Idiopathic Short Stature Children Research Articles

Factor analysis of traditional Chinese medicine symptoms for identification of syndrome patterns associated with idiopathic short stature in children

ABSTRACT Objectives: Diagnosing idiopathic short stature (ISS) in Traditional Chinese Medicine (TCM) remains challenging partly because the symptoms and syndrome patterns vary among ISS patients and studies. We aimed to use factor analysis of TCM symptoms to identify syndrome patterns associated with ISS in children on the basis of TCM theory. Materials and Methods: A cross-sectional study was conducted at Taipei Tzu Chi Hospital, New Taipei City, Taiwan, from October 1, 2014, to February 28, 2016. The study included 957 individuals who were newly diagnosed with ISS through simple random sampling. The outcome measures comprised 34 TCM symptoms related to children’s growth, and these symptoms were assessed using a five-level self-report questionnaire, which was completed by children and their parents. A factor analysis was conducted for the extraction of underlying factors. Results: A total of 26 symptoms had factor loadings higher than the exact threshold value (0.4), and five factors were extracted. Factor 1, comprising seven symptoms, was interpreted as “yin deficiency and fire hyperactivity of kidney syndrome.” Factor 2, which included eight symptoms, was interpreted as “phlegm dampness stagnation of spleen syndrome.” Factor 4, which included five symptoms, was interpreted as “liver qi invading the spleen syndrome.” Factor 5, which included four symptoms, was interpreted as “spleen-stomach weakness syndrome.” Factor 3, which included four symptoms, was uninterpretable. Factors 1–5 accounted for 10%, 9%, 8%, 7%, and 6% of the total variance. Conclusion: Four major TCM syndrome patterns, namely, “yin deficiency and fire hyperactivity of kidney syndrome,” “phlegm dampness stagnation of spleen syndrome,” “Liver qi invading the spleen syndrome,” and “spleen–stomach weakness syndrome” were identified and accounted for 40% of the total variance of the 34 TCM symptoms surveyed in children with ISS. Our findings may facilitate the diagnosis of ISS and the optimization of treatment strategies.

Therapeutic efficacy of recombinant human growth hormone in children with different etiologies of dwarfism from a pharmacoeconomic point of view.

Treatment outcomes for different causes of childhood dwarfism vary widely, and there are no studies on the economic burden of treatment in relation to outcomes. This paper compared the efficacy and healthcare costs per unit height of recombinant human growth hormone (rhGH) for the treatment of growth hormone deficiency (GHD) and idiopathic short stature (ISS) with a view to providing a more cost-effective treatment option for children. We retrospectively analyzed 117 cases (66 cases of GHD and 51 cases of ISS) of short-stature children who first visited Weifang People's Hospital between 2019.1 and 2022.1 and were treated with rhGH for 1 to 3 years to track the treatment effect and statistically analyzed by using paired t tests, non-parametric tests, and chi-square tests, to evaluate the efficacy of rhGH treatment for GHD and ISS children and the medicinal cost. The annual growth velocity (GV) of children with GHD and ISS increased the fastest during 3 to 6 months after treatment and then gradually slowed down. The GV of the GHD group was higher than that of the ISS group from 0 to 36 months after treatment (P < .05 at 3, 6, 9, and 12 months); the height standard deviation scores (HtSDS) of the children in the GHD and ISS groups increased gradually with the increase of the treatment time, and the changes in the height standard deviation scores (ΔHtSDS) of the GHD group were more significant than those of the ISS group (P < .05 at 3, 6, 9, and 12 months). (2) The medical costs in the pubertal group for a 1-cm increase in height were higher than those of children in the pre-pubertal group at the same stage (3 to 24 months P < .05). The longer the treatment time within the same group, the higher the medical cost of increasing 1cm height. RhGH is effective in treating children with dwarfism to promote height growth, and the effect on children with GHD is better than that of children with ISS; the earlier the treatment time, the lower the medical cost and the higher the comprehensive benefit.

