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Objective: To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature., Methods: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed., Results: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001)., Conclusion: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Chronic inflammatory conditions, such as juvenile idiopathic arthritis, are associated with growth failure. Growth failure appears to be correlated with both the effects of inflammation and negative effects of glucocorticoids (used as therapeutic option) on the growth hormone axis and locally on the growth plate and bone metabolism. In the last decade, the introduction of biologics has changed the disease course regarding consequences and outcomes. Anyway in some cases, treatment with biologics has failed in restoring normal growth in patients with juvenile idiopathic arthritis; in contrast, several studies have reported improved height velocity and growth rate in patients with juvenile idiopathic arthritis treated with growth hormone. This study aimed to evaluate the impact of growth hormone treatment on the growth and pubertal development in juvenile idiopathic arthritis patients through a narrative review of the literature over the last four decades., Competing Interests: The authors have nothing to declare., (2024©The Japanese Society for Pediatric Endocrinology.)

Background: Floating-Harbor syndrome (FHS) is a rare autosomal dominant inherited disease characterized primarily by short stature, delayed language development, and typical facial features. There are currently few case reports, diagnoses and treatments for these syndromes at home and abroad., Case Description: This study reports a case of a boy with "growth and language development delay" as the predominant clinical manifestation. FHS was clinically diagnosed based on his growth hormone (GH) deficiency, significant bone age delay, left testicular hydrocele, and the whole exon gene in peripheral blood, which indicated heterozygous mutation of SRCAP gene. Following the treatment with recombinant human GH (rhGH), the child exhibited height increase benefits, and his articulation improved after language therapy., Conclusion: Genetic testing facilitates early detection, diagnosis, and treatment of the FHS. Additionally, treatment with rhGH effectively increases the height of these children, and language rehabilitation is especially important for their language development., Competing Interests: The authors declare that they have no competing interests in this work., (© 2023 Yang et al.)

Objectives: This study was performed to investigate the effectiveness of the combination of letrozole and recombinant human growth hormone (rhGH) to improve the predicted adult height (PAH) and final adult height (FAH) of Chinese short pubertal boys., Methods: In total, 171 Chinese short pubertal boys were recruited for this study. 96 of them received letrozole (2.5 mg/d) combined with rhGH (33.3-66.6 μg/kg.d), and the others received rhGH alone. Follow-up visits were conducted at 1, 3, 6, 9, and 12 months or regularly after the first treatment. During each visit, plasma samples were collected for clinical tests and biomedical analyses, all of which were performed according to standard protocols. This study was registered at www.chictr.org.cn under ID number ChiCTR1900026142., Results: After receiving treatment for at least 3 months, 68 boys (91 %) in the rhGH therapy group and 90 (94 %) in the letrozole combined with rhGH (letrozole+rhGH) therapy group achieved an increase in PAH, with the latter treatment leading to a more effective slowing of bone age (BA) advancement. Moreover, the increased PAH showed a significant positive correlation with treatment time in both groups, and letrozole+rhGH increased the PAH to a greater degree than rhGH alone (p=0.0023). And letrozole+rhGH not only slowed the increase in BA more efficiently than rhGH therapy alone (p=0.0025), but also achieved a higher FAH (p=0.0078)., Conclusions: Letrozole combined with rhGH treatment is a promising therapy to increase the PAH and FAH of Chinese short pubertal boys., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objective: This Italian survey aims to evaluate real-life long-term efficacy and safety of recombinant human growth hormone (rhGH) therapy in children with short stature homeobox-containing gene deficiency disorders (SHOX-D) and to identify potential predictive factors influencing response to rhGH therapy., Design and Methods: This is a national retrospective observational study collecting anamnestic, anthropometric, clinical, instrumental and therapeutic data in children and adolescents with a genetic confirmation of SHOX-D treated on rhGH. Data were collected at the beginning of rhGH therapy (T0), yearly during the first 4 years of rhGH therapy (T1, T2, T3 and T4) and at near-final height (nFH) (T5), when available., Results: One hundred and seventeen SHOX-D children started rhGH therapy (initial dose 0.23 ± 0.04 mg/kg/week) at a mean age of 8.67 ± 3.33 years (74% prepubertal), 99 completed the first year of treatment and 46 reached nFH. During rhGH therapy, growth velocity (GV), standard deviation score (SDS) and height (H) SDS improved significantly. Mean H SDS gain from T0 was +1.14 ± 0.58 at T4 and +0.80 ± 0.98 at T5. Both patients carrying mutations involving intragenic SHOX region (group A) and ones with regulatory region defects (group B) experienced a similar beneficial therapeutic effect. The multiple regression analysis identified the age at the start of rhGH treatment (β = -0.31, P = 0.030) and the GV during the first year of rhGH treatment (β = 0.45, P = 0.008) as main independent predictor factors of height gain. During rhGH therapy, no adverse event of concern was reported., Conclusions: Our data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless the wide variety of genotype., Significance Statement: Among children with idiopathic short stature, the prevalence of SHOX-D is near to 1/1000-2000 (1.1-15%) with a wide phenotypic spectrum. Current guidelines support rhGH therapy in SHOX-D children, but long-term data are still few. Our real-life data confirm the efficacy and safety of rhGH therapy in SHOX-D children, regardless of the wide variety of genotypes. Moreover, rhGH therapy seems to blunt the SHOX-D phenotype. The response to rhGH in the first year of treatment and the age when rhGH was started significantly impact the height gain.

