INTRODUCTION:Idiopathic short stature (ISS) is characterized by short stature without identifiable underlying disorders. Long-acting PEGylated recombinant human growth hormone (PEG-rhGH) has emerged as a promising treatment option for ISS children. The objective of this study was to evaluate the long-term efficacy and safety of weekly PEG-rhGH in ISS children. METHODS:This multicenter, open-label, uncontrolled extension study (extension phase) followed the initial 52-week trial (main phase). All subjects received once-weekly PEG-rhGH at 0.2 mg/kg/week with dose adjustment (up to 0.4 mg/kg/week) based on height velocity (HV) and insulin-like growth factor-1 (IGF-1) standard deviation score (SDS). The primary endpoint was change in height SDS (ΔHT SDS) from baseline; secondary endpoints mainly included HV, changes in bone age/chronological age ratio, IGF-1 SDS, and average annual prescribed dose. Safety was evaluated through adverse events and clinical findings. RESULTS:Of 280 children enrolled in extension study, 268 completed 52-week treatment. This analysis included results up to week 104, representing 52-week extension phase following the 52-week main phase. At week 104, the least squares means of ΔHT SDS were 1.52, 1.24, and 1.07 for PEG-rhGH 0.2/0.2 mg/kg/week, 0.1/0.2 mg/kg/week, and 0/0.2 mg/kg/week groups, respectively. The 0.2/0.2 mg/kg/week group maintained significantly greater height improvements. HV was highest in the 0/0.2 mg/kg/week group (9.16 ± 1.33 cm/year), reflecting typical first-year catch-up growth. Mean IGF-1 SDS remained within 2SDS during 2 years. CONCLUSION:Once-weekly PEG-rhGH in children with ISS showed sustained efficacy over 2 years in all assessed height-based outcomes. Treatment remained safe and well tolerated with no new safety signals.

BACKGROUND:Nijmegen breakage syndrome-like disorder (NBSLD) is a rare chromosomal instability syndrome caused by biallelic pathogenic variants in RAD50, which is a key component of the MRE11-RAD50-NBS1 (MRN) complex involved in DNA double-strand break repair. Merely few cases have been reported worldwide, and its phenotypic spectrum remains incompletely defined. CASE PRESENTATION:We report a 6-year-old Chinese boy, who presented with bilateral cryptorchidism, severe microcephaly, growth retardation, multiple café-au-lait macules, brachydactyly, and distinctive craniofacial features, including a sloping forehead, midface prominence, and receding mandible. Mild intellectual impairment was confirmed on formal neurocognitive testing. The immunological assessment revealed borderline lymphopenia without overt immunodeficiency. GENETIC FINDINGS:Whole-exome sequencing (WES) identified compound heterozygosity for two variants in RAD50 (NM_005732.3): a paternally inherited frameshift variant c.2165_2166insT (p.Lys722Asnfs*6) and a maternally inherited splice-site variant c.3752 + 4_3752 + 7dup. The minigene splicing assay revealed that the latter disrupts normal splicing, leading to partial intron retention and a premature stop codon (p.Ile1252*). DIAGNOSIS AND TREATMENT:Based on the clinical features and molecular confirmation, the patient was diagnosed with NBSLD. Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a potential therapeutic option for DNA damage repair disorders. However, it is not presently required for this patient, who is managed with regular surveillance. OUTCOME AND SIGNIFICANCE:The present case expands the clinical and mutational spectrum of RAD50-associated NBSLD. It emphasizes the importance of combining clinical assessment, genomic analysis, and functional assays for the accurate diagnosis of rare chromosomal breakage disorders.

