Osteometabolic profile and bone mass in the transition phase: ethnic differences in Brazilians treated with somatropin during childhood

Abstract Objective: The main growth hormone action is to promote linear growth increasing protein synthesis stimulation and osteoblastic activity. Peak bone mass extends from adolescence to 30 years of age. Several factors may influence this acquisition and prevent fracture risk in adulthood, such as genetic potential, GH, ethnicity, and lifestyle factors. This study aims to compare bone mass and osteometabolic profile of white and Afro-descendant Brazilian adolescents in the transition phase, who were treated with human recombinant growth hormone in childhood. Methods: The authors selected 38 adolescents from the Transition Outpatient Clinic of the University of São Paulo. Lumbar spine and total body bone mineral density (BMD) and bone mineral content (BMC), serum calcium, 25-OH-vitamin D and bone markers were analyzed at the rhGH withdrawal. Results: The mean age was 16.8 ± 1.6 years. There were 21 Afro-descendant and 17 whites. Thirty-four percent of the sample presented vitamin D insufficiency, 66% inadequate calcium intake and 44.7% physical inactivity. The Afro-descendants showed a lower lumbar spine and total body Z scores than those of the whites (p = 0.04 and p = 0.03, respectively), as well as their mean body weight (p = 0.03). There were no differences in the remaining osteometabolic parameters. Conclusion: As most adolescents had vitamin D insufficiency, low calcium intake, and physical inactivity, calcium, and cholecalciferol supplementation and lifestyle changes should be encouraged. The Brazilian Afro-descendant may be a vulnerable group for low bone mass, requiring

Optimization of glycosylation type of recombinant human growth hormone-Fc fusion protein expressed in CHO cells / 中国生物制品学杂志

@#Objective To optimize the expression of recombinant human growth hormone-Fc(rhGH-Fc)fusion protein in CHO cells in order to obtain better glycosylation ratio and lower content of highmannose.Methods CHO cells expressing rhGH-Fc were cultured in a 7 L bioreactor.The glycosylation modifications of rhGH-Fc were adjusted by improving the composition of feeding media(using three commercial media:Gly-1:EX-CELL Glycosylation Adjust,Gly-2:SHEFF-CHO PLUS PG ACF and Gly-3:EfficientFeed C + AGT Supplement & GlycanTune C + Total Feed),and the glycosylation type and proportion of the target proteins were analyzed by mass spectrometry.Results The G0F(main glycosylation types:G0,G1 and G2;F:fucose)of Gly-1,Gly-2 and Gly-3 were 32.89%,58.66% and 33.28%,the G1F were 31.39%,18.03%and 34.90%,and the G2F were 31.39%,18.03% and 34.90%,respectively.Gly-1 and Gly-3 made the target protein contain less G0F while more G2F;Gly-3 feeding scheme-showed less high mannose modification than the other two schemes.Conclusion Gly-1 medium changed the glycosylation modification from G0F to G1F and G2F,while Gly-2 medium changed that from G2F and G1F to G0F.However,Gly-3 medium changed the glycosylation modification from G0F to G1F and G2F,and the contentof high mannose was less than 5%,which may have a better effect on modifying glycosylation type and proportion of the target protein.

Therapeutic effect of recombinant human growth hormone on children with growth hormone deficiency and different pituitary developmental conditions: a prospective study / 中国当代儿科杂志

