Prediction model of therapeutic effect on children with idiopathic short stature based on vitamin K2,IGFBP-3 and Omentin-1 / 国际检验医学杂志

Objective To investigate the relationship between vitamin K2,insulin-like growth factor bind-ing protein 3(IGFBP-3),Omentin-1 and the therapeutic effect on children with idiopathic short stature(ISS),and to build a prediction model.Methods A total of 242 ISS children in Jinan Second Maternal and Child Health Hospital from 2019 to 2021 were selected.All of them received recombinant human growth hormone(rhGH)treatment and were divided into effective group and ineffective group according to the therapeutic effect after 12 months of treatment.The general data,vitamin K2,IGFBP-3 and Omentin-1 in the two groups were analyzed.The influencing factors of ISS children's therapeutic effect were analyzed by Logistic regression model and decision tree model.The predictive performance of two models was analyzed by using receiver oper-ating characteristic(ROC)curve.Results There were statistically significant differences in 25-hydroxy vita-min D[25(OH)D],parathyroid hormone(PTH),thyroid stimulating hormone(TSH),vitamin K2,IGFBP-3,Omentin-1,rhGH dosage and weekly outdoor exercise time between the two groups(P＜0.05).Logistic re-gression showed that PTH(OR=7.011,95％CI:2.456-20.014),vitamin K2(OR=0.605,95％CI:.0.465-0.788),IGFBP-3(OR=0.458,95％CI:0.321-0.654),Omentin-1(OR=0.514,95％CI:0.389-0.679)and rhGH dose(OR=0.563,95％CI:0.445-0.712)]were the influential factors for treatment ineffectiveness in ISS children(P＜0.05).The decision tree model showed that vitamin K2,IGFBP-3 and Omentin-1 were the factors influencing the therapeutic effect of ISS,and IGFBP-3 had the most significant impact.ROC curve re-sults showed that the area under the curve of decision tree model and Logistic regression model were 0.922 and 0.908,respectively,with good classification effect.Conclusion The therapeutic effect of ISS children is in-fluenced by factors such as vitamin K2,IGFBP-3,Omentin-1,and so on,and IGFBP-3 has the most significant impact.Logistic regression model and decision tree model could complement each other so as to provide refer-ence for improving the therapeutic effect of ISS children from different aspects.

Expression of Serum Vaspin and SFRP5 in Children with Idiopathic Nanosomia and Their Diagnostic Value / 现代检验医学杂志

Objective To explore the expression level of visceral adipose tissue-derived serine protease inhibitor(Vaspin)and secreted frizzled-related protein5(SFRP5)in the serum of children with idiopathic short stature(ISS)and its diagnostic value.Methods 70 children with ISS diagnosed in the First Hospital of Zhangjiakou from December 2021 to February 2023 were selected as the disease group,while 72 healthy volunteer children who underwent physical examination were collected as the control group.Immunoluminescence was applied to detect the expression level of VASPIN,Enzyme-linked immunosorbent assay(ELISA)was applied to detect the expression level of SFRP5 the clinical data of children in two groups were analyzed.Receiver operating characteristic(ROC)curve was applied to analyze the diagnostic value of serum Vaspin and SFRP5 for ISS,multivariate Logistic regression was used to analyze the influencing factors of ISS.Results Compared with the control group,the serum Vaspin level in the disease group was obviously increased(2.89±0.92 ng/ml vs 1.81±0.42 ng/ml),while the SFRP5 level was obviously reduced(10.22±2.84 pg/ml vs 13.21±3.53 pg/ml),the differences were statistically significant(t=9.040,5.552,all P＜0.05).The weight,height,body mass index(BMI)and proportion of sexual development stage II～V of children in the disease group were obviously lower than those in the control group,and the differences were statistically significant(t=7.687,6.330,5.559,7.024,all P＜0.05).The area under ROC curve showed that the AUC of Vaspin and SFRP5 and their combined detection in the diagnosis of ISS were 0.768,0.849 and 0.925,respectively,the combined diagnosis efficacy of Vaspin and SFRP5 was better than that of serum Vaspin and SFRP5 alone(Z =3.829,P＜0.001;Z =2.141,P=0.032).Multivariate Logistic regression analysis showed that BMI(OR=0.508,95%CI:0.260～0.991),Vaspin(OR=3.458,95%CI:1.125～10.631)and SFRP5(OR=0.378,95%CI:0.153～0.935)were the influencing factors for ISS(all P＜0.05).Conclusion The expression level of Vaspin in the serum of children with ISS is obviously increased,while the expression level of SFRP5 is obviously reduced.The two are influencing factors of ISS,and the combined detection of their expression levels has certain value in the diagnosis of ISS.

