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Context: Clinical genetic evaluation has been demonstrated as an important tool to elucidate the causes of growth disorders. Genetic defects of collagen formation (the collagenopathies) have been reported to be associated with short stature and skeletal dysplasias. Etiological diagnosis of skeletal abnormality-related short stature is challenging, and less is known about recombinant human growth hormone (rhGH) therapy. Objective: This is a single-center cohort study which aims at exploring the genetic architecture of short-stature children with skeletal abnormalities and evaluating the frequency of collagenopathies to determine their phenotype, including the rhGH treatment response. Patients and Methods: One hundred and six children with short stature and skeletal abnormalities were enrolled who were evaluated by next-generation sequencing (NGS) to detect variants in the skeletal collagen genes including COL1A1, COL1A2, COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1 , and COL11A2. The results were evaluated using American College of Medical Genetics and Genomics (ACMG) guidelines. Clinical characteristics and rhGH treatment response were summarized. Results: Twenty-four pathogenic or likely pathogenic variants of collagen genes were found in 26 of 106 (24.5%) short-stature patients with skeletal abnormalities, of which COL2A1 mutations were the most common, accounting for about 57.7%. Other frequent mutations associated with skeletal development include FGFR3 , ACAN , NPR2 , COMP , and FBN1 in 12.2%, 0.9%, 0.8%, 0.4%, and 0.4%, respectively, resulting in significantly different degrees of short stature. An overview of clinical features of collagenopathies showed growth retardation, skeletal abnormalities, and heterogeneous syndromic abnormalities involving facial, eye, hearing, and cardiac abnormalities. The average height of 9 patients who received rhGH treatment improved from a median of -3.2 ± 0.9 SDS to -2.2 ± 1.3 SDS after 2.8 ± 2.1 years. The most significant height improvement of 2.3 SDS and 1.7 SDS was also seen in two patients who had been treated for more than 6 years. Conclusions: A proband-based NGS revealed that distinct genetic architecture underlies short stature in varying degrees and clinical features. Skeletal abnormality-related short stature involving multiple systems should be tested for skeletal collagen gene mutation. Limited rhGH treatment data indicate an improved growth rate and height, and close monitoring of adverse reactions such as scoliosis is required. [ABSTRACT FROM AUTHOR]

Background: Ring chromosome 15 [r (15)] is an uncommon finding with various clinical manifestations. A common phenotype for these patients has not been established and data on the efficacy of recombinant human growth hormone (rhGH) treatment in patients with r (15) syndrome are limited. Methods: One short stature patient in our hospital with r (15) syndrome by whole exome sequencing (WES) and karyotype examination was included. All published r (15) syndrome cases as of March 15, 2021, were searched, and their clinical information was recorded and summarized. Results: One 11.5‐year‐old female with prenatal and postnatal growth retardation, ventricular septal defect, intellectual disability, downward corners, short fifth metacarpal bone, scattered milk coffee spots, and a right ovarian cyst was included. Her height was 126.9 cm (−3.45 SDS). Karyotype analysis showed 46, XX, r (15). WES revealed a 4.5 Mb heterozygous deletion in the chromosome 15q26.2‐q26.3 region, encompassing genes from ARRDC4 to OR4F15. Gonadotrophin‐releasing hormone analogue (triptorelin) and rhGH were administered for 6 months. The height has increased 3.8 cm (+0.2SDS) and the calculated growth rate has improved from 4.7 to 7.6 cm/y. The literature review indicated the main clinical manifestations of r (15) syndrome with prenatal and postnatal growth retardation, characteristic craniofacial features, and multisystem abnormalities, and rhGH treatment is beneficial for r (15) syndrome patients with short stature. Conclusion: We delineate the clinical spectrum of r (15) syndrome with the identification of an additional individual and rhGH treatment is beneficial for r (15) syndrome patients with short stature. [ABSTRACT FROM AUTHOR]