OBJECTIVES@#To investigate the therapeutic effect of recombinant human growth hormone (rhGH) on children with growth hormone deficiency (GHD) and different pituitary developmental conditions.@*METHODS@#A prospective study was performed on 90 children with GHD who were admitted to Xuchang Maternity and Child Health Hospital from June 2020 to December 2021. According to pituitary height on the median sagittal plane, they were divided into three groups: pituitary dysplasia group (n=45), normal pituitary group (n=31), and enlarged pituitary growth group (n=14). The changes in body height, growth velocity, height standard deviation score and serum levels of insulin-like growth factor binding protein-3 (IGFBP-3) and insulin-like growth factor-1 (IGF-1) were examined after treatment in the above three groups, and the differences of the above indices before and after treatment were compared among the three groups.@*RESULTS@#After treatment, all three groups had significant increases in body height, growth velocity, height standard deviation score, and the serum levels of IGFBP-3 and IGF-1 (P<0.05). Compared with the normal pituitary group, the pituitary dysplasia group and the enlarged pituitary growth group had significantly higher values in terms of the differences in body height, growth velocity, height standard deviation score, IGF-1, and IGFBP-3 before and after treatment (P<0.05). There was no significant difference in the incidence rate of adverse reactions among the three groups (P>0.05).@*CONCLUSIONS@#In GHD children with different pituitary developmental conditions, rhGH can promote bone growth and increase body height, especially in children with pituitary dysplasia and pituitary hyperplasia, with good safety.

Optimization and verification of size exclusion chromatography-high performance liquid chromatography for determination of recombinant human growth hormone-Fc immunofusion protein polymer / 中国生物制品学杂志

@#Objective To optimize and verify the size exclusion chromatography-high performance liquid chromatography(SEC-HPLC) method for the determination of recombinant human growth hormone(rhGH)-Fc immunofusion protein polymer.Methods The multimer content of rhGH-Fc immunofusion protein was detected by SEC-HPLC.The detection conditions(salt concentration,mobile phase pH,flow rate,column temperature and column model) were optimized to observe the separation effect of the target proteins and polymers.The system suitability,specificity,linearity and range,precision,accuracy and limit of quantification of the method were verified.Results The optimized method was to use TSK-gel G2000SW_(x1)column(5 μm,7.8 mm × 300 mm),mobile phase of 50 mmol/L phosphate buffer(pH 6.80),detection wavelength of280 nm,injection volume of 100 μL,flow rate of 0.6 mL/min and column temperature of 45 ℃.The resolution of rhGHFc immunofusion protein and polymer,the theoretical plate number and the tailing factor all met the requirements;the peak time of rhGH-Fc immunofusion protein was the same as that of the control,while the peak time of GH national standard was different from that of the control,and the protein buffer showed no peak;the concentration of rhGH-Fc immunofusion protein was in the range of 0.307～1.842 mg/mL with good linear correlation between the peak area integral value and the injection volume(R~2=0.999 4);the RSD of peak area and purity in repeatability verification were 0.7% and 0.1%,respectively;the RSD of intermediate precision verification was 0.8%;the average recovery rate of accuracy verification was 99.1% with the RSD of 1.9%;the limit of quantification was 6 μg/mL.Conclusion The optimized SEC-HPLC method was used to detect the content of polymer in rhGH-Fc immunofusion protein with improved accuracy,and the column efficiency and separation were in accordance with the relevant requirements of Chinese Pharmacopoeia(Volume Ⅳ,2020edition),which could be used for the detection of polymer content in samples.

Development and verification of whole-column imaging capillary isoelectric focusing electrophoresis analysis method for charge heterogeneity of human growth hormone Fc fusion protein / 中国生物制品学杂志