The mechanism of miR-10b targeting TGFBR1/SMAD3 pathway on chondrocyte proliferation and hypertrophy in idiopathic short stature / 天津医药

Objective To investigate the effect and mechanism of microRNA-10b(miR-10b)on idiopathic short stature(ISS).Methods A total of 54 children with ISS and 54 healthy children were collected.The serum expression of miR-10b was detected by RT-qPCR,and the relationship between serum miR-10b expression and clinical data of children with ISS was analyzed.miR-10b inhibitor,si-TGFBR1 and their negative control transfection C28/I2 cells were used.CCK-8 experimental detection was used to detect C28/I2 cell proliferation.Western blot assay was used to detect gnome related transcription factor 2(RUNX2),collagen type X alpha 1 chain(COL10A1),transforming growth factor beta receptor 1(TGFBR1),SMAD3 and pSMAD3 protein expression.The target of miR-10b was screened in StarBase database,and the targeting relationship between miR-10b and TGFBR1 was verified by dual luciferase reporter gene assay.Results The serum expression of miR-10b was higher in the ISS group than that of the healthy control group,and the higher the miR-10b expression,the more obvious the decrease of child height,IGF-1 and alkaline phosphatase(P＜0.05).Compared with the NC group,the cell proliferation ability and RUNX2,COL10A1,TGFBR1,and pSMAD3 protein expression were up-regulated in the miR-10b inhibitor group(P＜0.05).StarBase database suggested that miR-10b had a binding site of TGFBR1,and dual luciferase reporter gene assay confirmed that TGFBR1 interacted with miR-10b(P＜0.05).Compared with the si-NC group,the expression of TGFBR1 was down-regulated and the cell proliferation ability was decreased in the si-TGFBR1 group(P＜0.05).Conclusion miR-10b inhibits chondrocyte proliferation and hypertrophy in idiopathic short stature by targeting TGFBR1/SMAD3 pathway.

Advances in biomarkers related to multi-omics of idiopathic short stature / 国际儿科学杂志

Idiopathic short stature(ISS)is a group of short stature with unclear etiology and pathogenesis, of which the cause is heterogeneous and complex, primarily due to a combination of genetic and environmental factors.ISS is generally exclusionary diagnosis due to the lack of specific symptoms, signs and biomarkers.Recently, with the development of various high-throughput detection technologies, the study of transcriptomics, proteomics, metabolomics, and microbiomics related to ISS has gradually become a hot topic, providing new ideas for elucidating the etiology, making an early diagnosis, and guiding treatment of ISS.In this paper, advances in the pathogenesis and early diagnosis of ISS by biomarkers associated with multi-omics are reviewed.

Relationship between serum BMP9 and SMAD3 expression and growth and bone age in children with idiopathic short stature / 国际检验医学杂志

Objective To investigate the relationship between serum levels of bone morphogenetic protein(BMP)9,Drosophila mother anti-cerebral palsy protein(SMAD)3 and growth and bone age in children with idiopathic short stature(ISS).Methods A total of 110 children with ISS admitted to the Qingdao Eighth Peo-ple's Hospital from September 2020 to September 2022 were selected as the ISS group,and 110 healthy chil-dren who underwent physical examination in the hospital during the same period were selected as the control group.The serum BMP9 and SMAD3 levels were compared between the two groups.Pearson correlation analysis was used to analyze the correlation between BMP9,SMAD3 and sexual development status,height,weight,body mass index(BMI),osteocalcin(Ost),Leptin,bone age index(BAI),bone age difference(BAD)in children with ISS.Re-ceiver operating characteristic(ROC)curve was used to analyze the diagnostic value of BMP9 and SMAD3 in ISS.Multivariate Logistic regression was used to analyze the risk factors of ISS.Results Compared with the control group,the level of BMP9 was significantly increased and the level of SMAD3 was significantly de-creased in the ISS group(P<0.05).There were significant differences in sexual development status,BMI,BAI,BAD,Ost and Leptin levels between the control group and ISS group(P<0.05).Correlation analysis showed that the serum level of BMP9 was negatively correlated with SMAD3,sexual development status,height,weight,BMI,Ost,Leptin,BAI,and BAD in children with ISS(r=-0.497,-0.523,-0.447,-0.486,-0.501,-0.465,-0.502,-0.434,-0.520,P<0.05).Serum SMAD3 level was positively corre-lated with sexual development status,height,weight,BMI,Ost,Leptin,BAI,and BAD(r=0.432,0.458,0.431,0.465,0.503,0.467,0.515,0.527,P<0.05).ROC curve analysis showed that BMP9,SMAD3 joint in-spection ISS area under curve was higher than the two separate detection(Z=2.774,2.958,P<0.05).Multi-variate Logistic regression analysis showed that serum BMP9 level was an independent risk factor for ISS,and SMAD3 level was an independent protective factor(P<0.05).Conclusion The serum level of BMP93 is in-creased and SMAD3 is decreased in children with ISS,and they are closely related to the growth and bone age of children with ISS,which can be used as molecular markers to evaluate the condition of children with ISS.