Pathogenic variants in the transcription factor CCCTC-binding factor (CTCF) are associated with mental retardation, autosomal dominant 21 (MRD21, MIM#615502). Current studies supported the strong relationship between CTCF variants and growth, yet the mechanism of CTCF mutation leading to short stature is not known. Clinical information, treatment regimens, and follow-up outcomes of a patient with MRD21 were collected. The possible pathogenic mechanisms of CTCF variants leading to short stature were investigated using immortalized lymphocyte cell lines (LCLs), HEK-293T, and immortalized normal human liver cell lines (LO2). This patient received long-term treatment with recombinant human growth hormone (rhGH) which resulted in an increased height of 1.0 SDS. She had low serum insulin-like growth factor 1 (IGF1) before the treatment and the IGF1 level was not significantly increased during the treatment (-1.38 ± 0.61 SDS). The finding suggested that the CTCF R567W variant could have impaired IGF1 production pathway. We further demonstrated that the mutant CTCF had a reduced ability to bind to the promoter region of IGF1, consequently significantly reducing the transcriptional activation and expression of IGF1. Our novel results demonstrated a direct positive regulation of CTCF on the transcription of the IGF1 promoter. The impaired IGF1 expression due to CTCF mutation may explain the substandard effect of rhGH treatment on MRD21 patients. This study provided novel insights into the molecular basis of CTCF-associated disorder.

The secretion efficiency of a heterologous protein in E. coli is mainly dictated by the N-terminal signal peptide fused to the desired protein. In this study, we aimed to select and introduce mutations into the - 1, - 2 and - 3 positions of the gIII signal peptide (originated from filamentous phage fd Gene III) fused to the N-terminus of the human growth hormone (hGH), and study its effect on the secretion efficiency of the recombinant hGH into the periplasmic space of E. coli Top10. Bioinformatics software such as SignalP-5.0 and PrediSi were employed to predict the effects of the mutations on the secretion efficiency of the recombinant hGH. Site-directed mutagenesis was applied to introduce the desired mutations into the C-terminus of the gIII signal peptide. The periplasmic expression and the secretion efficiency of the recombinant hGH using the native and mutant gIII signal peptides were compared in E. coli Top10 under the control of araBAD promoter. Our results from bioinformatics analysis indicated that the mutant gIII signal peptide was more potent than the native one for secretion of the recombinant hGH in E. coli. While our experimental results revealed that the mutation had no effect on hGH secretion. This result points to the importance of experimental validation of bioinformatics predictions., (© 2022. The Author(s).)