@#Objective To develop and verify a whole-column image capillary isoelectric focusing(iCIEF) electrophoresis method to analyze the charge heterogeneity of recombinant human growth hormone Fc fusion protein(Fc-rhGH).Methods The iCIEF analysis method of Fc-rhGH was developed by optimizing the target protein concentration,cosolvent(urea)concentration and focusing time.The target protein was simultaneously analyzed by this method and traditional flat plate isoelectric focusing(IEF) electrophoresis,and the results were compared;The specificity,accuracy,precision,limit of quantitation(LOQ) and durability of the developed method were verified.Results The optimized method was using the mixed solution of 8 mol/L urea,0.35% methyl cellulose(MC),4% amphoteric electrolyte and 0.5% isoelectric point marker as the sample buffer,and the focusing condition was 1 500 V 1 min,3 000 V 5.5 min.IEF was not suitable for analyzing the charge heterogeneity of Fc-rhGH solution.Using the optimized iCIEF for analysis,the target protein was significantly different from the unrelated protein,and the baseline of blank reagent was stable;The recovery rate of accuracy verification was within 90%～110%,and the linear range was 0.25～0.75 mg/mL(50%～150% of the target loading volume);The RSD of each isomer pI in the repeatability verification was less than 0.3%,and the RSD of peak area percentage was less than 5%;The LOQ was 0.04 mg/ml.The sample storage time durability,amphoteric electrolyte pharmalyte 3-10 durability and MC durability of this method were good.Using this method to analyze the charge heterogeneity of Fc-rhGH physicochemical reference substance,eight charge heterogeneities of the reference substance were effectively separated,and the pI ranged from 5.9 to 6.4.Conclusion The developed iCIEF method had good specificity,accuracy,precision and durability,and was more suitable for efficient analysis of charge heterogeneity of Fc-rhGH than traditional flat plate IEF,which was of great significance for the quality control of Fc-rhGH and other Fc fusion proteins.

Reporter gene assay for detection of biological activity of human growth hormone / 中国生物制品学杂志

@#Objective To develop and verify a reporter gene assay(RGA) for the detection of biological activity of human growth hormone(hGH).Methods The biological activity of hGH was evaluated by the expression of luciferase(Luc)activated by hGH binding to hGH receptor(hGHR) on HEK293/GH-Luc cell membrane.The developed detection conditions were as follows:the initial concentration of sample was 1 μg/mL;the cell inoculation amount was(2.45～2.66) × 10~4 cells/well;the sample was of 3-fold serial dilution,with a total of 8 dilutions and the incubation time was 18～24 h.The relative biological activity of the sample was calculated by measuring Luc intensity and comparing it with the national standard by four-parameter fitting.The developed method was verified for specificity,repeatability,intermediate precision,relative accuracy,linear range and durability.Results The excipient components in product and the serum components in culture medium showed no effect on the activity detection results;The geometric coefficient of variation(GCV) of relative titer of one batch of samples in six repeated detections was 6.794%,much lower than 20%.The relative titer GCV detected by two experimenters in different batches of samples at different times were both lower than 20%;The relative deviations of the relative titer determination values of samples at different concentrations were within ±12%,the slope of linear regression equation was 0.982,the linear range was 0.6～1.6 μg/mL,and the coefficient of determination(R~2) was 0.997;The GCV of three batches of stock solutions and one batch of finished products were 4.758%,4.430%,7.294% and 2.771% respectively under the conditions of different cell generation,cell density and sampling location,all of which were less than 20%.Conclusion The developed RGA showed good specificity,repeatability,intermediate precision,relative accuracy,linear range and durability,which met the application requirements and was expected to replace the traditional in vivo biological activity detection methods for the activity evaluation and quality control of hGH.

Advances in the pathogenesis and treatment of short stature in Noonan syndrome / 国际儿科学杂志

Noonan syndrome(NS)is an inherited disease involving multiple systems.The main clinical manifestations include distinctive facial features, short stature, heart defects, developmental delay and chest deformity.Short stature, reported in up to 70% of NS patients, is one of the main reasons NS patients seek medical treatment.The pathogenesis is associated with the up-regulation of RAS-mitogen activated protein kinase(RAS-MAPK)signal pathway.Further study is needed for some further specific mechanisms.Recombinant human growth hormone(rhGH)therapy has been approved for NS patients with short stature and has achieved a good therapeutic effect.However, the knowledge of drug dosage, influencing factors, long-term efficacy and risk of rhGH treatment is still insufficient.This paper reviews the pathogenesis and treatment of short stature in NS, providing help for the treatment and management of the disease.

