Response of children with Turner syndrome with different types of karyotype abnormalities to growth hormone treatment
Article information
Abstract
Purpose
Short stature is the main characteristic of Turner syndrome (TS) patients and growth hormone (GH) therapy has been essential for achieving the final adult height (Ht). In the present study, the response of TS patients with different types of karyotype abnormalities to GH therapy was analyzed.
Methods
The clinical parameters of 194 TS patients registered in the LG Growth Study were retrospectively reviewed. Data for 4 groups of subjects were obtained as follows: monosomy X (n=56); X structural abnormality (n=26); X mosaicism without structural abnormality (n=41); X mosaicism with structural abnormality (n=71). Clinical characteristics and growth response parameters were compared over 3 years of GH treatment.
Results
The baseline Ht standard deviation score (SDS) of all patients was -2.85±0.86. The baseline Ht SDS, body mass index SDS, and chronological age (years)-bone age (years) were significantly different based on chromosomal abnormalities. The growth velocity (GV; cm/yr) in the first year was the highest and significantly different among the groups. The GV in the second year also showed an increase in the X mosaicism without structural abnormality group compared with the monosomy X group. The change in Ht SDS (ΔHt SDS) over 3 years was not statistically different between karyotypes.
Conclusions
The response to 3 years of GH therapy did not differ based on the karyotype of TS patients although the initial Ht SDS was the lowest in the monosomy X group.
Highlights
· Growth hormone therapy improved height in Turner syndrome patients regardless of karyotype.
· Growth velocity differed among groups, with the highest increase seen in the first year of treatment.
· Initial height standard deviation score was lowest in the monosomy X group, but 3-year growth response was similar across karyotypes.
Introduction
Turner syndrome (TS) affects approximately 1 in 2,500–10,000 females born and is one of the most common chromosomal abnormalities. Short stature is the most common physical abnormality observed in TS. Untreated adults are reportedly approximately 20 cm shorter than adults in the general female population [1,2]. The short stature in TS can be attributed to the deleterious effect of SHOX haploinsufficiency. Furthermore, TS is generally associated with relative growth hormone (GH) deficiency with reduced GH sensitivity [3,4]. The decline in growth velocity (GV) is gradual, typically commencing around 18 months of age [5].
Recombinant human GH (rhGH) therapy is considered essential for TS patients to achieve their final adult height (Ht) [6-8]. TS patients require higher doses of GH compared with patients with GH deficiency (GHD). However, the response to GH therapy can vary among TS patients and the final Ht remains uncertain [9-12]. In a recent meta-analysis, GH therapy led to an increase in the final Ht by approximately 7.2 cm with a corresponding increase in Ht standard deviation scores (SDSs) of around 1.22 [2]. In another domestic study, effects of GH in TS were investigated using a machine learning approach; midparental height (MPH) and younger chronological age (CA) were identified as significant factors [10]. In a Dutch study, differences in treatment outcomes based on the GH dosage were observed. The authors found treatment with 6 IU/m2/day was more effective than with 4 IU/m2/day; however, increasing the dosage to 8 IU/m2/day did not result in significant differences [11]. Overall, the results indicated that treatment outcomes did not differ significantly beyond a certain threshold dosage [11]. The karyotype may potentially affect the severity of phenotypic features, which is considered associated with the quantitative loss of X chromosome material. Based on current research findings, the 45,X karyotype is associated with pronounced morbidity and mortality and mosaic karyotypes exhibit a more favorable phenotype [13,14].
To date, differences in GH therapy responsiveness based on TS karyotype, particularly in the Korean population, have been investigated in only a few studies. Therefore, how TS patients with different types of karyotype abnormalities respond to GH therapy was analyzed in the present study using retrospective data from the LG Growth Study (LGS).