Idiopathic short stature (ISS), a common cause of unexplained growth failure in children, remains poorly characterized at the genetic level. This study aimed to investigate the contribution of rare variant burdens in growth-related genes and pathways to the etiology of ISS using next-generation sequencing and gene-based burden testing, thereby identifying novel genetic contributors to the polygenic landscape of ISS. We analyzed 212 pediatric patients with short stature who remained undiagnosed following trio-based whole-exome sequencing. The comparison cohort included 352 healthy adults with normal stature and 4327 internal samples from the Exome Aggregation Consortium database. Gene-based burden testing was performed using an optimized TRAPD (testing rare variants using public data) framework. Functional enrichment analyses, including Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway analyses, were conducted to delineate the biological processes associated with the identified candidate genes. Under a dominant inheritance model, 3907 genes were significantly enriched in rare variants (P < 0.05), whereas 85 genes were significantly enriched under a recessive model (P < 0.05). The top 10 most significantly associated genes identified through primary modeling included FCGBP, FRAS1, MPDZ, and OBSCN, among which highly significant signals were identified (P < 1 × 10−⁹). Pathway analyses revealed enrichment in steroid hormone biosynthesis, ascorbate and aldarate metabolism, pentose and glucuronate interconversions, and porphyrin metabolism. Key genes such as OBSCN, FRAS1, and MPDZ were involved in multiple enriched pathways. This study implicates rare variant burdens in growth-related genes as contributors to ISS pathogenesis, highlighting key genes (OBSCN, FCGBP, FRAS1, and MPDZ) and pathways involved. These findings suggest that the dysregulation of hormonal signaling, the extracellular matrix, and muscle-skeletal interactions impairs linear growth, suggesting potential diagnostic and therapeutic targets for ISS.

Disclosure: J. Chen: None. Y. Lv: None. H. Du: None. Y. Ma: None. L. Han: None. F. Luo: None. G. Li: None. L. Chen: None. B. Cao: None. M. Qin: None. C. Su: None. L. Wei: None. Q. Wang: None. P. Li: None. Z. Xu: None. R. Xie: None. X. Chen: None. H. Wu: None. J. Xia: Jing Xia is employee of Changchun GeneScience Pharmaceutical Co., Ltd. D. Pang: Dongqing Pang is employee of Changchun GeneScience Pharmaceutical Co., Ltd.. C. Gong: None. Objective: To evaluate the efficacy and safety of weekly PEGylated recombinant human growth hormone (PEG-rhGH, Jintrolong) over 3-year in prepubertal children with Turner Syndrome (TS). Methods: This multicenter, randomized, negative-controlled phase 2 study (NCT03189160) included a 52-week main phase followed by an ongoing open-label extension. Prepubertal patients with genetically confirmed TS, bone age <12 years, height≤-2.5 SD for age, and no prior GH therapy were randomized 1:1:1 across 8 centers to receive weekly subcutaneous Jintrolong at 0.1 mg/kg, 0.2 mg/kg, or no treatment with monitoring only. Patients completing the main phase entered the open-label extension, during which all received Jintrolong (0.1-0.4 mg/kg/week). Doses were adjusted every 13 weeks based on annualized height velocity (AHV), IGF-1 SDS, and clinical guidelines. Treatment continued until near-adult height, with follow-up every 26 weeks thereafter until final height was attained. The primary endpoint was change in height SDS (HT-SDS) calculated using the LMS method from baseline at Week 52 and every 52 weeks during extension. Other growth-related parameters and safety were also evaluated. Results: A total of 177 patients were included in the main phase analysis, and 170 in the extension phase. The mean (SD) age at baseline was 7.87 (3.01) years, and mean HT-SDS was -3.33 (0.63). At Week 52, mean (SD) changes in HT-SDS from baseline were -0.07 (0.29) in the control group, 0.28 (0.35) in the 0.1 mg/kg/week group, and 0.60 (0.41) in the 0.2 mg/kg/week group. Both treatment groups showed significantly improvement compared with control (p<0.0001 for each), and the 0.2 mg/kg/week group improved significantly than the 0.1 mg/kg/week group (p<0.0001). After two years of extension (Year 3 overall), mean (SD) increases in HT-SDS from baseline were 0.81 (0.68) and 1.15 (0.63) in the 0.1 and 0.2 mg/kg/week groups, respectively, indicating sustained benefit, particularly in patients initially received the higher dose. AHV in both Jintrolong groups peaked at Week 52 and gradually declined over time but remained above baseline at Week 104 and Week 156. During the extension, 84.1% of patients (143/170) underwent dose escalation. The incidence of adverse events (AEs) and treatment adherence were comparable across groups during the main phase. Most AEs during long-term treatment were mild to moderate and consistent with the known GH safety profile. Conclusion: Weekly Jintrolong at 0.1 to 0.4 mg/kg/week provided sustained and clinically meaningful growth improvements over 3 years in girls with TS. Most patients required dose escalation after the first year to achieve optimal growth velocity. This dosing range was appropriate for most patients and associated with a favorable long-term safety profile. Jintrolong offers a convenient long-acting formulation for managing short stature associated with TS. Presentation: Saturday, July 12, 2025