Gut Microbiota Moderates Multimodal Brain Structure-Function Integration and Behavioral Cognition in Growth Hormone Deficient Children

Introduction: Previous brain studies of growth hormone deficiency (GHD) often used single-modal neuroimaging, missing the complexity captured by multimodal data. Growth hormone affects gut microbiota and metabolism in GHD. However, from a gut-brain axis (GBA) perspective, the relationship between abnormal GHD brain development and microbiota alterations remains unclear. The ultimate goal is to uncover the manifestations underlying GBA abnormalities in GHD and idiopathic short stature (ISS). Methods: Participants included 23 GHD and 25 ISS children. The fusion independent component analysis was applied to integrate multimodal brain data (high-resolution structural, diffusion tensor, and resting-state functional MRI) covering regional homogeneity (ReHo), amplitude of low frequency fluctuations (ALFF), and white matter fractional anisotropy (FA). Gut microbiome diversity and metabolites were analyzed using 16S sequencing and proton nuclear magnetic resonance (1H-NMR). Associations between multimodal neuroimaging and cognition were assessed using moderation analysis. Results: Six independent components (IC) of ReHo, ALFF, and FA differed significantly between GHD and ISS patients, with three functional components linked to the processing speed index. GHD individuals showed higher levels of acetate, nicotinate, and lysine in microbiota metabolism. Higher alpha diversity in GHD strengthened connections between ReHo-IC1, ReHo-IC5, ALFF-IC1, and the processing speed index, while increasing agathobacter levels in ISS weakened the link between ALFF-IC1 and the speech comprehension index. Conclusions: Our findings uncover differing brain structure and functional fusion in GHD, alongside microbiota metabolism of short-chain fatty acids. Additionally, microbiome influences connections between neuroimaging and cognition, offering insight into diverse GBA patterns in GHD and ISS, enhancing our understanding of the disease’s pathophysiology and interventions.

Children with idiopathic short stature have significantly different gut microbiota than their normal height siblings: a case-control study.

To investigate the role of gut microbiota (GM) in pathogenesis of idiopathic short stature (ISS) by comparing GM of ISS children to their normal-height siblings. This case-control study, conducted at the Schneider Children's Medical Center's Institute for Endocrinology and Diabetes between 4/2018-11/2020, involved 30 pairs of healthy pre-pubertal siblings aged 3-10 years, each comprising one sibling with ISS and one with normal height. Outcome measures from fecal analysis of both siblings included GM composition analyzed by 16S rRNA sequencing, fecal metabolomics, and monitoring the growth of germ-free (GF) mice after fecal transplantation. Fecal analysis of ISS children identified higher predicted levels of genes encoding enzymes for pyrimidine, purine, flavin, coenzyme B, and thiamine biosynthesis, lower levels of several amino acids, and a significantly higher prevalence of the phylum Euryarchaeota compared to their normal-height siblings (p<0.001). ISS children with higher levels of Methanobrevibacter, the dominant species in the archaeal gut community, were significantly shorter in stature than those with lower levels (p=0.022). Mice receiving fecal transplants from ISS children did not experience stunted growth, probably due to the eradication of Methanobrevibacter caused by exposure to oxygen during fecal collection. Our findings suggest that different characteristics in the GM may explain variations in linear growth. The varying levels of Methanobrevibacter demonstrated within the ISS group reflect the multifactorial nature of ISS and the potential ability of the GM to partially explain growth variations. The targeting of specific microbiota could provide personalized therapies to improve growth in children with ISS.