Introduction: This study described a Chinese case of X-linked acrogigantism (X-LAG) and summarized the characteristics and treatment of all reported cases. Methods: Clinical materials and biological samples from a 5-year and 2-month-old female due to "growth acceleration for 4 years" were collected. Array comparative genomic hybrid (aCGH) and further verification were performed. All X-LAG cases from the PubMed and Web of Science databases were collected and summarized with available data. Results: The patient presented accelerating growth since 1 year, and her height reached 134.6 cm (+5.24 standard deviation score [SDS]) when she was 5-year and 2-month old. She also had coarsening facial features, snoring, and acral enlargement. Growth hormone (GH) was not suppressed by the glucose-GH inhibition test, and insulin-like growth factor 1 (IGF-1) and prolactin (PRL) levels were elevated. Pituitary MRI revealed a pituitary enlargement with a maximum diameter of 22.3 mm. Octreotide imaging indicated the presence of a pituitary adenoma. The tumor shrank slightly after 3 courses of somatostatin analog but without clinical or biochemical remissions, of which the GH nadir value was 9.4 ng/mL, and IGF-1 was elevated to 749 ng/mL. Therefore, she underwent transsphenoidal surgery. Immunohistochemistry showed GH-positive and PRL-positive cells in the pituitary adenoma. Xq26.3 microduplication of the patient's germline DNA was identified by aCGH. Of all 35 reported cases, females accounted for 71.43%. There were 93.10% and 53.83% patients with hyperprolactinemia and hyperinsulinemia, respectively. Pathology showed that 75.00% of cases were adenomas. Ninety percent of cases had germline variants. The clinical and biochemical remission rates were 78.26% and 82.61%, respectively. However, the rate of complication occurrence during therapy reached 80%. Conclusion: It is important to recognize the possibility of X-LAG when a child under 2-year old presents overgrowth. Early diagnosis and treatment are of great importance for better treatment efficacy and clinical outcome. [ABSTRACT FROM AUTHOR]

Purpose: Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder, and cases caused by variants in SMC3 are infrequent. This article describes a case of CdLS related to a pathogenic variant in SMC3 and performs a literature review. Methods: We collected clinical data and biological samples from a 12-year-old boy with "short stature for 11 years". Gene variants in the proband were detected by whole-exome sequencing, and the variants in his parents were verified by Sanger sequencing. All SMC3 -related CdLS patients from the PubMed and Web of Science databases were collected and summarized using the available data. Results: A pathogenic variant in SMC3 in the proband, c.1942A>G, was identified. Neither of his parents carried the same variant. Twenty-eight patients were diagnosed with CdLS with variants in SMC3 , including the cases in this study and those reported in the literature, where half of the variant types were missense, followed by 32% (9/28) with a deletion and 11% (3/28) with a duplication. All patients showed symptoms of verbal development delay and intellectual disability to different degrees, and 90% patients had long eyelashes while 89% patients had arched eyebrows. Conclusion: This study summarized different gene variants in SMC3 and the frequencies of the various clinical manifestations according to the reported literature. For CdLS caused by SMC3 variants, short stature and facial dysmorphic features are the two most important clinical clues. Definite diagnosis of this rare disease may be challenging clinically; thus, it is significant to use molecular diagnosis. [ABSTRACT FROM AUTHOR]

Background: Growth hormone deficiency (GHD) is a developmental disorder in children characterized by low growth hormone (GH), short stature and unfavorable lipid profiles. Familial hypercholesteremia (FH) is an inborn disorder of low-density lipoprotein cholesterol (LDL-C) metabolism which results in premature cardiovascular events. The co-occurrence of GHD and FH, which may aggravate the hypercholesteremic condition in the affected individuals, had rarely been discussed in previous publication. Methods: This work reports two cases of GHD with FH, and explores the lipid profiles of GHD children and their therapeutic response to recombinant human growth hormone (rhGH). The diagnosis of GHD is based on low peak GH level (<7 ng/mL) in GH provocation test. FH is diagnosed by high LDL-C level (≥ 4 mmol/L) and confirmed genetic mutations in the LDL-C metabolic pathway. We also searched all previously published metabolic studies on GHD children as of December 31, 2020. Information on their LDL-C, duration and dose of rhGH treatment were retrieved and summarized. Results: The first case was a 5.3 year-old boy. His height was 103.6 cm (SDS = -2.29) and his peak GH in provocative test was 6.37 ng/mL. Additionally, his LDL-C was 4.80 mmol/L and he harbored a heterozygous mutation for the apolipoprotein B (APOB) gene (c.10579 C > T). The second case was a 9-year-old girl at the height of 117.3 cm (SDS = -2.91). Her GH peaked at 4.99 ng/mL in insulin-induced hypoglycemic test and 2.80 ng/mL in L-dopa test. Her LDL-C was 6.16 mmol/L, and she carried a mutated copy of the low-density lipoprotein receptor (LDLR) gene (c.809 G > A). Literature review indicated that GHD children suffered from higher baseline LDL-C, but it was significantly reduced after rhGH treatment. Conclusions: FH should be considered if a GHD child has remarkably elevated LDL-C that cannot be attributed to low GH level alone. Genetic mutations in the LDL-C metabolic pathway prevent the body from effectively metabolizing lipids, thereby resulting in early-onset hypercholesteremia and probably playing a negative role in children's growth. [ABSTRACT FROM AUTHOR]