Materials and methods
1. Study design and patients
The LGS is a comprehensive observational research project conducted across dozens of centers to evaluate the safety, efficacy, and growth-related outcomes of rhGH products including Eutropin pen, Eutropin 12 IU, Eutropin 4 IU, and Eutropin S Pen (LG Chem, Osong, Korea) injected 3 times daily. The study design has been previously described in detail [15].
Study subjects were screened for eligibility if they were treated daily with GH in the LGS from December 2011 to November 2021. All enrolled patients were treated with GH for more than 3 years. Annual changes in clinical variables were recorded every 12±2 months during the 3 years of GH treatment.
The flow diagram of the selection process for TS patients included in the present study is shown in Fig. 1. A total of 85 patients with TS were excluded from the analysis and included 32 individuals who did not undergo chromosome testing, 8 individuals with insufficient chromosome test data at diagnosis, 9 individuals with concurrent chronic systemic disease, 25 individuals who received estrogen therapy within 3 years of treatment initiation, and 11 individuals who lacked Ht measurements at the screening stage. Finally, 194 patients with TS whose data for the 3 years of GH treatment were complete and valid were enrolled in the study.
Based on the karyotype abnormality, all subjects were divided into 4 groups and their clinical manifestations, GH therapy effects, and outcomes analyzed.
2. Statistical analysis
All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Analysis of variance (ANOVA) and linear regression were used to compare the clinical features of TS patients based on karyotypes. In ANOVA, significant variables were subjected to post hoc analysis which involved t-tests with Bonferroni method. Multiple linear regression analysis was performed to investigate the independent association between variables and third year change in Ht SDS (ΔHt SDS). A P-value of <0.05 was considered statistically significant. Changes in the GH dosage and GV were analyzed using ANOVA.
All variables are presented as the mean and standard deviation for continuous variables. The SDS values for Ht, weight (Wt), body mass index (BMI), and MPH were computed using the 2017 growth reference for Korean children and adolescents [16]. Serum insulin-like growth factor -1 (IGF-1) and insulin like growth factor-binding protein-3 (IGFBP-3) levels were transformed into SDSs based on normative data for the Korean population [17].
3. Ethics statement
The study protocols were performed after approval by the Institutional Review Board (IRB) of Ewha Womans University Seoul Hospital (Seoul, South Korea), and written informed consent was obtained from the patients and their legitimate guardians (IRB No. 2022-09-044).
Results
1. Baseline auxological and biochemical characteristics of TS patients
Table 1 shows the karyotypes of subjects with TS registered in the LGS. Among a total of 194 TS patients, 29% (56 of 194), 13% (26 of 194), and 21% (41 of 194) of patients were in the monosomy X, X structural abnormality, and X mosaicism without structural abnormality groups, respectively. The largest group was X mosaicism with structural abnormality (71 patients), accounting for 37% of all patients (Fig. 1). The auxological and biochemical characteristics of the 4 groups are summarized in Table 2. Differences in CA and bone age (BA) were not observed among the 4 groups. There were statistically significant differences in CA–BA (years) among the 4 groups, particularly in the monosomy X and X mosaicism with structural abnormality groups compared with the X mosaicism without structural abnormality group. The monosomy X group had the lowest Ht SDS. BMI and BMI SDS were different among the 4 groups, with the X structural abnormality group exhibiting the highest values. The baseline value for IGFBP-3 was significantly elevated in the monosomy X group. Significant differences were not observed in the remaining biochemical variables among the groups.
2. Comparison of patients based on karyotypes during 3 years of GH treatment
The GV (cm/yr) in the first year was 7.05±1.69 cm in the monosomy X group, 7.85±1.54 cm in the X structural abnormality group, 7.75±1.54 cm in the X mosaicism with structural abnormality group, and 8.54±1.73 cm in the X mosaicism without structural abnormality group (P<0.001). The GV during GH treatment was the highest in the first year and gradually decreased in the second and third year. In the first year, the GV increased 8.54±1.73 cm in the mosaicism without X structural abnormality group, which was significantly higher than 7.05±1.69 cm observed in the monosomy X group (P<0.001). In the second year, the GV in the X mosaicism without structural abnormality group was 7.54±1.49 cm, which was higher than 6.59±1.4 cm observed in the monosomy X group (P=0.03). In the third year, the GV did not differ among the 4 groups (P=0.492). The GH dosage administered to TS patients was not different between groups or across years (Table 3).