Background:Brachydactyly type E (BDE) is characterized by variable shortening of metacarpals or metatarsals, often involving phalanges. It may occur as an isolated anomaly or as part of congenital syndromes. With advancements in molecular diagnostic technologies, how genetic testing enhances the precise diagnosis of BDE remains unclear. Our aims were to establish an algorithm for molecular genetic diagnostics in Chinese children with BDE and to explore the phenotype-genotype correlations of Chinese patients with BDE. Methods:We reviewed left-hand wrist X-rays from children visiting Children's Hospital of Soochow University (Jun 2021-Dec 2023). From 60,650 films, 135 BDE cases were identified, and their comprehensive phenotypes were collected. Whole-exome sequencing (WES) with copy number variation (CNV) analysis was performed on 60 patients and their parents. Sanger sequencing was used to validate single nucleotide variants (SNV) and indels. Results:Causative variants were found in 19 patients. SNVs and indels affecting 10 genes were identified in 15 patients, and CNVs in four. GNAS mutations were the leading cause (four cases), followed by EXT1 and ACAN defects. The diagnostic yield was 19.1% in patients with isolated brachydactyly; 75% in patients with brachydactyly combined with short stature; 77.8% in patients with brachydactyly combined with facial dysmorphism; 83.3% in patients with brachydactyly combined with intellectual disability. Conclusion:Through comprehensive evaluation of genotype-phenotype correlations, we propose a diagnostic algorithm for precise molecular diagnosis in Chinese children with BDE.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations of MC2R, MRAP, STAR, NNT, and TXNRD2 have been implicated in FGD pathogenesis. To date, only four families with TXNRD2-associated familial Glucocorticoid Deficiency Type 5 (FGD5) have been reported worldwide. We report a patient with clinical features consistent with FGD5, increasing the total number of reported cases. Including this case, 11 probands across five independent kindreds have now been identified globally. Functional studies demonstrated that the novel compound heterozygous variants (c.1391A > G; p.H464R and c.1141C > T; p.R381W) reduce TXNRD2 protein levels in a heterologous expression system. This case expands the genetic spectrum of FGD5 and suggests a potential association between TXNRD2 variants and electrocardiographic abnormalities. Our findings underscore the importance of TXNRD2 in adrenal redox homeostasis and provide new insights for FGD5 diagnosis.

