ∆ SDS
(per year)
1 10.6 5.9 0.27 119.8 158.1 6.54 –3.96 –2.17 0.30
1 14.6 2.7 0.20 141.2 151.8 3.88 –3.33 –3.89 –0.20
1 5.1 1.8a 0.28 89 91.8 1.58 –5.24 –5.79 –0.31
1 8.9 5.5 0.26 109 142 6.03 –4.98 –2.99 0.36
2 11.4 0.5a 0.26 128 129 1.99 –3.01 –3.13 –0.24
2 13.2 4.8 0.23 128.5 159.4 6.47 –3.78 –2.65 0.24
2 14.4 3.5 0.29 111.3 128.2 4.82 –5.39 –8.38 –0.85
2 13.3 2.9 0.30 133.3 142.8 3.30 –3.30 –3.84 –0.19
2 12.4 3.0 0.29 142.3 160.4 6.09 –1.65 –1.58 0.02
Mean±SD
I 9.80±3.94 3.96±2.01 0.25±0.04 114.75±21.77 135.93±30.15 4.51±2.27 –4.38±0.89 –3.99±1.87 –0.04±0.34
I/M 12.6±2.83 4.29±2.21 0.23±0.05 130.5±15.13 154.95±4.45 5.21±1.88 –3.64±0.44 –3.16±1.01 0.03±0.32
I/F 7.0±2.69 3.62±2.61 0.27±0.01 99.0±14.14 116.9±35.50 3.81±3.15 –5.11±0.18 –4.82±2.59 –0.22±0.82
II 12.94±1.12 2.93±1.55 0.27±0.03 128.68±11.29 143.96±15.67 4.54±1.89 –3.42±1.35 –4.17±2.83 –0.20±0.41
Total 11.54±3.03 3.38±1.74 0.26±0.03 122.49±17.18 140.39±21.95 4.52±1.93 –3.85±1.21 –4.09±2.31 –0.10±0.38
P-value* 0.11 0.22 0.17 0.16 0.33 0.49 0.12 0.46 0.18

MPS, mucopolysaccharidosis; hGH, human growth hormone; Ht, height; GV, growth velocity; SDS, standard deviation score; M, male; F, female; SD, standard deviation.

ahGH treatment was in effective in these patients, and treatment was terminated early within 24 months.

*P-value <0.05.


Basic treatment information of patients categorized by MPS groups

No. Age at diagnosis (yr)/sex Diagnosis Age
at first visit (yr)
Age at starting ERT (yr) Age at starting hGH (yr) Duration of hGH (yr) BA
at start hGH (yr)
BA at ending hGH (yr) Skeletal problems before hGH treatment Skeletal problems after hGH treatment Other endocrinologic problem
1 2.8/M MPS I, attenuated type, normal GH response 4.3 7.9 10.6 5.9 5.0 16.0 None (a) None
2 7.0/M MPS I, attenuated type, GHD 7.0 10.1 14.6 2.7 9.0 17.0 None (b) None
3 2.3/F MPS I, normal GH response 2.3 2.5 5.1 1.8 2.1 NA None (c) None
4 2.7/F MPS I, normal GH response 2.9 2.9 8.9 5.5 4.6 14.6 Kyphosis (d) None
5 5.0/M MPS II, attenuated typea 5.0 19.5 11.4 0.5 5.4 NA None (e) None
6 4.1/M MPS II, attenuated type, GHD 4.1 11.0 13.2 4.8 6.0 16.9 NA NA None
7 2.2/M MPS II, attenuated typea 2.2 10.0 14.4 3.5 13.3 17.0 NA NA None
8 1.9/M MPS II, attenuated type, normal GH response 5.0 8.0 13.3 2.9 11.6 15.9 None (f) None
9 5.3/M MPS II, attenuated typea 5.3 5.3 12.4 3.0 13.0 15.6 Genu valgum, hallux valgus NA None
Mean±SD 3.7±1.57 4.2±1.57 8.6±5.13 11.5±3.03 3.4±1.75 7.8±4.07 16.1±0.89

(a) Valgus knee, deformity of 1st and 5th lumbar spine with mild thoraco-lumbar kyphosis, narrowing of cranio-cervical junction, hallux varus, equinus cavovarus. (b) Bony canal stenosis on cranio-cervical junction. (c) Cervical spinal stenosis. (d) Acetabular dysplasia, genu valgum, cervical stenosis of cervical vertebrae 0 to 6, thoracolumbar kyphosis, HIVD at the level of 1st-2nd lumbar spine, moderate cervico-lumbar spinal stenosis, mild stenosis of at the level of 2nd-3rd lumbar spine, moderate stenosis at the level of 3rd-4th lumbar spine, acetabular dysplasia. (e) HIVD at the level of 6th-7th cervical spine, foraminal stenosis at the level of 5th lumbar spine. (f) Bilateral hallux valgus, scoliosis.

No., patient number; M, male; F, female; hGH, human growth hormone; MPS, mucopolysaccharidosis; GH, growth hormone; GHD, growth hormone deficiency; ERT, enzyme replacement therapy; BA, bone age; HIVD, herniated intervertebral disc; NA, not assessed; SD, standard deviation.

aNot assessed GHD.


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