A novel bioassay to assess bioactivity of PEG-rhGH using Nb2-11 cells / 药学学报

In this study, we established a novel bioassay to determine the activity of polyethylene glycolated recombinant human growth hormone (PEG-rhGH) using Nb2-11 cells. We performed experimental condition optimization and methodological verification, and then detected the relative potency of PEG-rhGH products using this method. We demonstrated that the bioactivity of PEG-rhGH in promoting Nb2-11 cell proliferation displays a dose-response relationship, which conformed to the four-parameter model. Using PEG-rhGH reference as a control, we analyzed the relative potency of six batches of PEG-rhGH products, as well as linearity, regression and parallelism of the obtained curves. The relative potency of six batches of PEG-rhGH products was 95% to 105%. These results implied that the new bioassay established may be employed in quality control of PEG-rhGH products.

Application of Design of Experiment in development of purification process of recombinant human growth hormone-Fc fusion protein / 中国生物制品学杂志

@#ObjectiveTo optimize the condition for anion exchange chromatography in purification process of recombinant human growth hormone-Fc(rhGH-Fc)fusion protein by Design of Experiment(DOE)so as to decrease the content of host cell protein(HCP)in bulk of protein.MethodsA complete factorial experimental design with four factors at two levels was established by the DOE in Minitab 19 software.The condition(flow rate,sample load,pH value of buffer and salt concentration of eluent)for anion exchange chromatography in purification process of rhGH-Fc was optimized by DOE to find out the operating space.ResultsThe experimental results were predicted accurately by the established DOE model.The sample load,pH value of buffer,salt concentration of eluent as well as the interaction of pH value of buffer and salt concentration of eluent showed significant influence on the HCP content in the harvest.The optimal sample load,flow rate as well as pH value and salt concentration of eluent were 15 mg/mL,120 cm/h,7.0 ～ 8.0 and 0.1 mol/L respectively.The HCP contents in eluents under the optimal condition were less than 400 ng/mg,which met the requirements for verification within the range of results in determined operating space.ConclusionThe condition for removal of HCP by anion exchange chromatography was successfully optimized by DOE,which provided a reference for further application of DOE in the biopharmaceutical field.

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.

Case report of acromesomelic dysplasia Maroteaux type caused by the NPR2 gene mutation / 中华实用儿科临床杂志

Clinical data of a child with acromesomelic dysplasia Maroteaux type (AMDM) treated in the Department of Pediatrics, Tianjin Medical University General Hospital at November 2018 was retrospectively analyzed.The female child aged 3 years and 3 months old with 83 cm height (-3.84 SD) had clinical manifestations of disproportionate short stature, disproportionate shortening of forearms and forelegs, and stubby fingers and toes.Gene sequencing identified compound heterozygous mutations, c.1640T>A(p.Val547Asp)/c.682G>A(p.Gly228Ser), in the NPR2 gene, which have not been reported in the Human Gene Mutation Database.Their protein function was predicted harmful.The child was diagnosed as AMDM.During the follow-up until 4 years and 8 months old, the child was 90 cm tall (-4.35 SD), with a growth velocity of 4.9 cm/year.She was treated with recombinant human growth hormone (rhGH) treatment for 9 months and regularly followed up.The child was now 98.2 cm height (-3.07 SD) and she had a growth velocity of 10.9 cm/year.This case report enriched the gene mutation spectrum of AMDM.Treatment with rhGH can effectively improve the height of the child, but the long-term effect needs further follow-up and observation.

Eficácia e segurança de Somatropina para o tratamento de crianças nascidas pequenas para a idade gestacional: revisão rápida de evidências / Efficacy and safety of Somatropine for the treatment of children born small for gestational age: a rapid response review of evidence

Tecnologia: Somatropina. Indicação: Transtorno de crescimento em crianças nascidas pequenas para a idade gestacional (PIG). Pergunta: A somatropina é eficaz e segura para promover aumento da curva de crescimento em crianças nascidas PIG? Métodos: Levantamento bibliográfico foi realizado na base de dados PUBMED, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews version 2). Resultados: Foi selecionada uma revisão sistemática que atendeu aos critérios de inclusão. Conclusão: evidências de moderada certeza indicam que somatropina é eficaz e segura para tratamento de crianças nascidas PIG, pois promove recuperação do crescimento e não há relatos de eventos adversos graves na literatura científica