Efficacy and safety of polyethylene glycol-recombinant human growth hormone in the treatment of growth hormone deficiency and idiopathic dwarf disease / 中华全科医师杂志

Objective:To investigate the efficacy and safety of polyethylene glycol-recombinant human growth hormone (PEG-rhGH) in the treatment of preadolescent growth hormone deficiency (GHD) and idiopathic short stature (ISS).Methods:Clinical data of children with preadolescent GHD or ISS diagnosed in Chengdu Women and Children′s Central Hospital from January 2014 to October 2022 were retrospectively analyzed. Among them, 36 children with GHD received (0.19±0.02) mg·kg -1·week -1 PEG-rhGH for treatment; and 21 children with ISS received (0.20±0.01) mg·kg -1·week -1 PEG-rhGH. The changes of height, weight, bone age, insulin-like growth factor-1 (IGF-1), thyroid function, fasting blood glucose and fasting insulin were observed in the two groups during treatment. Results:The height of children in GHD group was (107.56±8.38)cm and (111.68±7.94)cm 6 and 12 months after treatment, which was significantly higher than that before treatment ((101.62±8.83) cm, P<0.05). The height of children in ISS group was (108.69±12.59)cm and (114.66±11.47)cm 6 and 12 months after treatment, which was significantly higher than that before treatment ((103.40±12.66) cm, P<0.05). The height of the two groups was increased the most during 0-3 months of treatment ((3.15±0.99) cm and (2.91±0.73) cm, respectively). After 12 months of treatment, body mass index and IGF-1 were significantly higher than those before treatment ( P<0.05), and bone age and maturity were not significantly different ( P>0.05). In the GHD group, growth rate was negatively correlated with actual age, bone age, height, weight, IGF-1 and fasting insulin before treatment. In the ISS group, growth rate was negatively correlated with pre-treatment height standard deviation score (HtSDS). During treatment, hypothyroidism occurred in 2 cases (1 case in GHD group and 1 case in ISS group), and serum IGF-1 level increased in 9 cases (6 cases in GHD group and 3 cases in ISS group), there was no severe adverse reactions. Conclusion:PEG-rhGH treatment has good efficacy in treatment of GHD and ISS, and the children with GHD may have better curative effect than those with ISS. The children in both groups have the fastest growth rate within 3 months after treatment. Short-term use of PEG-rhGH does not increase the body mass index and promote bone maturity, and has no significant effect on the level of thyroid function, blood sugar and insulin, and has no serious adverse reactions.

Effect of recombinant human growth hormone on serum Klotho and fibroblast growth factor 23 in children with idiopathic short stature / 中国当代儿科杂志

OBJECTIVES@#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.@*METHODS@#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.@*RESULTS@#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).@*CONCLUSIONS@#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.

PTPN11 gene mutation mediated Noonan syndrome in children with idiopathic short stature / 中华内分泌代谢杂志

Objective:To analyze the genetic etiology of idiopathic short stature(ISS) children, and to investigate the clinical characteristics of Noonan syndrome caused by PTPN11 gene mutation, and the response to recombinant human growth hormone(rhGH) as well.Methods:Genomic DNA was extracted from the peripheral blood of 232 ISS patients, and the genome was detected by whole exon sequencing. The gene variation was analyzed according to the guideline of American College of Medical Genetics and Genomics(ACMG), and clinical baseline data and follow-up data of rhGH treatment were collected from PTPN11 gene pathogenic patients.Results:Among 232 ISS patients, 6 were found to have PTPN11 pathogenic gene variants(c.1507G>C, c. 317A>G, c. 923A>G, c. 922A>G, c. 236A>G, c. 922A>G), diagnosed as Noonan syndrome. Together with 3 cases of Noonan syndrome patients(all PTPN11 gene variation C. 1510A>G) previously diagnosed in our hospital, the clinical characteristics of patients were analyzed. Among the 9 Noonan syndrome patients, 7 were boys and 2 were girls. The average age was 10.2(4.5, 14.7) years old, and their height standard deviation score was -3.06 SD(95% CI -2.29 SD--3.94 SD). Among them, 4 patients received rhGH treatment with an average treatment duration of 2.25(1.5, 3.5) years. After treatment, their height increased by 14.3(8.6, 23.9) cm, and the change in height standard deviation score improved by 0.21 SD(95% CI 0.12 SD-0.27 SD). Conclusion:Noonan syndrome has a wide range of clinical phenotypes. For children with short stature, heart defects and cryptorchidism, the possibility of Noonan syndrome should be considered. PTPN11 is the common pathogenic gene for Noonan syndrome, and genetic testing facilitates the early diagnosis, treatment, and follow-up prognosis of Noonan syndrome patients.