Background: To evaluate the safety and efficacy of daily somatropin (Jintropin ® ), a recombinant human growth hormone, in prepubertal children with ISS in China., Methods: This study was a multicenter, randomized, controlled, open-label, phase 3 study. All subjects were randomized 3:1 to daily somatropin 0.05 mg/kg/day or no treatment for 52 weeks. A total of 481 subjects with a mean baseline age of 5.8 years were enrolled in the study. The primary endpoint was change in (△) height standard deviation score (HT-SDS) for chronological age (CA). Secondary endpoints included △height from baseline; △bone age (BA)/CA; △height velocity (HV) and △insulin-like growth factor 1 (IGF-1 SDS)., Results: △HT-SDS at week 52 was 1.04 ± 0.31 in the treatment group and 0.20 ± 0.33 in the control group ( P < 0.001). At week 52, statistical significance was observed in the treatment group compared with control for △height (10.19 ± 1.47 cm vs. 5.85 ± 1.80 cm; P < 0.001), △BA/CA (0.04 ± 0.09 vs. 0.004 ± 0.01; P < 0.001), △HV (5.17 ± 3.70 cm/year vs. 0.75 ± 4.34 cm/year; P < 0.001), and △IGF-1 SDS (2.31 ± 1.20 vs. 0.22 ± 0.98; P < 0.001). The frequencies of treatment-emergent adverse events (TEAEs) were similar for the treatment and the control groups (89.8% vs. 82.4%); most TEAEs were mild to moderate in severity and 23 AEs were considered study-drug related., Conclusions: Daily subcutaneous administration of somatropin at 0.05 mg/kg/day for 52 weeks demonstrated improvement in growth outcomes and was well tolerated with a favorable safety profile., Trial Registration: ClinicalTrials.gov (identifier: NCT03635580). URL: https://clinicaltrials.gov/ct2/show/NCT03635580., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yuan, Fu, Wei, Zhang, Xiao, Du, Gu, Li, Chen, Luo, Zhong and Gong.)

Objectives: The safety of recombinant human growth hormone (rhGH) treatment in childhood and the role of rhGH therapy in promoting tumorigenesis and progression have been the subject of debate for decades. We aimed to systematically assess the relationship between rhGH therapy in children and adolescents and clinical outcomes, including all-cause mortality, cancer mortality, cancer incidence, and risk of the second neoplasm., Methods: Literature retrieval, study selection, and data extraction were completed independently and in duplicate. Effect-size estimates are expressed as standardized mortality ratios (SMRs), standardized incidence ratio (SIR), and relative risk (RR) with a 95% CI., Results: Data from 24 articles, involving 254,776 persons, were meta-analyzed. Overall analyses revealed the association of rhGH therapy was not statistically significant with all-cause mortality (SMR = 1.28; 95% CI: 0.58-2.84; P = 0.547; I 2 = 99.2%; Tau 2 = 2.154) and cancer mortality (SMR = 2.59; 95% CI: 0.55-12.09; P = 0.228; I 2 = 96.7%; Tau 2 = 2.361) and also cancer incidence (SIR = 1.54; 95% CI: 0.68-3.47; P = 0.229; I 2 = 97.5%; Tau 2 = 0.055). Differences in the geographic region, gender, treatment duration, mean rhGH dose, overall rhGH exposure dose, and initial disease accounted for heterogeneity in the subgroup analyses.P = 0.001; I 2 = 26.7%; Tau 2 = 0.055). Differences in the geographic region, gender, treatment duration, mean rhGH dose, overall rhGH exposure dose, and initial disease accounted for heterogeneity in the subgroup analyses., Conclusion: Our findings indicate that the rhGH therapy is not related to all-cause mortality and cancer mortality and cancer incidence, yet it seems to trigger a second tumor risk. Future prospective studies are needed to confirm our findings and answer the more challenging question regarding the optimal dose of rhGH therapy in children and adolescents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 He, Deng, Wang, Wan, Huang, Zhang and Niu.)