Technology: Somatropin. Indication: Growth disorder in children born small for gestational age (SGA). Question: Is somatropin effective, safe and cost effective for promoting height gain in children born SGA? Methods: A bibliographic search was done in PUBMED database, following predefined search strategies. The methodological quality of systematic reviews was evaluated using the AMSTAR-2 tool (A MeaSurement Tool to Assess systematic Reviews version 2). Results: Only a systematic review met the inclusion criteria and was selected. Conclusion: Evidence of moderate certainty indicates that somatropin is effective and safe for the treatment of children born SGA, because the treatment improve the growth and there are no reports of serious adverse events in the scientific literature

Effect of recombinant human growth hormone on corneal epithelial wound healing / 国际眼科杂志(Guoji Yanke Zazhi)

@#AIM:To explore the effects of recombinant human growth hormone(rHGH)on early rehabilitation in rabbit corneal epithelial wound. <p>METHODS:Thirty-two New Zealand rabbits were selected to establish the corneal epithelial defects models. One eye was treated with normal saline(NC group)and the other eye was treated with 20nmol/L rHGH(rHGH group)in a randomized double-blinded way. The corneal healing process was monitored by the corneal fluorescein staining scores at 0h, 24h, 48h, and 72h after the surgery. The central corneal sensitivity was detected by Cochet-Bonnet corneal esthesiometer and the concentrations of inflammatory mediators interlecukin-1α(IL-1α), interlecukin-17(IL-17), interlecukin-21(IL-21), Leptin, matrix metalloproteinase-9(MMP-9)and tumor necrosis factor-α(TNF-α)in collected tears were measured by multiplex antibody microarray. <p>RESULTS: The corneal epithelial healing rates of the NC group and rHGH group were(62.52±6.73)% and(79.62±10.62)%(<i>P</i><0.05),(90.56±9.57)% and(98.43±3.65)%(<i>P</i><0.05)at 48h and 72h postoperatively. The central corneal sensitivity of rHGH group(4.22±0.26)cm was better than that in NC group(3.22±0.42)cm at 48h after surgery(<i>P</i><0.05). The expressions of TNF-α and IL-1α increased in both groups at each time point after operation, and the expressions in NC group were higher than those in the rHGH group. Both groups had higher MMP-9 concentrations in the tear fluid at 24 and 48h postoperation in comparison with the point before the operation. The MMP-9 expression in NC group was higher than that in the rHGH group at 48h postoperatively. The expressions of IL-21 in NC group were higher than those in the rHGH group at 24 and 48h postoperation in comparison with the point before the operation(<i>P</i><0.05). No significant differences in tearIL-17 and Leptin were observed between groups before and after surgery(<i>P</i>>0.05).<p>CONCLUSION: Topical application of rHGH can accelerate the early stage of rabbit corneal epithelial wound healing <i>in vivo</i>.

Recomendaciones para el uso de la hormona de crecimiento humana recombinante en pacientes pediátricos de talla baja en Colombia / Recommendations for treatment with recombinant human growth hormone in pediatric patients in Colombia

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Abstract In Colombia there are no guidelines for diagnosis and management of patients with short stature and for the use of recombinant human growth hormone, mainly caused by the diversity of training centers in pediatric endocrinology. In response to this situation, the Asociación Colegio Colombiana de Endocrinología Pediátrica leds the first colombian short stature expert committee in order to standardize the use of human recombinant growth hormone. This work had the participation and endorsement of a consortium of clinical experts representing the Sociedad Colombiana de Pediatría, Secretaría Distrital de Salud de Bogotá- Subred Integrada de Servicios de Salud Suroccidente, Fundación Universitaria Sanitas, Universidad de los Andes and some public and private health institutions in the country, in addition to the participation of methodological experts from the Instituto Global de Excelencia Clínica Keralty. By reviewing the literature and with the best available evidence, we proposed to unify definitions, a diagnostic algorithm, biochemical and dynamic tests with their reference parameters, a description of the considerations about growth hormone use among the indications approved by regulatory agency for medications and food in Colombia and finally a proposal for an informed consent and a medication fact sheet available for parents and patients.