Therapeutic effect of children's growth patch combined with recombinant human growth hormone in treatment of idiopathic short stature / 中国现代医生

Objective To investigate the therapeutic effect of children's growth patch combined with recombinant human growth hormone on idiopathic short stature. Methods A retrospective analysis of 45 children patients with idiopathic short stature from February 2016 to February 2017 was carried out, according to the treatment method, they were divided into the control group, the observation group 1 and the observation group 2, with 15 cases in each group. The control group was those who rejected all medications. The observation group 1 was those who were given children's growth patch; the observation group 2 was those who were given growth patch combined with recombinant human growth hormone therapy. The treatment lasted for 12 months. The height growth, genetic height, and predicted adult height were compared. Results The control group, the observation group 1 and the observation group 2 were compared, and the height growth values were (3.87±1.25) cm, (7.93±1.53) cm, and (10.20±1.97) cm, respectively, and the difference was significant (F=59.48, P<0.01); the genetic heights were (156.80±4.94) cm, (156.07±3.97) cm, (156.13±4.58) cm, respectively, and the difference was not significant (F=0.12, P>0.05); the predicted adult heights were (155.73±3.31) cm, (164.80±5.24) cm, and (167.87±5.68) cm, respectively, and the difference was significant (F=25.35, P<0.01). Conclusion Children's growth patch combined with recombinant human growth hormone in the treatment of idiopathic short stature can significantly increase the height growth value and increase the predicted value of adult height.

Sensitivity of supplementation of thyroid hormone on treatment of idiopathic short-stature children during therapy with recombinant human growth hormone / 医学前沿

This study aimed to evaluate the effects of thyroid hormone supplementation on growth rate of children with idiopathic short stature (ISS) and low-normal serum free thyroxine FT4 who were receiving growth hormone therapy. We selected 64 prepubertal children with FT4 levels in the lowest third of the normal range as the lower FT4 group, and these children were divided randomly into two subgroups: L-thyroxine (L-T4)-treated subgroup was treated with L-T4 (0.5-3.0 g/(kg·d)) from the beginning of the study, and the non-L-T4-treated subgroup received placebo. We also selected 39 ISS children with FT4 in the upper two-thirds of the normal range as the higher FT4 group. During the first year, the lower FT4 group featured lower FT3, FT4, thyroid stimulating hormone (TSH), and insulin-like growth factor-I standard deviation score (IGF-I SDS) and significantly lower height velocity (HV) compared with the higher FT4 group. However, in the lower FT4 group, the L-T4-treated subgroup presented higher FT4, FT3, TSH, and IGF-I SDS concentrations and significantly higher HV compared with children in the non-L-T4-treated subgroup. In children with ISS, the negative effect of thyroid hormone deficiency on growth rate should be considered when FT4 level lies in the low-normal range prior to recombinant human growth hormone treatment.

Effect of recombinant human growth hormone on the growth rate, glucose and lipid metabolism and bone metabolism in children with idiopathic short stature / 中国医师进修杂志

