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Growth hormone deficiency (GHD) and idiopathic short stature (ISS) are the most common types of short stature (SS), but little is known about their pathogenesis, and even less is known about the study of adolescent SS. In this study, nuclear magnetic resonance (NMR)-based metabolomic analysis combined with least absolute shrinkage and selection operator (LASSO) were performed to identify the biomarkers of different types of SS (including 94 preadolescent GHD (PAG), 61 preadolescent ISS (PAI), 43 adolescent GHD (ADG), and 19 adolescent ISS (ADI)), and the receiver operating characteristic curve (ROC) was further used to evaluate the predictive power of potential biomarkers. The results showed that fourteen, eleven, nine, and fifteen metabolites were identified as the potential biomarkers of PAG, PAI, ADG, and ADI compared with their corresponding controls, respectively. The disturbed metabolic pathways in preadolescent SS were mainly carbohydrate metabolism and lipid metabolism, while disorders of amino acid metabolism played an important role in adolescent SS. The combination of aspartate, ethanolamine, phosphocholine, and trimethylamine was screened out to identify PAI from PAG, and alanine, histidine, isobutyrate, methanol, and phosphocholine gave a high classification accuracy for ADI and ADC. The differences in metabolic characteristics between GHD and ISS in preadolescents and adolescents will contribute to the development of individualized clinical treatments in short stature.

BackgroundChildren with short stature of undefined aetiology (SS-UA) may have undiagnosed genetic conditions.PurposeTo identify mutations causing short stature (SS) and genes related to SS, using candidate gene sequence data from the European EPIGROW study.MethodsFirst, we selected exonic single nucleotide polymorphisms (SNPs), in cases and not controls, with minor allele frequency (MAF) < 2%, whose carriage fitted the mode of inheritance. Known mutations were identified using Ensembl and gene-specific databases. Variants were classified as pathogenic, likely pathogenic, or variant of uncertain significance using criteria from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. If predicted by ≥ 5/10 algorithms (eg, Polyphen2) to be deleterious, this was considered supporting evidence of pathogenicity. Second, gene-based burden testing determined the difference in SNP frequencies between cases and controls across all and then rare SNPs. For genotype/phenotype relationships, we used PLINK, based on haplotype, MAF > 2%, genotype present in > 75%, and Hardy Weinberg equilibrium P > 10–4.ResultsFirst, a diagnostic yield of 10% (27/263) was generated by 2 pathogenic (nonsense in ACAN) and a further 25 likely pathogenic mutations, including previously known missense mutations in FANCB, IGFIR, MMP13, NPR2, OBSL1, and PTPN11. Second, genes related to SS: all methods identified PEX2. Another 7 genes (BUB1B, FANCM, CUL7, FANCA, PTCH1, TEAD3, BCAS3) were identified by both gene-based approaches and 6 (A2M, EFEMP1, PRKCH, SOS2, RNF135, ZBTB38) were identified by gene-based testing for all SNPs and PLINK. ConclusionsSuch panels improve diagnosis in SS-UA, extending known disease phenotypes. Fourteen genes related to SS included some known to cause growth disorders as well as novel targets.

Abstract The first step in the evaluation of the short child is to decide whether growth parameters in the context of the history are abnormal or a variant of normal. If growth is considered abnormal, system and hormonal tests are likely to be required, followed by more directed testing, such as skeletal survey and/or genetic screening with karyotype or microarray. In a small percentage of short children in whom a diagnosis has not been reached, this will need to be followed by detailed genetic analysis; currently, exome sequencing using targeted panels relevant to the phenotype is the commonly used test. Clinical scenarios are presented that illustrate how such genetic testing can be used to establish a molecular diagnosis, and how that diagnosis contributes to the management of the short child. New genetic causes for short stature are being recognized on a frequent basis, while the clinical spectrum for known genes is being extended. We recommend that an international repository for short stature conditions is established for new findings to aid dissemination of knowledge, but also to help in the definition of the clinical spectrum both for new and established conditions.