Perspectives on long-acting growth hormone therapy in children and adults

ABSTRACT Growth hormone therapy with daily injections of recombinant human growth hormone has been available since 1985, and is shown to be safe and effective treatment for short stature in children and for adult growth hormone deficiency. In an effort to produce a product that would improve patient adherence, there has been a strong effort from industry to create a long acting form of growth hormone to ease the burden of use. Technologies used to increase half-life include depot formulations, PEGylated formulations, pro-drug formulations, non-covalent albumin binding growth hormone and growth hormone fusion proteins. At present, two long acting formulations are on the market in China and South Korea, and several more promising agents are under clinical investigation at various stages of development throughout the world. Arch Endocrinol Metab. 2019;63(6):601-7

Velocidad de crecimiento en pacientes con síndrome de Turner que recibieron hormona recombinante de crecimiento / Growth rate in patients with Turner syndrome who received recombinant growth hormone

El síndrome de Turner (ST) afecta a uno de cada 2000-2500 recién nacidos vivos y tiene una prevalencia de 50 por cada 100 000 mujeres. Las manifestaciones clínicas son variables, dependiendo del tipo de alteración cromosómica y de la edad de presentación. Una de las características más prevalentes y sobresalientes del síndrome es su estatura extremadamente baja. La hormona de crecimiento humana recombinante (rh-GH) se ha usado para aumentar el crecimiento y la estatura final en las niñas que tienen el síndrome de Turner. Para valorar los efectos de la hormona de crecimiento recombinante en las niñas y adolescentes con ST, hemos tomado en cuenta el efecto de la hGH, considerando la velocidad en la talla de crecimiento como un punto importante del estudio observacional retrospectivo. Resultados principales: El uso de rh-GH tiene una relación estadísticamente significativa (p0.049 <0.05), que se asocia con un factor de influencia positiva en relación con la velocidad de crecimiento, como variable principal. Al comparar a las pacientes que recibieron la hormona de crecimiento con las que no la recibieron, en las primeras existe la tendencia a acercarse a la curva del percentil 10 en comparación con la de aquellas que no recibieron la rh-GH, que estuvieron más lejos de la curva.

Turner syndrome (TS) affects about one in 1500 to 2500 live-born females. One of the most prevalent and salient features of the syndrome is extremely short stature. Recombinant human growth hormone (rh-GH) has been used to increase growth and final height in girls who have Turner syndrome. To assess the effects of recombinant growth hormone in children and adolescents with TS we have evaluated the effect of HGH considering growth rate as an important point through a retrospective observational study. Main results: The use of rh-GH has a statistically significant relationship (p0.049 <0.05) that is associated with an influencing factor in favor of the use of rh-GH in relation to the variable growth rate. When comparing the patients who received growth hormone with those who did not receive, there is the tendency to arrive closer to the 10th percentile curve compared to the curve of the patients who did not receive rh-GH, which is further away.