Objective To investigate the effect of recombinant human growth hormone (rhGH) on the growth rate, glucose and lipid metabolism and bone metabolism in children with idiopathic short stature (ISS). Methods The clinical data of 150 children with ISS admitted to the hospital from January 2010 to January 2015 were collected. The children were divided into the routine group (68 patients) and rhGH group (82 patients) according to the treatment methods. The routine group was given enhanced nutritional guidance, enhanced protein and calcium intake, and guidance for exercise. On this basis, rhGH group was additionally treated with rhGH. The intervention lasted for 12 months, and changes of height, weight, bone age (BA) and growth velocity (GV) in two groups were statistically analyzed. Changes in fasting blood glucose (FBG), insulin (INS), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and other glucose and lipid metabolism indicators before and after treatment were detected. The insulin sensitivity index (ISI) was calculated, and changes in serum insulin-like factor 1 (IGF-1), osteocalcin (OC), bone alkaline phosphatase (BAP), typeⅠprocollagen amino-terminal propeptide (PINP), β-collagen degradation products (β-CTX) and other bone metabolism parameters before and after treatment were determined. The incidence of adverse reactions in both groups was statistically analyzed. Results There were no significant differences in height, weight, BA or GV between two groups before treatment (P>0.05). After 12 months of treatment, the above indicators in both groups were increased (P<0.05). The height, weight, BA and GV were (132.12 ± 7.26) cm, (26.21 ± 1.74) kg, (9.41 ± 0.37) years old and (10.03 ± 2.41) cm/year of the rhGH group, which were significantly higher than those of the routine group [(124.22 ± 6.31) cm, (24.13 ± 1.92) kg, (8.96 ± 0.42) years old and (5.85 ± 1.76) cm/year (P<0.05)]. There were no significant differences in glucose and lipid metabolism levels between two groups before and after treatment (P>0.05). There was no statistical difference in bone metabolism indexes between two groups before treatment (P>0.05). After 12 months of treatment, PINP, IGF-1, OC and BAP in both groups increased while β-CTX decreased (P<0.05). PINP, IGF-1, OC and BAP in rhGH group [(598.21 ± 78.57) μg/L, (301.23 ± 51.45) μg/L, (78.52 ± 12.65) μg/L, (171.26 ± 42.17) U/L] were higher than those in routine group [(520.14 ± 47.55)μg/L, (244.35 ± 46.38)μg/L, (70.25 ± 9.77) μg/L, (120.55 ± 38.42) U/L] (P<0.05), whileβ-CTX was lower than that in routine group [(0.48 ± 0.26)μg/L vs (0.63 ± 0.24) μg/L] (P<0.05). There were no significant difference in adverse reaction between two groups [3.66％(3/82) vs. 0, P>0.05]. Conclusions The rhGH treatment of children with ISS can obviously promote the growth and improve bone metabolism and growth rate of children, without significant adverse effect on their glucose and lipid metabolism and with certain safety.

Design of the long-term observational cohort study with recombinant human growth hormone in Korean children: LG Growth Study

PURPOSE: Regarding recombinant human growth hormone (rhGH) use in the pediatric population, no long-term follow-up data are available for Korean patients. To fill in the gap of knowledge, a registry study (LG Growth Study) was initiated to assess the safety and effectiveness of four types of rhGH products in real-life settings. METHODS: A total of 4,000 children will be registered and prospectively followed up at 6-month intervals until 2 years after epiphyseal closure to collect data on treatment and adverse events, with primary interest in malignancies and growth outcomes. RESULTS: As of 22 March 2017, approximately 50% (2,024) of the target number of patients have been included in the analysis set: growth hormone deficiency, 1,297 (64.1%); idiopathic short stature, 315 (15.6%); small for gestational age, 206 (10.2%); Turner syndrome, 197 (9.7%); and chronic renal failure, 9 (0.4%). At baseline, median age (years) was 8 (interquartile range [IQR], 5–11); 52% (1,048) were boys; and the majority were at Tanner stage I (83% based on breast/external genitalia, 97% on pubic hair). Median height standard deviation score was -2.26 (IQR, -2.69 to -2.0), and median bone age delay (years) was -1.46 (IQR, -2.26 to -0.78). CONCLUSIONS: This registry study will provide the opportunity to assess the risk of malignancies as well as the general safety data in Korean pediatric patients receiving rhGH. In addition, the long-term effectiveness of rhGH and comparative data between different disease entities will provide practical insight on the standard rhGH treatment.

Screening of SHOX gene sequence variants in Saudi Arabian children with idiopathic short stature / 소아과

PURPOSE: Short stature affects approximately 2%–3% of children, representing one of the most frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions in the short stature homeobox-containing gene (SHOX) are frequently detected in subjects with short stature. Idiopathic short stature (ISS) refers to patients with short stature for various unknown reasons. The goal of this study was to screen all the exons of SHOX to identify related mutations. METHODS: We screened all the exons of SHOX for mutations analysis in 105 ISS children patients (57 girls and 48 boys) living in Taif governorate, KSA using a direct DNA sequencing method. Height, arm span, and sitting height were recorded, and subischial leg length was calculated. RESULTS: A total of 30 of 105 ISS patients (28%) contained six polymorphic variants in exons 1, 2, 4, and 6. One mutation was found in the DNA domain binding region of exon 4. Three of these polymorphic variants were novel, while the others were reported previously. There were no significant differences in anthropometric measures in ISS patients with and without identifiable polymorphic variants in SHOX. CONCLUSION: In Saudi Arabia ISS patients, rather than SHOX, it is possible that new genes are involved in longitudinal growth. Additional molecular analysis is required to diagnose and understand the etiology of this disease.