To assess the growth response based on the karyotype, the ΔHt SDS over 3 years of GH treatment was compared. Ht SDS increased during the 3 years of GH treatment. The ΔHt SDS (0.47±0.36 in monosomy X; 0.63±0.37 in X mosaicism without structural abnormality; 0.6±0.33 in X mosaicism with structural abnormality; 0.61±0.35 in X structural abnormality) was increased after 1 year of GH treatment; the values did not differ significantly among the 4 groups (P=0.133). Furthermore, the ΔHt SDS over 3 years was not statistically different between karyotypes (Table 3).
The trend in the Ht SDS over 3 years of GH treatment is shown in Fig. 2. The results were based on 194 patients with data available at the screening time, corresponding to the subjects in Table 2. Among the groups, the monosomy X group started with the lowest baseline Ht SDS, which remained the lowest even after 3 years. The X mosaicism without structural abnormality group had the highest baseline Ht SDS, which remained the highest after 3 years.
3. Factors contributing to the growth response after 3 years of GH treatment
Baseline auxological factors that could affect the baseline third year ΔHt SDS after GH treatment were evaluated. Univariate linear regression analysis was conducted to examine the individual effect of each variable on the third year ΔHt SDS. The results revealed significant associations with BA (years), CA–BA (years), Ht (cm), and Ht SDS in relationship to the third year Δ Ht SDS. However, significant associations were not observed for GH dosage or BMI. Following univariate analysis, stepwise selection was used to select specific variables for multiple regression. This process involved selecting a subset of variables considered the most relevant for predicting the third year Δ Ht SDS (Tables 4 and 5). Based on stepwise selection, BMI SDS and GH dosage (mg/kg/wk) remained contributing variables to explain third year Δ Ht SDS; however, neither variable was associated with third year Δ Ht SDS.
Discussion
This study was performed to determine the effect of GH therapy on different TS karyotypes. Statistically significant difference was not observed in the ΔHt SDS over 3 years based on karyotype. Despite the lack of significant differences in the ΔHt SDS, GH treatment led to an improvement in Ht SDS for children with TS. The GV was greatest in the first year of treatment and gradually decreased over time with GH treatment. The X mosaicism without structural abnormality group had the highest GV and the monosomy X group had the lowest GV. The variables that explained third year Δ Ht SDS were baseline BMI SDS and GH dosage based on stepwise multiple regression.
The results are consistent with those of a prior study showing that differences in subject karyotypes did not affect the outcome of GH therapy or Ht gain [1]. In another study, sexual development and adult Ht achievement were poorer with a monosomy karyotype compared with other karyotypes [12]. In a study in Japan, difference in age or anthropometric indices was not observed between the 45,X and non-45,X karyotypes [9]. In a recent Polish study, monosomy or isochromosome patients showed a poorer response to GH treatment; however, the sample size was relatively small with only 46 individuals [18]. A simplified karyotype classification method was used in previous studies. In contrast, a more comprehensive approach to categorize patients was used in the present study and the results are consistent with the prevalence rates reported in a recent review of TS [19-21].