PURPOSE:Due to disease progression and drug resistance, non-small cell lung cancer(NSCLC) mortality remains high, and the study of new targets that can inhibit tumor growth is very necessary. The purpose of this study was to investigate the role of Rab5if in the occurrence and development of NSCLC and explore its potential role in the treatment of NSCLC. MATERIALS AND METHODS:Rab5if overexpression and knockdown non-small cell lung cancer cell lines were constructed by lentivirus. Cellular assays were conducted to assess the impact of Rab5if on the functionality of lung cancer cells, The mechanism by which Rab5if influences the function of lung cancer cells was confirmed through Western blot analysis. The in vivo experiment was used to further verify the results of the in vitro experiment. RESULTS:Bioinformatics research found Rab5if mRNA increased in patients with NSCLC. Increased mRNA and protein levels of Rab5if were confirmed in local human NSCLC tissues. Knockdown of Rab5if in NSCLC cell lines by lentivirus significantly inhibited cell vigour, propagation and migration. In addition, mitochondrial function was impaired in lung cancer cells after Rab5if knockdown. In contrast, Rab5if overexpression promoted the proliferation and migration of NSCLC. Moreover, the impact Rab5if on the function of lung cancer cells was realized through the AKT-mTOR pathway. In the in vivo study, growth inhibition were observed in lung cancer xenografts transfected with Rab5if shRNA in nude mice. Similarly, xenografts of nude mice overexpressing Rab5if grew rapidly. The same pathway as in vitro was confirmed in vivo. CONCLUSION:Rab5if is expected to be a novel therapeutic target for NSCLC.

Maternal exposure to polystyrene nanoplastics (PS-NPs) during pregnancy and lactation has been linked to adverse effects on offspring kidney development, with sex-specific outcomes. This study investigated the impact of maternal PS-NPs exposure on kidney weight, histology, transcriptomics, and functional pathways in offspring mice. Offspring exposed to PS-NPs exhibited significantly lower body weight (P < 0.05) and an increased kidney-to-body weight ratio (P < 0.05), particularly in males. Histological analysis revealed a reduction in glomerular number in PS-NP-treated groups. Transcriptome profiling identified 758 differentially expressed genes (DEGs) in male and 101 DEGs in female offspring, with males showing a more pronounced alteration in gene expression. KEGG pathway enrichment highlighted disruptions in immune response, cell cycle regulation, and metabolism, with males exhibiting more extensive pathway changes than females. Additionally, PS-NPs exposure increased renal fibrosis (P < 0.05), with molecular analyses confirming sex-specific gene expression patterns linked to fibrosis and apoptosis. Immunohistochemical analysis revealed enhanced macrophage infiltration and cleaved caspase-3 expression, indicating heightened immune and apoptotic responses in males. Further investigation identified small molecules BI-D1870 and Resatorvid as potential therapeutic agents, reducing fibrosis, inflammation, and apoptosis in male and female offspring, respectively. These findings demonstrate that maternal PS-NPs exposure induces sex-specific kidney injury in offspring, disrupting key biological processes and pathways. The study underscores the need for targeted therapeutic interventions to mitigate these effects and highlights potential compounds for future treatment.

IntroductionMaternal diet is a key determinant of fetal organ development, and excessive salt intake has been increasingly linked to long-term metabolic disorders. This study investigated the effects of maternal high-salt diet (HSD) on offspring liver health, with a focus on sex-specific structural and molecular alterations.MethodsPregnant C57BL/6J mice were fed either standard chow or an HSD (4% NaCl) during gestation and lactation. At 4 weeks of age, offspring livers were analyzed using histology, RNA sequencing, immunofluorescence, and biochemical assays. Connectivity Map (CMap) was applied to identify candidate therapeutic compounds.ResultsMaternal HSD significantly increased liver weight and hepatocyte size in offspring, with more pronounced effects in males. RNA sequencing identified 466 differentially expressed genes (DEGs) in males and 309 in females, indicating sex-dependent dysregulation of pathways related to metabolism, fibrosis, inflammation, and apoptosis. Masson's trichrome staining revealed increased collagen deposition, particularly in males, consistent with transcriptomic signatures of fibrosis. Immunofluorescence confirmed upregulation of apoptosis-related markers. CMap analysis identified potential therapeutic agents, including ketoprofen and BRD-K88741031, which alleviated HSD-induced hepatic injury in preliminary validation.DiscussionMaternal high-salt intake induces sex-specific structural and molecular liver injury in offspring, highlighting the developmental origins of liver disease. These findings emphasize the importance of maternal nutrition in shaping offspring hepatic health and suggest potential pharmacological strategies to counteract early-life dietary insults.