Effects of growth hormone on serum levels of Ghrelin, LP, IGF-1 and IGFBP3 in children with idiopathic short stature / 中国生化药物杂志

Objective To study the effect of growth hormone on serum levels of Ghrelin, leptin(LP), insulin like growth factor-1(IGF-1) and insulin-like growth factor binding protein 3(IGFBP3) in children with idiopathic short stature(ISS).Methods 86 patients of ISS who received therapy from September 2013 to September 2015 were selected.According to random number table,those patients were divided into observation group ( n=43) and the control group (n=43).Control group was treated with routine nutrition therapy, while the observation group was added with recombinant human growth hormone.The Ghrelin, LP, IGF-1, IGFBP3 levels and height pre-and post-treatment were compared.Results After treatment, the level of Ghrelin in observation group [ ( 4.85 ±0.41 ) ng/mL ] was lower than that of control group [ ( 5.63 ±0.62 ) ng/mL ] , the level of LP [ ( 6.53 ± 0.78)mg/L] was higher than that of control group[(5.49 ±0.62)mg/L](all P<0.05); the levels of IGF-1[(387.94 ±47.38)ng/mL] and IGFBP3 [(6.74 ±0.73)μg/mL]in the observation group were higher than that of the control group[(243.54 ±36.82)ng/mL,(4.85 ±0.61)μg/mL](all P<0.05); the height in the observation group[(110.17 ±8.12)cm] was higher than that of control group[(114.58 ±9.40)cm](P<0.05).Conclusion Recombinant human growth hormone is well for ISS, which can effectively improve Ghrelin, LP, promote physical growth IGF-1, IGFBP3 levels, promote growth.

Effect of growth hormone treatment on children with idiopathic short stature and idiopathic growth hormone deficiency

PURPOSE: There are inconsistencies in the results reported in a small number of previous studies into growth hormone (GH) treatment in Korean children with idiopathic short stature (ISS) and idiopathic growth hormone deficiency (IGHD). Thus, the authors retrospectively compared the effects of GH in ISS and IGHD. METHODS: From the medical records of 26 ISS and 30 IGHD children, auxological and biochemical changes including chronologic age (CA), bone age (BA), height standard deviation score (HT-SDS), predicted adult height (PAH), midparental height (MPH), insulin-like growth factor-1 (IGF-1), and insulin-like growth factor binding protein-3 (IGFBP-3) were compared. RESULTS: Before treatment, IGHD group had younger BA, lower BA/CA ratio, and lower IGF-1 level than those in the ISS group. During GH treatment, the levels of IGF-1 and IGFBP-3 were not different. Although annual BA increment was higher in IGHD group, and annual PAH-SDS increment was higher in ISS group, annual HT-SDS increments were not different. Both HT-SDS and PAH-SDS in the ISS group increased significantly until the end of the second year, and then those were not significantly different from MPH-SDS. In the IGHD group, the HT-SDS showed a significant increase till the end of the second year, and the PAH-SDS was not significantly changed at each year, but both HT-SDS and PAH-SDS were not significantly different from MPH-SDS at the end of the third year. CONCLUSION: During GH treatment, both HT-SDS and PAH-SDS approached the genetic target range of MPH-SDS after 2 years in ISS children and 3 years in IGHD children.

Novel genetic cause of idiopathic short stature

Traditionally, the growth hormone – insulin-like growth factor I (GH – IGF-I) axis is the most important signaling pathway in linear growth, and defects in this axis present as growth hormone deficiencies or IGF-I deficiencies. However, subtle changes in serum levels of GH or IGF-I, caused by gene mutations involved in the GH – IGF-I axis, can present as idiopathic short stature (ISS). This paper briefly discusses GHR and IGFALS. In addition, recent studies have shown that many factors, including paracrine signals, extracellular matrix, and intracellular mechanisms of chondrocytes, regulate the growth plate independent of the GH – IGF-I system. Rapid development of diagnostic technologies has enabled discovery of many genetic causes of ISS. This paper discusses 5 genes, SHOX, NPR2, NPPC, FGFR3, and ACAN, that may lead to better understanding of ISS.

