Short stature refers to individuals in a similar living environment and of the same race, same sex, and similar age who are 2 standard deviations lower than the average height of the normal population [
This study describes the clinical data of children admitted to the Department of Endocrinology, Affiliated Hospital of Jining Medical University, for the evaluation of short stature and poor growth during the period of 2013–2019 in eastern China. This study is aimed at identifying the aetiology of growth and development diseases and assessing the long-term effectiveness of rhGH therapy in a real-life clinical setting and providing better guidance for clinical strategy and decision making. Growth and Development Diseases in Shandong Province: a cohort follow-up (GDDSD) study was specifically designed by the Affiliated Hospital of Jining Medical University to collect enrolment demographics as well as clinical and laboratory data from children and adolescents who were referred to the hospital for growth failure or were treated with rhGH.
The GDDSD study is an ongoing prospective, observational, open cohort study to evaluate the aetiology of growth and development diseases and the long-term safety and effectiveness of growth hormone therapy in a real-life clinical setting. All subjects were enrolled from the GDDSD study (
The study was approved by the Human Ethics Committee of the Affiliated Hospital of Jining Medical University (Shandong, China). All of the families of the patients were informed of the aims of the study, and a specific written informed consent form, from a standard source, was signed by all of the participants’ parents.
Height and weight were assessed following standard procedures. Height was expressed as the SDS based on normative values for Chinese children [
Two stimulating tests were performed to assess growth hormone (GH) secretion (the first one, 500 mg of levodopa for those weighing more than 30 kg; 250 mg of levodopa for those weighing less than 30 kg, orally; and the second one, 0.1 U/kg insulin, subcutaneously). GH concentration measurements were performed at 0, 30, 60, 90, and 120 min after administration. A chemiluminescence method was used to assess the GH concentration (ACCESS2, Beckman Coulter; USA), and the sensitivity was 0.010
BA was assessed using a radiograph of the left hand and wrist (Ysio, SIEMENS, and Germany). All radiographs were analysed by an experienced radiologist blinded to the patients’ chronological ages using the Greulich and Pyle method [
Statistical analysis was performed with R 3.4.3 (
The aetiology classification and rhGH treatment with short stature are shown in Table
Aetiology classification and rhGH treatment with short stature.
Aetiology classification | Cases | rhGH treatment | ||
---|---|---|---|---|
Boy/girl | Boy/girl | |||
730 | 464/266 | 334 | 216/118 | |
GHD | 579 | 374/205 | 271 | 178/93 |
Complete GHD | 219 | 145/74 | 111 | 77/34 |
Partial GHD | 360 | 229/131 | 160 | 101/59 |
MPHD | 8 | 6/2 | 6 | 4/2 |
Hypothyroidism | 46 | 24/22 | 26 | 15/11 |
SGA | 40 | 29/11 | 15 | 9/6 |
Skeletal development disorder | 12 | 5/7 | 3 | 2/1 |
Intracranial tumour | 12 | 10/2 | 0 | 0 |
Chromosomal disease | 16 | 2/14 | 6 | 1/5 |
Turner syndrome | 14 | 0/14 | 5 | 0/5 |
Other chromosomal disease | 2 | 2/0 | 1 | 1/0 |
Chronic systemic disease | 17 | 14/3 | 7 | 7/0 |
415 | 276/139 | 150 | 100/50 | |
ISS | 276 | 174/102 | 85 | 53/32 |
FSS | 122 | 88/34 | 63 | 45/18 |
Physical puberty delay | 17 | 14/3 | 2 | 2/0 |
Total | 1145 | 740/405 | 484 | 316/168 |
Abbreviations: rhGH: recombinant human growth hormone; GHD: growth hormone deficiency; MPHD: multiple pituitary hormone deficiency; SGA: small for gestational age; ISS: idiopathic short stature; FSS: familial short stature.
The clinical and biochemical characteristics of the children and adolescents with short stature are summarized in Table
Baseline clinical and biochemical characteristics of the subjects.