Effect of recombinant human growth hormone on serum Klotho and fibroblast growth factor 23 in children with idiopathic short stature

To investigate the changes in the serum levels of Klotho, fibroblast growth factor 23 (FGF23), and insulin-like growth factor-1 (IGF-1) in children with idiopathic short stature (ISS) before and after recombinant human growth hormone (rhGH) treatment, as well as the correlation of Klotho and FGF23 with the growth hormone (GH)/IGF-1 growth axis in these children. A prospective study was conducted on 33 children who were diagnosed with ISS in the Department of Pediatrics, Hebei Provincial People's Hospital, from March 10, 2021 to December 1, 2022 (ISS group). Twenty-nine healthy children, matched for age and sex, who attended the Department of Child Healthcare during the same period, were enrolled as the healthy control group. The children in the ISS group were treated with rhGH, and the serum levels of Klotho, FGF23, and IGF-1 were measured before treatment and after 3, 6, and 9 months of treatment. A correlation analysis was conducted on these indexes. There were no significant differences in the serum levels of IGF-1, Klotho, and FGF23 between the ISS and healthy control groups (P>0.05). The serum levels of Klotho, FGF23, and IGF-1 increased significantly in the ISS group after 3, 6, and 9 months of rhGH treatment (P<0.05). In the ISS group, Klotho and FGF23 levels were positively correlated with the phosphate level before treatment (P<0.05). Before treatment and after 3, 6, and 9 months of rhGH treatment, the Klotho level was positively correlated with the IGF-1 level (P<0.05), the FGF23 level was positively correlated with the IGF-1 level (P<0.05), and the Klotho level was positively correlated with the FGF23 level (P<0.05), while Klotho and FGF23 levels were not correlated with the height standard deviation of point (P>0.05). The rhGH treatment can upregulate the levels of Klotho, FGF23, and IGF-1 and realize the catch-up growth in children with ISS. Klotho and FGF23 may not directly promote the linear growth of children with ISS, but may have indirect effects through the pathways such as IGF-1 and phosphate metabolism. The consistent changes in Klotho, FGF23 and IGF-1 levels show that there is a synergistic relationship among them in regulating the linear growth of ISS children.

Levels and diagnostic values of serum visceral adipose tissue-derived serine protease inhibitor and secreted frizzle-related protein 5 in children with idiopathic short stature

Abstract Background: Idiopathic short stature (ISS) is a common type of short stature. We aimed to analyze the diagnostic values of serum visceral adipose tissue-derived serine protease inhibitor (Vaspin) and secreted frizzle-related protein 5 (SFRP5) for ISS children. Methods: Sixty-five ISS children treated from February 2019 to June 2022 were selected as an ISS group, while another 65 healthy children receiving physical examination in the same period were selected as a healthy group. Their general data, physical development status, levels of serum Vaspin and SFRP5, and levels of serum growth hormone-releasing hormone (GHRH)/growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis-related indicators were compared. Results: The ISS group had lower body height, body weight, bone age, growth velocity and serum SFRP5 level and higher serum Vaspin level than those of the healthy group (P&lt;0.05). The levels of serum GHRH, GH and IGF-1 were lower in the ISS group than those in the healthy group (P&lt;0.05). Body height, body weight, bone age, growth velocity, and levels of GHRH, GH and IGF-1 were negatively correlated with serum Vaspin level (r&lt;0, P&lt;0.05) but positively correlated with serum SFRP5 level (r&gt;0, P&lt;0.05). The areas under the ROC curves of serum Vaspin and SFRP5 and their combination for the diagnosis of ISS were 0.871 [95% confidence interval (CI): 0.812-0.929], 0.880 (95% CI: 0.824-0.935) and 0.942 (95% CI: 0.907-0.977), respectively. Conclusions: Children with ISS have a higher level of serum Vaspin but a lower level of SFRP5, and the combined detection has a higher diagnostic value for ISS.

Plasma exosome miRNA-26b-3p derived from idiopathic short stature impairs longitudinal bone growth via the AKAP2/ERK1/2 axis