Factors that may influence the final adult Ht in TS patients administered GH therapy have previously been identified, including tall Ht at initiation of therapy, longer period of treatment before induction of puberty, longer duration of GH therapy, and higher GH dosage [19]. In the present study, the GV differed among karyotypes in the first and second years; however, by the third year, the differences among karyotypes were no longer statistically significant. The first and second years of GH treatment are commonly acknowledged as a catch-up period, whereas the subsequent years represent a stabilization phase of the treatment effect [18]. Patients with TS should undergo GH therapy to improve their adult Ht and body composition [22]. Sas et al. [23] assessed the effects of GH therapy on 68 young girls (mean age, 6–7 years) with TS. The authors reported the normalization of Ht when treatment was started at a younger age with a higher GH dosage. In another study involving 60 TS subjects undergoing long-term GH therapy, 83% of subjects achieved a Ht within the normal adult range [24]. In a recent cohort study, a positive correlation with adult Ht was observed with the addition of low-dose oral estrogen [25-27]. In the present study, to isolate the effects of GH, patients who underwent estrogen therapy were excluded from analysis.
Haploinsufficiency of the SHOX gene is associated with the short stature phenotype of TS; however, this is not the only mechanism underlying short stature. In the present study, the better growth rate in patients with X mosaicism without structural abnormalities than in subjects with monosomy X can be explained by the haploinsufficiency of the SHOX gene in monosomy X. The SHOX gene plays a crucial role in bone growth and the maturation differentiation of chondrocytes. This association is also observed in the growth retardation in TS [18]. In a recent study, the GV of girls with TS was suggested to also be influenced by polymorphisms in genes not located on the X chromosomes [28]. Significant associations have been found between the signaling molecule KRAS and the pituitary transcription factor LHX4 and the GV of girls with TS. Variations in these genes were suggested to be associated with a better response to GH therapy [18].
In comparison with the reported effect of GH treatment in idiopathic short stature (ISS) and GHD based on domestic LGS data, significant difference was not found between ISS and GHD groups in baseline Ht SDS. According to the reported findings on growth response in that study, growth response after 1 year of GH treatment indicated that complete GHD was the highest at 9.52±1.93 cm and ISS was the lowest at 8.72±1.64 cm [29]. In the present study, the first year GV in TS patients after GH treatment changed from 7.05±1.69 cm to 8.54±1.73 cm and was lower than in patients with ISS and GHD. In another domestic study, the GH treatment effects in the group of childhood leukemia survivors with GHD showed a significant increase in GV after GH treatment, reaching 6.53 cm/yr and the ΔHt SDS increased by 0.35 [30]. When comparing these results to TS patients, the effects of GH treatment indicated the GV was highest in patients with GHD, followed by partial GHD, ISS, TS, and childhood leukemia survivors with GHD. However, establishing statistical significance is difficult due to differences in the types of hormones used, dosage, and treatment duration across studies.
The present study had several limitations. Retrospective data from the LGS were used, which may result in missing data. Furthermore, clinical and laboratory data such as BA, IGF-1, and IGFBP-3 levels were collected from 73 different centers; thus, a possibility of bias exists in interpretation and measurement across different institutions. In addition, unconsidered confounding factors, such as other genetic variations, could be present that influence the response of TS patients to GH therapy. Future studies should include a larger cohort as well as longer-term follow-up data.
Despite the limitations, the present study had several strengths. First, the focus was specifically on the response of TS patients with different types of karyotype abnormalities to GH therapy. Second, data from the LGS, which included a large sample of homogeneous subjects with the same treatment modality from a single ethnic group, were analyzed. Third, a wide range of clinical and growth-related parameters, including baseline measurements, GV, BMI, MPH, and GH dosage were considered. This comprehensive approach allowed for identification of potential contributing factors to the growth response with regression analysis.
In conclusion, different types of karyotype abnormalities did not affect GH treatment outcomes in TS patients.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Funding
This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data availability
The data that support the findings of this study can be provided by the corresponding author upon reasonable request.
Acknowledgments
We thank all physicians who contributed their patient data to the LG Growth Study and LG Chem, Ltd. for providing statistical analysis.
Author contribution
Conceptualization: JEC, HSK; Methodology: JEC, HSK; Project administration: HSK; Visualization: JEC, JSY, MJP, HSK; Writing original draft: JEC, HSK; Writing the review and editing: JEC, JSY, MJP, HSK