Purpose: Laron syndrome (LS) is a severe growth disorder caused by GHR gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized, GHR gene variants were investigated and further in vitro functional verification was carried out. Methods: Four patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, and GHR gene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting. Results: All of the four patients were male, and the median height was -4.72 SDS. Four GHR gene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05). Conclusions: Two novel GHR gene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that the GHR mutations contributed to the pathological condition of LS patients. [ABSTRACT FROM AUTHOR]

Troyer syndrome is an autosomal recessive disease characterized by spastic paralysis, dysarthria, distal amyotrophy, and short stature. Recently, two siblings (an older brother and a younger sister) were admitted to our hospital for the chief complaints of "short stature and intellectual disability." Through whole exome sequencing of the sister, who is the proband, it was found that her SPG20 gene had compound heterozygous mutations: c.364_365delAT (p.Met122Valfs*2) and c.892delA (p.Thr298Glnfs*30). Target testing revealed that the brother had the same genotype as the sister, and the former mutation originated from the father, while the latter mutation originated from the mother. In summary, this is the first report of Troyer syndrome in a family caused by SPG20 compound heterozygous mutations. A novel SPG20 mutation was found, namely c.892delA (p.Thr298Glnfs*30). In addition, we also summarize these Troyer syndrome patients' heights and their clinical characteristics, and provide a brief review of all known pathogenic mutations of SPG20. [ABSTRACT FROM AUTHOR]

Short stature, skeletal abnormalities, collagenopathies, next-generation sequencing, growth hormone treatment Also, in the B Results b , subsection " I Comparison of Collagen Gene-Related Short Stature With Other Short Stature Genes and Growth Response to rhGH Treatment i ", final paragraph, incorrect height Z scores were presented. Keywords: short stature; skeletal abnormalities; collagenopathies; next-generation sequencing; growth hormone treatment EN short stature skeletal abnormalities collagenopathies next-generation sequencing growth hormone treatment 1 1 1 04/08/22 20220406 NES 220406 In the B Results b , subsection " I Comparison of Collagen Gene-Related Short Stature With Other Short Stature Genes and Growth Response to rhGH Treatment i ", paragraph 2 as published originally, B Table 4 b was incorrectly cited. [Extracted from the article]

Background: Irisin plays a role in bone-muscle crosstalk, but the relationship between the serum irisin level and bone microarchitecture remains unknown., Objective: This study aimed to investigate the relationships between serum irisin level and fall risk, muscle strength, bone mineral density (BMD), and bone microarchitecture among Chinese postmenopausal women., Methods: In all 138 postmenopausal women, handgrip strength, short physical performance battery (SPPB), and the timed up-and-go test were performed to evaluate muscle strength, physical performance, and fall risk, respectively. The serum irisin was measured. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed to acquire volumetric BMD and bone microarchitecture. Bivariate analysis was used to explore relationships between serum irisin level and muscle strength and HR-pQCT parameters. Univariate and multivariate linear regression analyses were performed to determine associations between serum irisin level and vBMD and cortical porosity (Ct.Po)., Results: All participants had a median serum irisin level of 3.91 μg/ml. Participants with high fall risk had significantly lower serum irisin levels than those with low fall risk (2.22 μg/ml vs. 4.16 μg/ml, p=0.024). Irisin level was positively related to handgrip strength (rs=0.185, p=0.030) and SPPB performance. In univariate linear regression, serum irisin level was positively associated with cortical volumetric BMD (Ct.vBMD, radius: standardized β=0.184, p=0.031; tibia: standardized β=0.242, p=0.004), but it had no significant associations with Ct.vBMD after multivariate adjustment. After adjusting by age, height, serum sclerostin level, and body fat ratio, only Ct.Po at the distal radius had a significantly negative association with serum irisin level (standardized β=-0.276, p=0.003)., Conclusion: Postmenopausal women with lower serum irisin levels have a higher fall risk, weaker muscle strength, and higher cortical porosity. Moreover, serum irisin level has a positive association with Ct.vBMD, but it is affected by factors such as age., 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 © 2023 Liang, Qi, Jiajue, Chi, Liu, Wang, Li, Xing, Yu, Jiang and Xia.)