Background: Short stature affects approximately 2% of children, representing one of the more frequent disorders for which clinical attention is sought during childhood. Despite assumed genetic heterogeneity, mutations or deletions of the short stature homeobox-containing gene (SHOX) are found quite frequently in subjects with short stature. Haploinsufficiency of the SHOX gene causes short stature with highly variable clinical severity, ranging from isolated short stature without dysmorphic features to Léri-Weill syndrome, and with no functional copy of the SHOX gene, Langer syndrome. Methods: To characterise the clinical and molecular spectrum of SHOX deficiency in childhood we assessed the association between genotype and phenotype in a large cohort of children of short stature from 14 countries. Results: Screening of 1608 unrelated individuals with sporadic or familial short stature revealed SHOX mutations or deletions in 68 individuals (4.2%): complete deletions in 48 (70.6%), partial deletions in 4 (5.9%) and point mutations in 16 individuals (23.5%). Although mean height standard deviation score (SDS) was not different between participants of short stature with or without identified SHOX gene defects (–2.6 vs –2.6), detailed examination revealed that certain bone deformities and dysmorphic signs, such as short forearm and lower leg, cubitus valgus, Madelung deformity, high-arched palate and muscular hypertrophy, differed markedly between participants with or without SHOX gene defects (p<0.001). Phenotypic data were also compared for 33 children with Turner syndrome in whom haploinsufficiency of SHOX is thought to be responsible for the height deficit. Conclusion: A phenotype scoring system was developed that could assist in identifying the most appropriate subjects for SHOX testing. This study offers a detailed genotype-phenotype analysis in a large cohort of children of short stature, and provides quantitative clinical guidelines for testing of the SHOX gene.

Abstract Context The assessment and treatment of children with growth retardation is increasingly complex, and due to availability of targeted genetic sequencing, an ever-expanding number of conditions impeding growth are being identified. Among endocrine-related etiologies of short stature amenable to hormonal treatment, defects in the growth hormone (GH)–insulin-like growth factor I axis remain pre-eminent, with a multiplicity of disorders causing decreased secretion or insensitivity to GH action. Sex steroids in puberty increase epiphyseal senescence and eventual growth plate closure. This is mediated mostly via estrogen receptor (ER)α in males and females, effects that can greatly limit time available for growth. Evidence Acquisition Extensive literature review through PubMed and other search engines. Evidence Synthesis Therapeutic strategies to be considered in peripubertal and pubertal children with disordered growth are here discussed, including daily and weekly GH, low-dose sex steroids, gonadotropin hormone releasing hormone (GnRH) analogues in combination with GH, aromatase inhibitors (AIs) alone and in combination with GH in boys. When used for at least 2 to 3 years, GnRH analogues combined with GH can result in meaningful increases in height. AIs used with GH permit puberty to progress in boys without hindrance, selectively decreasing estrogen, and resulting in taller height. With more than 20 years of cumulative experience in clinical use of these medications, we discuss the safety profile of these treatments. Conclusion The approach of growth retardation in the peripubertal and pubertal years must consider the sex steroid milieu and the tempo of bone acceleration. Treatment of affected children in this period must be individualized.

Abstract Context Aggrecan, encoded by the ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated. Objective We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone therapies. Patients and Methods Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by next-generation sequencing–based test. Result We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort; it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, 5 of 11 ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SD score improvement. Conclusion Our data suggest that ACAN mutation is 1 of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.

Growth hormone deficiency (GHD) and idiopathic short stature (ISS) are the major etiologies of short stature in children. For the diagnosis of GHD and ISS, meticulous evaluations are required, including growth hormone provocation tests, which are invasive and burdensome for children. Additionally, sella magnetic resonance imaging (MRI) is necessary for assessing etiologies of GHD, which cannot evaluate hormonal secretion. Recently, radiomics has emerged as a revolutionary technique that uses mathematical algorithms to extract various features for the quantitative analysis of medical images. This study aimed to develop a machine learning-based model using sella MRI-based radiomics and clinical parameters to diagnose GHD and ISS. A total of 293 children with short stature who underwent sella MRI and growth hormone provocation tests were included in the training set, and 47 children who met the same inclusion criteria were enrolled in the test set from different hospitals for this study. A total of 186 radiomic features were extracted from the pituitary glands using a semiautomatic segmentation process for both the T2-weighted and contrast-enhanced T1-weighted image. The clinical parameters included auxological data, insulin-like growth factor-I, and bone age. The extreme gradient boosting algorithm was used to train the prediction models. Internal validation was conducted using 5-fold cross-validation on the training set, and external validation was conducted on the test set. Model performance was assessed by plotting the area under the receiver operating characteristic curve. The mean absolute Shapley values were computed to quantify the impact of each parameter. The area under the receiver operating characteristic curves (95% CIs) of the clinical, radiomics, and combined models were 0.684 (0.590-0.778), 0.691 (0.620-0.762), and 0.830 (0.741-0.919), respectively, in the external validation. Among the clinical parameters, the major contributing factors to prediction were BMI SD score (SDS), chronological age-bone age, weight SDS, growth velocity, and insulin-like growth factor-I SDS in the clinical model. In the combined model, radiomic features including maximum probability from a T2-weighted image and run length nonuniformity normalized from a T2-weighted image added incremental value to the prediction (combined model vs clinical model, P=.03; combined model vs radiomics model, P=.02). The code for our model is available in a public repository on GitHub. Our model combining both radiomics and clinical parameters can accurately predict GHD from ISS, which was also proven in the external validation. These findings highlight the potential of machine learning-based models using radiomics and clinical parameters for diagnosing GHD and ISS.