As a key regulatory enzyme in mitochondria, YME1L is crucial for regulation of mitochondrial dynamic balance and metabolic plasticity in tumors. Yet its role in non-small cell lung cancer (NACLC) and underlying mechanism are still unclear. In this study, we found YME1L was highly expressed at both protein and RNA levels in NSCLC tissues, which was consistent with the result of database analysis. The bioinformatics analysis also showed that YME1L expression negatively correlated with survival rate. The significance of YME1L was investigated through gain- and loss-of-function studies in vivo and vitro. As expected, the protease activity was consistent with the expression of YME1L. Knockdown of YME1L significantly inhibited mitochondrial activity, proliferation and migration of NACLC cell lines, and suppressed the growth of xenografted tumors in nude mice. While over-expression of YME1L promoted the development of tumors. Further study revealed that YME1L increased the proportion of S-phase and reduced the number of G0/G1 ratio in NSCLC cells, suggesting the strong proliferation activity. Mechanically, knockdown of YME1L decreased the expression of Gαi1 and the phosphorylation of Akt, and on the contrary, YME1L over-expression increased the Gαi1 expression and Akt activation, which in turn stimulated cell proliferation, migration and survival, and promoted the progression of NSCLC. In this study, we revealed that YME1L played a novel oncogenic role in promoting NSCLC tumorigenesis and progression via the mitochondria-Gαi1-AKT axis, providing a new target for the treatment of lung cancer.

Circadian rhythms, the body’s intrinsic 24-h cycles, regulate essential physiological processes across multiple organ systems. Disruptions in these rhythms are increasingly recognized as significant contributors to chronic kidney disease and ocular diseases such as glaucoma, dry eye disease, and diabetic retinopathy. This review examines the interconnections between circadian rhythms in kidney and eye health, focusing on shared pathological pathways including oxidative stress, inflammation, and fibrosis. Current therapeutic strategies such as chronotherapy, light therapy, and time-restricted feeding show promise in mitigating disease progression by restoring circadian alignment. This review emphasizes integrated circadian-focused treatments to address these co-morbid conditions, paving the way for novel preventive and therapeutic interventions.

FLNB encodes the protein filamin B(FLNB),which is expressed in chondrocytes of the human growth plate[1].To date,pathogenic mutations in the FLNB gene have solely been found to cause skeletal deformities,indicating the cru-cial role of FLNB in skeletal development.FLNB-related disorders include spondylocarpotarsal synostosis(SCT,OMIM:272,460),Larsen syndrome(LS,OMIM:150,250),atelosteogenesis type I(OMIM:108,720),atelosteogen-esis type Ⅲ(OMIM:108,721),and boomerang dysplasia(OMIM:112,310).

Background:Graves' disease (GD) is an autoimmune thyroid disorder. Our previous study has demonstrated a significant decrease in flavone levels among children with GD compared to the control group. Puerarin, a well-known flavonoid with anti-inflammatory and antioxidant properties. We wanted to investigate its potential impact on GD pathogenesis, aiming to determine whether increasing puerarin intake could prevent or delay the onset of GD.Methods:Adenovirus with TSHR-289 subunit was used to establish a GD mice model, and mice were intragastrically administered with puerarin or sterilized water daily. Thyroid function and inflammatory cytokine levels were quantified using ELISA, lymphocyte subsets were analyzed via flow cytometry, oxidative stress (OS) markers were measured with a microplate reader, and the expression of pertinent signaling pathway proteins were assessed by Western blot.Results:The results demonstrated that puerarin treatment significantly decreased thyroxin levels and alleviated thyroid pathological changes in GD mice. Furthermore, the immune imbalance of GD mice was improved, as evidenced by reduced inflammatory indexes, elevated antioxidant levels, and decreased malondialdehyde (MDA) levels compared to untreated GD mice. Puerarin-treated GD mice exhibited significantly lower expressions of heat shock protein (HSP): HSP70, HSP90, phosphorylated extracellular regulated kinases (p-ERK) and phosphorylated protein kinase B (p-AKT) than untreated GD mice. Moreover, low dosage puerarin (400 mg/kg) was associated with a better protective effect than high dosage (1,200 mg/kg).Conclusions:Puerarin may have the potential to mitigate GD by inhibiting inflammatory and OS, through downregulating the expression of HSP70 and HSP90 and suppressing the activation of the PI3K/AKT/ERK signaling pathway. Furthermore, a lower dose exhibited superior protective effects compared to a higher dose.