In Japan, a pituitary-extracted human GH (phGH), Crescormon®, was approved for the treatment of pituitary dwarfism in 1975. The Study Group of Pituitary Dysfunction was organized by the Ministry of Health and Welfare (MHW) in 1973 and prepared the "Diagnostic Handbook: Pituitary Dwarfism" guidelines in 1974. Eligibility assessments for phGH treatment were conducted by the research group on pituitary dwarfism (later the Foundation for Growth Science [FGS] GH Treatment Eligibility Assessment Committee); however, there were 200-300 patients on the waiting list. GH treatment has been financially supported by the Grant-in-Aid Program for Chronic Diseases in Childhood, MHW, since 1974. In 1984, phGH was discontinued in the United States due to reports of the onset of Creutzfeldt-Jakob disease in patients treated with phGH. Japan approved the use of methionyl hGH in 1986 and recombinant hGH in 1988. As a result, the phGH disappeared from the market. The role of the Eligibility Assessment Committee of the FGS shifted to the provision of second opinions about diagnoses and treatment appropriateness. Since then, the indications for GH treatment of pediatric growth disorders have expanded to include other pediatric growth disorders such as Turner syndrome, achondroplasia/hypochondroplasia, etc., Competing Interests: The author has received consultation fees/honoraria from JCR Pharmaceuticals and has received honoraria from Pfizer., (2022©The Japanese Society for Pediatric Endocrinology.)