Year | All | 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | 2019 |
---|---|---|---|---|---|---|---|---|
Number | 1145 | 68 | 90 | 86 | 155 | 178 | 252 | 316 |
Sex (male %) | 740 (64.63%) | 45 (66.18%) | 59 (65.56%) | 56 (65.12%) | 108 (69.68%) | 111 (62.36%) | 150 (59.52%) | 211 (66.77%) |
Age (years) | ||||||||
Bone age (years) | ||||||||
Height (cm) | ||||||||
Height SDS | ||||||||
Weight (kg) | ||||||||
BMI (kg/m2) | ||||||||
BMI SDS | -0.15 (-0.91-0.78) | -0.38 (-1.45-0.39) | -0.45 (-0.96-0.33) | -0.33 (-1.18-0.60) | -0.10 (-0.79-0.83) | -0.16 (-0.86-0.95) | 0.03 (-0.62-0.97) | -0.18 (-0.91-0.73) |
Peak GH (ng/ml) | 7.44 (4.83-11.49) | 7.03 (5.68-10.20) | 8.92 (4.07-12.81) | 9.25 (5.77-14.80) | 7.53 (4.86-12.21) | 8.02 (4.77-11.96) | 6.58 (4.45-9.57) | 7.72 (5.11-10.79) |
IGF-1 (ng/ml) | 197.00 (114.00-319.00) | 157.50 (83.03-218.01) | 189.00 (98.10-279.00) | 168.00 (109.25-279.50) | 173.00 (90.55-284.00) | 200.50 (125.75-296.50) | 220.00 (139.00-360.00) | 212.00 (126.00-345.23) |
IGF-1 SDS | -1.01 (-1.83--0.16) | -1.25 (-1.96--0.47) | -1.35 (-2.36--0.34) | -1.23 (-2.08--0.34) | -1.08 (-1.89--0.22) | -0.96 (-1.79--0.18) | -0.77 (-1.58-0.04) | -1.02 (-1.70--0.12) |
IGFBP-3 ( | ||||||||
Pubertal stage | ||||||||
In prepuberty (%) | 658 (57.47%) | 36 (52.94%) | 53 (58.89%) | 55 (63.95%) | 88 (56.77%) | 106 (59.55%) | 134 (53.17%) | 186 (58.86%) |
In puberty (%) | 487 (35.37%) | 32 (47.06%) | 37 (41.11%) | 31 (36.05%) | 67 (43.23%) | 72 (40.45%) | 118 (46.83%) | 130 (41.14%) |
Abbreviations: height SDS: height standard deviation scores; BMI SDS: body mass index standard deviation scores; IGF-1 SDS: insulin-like growth factor-1 standard deviation scores; IGFBP-3: insulin-like growth factor-binding protein-3; peak GH: peak growth hormone; normal distribution of data was presented as
Number (a) and height SDS (b) of patients for the entire group from 2013 to 2019.
As shown in Table
Clinical and biochemical characteristics of the rhGH-treated subjects.
Year | All | 2013 | 2014 | 2015 | 2016 | 2017 | 2018 | 2019 |
---|---|---|---|---|---|---|---|---|
Number | 484 | 20 | 33 | 38 | 76 | 82 | 75 | 160 |
Sex (male %) | 316 (65.29%) | 14 (70.00%) | 19 (57.58%) | 28 (73.68%) | 51 (67.11%) | 58 (70.73%) | 45 (60.00%) | 101 (63.12%) |
Age (years) | ||||||||
Bone age (years) | ||||||||
Height (cm) | ||||||||
Height SDS | ||||||||
BMI (kg/m2) | ||||||||
Peak GH (ng/ml) | 6.78 (4.34-9.88) | 6.73 (5.66-7.85) | 4.34 (2.92-9.24) | 7.44 (5.20-10.94) | 6.70 (4.52-10.91) | 6.64 (4.13-11.21) | 7.11 (4.73-9.51) | 6.38 (4.79-9.98) |
IGF-1 (ng/ml) | 196.00 (125.25-316.75) | 173.87 (48.97-217.19) | 171.50 (122.00-218.75) | 158.00 (109.75-293.25) | 180.00 (95.00-240.00) | 201.50 (128.25-355.00) | 216.50 (154.00-349.00) | 206.00 (137.00-358.00) |
IGF-1 SDS | -1.02 (-1.77--0.19) | -1.15 (-1.67--0.64) | -1.38 (-2.30--1.02) | -1.37 (-2.30--0.10) | -1.08 (-1.79--0.28) | -1.00 (-1.79--0.19) | -1.07 (-1.71--0.22) | -0.58 (-1.35-0.26) |
Duration of rhGH treatment (years) | 1.00 (1.00-2.00) | 2.00 (1.00-3.50) | 2.00 (1.00-3.00) | 1.00 (1.00-2.00) | 1.00 (1.00-2.00) | 1.00 (1.00-2.00) | 1.00 (1.00-2.00) | 1.00 (1.00-1.00) |
Pubertal stage | ||||||||
In prepuberty (%) | 273 (56.40%) | 11 (55.00%) | 21 (63.64%) | 25 (65.79%) | 41 (53.95%) | 47 (57.32%) | 42 (56.00%) | 86 (53.75%) |
In puberty (%) | 211 (43.60%) | 9 (45.00%) | 12 (36.36%) | 13 (34.21%) | 35 (46.05%) | 35 (42.68%) | 33 (44.00%) | 74 (46.25%) |
Abbreviations: height SDS: height standard deviation scores; IGF-1 SDS: insulin-like growth factor-1 standard deviation scores; peak GH: peak growth hormone; rhGH: recombinant human growth hormone; normal distribution of data was presented as
Height SDS by year of treatment (
Height SDS for patients by number of years treated.