Brazilian multicenter study on pegvisomant treatment in acromegaly

ABSTRACT Objective Investigate the therapeutic response of acromegaly patients to pegvisomant (PEGV) in a real-life, Brazilian multicenter study. Subjects and methods Characteristics of acromegaly patients treated with PEGV were reviewed at diagnosis, just before and during treatment. All patients with at least two IGF-I measurements on PEGV were included. Efficacy was defined as any normal IGF-I measurement during treatment. Safety data were reviewed. Predictors of response were determined by comparing controlled versus uncontrolled patients. Results 109 patients [61 women; median age at diagnosis 34 years; 95.3% macroadenomas] from 10 Brazilian centers were studied. Previous treatment included surgery (89%), radiotherapy (34%), somatostatin receptor ligands (99%), and cabergoline (67%). Before PEGV, median levels of GH, IGF-I and IGF-I % of upper limit of normal were 4.3 µg/L, 613 ng/mL, and 209%, respectively. Pre-diabetes/diabetes was present in 48.6% and tumor remnant in 71% of patients. Initial dose was 10 mg/day in all except 4 cases, maximum dose was 30 mg/day, and median exposure time was 30.5 months. PEGV was used as monotherapy in 11% of cases. Normal IGF-I levels was obtained in 74.1% of patients. Glycemic control improved in 56.6% of patients with pre-diabetes/diabetes. Exposure time, pre-treatment GH and IGF-I levels were predictors of response. Tumor enlargement occurred in 6.5% and elevation of liver enzymes in 9.2%. PEGV was discontinued in 6 patients and 3 deaths unrelated to the drug were reported. Conclusions In a real-life scenario, PEGV is a highly effective and safe treatment for acromegaly patients not controlled with other therapies.

Development of individualized treatment for congenital ovarian dysplasia syndrome / 中华实用儿科临床杂志

Congenital ovarian dysplasia syndrome is a feminine genetic disease which is rarely seen.Its clinical manifestations include short stature and primary ovarian insufficiency, in addition of which could cause multi-systema-tic complications.According to its therapeutic methods, recombinant human growth hormone and Estrogen are normally used to improve stature and the development of gonad.However, these methods are long-lasting and with great expense, which may result in economic and emotional burdens on patients and their family.On the contrary, individual therapies has a rather precise pharmacogenetical evaluation on patients and their disease, which could effectively decrease iatrogenic loss while enhancing the curative effect.

Comparison of effectiveness of growth hormone therapy according to disease-causing genes in children with Noonan syndrome / 소아과

PURPOSE: To analyze the growth response to growth hormone (GH) therapy in prepubertal patients with Noonan syndrome (NS) harboring different genetic mutations. METHODS: Twenty-three patients with prepubertal NS treated at Pusan National University Children’s Hospital between March 2009 and July 2017 were enrolled. According to the disease-causing genes identified, the patients with NS were divided into 4 groups. Three groups were positive for mutations of the PTPN11, RAF1, and SOS1 genes. The five genes undetected (FGU) group was negative for PTPN11, RAF1, SOS1, KRAS, and BRAF gene mutations. The influence of genotype was retrospectively analyzed by comparing the growth parameters after GH therapy. RESULTS: The mean chronological age at the start of GH treatment was 5.85±2.67 years. At the beginning of the GH treatment, the height standard deviation score (SDS), growth velocity (GV), and lower levels of insulin-like growth factor-1 (IGF)-1 levels were not statistically different among the groups. All the 23 NS patients had significantly increased height SDS and serum IGF-1 level during the 3 years of treatment. GV was highest during the first year of treatment. During the 3 years of GH therapy, the PTPN11, RAF1, and SOS1 groups showed less improvement in height SDS, IGF-1 SDS, and GV, and less increase in bone age-to-chronological age ratio than the FGU group. CONCLUSION: The 3-year GH therapy in the 23 prepubertal patients with NS was effective in improving height SDS, GV, and serum IGF-1 levels. The FGU group showed a better response to recombinant human GH therapy than the PTPN11, RAF1, and SOS1 groups.

Development of individualized treatment for congenital ovarian dysplasia syndrome / 中华实用儿科临床杂志

Congenital ovarian dysplasia syndrome is a feminine genetic disease which is rarely seen.Its clinical manifestations include short stature and primary ovarian insufficiency,in addition of which could cause multi-systematic complications.According to its therapeutic methods,recombinant human growth hormone and Estrogen are normally used to improve stature and the development of gonad.However,these methods are long-lasting and with great expense,which may result in economic and emotional burdens on patients and their family.On the contrary,individual therapies has a rather precise pharmacogenetical evaluation on patients and their disease,which could effectively decrease iatrogenic loss while enhancing the curative effect.