BackgroundCurrently, the etiology of idiopathic short stature (ISS) is still unclear. The poor understanding of the molecular mechanisms of ISS has largely restricted this strategy towards safe and effective clinical therapies.MethodsThe plasma exosomes of ISS children were co-cultured with normal human chondrocytes. The differential expression of exosome miRNA between ISS and normal children was identified via high-throughput microRNA sequencing and bioinformatics analysis. Immunohistochemistry, In situ hybridization, RT-qPCR, western blotting, luciferase expression, and gene overexpression and knockdown were performed to reveal the key signaling pathways that exosome miRNA of aberrant expression in ISS children impairs longitudinal bone growth.ResultsChondrocytes proliferation and endochondral ossification were suppressed after coculture of ISS plasma exosomes with human normal chondrocytes. High-throughput microRNA sequencing and RT-qPCR confirmed that plasma exosome miR-26b-3p was upregulated in ISS children. Meanwhile, exosome miRNA-26b-3p showed a high specificity and sensitivity in discriminating ISS from normal children. The rescue experiment showed that downregulation of miR-26b-3p obviously improved the repression of chondrocyte proliferation and endochondral ossification caused by ISS exosomes. Subsequently, miR-26b-3p overexpression inhibited chondrocyte proliferation and endochondral ossification once again. In situ hybridization confirmed the colocalization of miR-26b-3p with AKAP2 in chondrocytes. In vitro and in vivo assay revealed exosome miRNA-26b-3p impairs longitudinal bone growth via the AKAP2 /ERK1/2 axis.ConclusionsThis study is the first to confirm that miR-26b-3p overexpression in ISS plasma exosomes leads to disorders in proliferation and endochondral ossification of growth plate cartilage via inhibition of AKAP2/ERK1/2 axis, thereby inducing ISS. This study provides a new research direction for the etiology and pathology of ISS and a new idea for the biological treatment of ISS.Graphical

Hsa_circ_0008870 suppresses bone formation of growth plate through inhibition of miR-185-3p/ MAPK1 axis in idiopathic short stature.

Idiopathic short stature (ISS) is the most common clinical cause of the short stature with an unclear aetiology and a lack of effective treatment. Circular RNAs have been shown to play a significant regulatory role through various signal transduction pathways in a variety of diseases in recent years. However, the role of circular RNAs on ISS is not yet well-understood and requires a special attention. The differentially expressed circular RNAs were screened by microarray chip analysis, and RT-qPCR was used to verify the expression of hsa_circ_0008870 in ISS patients. Subsequently, in vitro and in vivo experiments were conducted to determine the biological functions of hsa_circ_0008870 in ISS. The authors first confirmed that hsa_ circ_0008870 was downregulated in ISS children. Meanwhile, we also observed that the downregulated hsa_circ _0008870 significantly inhibited chondrocyte proliferation and endochondral ossification in vivo and in vitro. Mechanistically, hsa_circ_0008870 regulates MAPK1 expression by sponge miR-185-3p. This mechanism of action was further verified through rescue experiments. Finally, the authors revealed that the silencing of hsa_circ_0008870 induces low expression of MAPK1 by impairing the sponge action of miR-185-3p, thereby inhibiting chondrocyte proliferation, hypertrophy, and endochondral ossification, which results in a short stature phenotype. In addition to these, we also observed an interesting phenomenon that upregulated of miR-185-3p can in turn inhibit the expression of hsa_circ_0008870 in chondrocytes. This suggests that hsa_circ_0008870 could potentially serve as a therapeutic target for the treatment of ISS.

Comparative effectiveness of East Asian traditional medicine for treatment of idiopathic short stature in children: systematic review and network meta-analysis

Brief Summary: This systematic review found that East Asian traditional medicine (EATM) therapies may have beneficial effects in children with idiopathic short stature, however, high-quality studies are necessary.

Skeletal and dental age discrepancy and occlusal traits in children with growth hormone deficiency and idiopathic short stature.

The aim of the study was to evaluate the dental and bone age delay and occlusal traits of children with growth hormone deficiency (GHD) and idiopathic short stature (ISS). The study group included 46 patients aged 5 to 14years: 15with ISS, 17 with GHD before growth hormone treatment, and 14 with GHD during substitution therapy. The control group consisted of 46 age and sex-matched subjects of normal height. A calibrated dentist assessed all subjects in terms of dental age and occlusal characteristics. Bone age was evaluated only in GHD and ISS children as a part of a hospital's diagnostic protocol. The subgroup of GHD before treatment differed significantly concerning dental age delay from their healthy peers (- 0.34 and 0.83year, respectively, p = 0.039). Dental age delay in short stature children was less marked than bone agedelay (- 0.12 and - 1.76, respectively, p < 0.00001). Dental crowding was recorded in 57% of ISS patients and 53% of GHD children before treatment compared to only 22% of the control subjects (p = 0.027 and p = 0.021, respectively). Dental age was retarded in GHD children before growth hormone (GH) therapy, but the delay does not seem clinically significant. ISS children and GHD children before therapy showed marked bone age delay and tendency to crowding. The different pace of teeth eruption and skeletal growth in short stature children should be considered when planning their dental treatment.