Clonidine-stimulated growth hormone concentrations (cut-off values) measured by immunochemiluminescent assay (ICMA) in children and adolescents with short stature

OBJECTIVES: To establish cut-off values for growth hormone concentrations using clonidine as a secretagogue and an immunochemiluminescent assay as the method of measurement and to analyze the response time as well as the influence of gender, nutritional status and pubertal stage. METHODS: A total of 225 tests were performed in 3 patient groups, categorized as group 1 (normal), group 2 (idiopathic short stature) and group 3 (growth hormone deficiency). Among the 199 disease-free individuals, 138 were prepubertal, and 61 were pubertal. Clonidine (0.1 mg/m2) was orally administered, and the growth hormone level was measured by immunochemiluminescent assay. The growth hormone peak and the difference between the growth hormone peak and the baseline level were then analyzed. Statistical analyses were performed using Student’s t-test or the Mann-Whitney test and Kruskal-Wallis test followed by Dunn’s post hoc test. Cut-off values were determined using a receiver operating characteristic curve. RESULTS: Group 1 and group 2 had no difference in growth hormone peak, gender, body mass index standard deviation score, or pubertal stage. Group 3 exhibited a significantly lower growth hormone peak than the other groups did. The receiver operating characteristic curve demonstrated that growth hormone concentrations ≥ 3.0 ng/mL defined responsiveness to clonidine. In total, 3.02% of individuals in group 1 and group 2 were considered false positive, i.e., these children lacked growth hormone deficiency and had a peak below 3.0 ng/mL. CONCLUSION: Clonidine-stimulated growth hormone concentrations ≥3 ng/mL, as measured by immunochemiluminescent assay, suggest responsiveness to the stimulus regardless of gender, body mass index standard deviation score or pubertal stage.

Estatura final en niños con talla baja idiopática tratados con hormona del crecimiento / Adult height of children with idiopathic short stature treated with growth hormone therapy

Introducción: La talla baja idiopática (TBI) se define como talla ≤ 2 desviaciones estándar (DE) sin causa precisada. El uso de la hormona de crecimiento (GH) en TBI es controvertido y no existen resultados de talla final (TF) en pacientes chilenos. El objetivo de este trabajo es comparar la TF de pacientes con TBI tratados con GH con la predicción de talla adulta al inicio de tratamiento. Pacientes y método: 18/47 pacientes con TBI tratados con GH y que alcanzaron su TF. Se definió TF con edad ósea (EO) ≥ 17 años en hombres y ≥ 15 años en mujeres. Para comparar se consideró la DE de la talla según curvas NCHS al inicio y final de tratamiento. El pronóstico de talla adulta (PTA) se calculó utilizando la EO mediante el método de Bayley-Pinneau. Resultados: La talla inicial fue 133,1 ± 6,8 cm (-2,1 ± 0,85 DE) y el PTA de -1,94 ± 0,86 DE. Los pacientes se trataron desde los 11,6 ± 1,2 años durante un tiempo de 1,56 ± 0,65 años. Al año de tratamiento su talla fue -1,64 ± 0,69 DE y la talla final fue -1,28 ± 0,62 DE (163,76 ± 7,22 cm). Se obtuvo un aumento en la TF de 2,67 ± 5,88 cm (equivalente a 0,67 ± 0,9 DE). Conclusión: Nuestros resultados demuestran que el tratamiento con GH fue eficaz para incrementar TF en pacientes con TBI, con una duración mayor a un año de tratamiento. Hasta donde sabemos este constituye el primer reporte de talla final en pacientes chilenos con TBI tratados con GH.

Introduction: Idiopathic short stature (ISS) is defined as a height of < - 2 standard deviations (SD) from the mean for age. The use of Growth Hormone (GH) in ISS is controversial, and there are not results for adult height (AH) in Chilean patients with ISS treated with GH. The objective of the study is to compare AH in patients treated with GH with the height prediction at beginning of treatment. Patients and Method: AH was considered with bone age ≥ 17 in males and ≥15 in females. The height SD according to the NCHS curves at beginning and ending of treatment were used for the comparison. Height prediction (HP) was calculated by Bayley-Pinneau method. Results: AH was reached by 18/47 patients with ISS treated with GH. Initial height -2.1 ± 0.85 SD (133.1 ± 6.8 cm) and HP -1.94 ± 0.86 SD, and were treated since 11.6 ±1.2 years old. After one year of treatment their height was -1.64 ±0.69 SD, and AH was -1.28 + -0.62 SD (163.76 +-7.22 cm). Conclusion: It is suggested that treatment with GH for ISS is effective to increase AH. Although with wide individual variability, a mean increase of 0.67 ± 0.9 SD (+2.67 cm) was obtained in the AH. This is the first report on Adult Height in Chilean patients.