Objectives: Some idiopathic short stature (ISS) patients may have varying degrees of insulin-like growth factor 1 (IGFI) deficiency. Others with growth hormone deficiency (GHD) (peak GH < 7 ng/dL after provocation) have normal IGFI levels. Do children with ISS or those with GHD with variable pretreatment IGFI standard deviation score (IGFISDS) have different IGFI and growth responses to recombinant human growth hormone (rhGH) therapy?, Methods: We studied the effect of GH therapy (0.035-0.06 mg/kg/day) on linear growth and weight gain per day (WGPD) in children with ISS (n=13) and those with GHD (n=10) who have low pretreatment IGFISDS (IGF SDS < -1.5) and compared them with age-matched prepubertal children with ISS (n=10) and GHD (n=17) who had normal pretreatment IGFISDS. An untreated group of children with ISS (n=12) served as a control group., Results: At presentation, the height standard deviation score (HtSDS) of children with ISS who had low pretreatment IGFISDS was significantly lower compared to the normal IGFI group. The age, body mass index (BMI), BMISDS, peak GH response to clonidine provocation and bone age did not differ between the two study groups. After 1 year of treatment with rhGH (0.035-0.06 mg/kg/day) IGFISDS increased significantly in both groups (p<0.05). Both had significantly increased HtSDS (catch-up growth). The increase in the HtSDS and WGPD were significantly greater in the lower pretreatment IGFISDS group. The IGFSDS, BMISDS, HtSDS and difference between HtSDS and mid-parental HtSDS were significantly greater in the rhGH treated groups vs. the not treated group. In the GHD groups (normal and low IGFISDS), after 1 year of GH therapy (0.03-0.05 mg/kg/day), the HtSDS increased significantly in both, (p<0.01). The WGPD and increment in BMI were significantly greater in children who had low pretreatment IGFISDS. There was a significant increase in the IGFSDS in the two treated groups (p<0.05), however, the WGPD was greater in the pretreatment low IGFISDS., Conclusions: IGFI deficiency represents a low anabolic state. Correction of IGFI level (through rhGH and/or improved nutrition) in short children (ISS and GHD) was associated with increased linear growth and WGPD denoting significant effect on bone growth and muscle protein accretion., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Context: Recombinant human growth hormone (rhGH) is approved for treatment of pediatric growth hormone deficiency (GHD), with greatest growth responses observed in those with severe GHD. Orally administered GH secretagogues (GHS) may be useful treatment in patients with moderate GHD. Distinguishing children with severe vs moderate GHD could identify children who would be better treated with rhGH or GHS., Objectives: Evaluate baseline insulin-like growth factor-I (IGF-I) and stimulated peak GH response as predictors of 12-month height velocity (HV) in children with GHD., Design: Data on children with GHD were analyzed in a legacy data base (GeNeSIS data)., Participants: 514 naïve to rhGH-treatment, prepubertal children with idiopathic isolated GHD for whom stimulated GH, baseline serum IGF-I, and first-year HV during rhGH treatment data are available., Outcome Measures: Children with severe or moderate GHD were categorized based on GH and IGF-I data and evaluated based on baseline auxologic and hormone profiles and first-year growth response to rhGH., Results: Cohorts of severe and moderate GHD were 81/514 (15.8%) and 433/514 (84.2%). Cohorts differed significantly with regard to indicators of GHD [eg, baseline height SD score (SDS), height SDS minus target height SDS, HV, HV SDS, and change in height SDS during rhGH treatment]. Multiple regression analysis showed IGF-I and stimulated GH were significant predictors of HV independent of other known variables. Expected first-year HV in moderate GHD was 8.3 cm/y., Conclusions: The combination of peak GH to GH stimulation testing and baseline IGF-I concentration are predictive enrichment markers for annualized HV responses to rhGH therapy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: X-linked hypophosphataemic rickets (XLHR) is the most common form of hypophosphataemic rickets (HR), which is caused by mutations in the PHEX gene. The aim of this work was to investigate the clinical phenotype, therapeutic strategies, and molecular background of HR in children hospitalised in our clinic., Material and Methods: Eleven patients aged 5.7-18.25 years were included in this study. Molecular analysis was performed using polymerase chain reaction (PCR) and direct sequencing. The PHEX gene was examined in all of the patients, whereas the FGF23 gene was analysed in 5 patients. All of them were treated with alphacalcidol and phosphorus, and 3 were additionally treated with recombinant human growth hormone (rhGH)., Results: The mean age at HR diagnosis was 4.05 ± 3.35 years. The mean htSDS was -2.99 ± 1.19. In 2 of the 3 patients treated with rhGH the height gain was +0.4SD and +0.3SD, respectively. In 10 of 11 patients, PHEX gene mutations were found. In 2 children, novel mutations in the PHEX gene were identified: c.325&#95;326dupCA, N110Ifs*7 in one patient and c.899&#95;900delTG, M300Kfs*4 in the remaining one, which coexisted with a known polymorphism c.1769-10C > T, rs3752433. In one patient, a novel deletion of exon 14 and 2 polymorphisms were detected: c.1646-46T > C, g.180417T > C, rs3213493 in intron 15 (known) and g.189156C > T in intron 17 (novel)., Conclusion: We report 3 novel mutations in the PHEX responsible for HR. Additionally, this study reports the effects of rhGH therapy for growth promotion in HR.

Introduction: A recent systematic review found that up to 71% of children with growth hormone deficiency and their families are non-adherent to treatment as prescribed. A key way to better understanding the complex issue of pediatric non-adherence is to explore the perceptions and experiences of the parent/caregiver. Our study is the first to look specifically at the potentially modifiable factors that influence non-adherence to rhGH treatment amongst parents/caregivers of children with this endocrine disorder., Methods: Fourteen semi-structured telephone interviews were conducted to explore parents/caregivers' perceptions and experiences of their child's condition and prescribed treatment, in addition to their perceived relationship with their healthcare professional. The findings were thematically analyzed and narratively synthesized, in line with the qualitative approach of Braun and Clarke (2006)., Results: Potentially modifiable factors that influence non-adherence to growth hormone treatment were grouped under four themes: 1. Device Burdens, 2. Treatment Considerations, 3. Logistical Interferences and 4. Interpersonal Influences., Conclusion: Our exploratory study presents the wide range of potentially modifiable factors that influence the way in which growth hormone treatment is used. These findings can, in turn, be used to inform and promote the development of targeted, adherence-focused interventions, to support growth hormone deficient children and their families and optimize the use of prescribed growth hormone treatment within endocrine clinical practice., Competing Interests: Professor John Weinman received an unrestricted educational grant from Merck Serono Ltd., which funded the research reported in this paper. Professor John Weinman has also received fees from Merck Serono Ltd., for conference presentations. The authors report no other conflicts of interest in this work., (© 2020 Graham et al.)