Globally, plastic pollution threatens human health, particularly affecting the hearts of offspring exposed to maternal environmental factors early in development. Few studies have specifically addressed sex-specific cardiac injury in offspring resulting from maternal exposure to polystyrene nanoplastics (PS-NPs). This study investigates the potential cardiac injury in offspring following maternal exposure to 1 mg/L PS-NPs. Pregnant C57BL/6J mice were exposed to PS-NPs until 3 weeks postpartum to establish a maternal exposure model. Heart tissues were collected and weighed, and the transcriptomes of the offspring hearts were sequenced and analyzed using high-throughput RNA sequencing. Immunohistochemical staining was performed to assess the effects of PS-NPs on cardiac immune infiltration, fibrosis, and apoptosis in the offspring. PS-NPs caused a significant reduction in heart and body weight in female offspring compared to males. Additionally, PS-NPs induced sex-specific transcriptional reprogramming and metabolic disruptions in the offspring. PS-NPs also induced significant fibrosis, apoptosis, and increased CD68+ macrophage infiltration in offspring hearts. Notably, PS-NPs induced distinct cardiovascular diseases in the offspring. Fluid shear stress and atherosclerosis were significantly enriched in PS-NP-treated male offspring, while viral myocarditis was predominantly enriched in PS-NP-treated females. Our findings suggest that PS-NPs induce cardiotoxicity in offspring by disrupting metabolism, impairing immunity, and triggering fibrosis and apoptosis, with sex-specific differences. This study provides novel insights and a foundation for understanding sex-specific pharmacological differences and interventions in PS-NP-induced cardiovascular disease in offspring.

OBJECTIVE:To explore the clinical manifestations and genetic characteristics of patients with congenital central hypothyroidism due to variants of IGSF1 gene.METHODS:Clinical data, results of genetic testing, and follow-up of four patients admitted to Children's Hospital of Soochow University during 2017 to 2021 were retrospectively analyzed.RESULTS:All of the four patients were males. Patient 1 had presented neonatal jaundice, patients 2 and 3 were admitted for growth retardation during childhood, and thyroid function test indicated slightly low free thyroxine (FT4), patient 4 was found to have reduced FT4 in the neonatal period. Genetic testing revealed that all of the four patients have harbored pathogenic variants of the IGSF1 gene, which were all inherited from their mothers. The thyroid functions in all patients were well controlled with oral levothyroxine and regular follow-up.CONCLUSION:Pathogenic variants of the IGSF1 gene probably underlay the congenital central hypothyroidism with a variety of clinical manifestations, and genetic testing can facilitate the diagnosis at an early stage.

目的 探讨儿童矮小症的遗传学病因.方法 选取2017年1月—2020年10月因生长缓慢就诊的矮小症患儿为研究对象.行矮小相关基因的全外显子测序,对发现的可能的染色体片段拷贝数变异者进一步完善基因芯片检查,比较基因检测阳性与阴性组之间临床表型差异.结果 共纳入186例矮小症患儿,中位年龄7.3(5.1～9.1)岁,男103例、女83例.共检测出69例阳性结果,阳性检出率37.1％.其中54例通过全外显子基因测序诊断,15例通过染色体微阵列分析诊断.二元logistic回归分析显示,特殊面容和骨骼发育异常是儿童矮小症基因检测结果阳性发生的预测因素(P均<0.05).结论 全外显子测序是检测儿童矮小症遗传病因的有效技术手段,伴有特殊面容和/或骨骼发育异常的患儿更可能检测到遗传病因.