Treatment years | Years treated | ||||||
---|---|---|---|---|---|---|---|
0 ( | 1 ( | 2 ( | 3 ( | 4 ( | 5 ( | 6 ( | |
0 | |||||||
1 | — | ||||||
2 | — | — | |||||
3 | — | — | — | ||||
4 | — | — | — | — | |||
5 | — | — | — | — | — | ||
6 | — | — | — | — | — | — |
Abbreviations: height SDS: height standard deviation scores.
In addition, we described height improvement in children treated with rhGH for more than one year according to different aetiologies of short stature (e.g., GHD, ISS, and FSS). We observed that the increase in height over time was consistent with the general population in each subgroup (Tables
Our study describes the general situation and treatment of short stature in China in the past 7 years. Our findings showed that the causes of short stature are complex and varied, and short stature in children and adolescents may be due to changes in normal growth or pathological conditions. In eastern China, the number of short patients whose parents sought medical attention and who were referred to endocrinologists is increasing every year. Furthermore, with rhGH therapy, which has been approved for patients with short stature, increases in the mean height SDS were observed with increasing treatment time, and most of the patients reached the normal range of height.
Our previous study found that the prevalence rate of short stature was 3.16% [
The prevalence of short stature has increased significantly in the past 7 years. Sex differences are more obvious in children with short stature in the hospital. There are obviously more boys than girls, which is consistent with previous study reports [
In our study, there was a large proportion of prepubescent children, suggesting that age plays an important role in the evaluation of patients with short stature. Early evaluation, diagnosis, and treatment are beneficial for height improvement. Polak et al. found that compared with older age at the beginning of treatment, younger age at the beginning of treatment is related to improvement in height [
Among the 1145 cases in this study, 484 children with short stature received rhGH therapy, with a treatment rate of 42.3%, which is similar to previous reports [
The present study has several limitations. First, this study is a retrospective study. In this study, we only described the aetiology and general characteristics of children with short stature but did not discuss the related relationship in depth. Second, we failed to study the underlying causes of the sex differences in the treatment of short children. Finally, in this study, the factors related to the efficacy of rhGH therapy were not explored and deserve further study.
In conclusion, increasing attention has been given to the height of children during the period of 2013–2019 in eastern China. The present findings indicate that children with short stature need to be referred to a specialist centre to diagnose the cause of growth failure. Early treatment with rhGH is recommended since children with short stature respond well to rhGH therapy. In addition, studies on the influencing factors of height growth and follow-up to adult lifetime height are directions for further research in the future.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors declare that they have no competing interests.
Qianqian Zhao carried out the studies and drafted the manuscript. Yuntian Chu and Mei Zhang helped with the statistical analysis. Hailing Sun participated in data collection. Hui Pan participated in the design of the study and revised the manuscript. Bo Ban participated in the concept and design of the study, revised it critically for important intellectual content, and approved the final version to be published. All authors read and approved the final manuscript.
We thank all subjects and their parents who participated in this study. This study was supported by the Jining Science and Technology Bureau (No. 2017SMN007).
Table S1: Height SDS of patients with GHD by number of years treated. Table S2: Height SDS of patients with ISS by number of years treated. Table S3: Height SDS of patients with FSS by number of years treated. Table S4: Height SDS of patients with hypothyroidism by number of years treated. Table S5: Height SDS of patients with SGA by number of years treated.