LCN2 is a new diagnostic biomarker and potential therapeutic target in idiopathic short stature.

Idiopathic short stature (ISS) is the most common paediatric endocrine disease. However, the underlying pathology of ISS remains unclear. Currently, there are no effective diagnostic markers or therapeutic strategies available for ISS. In this study, we aimed to identify differential plasma protein expression and novel biomarkers in patients with ISS, and elucidate the biological functions of candidate proteins in ISS pathogenesis. Four specimen pairs from four ISS children and age‐/sex‐matched control individuals were subjected to proteomics analysis, and 340 samples of children with a mean age 9.73 ± 0.24 years were utilized to further verify the differentially expressed proteins by enzyme‐linked immunosorbent assay (ELISA). The receiver‐operating characteristic (ROC) curve and the area under the ROC curve (AUC) were plotted. A total of 2040 proteins were identified, of which 84 were differentially expressed. In vitro and in vivo experiments confirmed the biological functions of these candidate proteins. LCN2 overexpression in ISS was verified using ELISA. Meanwhile, LCN2 showed high sensitivity and specificity in discriminating children with ISS from those with growth hormone deficiency, precocious puberty and normal control individuals. The upregulated expression of LCN2 not only suppressed food intake but also impaired chondrocyte proliferation and bone growth in chondrocytes and rats. As a result, the rats presented a short‐stature phenotype. Subsequently, we found that bone growth inhibition recovered after LCN2 overexpression was stopped in immature rats. To our knowledge, this is the first study to report that LCN2 may be a significant target for ISS diagnosis and treatment.

Therapeutic potential of a combination of recombinant human growth hormone (r-hGH) and vitamin D in children with idiopathic short stature

Purpose: To study the effectiveness and clinical significance of recombinant human growth hormone (rhGH) in combination with vitamin D in the treatment of idiopathic short-stature children.Methods: A total of 90 idiopathic short-stature children admitted at Children Health Care Center of Shiyan Maternal and Child Health Care Hospital, Shiyan between March 2017 and March 2020 were assigned to three groups: A, B and C, based on dose of r-hGH given. Group A received r-hGH at a dose of 0.26 mg/kg/week, while groups B and C received r-hGH at doses of 0.35 and 0.42mg/kg/week, respectively. All the patients were given vitamin D along with the r-hGH doses administered. Height, growth rate, bone age, height standard deviation score, fasting blood glucose, thyroid function and treatment effectiveness were determined and compared among the three groups before treatment, and one year after treatment.Results: Significantly higher height standard deviation score, growth rate, bone age, and height were observed in the three groups of patients after one year of treatment than before treatment, with group A &lt; group B &lt; group C (p &lt; 0.05). Fasting blood glucose and thyroid function were not significantly different amongst the three groups after treatment (p &lt; 0.05). Group C showed the highest treatment effectiveness, followed by group B, and then group A (p &lt; 0.05).Conclusion: The use of a combination of r-hGH and vitamin D produces a favorable treatment effectiveness in idiopathic short-stature children. However, further clinical trials are required to validate this treatment strategy.

A meta-analysis of combination therapy with gonadotrophin-releasing hormone agonist and growth hormone for children with idiopathic short stature and normal timed puberty.