Background:Globally, a high-salt diet (HSD) has become a threat to human health as it can lead to a high risk of cardiac damage. Although some studies investigating HSD have been carried out, the majority has been conducted in males, and there are few female-specific studies, thereby ignoring any effects of sex-specific damage on the heart. In this study, we determined how HSD induces different pathways of cardiovascular diseases through sex-specific effects on cardiac damage in mice.Methods:An HSD murine model of male and female C57BL/6J mice was fed with sodium-rich chow (4% NaCl). After 8 weeks, cardiac tissues were collected, and the whole gene transcriptome of the hearts of male and female mice was characterized and analyzed using high-throughput RNA sequencing. Immunohistochemistry staining was used to further assess the harmful effects of HSD on protein expression of genes associated with immunity, fibrosis, and apoptosis in male and female mice.Results:HSD drastically altered the cardiac transcriptome compared to that of the normal heart in both male and female mice and had a sex-specific effect on the cardiac composition in the transcriptome. HSD produced various differentially expressed genes and affected different KEGG pathways of the transcriptome in male and female mice. Furthermore, we found that HSD induced different pathways of cardiovascular disease in the male mice and female mice. The pathway of hypertrophic cardiomyopathy is significantly enriched in HSD-treated male mice, while the pathway of dilated cardiomyopathy is significantly enriched in HSD-treated female mice. Finally, metabolism, immunity, fibrosis, and apoptosis in the mouse heart showed sex-specific changes predicting cardiac damage.Conclusion:Our results demonstrate that HSD adversely impacts cardiac structure and function by affecting the metabolism, immunity, fibrosis, and apoptosis in the murine heart and induces the mouse to suffer from sex-specific cardiovascular disease. This study provides a new perspective and basis for the differences in the pharmacology and interventional treatment of sex-specific cardiovascular diseases induced by HSD in men and women.

Objective:To evaluate the safety and efficacy of weekly PEGylated-recombinant human growth hormone (PEG-rhGH) in children with idiopathic short stature (ISS) in China.Design and methods:This was a multicenter, phase II study in which all subjects were randomized 1:1:1 to weekly s.c. injections of PEG-rhGH 0.1 (low-dose (LD) group) or 0.2 mg/kg/week (high-dose (HD) group) or control for 52 weeks. The primary end point was change (Δ) in height s.d. score (HT-SDS) from baseline to week 52. Secondary end points were height velocity (HV), bone maturity, insulin-like growth factor-1 (IGF-1) SDS, and IGF-1/insulin-like growth factor-binding protein-3 (IGFBP-3) molar ratio.Results:A total of 360 children with ISS were recruited in the study (n = 120 in each group). At week 52, ΔHT-SDS was 0.56 ± 0.26, 0.98 ± 0.35, and 0.20 ± 0.26 in the LD, HD, and control groups, respectively (within-group P < 0.0001; intergroup P < 0.0001). Statistically significant values of ΔHV, IGF-1, IGF-1/IGFBP-3 ratio, and IGF-1 SDS at week 52 from baseline were observed in both treatment groups (P < 0.0001). There were clear dose-dependent responses for all auxological variables. PEG-rhGH was well tolerated throughout the treatment period with treatment-emergent adverse events (TEAEs) reported in 86.5%, 84.6%, and 91.3% of children in the HD, LD, and control groups, respectively. The incidence of TEAEs was similar in all treatment groups despite the difference in doses. A total of 27 (8.7%) children experienced drug-related TEAEs.Conclusion:Fifty-two-week treatment with PEG-rhGH 0.1 or 0.2 mg/kg/week achieved significant improvement in HT-SDS and other growth-related variables, including HV, IGF-1 SDS, and IGF-1/IGFBP-3 ratio, in a dose-dependent manner. Both doses were well tolerated with similar safety profiles.