Abstract Context Collagens are the most abundant proteins in the human body. In a growth plate, collagen types II, IX, X, and XI are present. Defects in collagen genes cause heterogeneous syndromic disorders frequently associated with short stature. Less is known about oligosymptomatic collagenopathies. Objective This work aims to evaluate the frequency of collagenopathies in familial short stature (FSS) children and to describe their phenotype, including growth hormone (GH) treatment response. Methods Eighty-seven FSS children (pretreatment height ≤ –2 SD both in the patient and his or her shorter parent) treated with GH were included in the study. Next-generation sequencing was performed to search for variants in the COL2A1, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, and COL11A2 genes. The results were evaluated using American College of Medical Genetics and Genomics guidelines. The GH treatment response of affected children was retrospectively evaluated. Results A likely pathogenic variant in the collagen gene was found in 10 of 87 (11.5%) children. Detailed examination described mild asymmetry with shorter limbs and mild bone dysplasia signs in 2 of 10 and 4 of 10 affected children, respectively. Their growth velocity improved from a median of 5.3 cm/year to 8.7 cm/year after 1 year of treatment. Their height improved from a median of –3.1 SD to –2.6 SD and to –2.2 SD after 1 and 3 years of therapy, respectively. The final height reached by 4 of 10 children differed by –0.67 to +1.0 SD and –0.45 to +0.5 SD compared to their pretreatment height and their affected untreated parent’s height, respectively. Conclusion Oligosymptomatic collagenopathies are a frequent cause of FSS. The short-term response to GH treatment is promising.

Abstract Context Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height. Objective To develop a polygenic risk score for adult height and evaluate its clinical utility. Design A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Subjects Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort. Interventions None. Main Outcome Measures Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature. Results Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child’s parent’s height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood. Conclusions A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.

Background/Objectives: This study aimed to evaluate quality of life in children and adolescents with normal variants of short stature compared to age- and sex-matched individuals with normal stature and to assess the agreement between children/adolescents-reported and parent-reported outcomes. Methods: A total of 65 child–parent dyads were enrolled, including 29 children and adolescents with short stature (15 males, 14 females; mean age: 11.2 + 2.0 years; mean height standard deviation score, HSDS: −2.10 + 0.57) and 36 children and adolescents with normal stature (19 males, 17 females; mean age: 11.3 + 1.93 years; mean HSDS: 0.56 + 0.78). Quality of life was assessed using the Quality of Life in Short Stature Youth (QoLISSY) questionnaire. Statistical analyses included independent samples t-tests, and effect sizes were computed using Cohen’s d. Results: Among short-statured children and adolescents, no significant correlations were found between HSDS and all domains of quality of life. Short-statured children and adolescents exhibited significantly lower QoL across all domains compared to their normal-statured peers. Coping was higher in children and adolescents with short stature compared to their peers of normal stature. Similarly, parents of short-statured children and adolescents perceived a lower QoL for their sons and daughters and reported greater concern about the future and a more perceived personal impact than parents of normal-statured children and adolescents. No statistically significant differences were found between sons/daughters and parent reports, indicating a relatively high level of agreement in quality of life (QoL) perceptions. Conclusions: These findings underscore the psychosocial impact of short stature and highlight the importance of incorporating both child and parent perspectives in the clinical assessment.