The aim of this meta-analysis is to evaluate whether the combination therapy with gonadotrophin-releasing hormone agonist (GnRHa) and recombinant human growth hormone (rhGH) are effective in the treatment of children with idiopathic short stature (ISS) and normal timed puberty by interrogating data from clinical controlled trials. Literature retrieval, trail selection, data abstraction and quality assessment were completed independently by two authors. STATA software (version 14.1) was used for data analyses. This meta-analysis was conducted based on 8 (4 randomized and 4 non-randomized) controlled trials. A total of 245 ISS children with normal timed puberty were financially analyzed. Overall, combination therapy with GnRHa and rhGH can slightly increase final height by 3.70 and 3.43 cm compared with GH treatment alone and no treatment, final height standard deviation score (FHSDS) by 0.10 and 0.22, final height minus predicted adult height (FH-PAH) by 1.5 and 5.32 cm, final height minus predicted adult height (FH-TH) by 7.70 and 4.32 cm, respectively. Subgroup and meta-regression analyses revealed that study type, sample size, GnRHa duration, and percentage of boys were potential sources of between-trial heterogeneity. There was a low probability of publication bias for above comparisons, as indicated by Egger's tests. Our meta-analytical findings indicate that the combination therapy with GnRHa and rhGH can slightly increase the final height of ISS children with normal timed puberty, and the effect was not more obvious than GH alone. We do not recommend the combination therapy as a routine treatment for ISS. CRD42019133438.

Response to growth hormone according to provocation test results in idiopathic short stature and idiopathic growth hormone deficiency.

Purpose To investigate growth response in children with either idiopathic short stature (ISS) or growth hormone (GH) deficiency (GHD).Methods The data of prepubertal GHD or ISS children treated using recombinant human GH were obtained from the LG Growth Study database. GHD children were further divided into partial and complete GHD groups. Growth response and factors predicting growth response after 1 and 2 years of GH treatment were investigated.Results This study included 692 children (98 with ISS, 443 partial GHD, and 151 complete GHD). After 1 year, changes in height standard deviation score (ΔHt-SDS) were 0.78, 0.83, and 0.96 in ISS, partial GHD, and complete GHD, respectively. Height velocity (HV) was 8.72, 9.04, and 9.52 cm/yr in ISS, partial GHD, and complete GHD, respectively. ΔHt-SDS and HV did not differ among the 3 groups. Higher initial body mass index standard deviation score (BMI-SDS) and midparental height standard deviation score (MPH-SDS) were predictors for better growth response after 1 year in ISS and the partial GHD group, respectively. In the complete GHD group, higher Ht-SDS and BMI-SDS predicted better growth response after 1 year. After 2 years of GH treatment, higher BMI-SDS and MPH-SDS predicted a better growth outcome in the partial GHD group, and higher MPH-SDS was a predictor of good growth response in complete GHD.Conclusions Clinical characteristics and growth response did not differ among groups. Predictors of growth response differed among the 3 groups, and even in the same group, a higher GH dose would be required when poor response is predicted.

POSC303 Comparative Effectiveness of Integrative Medicine for Treatment of Idiopathic Short Stature in Children: A Systematic Review and Network Meta-Analysis

Idiopathic short stature (ISS) is a common problem in children and causes many economic and social burdens. These days, integrative medicine therapies are widely used for children with ISS. In this study, we compared and ranked various integrative therapies for the treatment of pediatric ISS using network meta-analysis (NMA).

Analysis of the Influence of High-Dose rhGH Therapy on Serum Vitamin D and IGF-1 Levels in School-Age Children with Idiopathic Short Stature.