Background: Camurati-Engelmann disease (CED) is a sclerosing bone dysplasia caused by transforming growth factor β1 ( TGFB1 ) gene variants., Objective: We aim to summarize the clinical characteristics and the efficacy of glucocorticoids in 14 individuals with CED, and explore the correlation between the phenotype and the SNP of rs1800470 (c.29C>T)., Methods: Clinical, biochemical, radiological, and therapeutic data were collected from 14 patients. DNA was extracted for TGFB1 variants detection by Sanger sequencing., Results: The median onset and record age were 3.0 and 16.1 years, respectively. All patients manifested bone pain and decreased subcutaneous fat tissue. Inflammatory markers increased in over 60% of patients, and the median erythrocyte sedimentation rate (ESR) was 1.40 (0.50~3.67) of the upper limit of normal (ULN), and the median high sensitivity C reactive protein (hsCRP) was 1.71 (0.48~12.56) of ULN. There was a positive correlation between ESR and hsCRP (rs=0.806, p=0.003). Both ESR and hsCRP were negatively correlated with the levels of hemoglobin (HGB), calcium, and creatinine, but positively correlated with the level of alkaline phosphatase. Four known variants of TGFB1 were identified, including p.Tyr171Cys, p.Arg218Cys, p.Arg218His, and p.Cys225Arg. Moreover, 35.7% and 28.6% of them carried the heterozygous and homozygous SNP of c.29C>T, called C/T and T/T groups, respectively, but 35.7% of them were without c.29C>T (C/C group). The onset age, anthropometric data, percentages of different clinical manifestations, and biochemical parameters were comparable among the three groups. But there were increasing trends in levels of HGB and calcium and decreasing trends in ESR and hsCRP among C/C, C/T, and T/T groups in turn. Glucocorticoid improves the two inflammatory markers among CED patients., Conclusion: The phenotype of CED is highly heterogeneous. There is no clear genotype-phenotype correlation, but it seems to have better trends of biochemical parameters in patients with CED carrying the T allele of rs1800470., 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 Liang, Jiajue, Qi, Liu, Chi, Jiang, Wang, Li, Xing and Xia.)

Context: The natriuretic peptide receptor 2 gene (NPR2) is a causative gene of idiopathic short stature (ISS) with an incidence rate of 2% to 6%. The clinical characteristics of patients with NPR2 heterozygous mutations are atypical, and data on the efficacy of recombinant human growth hormone (rhGH) treatment in patients with NPR2 mutations are limited., Objectives: This work reports 6 cases with NPR2 mutation and explores the characteristics of patients with an NPR2 mutation and their therapeutic response to rhGH., Design, Settings, and Patients: Six Chinese short-stature patients in our hospital with NPR2 mutations by whole-exome sequencing were included. We also searched all previously published NPR2 mutation cases as of August 10, 2020, and information about their medical history, mutations, and rhGH treatment were recorded and summarized., Results: The clinical characteristics of patients with an NPR2 heterozygous mutation mainly included short stature, facial anomalies, and skeletal dysplasia. Skeletal dysplasia mainly included brachydactyly (56.2%), shortened metacarpals or metatarsals (particularly fourth to fifth; 26.1%), and clinodactyly (21.7%). rhGH treatment significantly improved the height SD score (SDS) of patients with NPR2 heterozygous mutations (median, -2.1 vs -2.9, P < .001), especially in girls. The height SDS change correlated negatively with initial age of treatment (r = -0.477; P = .034), and height SDS change of patients with NPR2 heterozygous mutations in the carboxyl-terminal guanylyl cyclase catalytic domain was significantly higher than that of the extracellular ligand-binding region domain (median, 1.9 vs 0.6, P = .019)., Conclusions: ISS patients with skeletal deformities should be tested for an NPR2 mutation. rhGH treatment is beneficial for short-stature patients with NPR2 heterozygous mutations and needs further study., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)