Objectives: Idiopathic short stature (ISS) is a recognized, albeit a controversial indication for treatment with recombinant human growth hormone (rhGH).The objective of the present study was to conduct a systematic review of the literature and meta-analyses of selected studies about the use of rhGH in children with ISS on linear growth and adult height (AH)., Methods: A systematic literature search was conducted to identify relevant studies published till February 28, 2017 in the following databases: Medline (PubMed), Scopus and Cochrane Central Registry of Controlled Trials. After exclusion of duplicate studies, 3,609 studies were initially identified. Of those, 3,497 studies were excluded during the process of assessing the title and/or the abstract. The remaining 112 studies were evaluated further by assessing the full text; 21 of them fulfilled all the criteria in order to be included in the current meta-analysis., Results: Children who received rhGH had significantly higher height increment at the end of the first year, an effect that persisted in the second year of treatment and achieved significantly higher AH than the control group. The difference between the two groups was equal to 5.3 cm (95% CI: 3.4-7 cm) for male and 4.7 cm (95% CI: 3.1-6.3 cm) for female patients., Conclusion: In children with ISS, treatment with rhGH improves short-term linear growth and increases AH compared with control subjects. However, the final decision should be made on an individual basis, following detailed diagnostic evaluation and careful consideration of both risks and benefits of rhGH administration., (© 2020 Walter de Gruyter GmbH, Berlin/Boston.)

Aim: Protein quantitation by digestion of a biological sample followed by LC-MS analysis of a signature peptide can be a challenge because of the high complexity of the digested matrix. Results/methodology: The use of LC with high-resolution (quadrupole-TOF) MS detection allowed quantitation of the 22-kDa biopharmaceutical somatropin in 60 μl of rat plasma down to 25 ng/ml with minimal further sample treatment. Reducing the mass extraction window to 0.01 Da considerably decreased the interference of tryptic peptides, enhanced sensitivity and improved accuracy and precision. Analysis with LC-MS/MS resulted in a less favorable limit of quantitation of 100 ng/ml., Conclusion: HRMS is an interesting option for the quantitation of proteins after digestion and has the potential to improve sensitivity with minimal method development.

Introduction: Recombinant human growth hormone (rhGH) is the first biosimilar drug approved by the European Medicines Agency in 2006, using the biosimilar registration process. It was authorised for the treatment of growth hormone deficiency, and growth disorders associated with Turner's syndrome, chronic renal failure, Prader-Willi syndrome, and growth disorders in children/adolescents born small for gestational age, and replacement therapy in adults with pronounced growth hormone deficiency., Materials and Methods: This review is focused on the scientific evidence published about this drug in the last ten years, including the clinical trials on which the approval of the regulatory authority is based, and the most relevant studies evaluating the clinical impact of the drug in clinical practice., Results: The equivalence between biosimilar and original product has been confirmed in the clinical trials published by Romer et al. and López-Siguero et al. Furthermore, studies carried out in real-life conditions confirm its long-term efficacy and safety, as well as the absence of clinical impact by switching treatment from the original to the biosimilar product., Conclusion: The number of patients receiving this medication has continuously increased since its approval. Its equivalence with the original product has been verified. Preliminary data from the post-authorisation PATRO study confirm the efficacy and safety of the biosimilar product in comparison with data from clinical trials. However, final results must be evaluated at the end of the study, which will provide additional information about the long-term efficacy and safety of the biosimilar drug., (Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