Objective To discuss the influence of high-dose recombinant human growth hormone (rhGH) therapy on serum vitamin D and insulin-like growth factor-1 (IGF-1) levels in school-age children with idiopathic short stature (ISS). Method A total of 103 school-age children with ISS were selected from June 2016 to June 2020 in our hospital. The enrolled cases were divided into the low-dose group (n = 59) and high-dose group (n = 44) according to the treatment dose of rhGH. After the treatment, the height (Ht), height standard deviation score (Ht SDS), growth velocity (GV), and other indicators were recorded. The serum 25-hydroxy vitamin D [25-(OH)D] and IGF-1 levels of the two groups were tested, and the occurrence of adverse reactions was recorded. Results After treatment, the high-dose group outperformed the low-dose group in various growth effect indicators such as Ht, Ht SDS, and GV (P < 0.05). After treatment, the serum 25-(OH)D of children with ISS in the two groups increased significantly, but there was no significant difference between the two groups (P > 0.05). After treatment, the serum IGF-1 of children with ISS in the two groups increased significantly, but there was no significant difference between the two groups (P > 0.05). For children with ISS, adverse reactions induced by rhGH therapy were very rare. There was no significant difference in the incidence of adverse reactions induced by different doses of rhGH in the treatment of ISS (P > 0.05). Conclusion rhGH has definite efficacy in the treatment of ISS children, for it can significantly increase the annual growth rate of ISS children in a dose-dependent manner. High-dose rhGH for ISS has a better therapeutic effect. At the same time, regardless of the dose level of rhGH, serum 25-(OH)D and IGF-1 levels in children with ISS were increased, with less adverse reactions and higher safety.

A Novel Diagnostic Predictive Model for Idiopathic Short Stature in Children.

ObjectiveIdiopathic short stature (ISS), an endocrine-related disease, is difficult to diagnose. Previous studies have shown that many children with some inflammation-related diseases often have short stature, but whether inflammation is the underlying mechanism of ISS has not been studied. Here, we attempt to explore the role of inflammation in the occurrence and development of ISS and to demonstrate an available clinical diagnostic model of ISS.MethodsFrozen serum samples were collected from ISS patients (n = 4) and control individuals (n = 4). Isobaric tags for relative and absolute quantitation (iTRAQ) combined with LC-MS/MS analysis were applied to quantitative proteomics analysis. To assess clusters of potentially interacting proteins, functional enrichment (GO and KEGG) and protein-protein interaction network analyses were performed, and the crucial proteins were detected by Molecular Complex Detection (MCODE). Furthermore, serum levels of two selected proteins were measured by ELISA between ISS patients (n = 80) and controls (n = 80). In addition, experiments in vitro were used to further explore the effects of crucial proteins on endochondral ossification.ResultsA total of 437 proteins were quantified, and 84 DEPs (60 upregulated and 24 downregulated) were identified between patients with ISS and controls. Functional enrichment analysis showed that the DEPs were primarily enriched in blood microparticle, acute inflammatory response, protein activation cascade, collagen-containing extracellular matrix, platelet degranulation, etc. According to the results of top 10 fold change DEPs and MCODE analysis, C1QA and C1QB were selected to further experiment. The expression levels of C1QA and C1QB were validated in serum samples. Based on the logistic regression analysis and ROC curve analysis, we constructed a novel diagnostic model by serum levels of C1QA and C1QB with a specificity of 91.2% and a sensitivity of 75% (AUC = 0.900, p <0.001). Finally, the western blotting analysis confirmed the expression levels of OCN, OPN, RUNX2, and Collagen X were downregulated in chondrocytes, and the outcome of Collagen II was upregulated.ConclusionOur study is the first to demonstrate the significant role of inflammation in the development of ISS. In addition, we identify C1QA and C1QB as novel serum biomarkers for the diagnosis of ISS.

Correlation of body mass index to Ghrelin and IGF-1 among children with short stature