Clinical significance of monitoring bone turnover markers changes before and after growth hormone treatment of prepubertal children with idiopathic short stature / 中华实用儿科临床杂志

Objective To detect the levels and study the clinical significance of serum procollagen type Ⅰ amino-terminal propeptide (PINP) and β-C-telopeptides of type Ⅰ collagen (β-CTX) as bone turnover markers in recombinant human growth hormone (rhGH) treatment of prepuberty idiopathic short stature (ISS) children.Methods Forty patients of ISS (18 boys and 22 girls) had been collected and treated with GH 0.15 IU/(kg · d) injection every night.Serum levels of PINP,β-CTX,insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP3) were measured by electrochemiluminescence immunoassay in ISS before treatment and after 3,6 months,and they were also measured in 50 healthy children of the healthy control group,and the height,weight,body mass index,height standard difference score (HtSDS),bone age and growth rate were recorded.Results (1) In ISS group,the serum level of PINP[(479.51 ± 134.61) μg/L] was lower than that of the healthy control group [(651.31 ± 212.41) μg/L],the level of β-CTX[(0.84 ± 0.33) μg/L] was higher than that of the healthy control group [(0.50 ± 0.15) μg/L].The differences were statistically significant (t =2.276,-2.709,all P ＜ 0.05).(2) The serum levels of PINP and β-CTX had no significant difference in 18 boys and 22 girls before and after GH treatment (P＞0.05) of ISS.After 3 months of GH treatment,the serum levels of PINP[(736.15 ± 156.59) μg/L] and β-CTX [(1.08 ± 0.27) μg/L] were higher than those before treatment in 40 cases,and the difference was statistically significant (t =4.736,2.497,all P ＜ 0.05),as the increase of PINP was particularly significant.HtSDS (-2.95 ±0.43),compared with before treatment (-2.69 ± 0.58),was significantly different (t =2.714,P ＜ 0.05).However,after 6 months of GH treatment,the levels of PINP[(860.90 ±254.59) μg/L] and β-CTX[(0.94 ±0.32) μg/L] increased slowly (t =1.366,-0.831,all P ＞ 0.05).HtSDS (-2.51 ± 0.54) showed no significant difference (t =1.609,P ＞ 0.05) compared with 3 months of treatment.(3) The serum level of PINP was positively correlated with IGF-1 and IGFBP3 (r =0.636,0.673,all P ＜ 0.05),and there was no correlation with β-CTX (r =0.336,P ＞0.05).PINP and β-CTX had significant correlation with HtSDS (r =0.655,0.782,all P ＜ 0.05).Conclusions The serum PINP and β-CTX as bone turnover markers in serum can be used as one of the early supplementary indicators to predict GH response of ISS.

The expression and significance of serum ghrelin, leptin, IGF-1, and IGFBP3 in children with idiopathic short stature / 中华内分泌外科杂志

Objective To examine the expressions of serum growth hormone (ghrelin), leptin (LP), in sulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP3) in children with id-iopathic short stature (ISS), and their significance. Methods A total of 40 patients with ISS were selected from May. 2012 to Oct. 2014 in Fuyang Maternal and Child Health Hospital, while a total of 40 children in good health were selected as the control group. Serum ghrelin and LP levels were measured by ELISA. Serum IGF-1 and IGF-BP3 levels were detected by chemiluminescence immune assay. Results were analyzed statistically. Results The height, weight, BMI, GH, serum LP, IGF-1, and IGFBP3 levels in the observation group were significantly lower than those in the control group, while serum ghrelin expression level was significantly higher than that in the control group(P<0.05). The correlation analysis showed that ghrelin and LP were negatively correlated(r=-0.611, P<0.01), ghrelin and IGF-1 levels were negatively correlated(r=-0.520, P<0.05), Ghrelin and IGFBP3 were pos-itively correlated (r=0.586, P<0.01), IGF-1 and IGFBP3 was negatively correlated (r=-0.576, P<0.01), and LP and IGFBP3 were negatively correlated (r=-0.609, P<0.01). Conclusions It shows that ghrelin, LP, IGF-1, and IGFBP3 levels in children with ISS are related to growth hormone secretion status. The interactions between ghre-lin and insulin-like growth factor axis regulate growth and development of children.