ABSTACT Recombinant human Growth Hormone (rhGH) is an important protein for human growth and is in high demand in clinics. Hence, it is necessary to develop an efficient fermentation process to produce highly pure rhGH. In this study, rhGH was expressed in Escherichia coli under alkaline phosphatase (phoA) promoter. The cultivation conditions for high expression level and purity of rhGH were investigated. The best initial phosphate concentration for rhGH expression, out of the 4 levels of initial phosphate concentration tests performed, was 12.6 mmol/L. Subsequently, 2 fed-batch cultivations under low dissolved oxygen (DO) (0% - 10%) and high DO (20% - 30%) conditions were carried out. High purity rhGH (92%) was obtained from 20% - 30% DO-stat cultivation, although the biomass did not show any significant difference. In summary, this research provided an efficient fermentation process for high purity rhGH production from E. coli under phoA promoter, which can lower the production and purification costs for large-scale production of rhGH.

The kidneys are thought to play an important role in the clearance of recombinant human growth hormone (rhGH), but the relative importance is not clear. Obtaining knowledge of clearance pathway is an important prerequisite for the development of new long acting growth hormone analogues targeted at treatment of patients with growth hormone disorders. The purpose of this study was to investigate the relative importance of the kidneys in the clearance of rhGH. The study employed a newly validated nephrectomy rat model and a population based pharmacokinetic approach to assess renal clearance of rhGH in non-anesthetized rats, anesthetized rats and in nephrectomized anesthetized rats. Clearance in non-anesthetized rats was 290 ml/h/kg. This was reduced to 185 ml/h/kg by anesthesia and further reduced to 18 ml/h/kg by nephrectomy. As nephrectomy was able to reduce clearance with 90%, we conclude that renal clearance plays a pivotal role in the elimination of rhGH in rats., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To explore linear growth, puberty, and predictors of linear growth impairment among pubertal liver transplant recipients., Study Design: Review of data collected prospectively through the Studies of Pediatric Liver Transplantation registry. Thirty-one variables were tested as risk factors for linear growth impairment, and factors significant at P < .1 were included in a logistic regression model. Risk factor analysis was limited to 512 patients who had complete demographic and medical data., Results: A total of 892 patients surviving their first liver transplant by >1 year, with ≥ 1 height recorded, who were between 8 and 18 years old between the years 2005 and 2009 were included. Median follow-up was 70.2 ± 38.6 months, mean age was 12.9 ± 3.3 years, and mean height z-score (zH) was -0.5 ± 1.4 SD. Twenty percent had linear growth impairment at last follow-up. Of 353 subjects with Tanner stage data, 39% of girls and 42% of boys ages 16-18 years were not yet Tanner 5. Growth impairment rates were higher among boys than girls (30% vs 7%, P < .05) at Tanner stage 4, and occurred in 8/72 (11%) of Tanner 5 subjects. Among patients with parental height data, zH were lower than calculated mid-parental zH (P < .005). Independent predictors of growth impairment included linear growth impairment at transplant (OR 11.53, P ≤ .0001), re-transplantation (OR 4.37, P = .001), non-white race (P = .0026), and primary diagnosis other than biliary atresia (P = .0105)., Conclusions: Linear growth impairment and delayed puberty are common in pubertal liver transplant recipients, with pre-transplant growth impairment identified as a potentially modifiable risk factor. Catch-up growth by the end of puberty may be incomplete., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Growth hormone treatment for children and adolescents with growth disorders has been used for more than five decades. Since 1985 recombinant human growth hormone (rhGH) is the only drug approved for treatment. In most of the countries rhGH is licensed for the treatment of children with growth hormone deficiency, Turner syndrome, Prader-Willi syndrome, chronic renal failure, and children born small for gestational age. The objective of the treatment is to improve the growth of these patients. The efficacy of rhGH treatment based on auxologic parameters has shown that growth response is variable and mostly dependent on each particular indication. Most of the reports on drug safety obtained from different databases that included thousands of patients, have shown that rhGH is a safe drug and that serious adverse events are rare. Regarding new indications to improve height in children, data on efficacy remains controversial, so we believe their ultimate indication must take into account potential risk versus benefits of this treatment.