ObjectiveTo assess the BMI among children with Growth Hormone Deficiency (GHD) and Idiopathic Short Stature (ISS) and its correlation to ghrelin, Growth Hormone (GH), and Insulin-like Growth Factor-1 (IGF-1) levels. MethodsA cross-sectional descriptive study in which 42 patients attending the Pediatric endocrine clinic were enrolled, allocated into two groups: group I: GHD children; group II: ISS children. Ghrelin, IGF-1 and GH in both groups were measured. ResultsGhrelin was significantly higher among GHD group (p < 0.001). Overall, there was a strong negative correlation between IGF-1 and ghrelin (r = -0.977, p-value = < 0.001) while a moderate positive correlation between ghrelin and BMI (r = 0.419, p-value = 0.006). There was a weak positive non-significant correlation between IGF-1 and BMI (r = 0.276, p-value = 0.077). In GHD group, there was a weak positive non-significant correlation between ghrelin and GHmax measurement (r = 0.052, p-value = 0.824), while a weak negative non-significant correlation between both variables in ISS group (r = -0.243, p-value = 0.288). In GHD group, there was a moderate positive correlation between ghrelin and BMI (r = 0.500, p-value = 0.021), but weak negative non-significant correlation between both variables in ISS group (r = -0.255, p-value = 0.265). ConclusionThere was a negative feedback loop between ghrelin and IGF-1, whereas a positive feedback between ghrelin and BMI. BMI was more affected in the ISS group but was non-significantly correlated with ghrelin. There was no significant compensatory response of ghrelin suggesting its contribution to the pathogenesis of ISS.

Development of a predictive model of growth hormone deficiency and idiopathic short stature in children.

The aim of the present study was to develop predictive models using clinical features and MRI texture features for distinguishing between growth hormone deficiency (GHD) and idiopathic short stature (ISS) in children with short stature. This retrospective study included 362 children with short stature from Children's Hospital of Hebei Province. GHD and ISS were identified via the GH stimulation test using arginine. Overall, there were 190 children with GHD and 172 with ISS. A total of 57 MRI texture features were extracted from the pituitary gland region of interest using C++ language and Matlab software. In addition, the laboratory examination data were collected. Receiver operating characteristic (ROC) regression curves were generated for the predictive performance of clinical features and MRI texture features. Logistic regression models based on clinical and texture features were established for discriminating children with GHD and ISS. Two clinical features [IGF-1 (insulin growth factor-1) and IGFBP-3 (IGF binding protein-3) levels] were used to build the clinical predictive model, whereas the three best MRI textures were used to establish the MRI texture predictive model. The ROC analysis of the two models revealed predictive performance for distinguishing GHD from ISS. The accuracy of predicting ISS from GHD was 64.5% in ROC analysis [area under the curve (AUC), 0.607; sensitivity, 57.6%; specificity, 72.1%] of the clinical model. The accuracy of predicting ISS from GHD was 80.4% in ROC analysis (AUC, 0.852; sensitivity, 93.6%; specificity, 65.8%) of the MRI texture predictive model. In conclusion, these findings indicated that a texture predictive model using MRI texture features was superior for distinguishing children with GHD from those with ISS compared with the model developed using clinical features.

Comparative effectiveness of East Asian traditional medicine for treatment of idiopathic short stature in children: A protocol for systematic review and network meta-analysis.

Background:There are many East Asian traditional medicine (EATM) therapies that are widely used and effective for idiopathic short stature (ISS) in children. However, the comparative effectiveness of these therapies remains unclear. We describe the methods that will be used to comparatively evaluate the efficacy and safety of EATM therapies for the treatment of pediatric ISS.Methods and analysis:Fourteen electronic English, Korean, Chinese, and Japanese databases will be searched up to August 2020 for relevant randomized controlled trials of various EATMs for the treatment of pediatric ISS, without language or publication status restrictions. The primary outcome will be growth-related anthropometric indicators, and acceptability, measured through drop-outs that occur during treatment for any reason. We will conduct a pairwise meta-analysis for direct comparisons if multiple studies use the same types of intervention, comparison, and outcome measure. A frequentist network meta-analysis will be performed to summarize the available direct and indirect evidence regarding various EATM options for pediatric ISS. The risk of bias for the included studies will be evaluated using the Cochrane Collaboration's risk of bias tool.Conclusions:The findings of this review will provide evidence for the comparative effectiveness and ranks of current EATMs and help to inform clinical practitioners, patients, and policy makers in decision making.Ethics and dissemination:Ethical approval is not required because individual patient data are not included. The findings of this systematic review will be disseminated through a peer-reviewed publication or conference presentations.Protocol registration number:OSF (URL: https://osf.io/s4vp7), PROSPERO CRD42020187160