Stature In Children Research Articles

Dynamic analysis of amplitude of low-frequency fluctuation in children with growth hormone deficiency

ObjectiveGrowth hormone (GH) affects brain activities and promotes growth and development. GH is a peptide hormone secreted by the anterior pituitary gland and is tied to behavior and cognitive function. Growth hormone deficiency (GHD) is the most common type of pathological short stature in children. Existing studies provide evidence that GHD may impact functional brain activities. The aim of this study was to investigate dynamic local brain activity in GHD children. MethodIn this study, we combined amplitude of low-frequency fluctuations (ALFF) and sliding-window techniques to examine the local brain activity of children with GHD. The resting-state functional magnetic resonance imaging (fMRI) data were collected from 26 children with GHD and 15 age- and sex-matched healthy controls (HC). ResultOur results showed significant abnormal temporal variability of dynamic ALFF in widespread regions in children with GHD, primarily in the frontal gyrus, temporal gyrus, and parietal lobule. ConclusionThe dALFF can capture dynamic changes in brain spontaneous activity, which are related to behavior and cognition. Based on this dynamic local brain activity, the results of this study provide a better understanding of the pathophysiological mechanism in children with GHD.

Exploring the Genetic Causes for Postnatal Growth Failure in Children Born Non-Small for Gestational Age.

The most common causes of short stature (SS) in children are familial short stature (FSS) and idiopathic short stature (ISS). Recently, growth plate dysfunction has been recognized as the genetic cause of FSS or ISS. The aim of this study was to investigate monogenic growth failure in patients with ISS and FSS. Targeted exome sequencing was performed in patients categorized as ISS or FSS and the subsequent response to growth hormone (GH) therapy was analyzed. We found 17 genetic causes involving 12 genes (NPR2, IHH, BBS1, COL1A1, COL2A1, TRPS1, MASP1, SPRED1, PTPTN11, ADNP, NADSYN1, and CERT1) and 2 copy number variants. A genetic cause was found in 45.5% and 35.7% of patients with FSS and ISS, respectively. The genetic yield in patients with syndromic and non-syndromic SS was 90% and 23.1%, respectively. In the 11 genetically confirmed patients, a gain in height from -2.6 to -1.3 standard deviations after 2 years of GH treatment was found. The overall diagnostic yield in this study was 41.7%. We identified several genetic causes involving paracrine signaling, the extracellular matrix, and basic intracellular processes. Identification of the causative gene may provide prognostic evidence for the use of GH therapy in non-SGA children.

Effects of different doses of long-acting growth hormone in treating children with growth hormone deficiency.

With the improvement of economy and living standards, the attention paid to short stature in children has been increasingly highlighted. Numerous causes can lead to short stature in children, among which growth hormone deficiency (GHD) is a significant factor. To investigate the long-term efficacy and safety of different doses of long-acting polyethylene glycol recombinant human growth hormone (PEG-rhGH) in the treatment of GHD in children. We selected 44 pediatric patients diagnosed with GHD who were treated at Wuhu First People's Hospital from 2014 to 2018. Total 23 patients were administered a high dose of long-acting PEG-rhGH at 0.2 mg/kg subcutaneously each week, forming the high-dose group. Meanwhile, 21 patients were given a lower dose of long-acting PEG-rhGH at 0.14 mg/kg subcutaneously each week, establishing the low-dose Group. The total treatment period was 2 years, during which we monitored the patients' height, annual growth velocity (GV), height standard deviation score (HtSDS), chronological age (CA), bone age (BA), and serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-3 (IGFBP-3) before treatment and at 6 mo, 1 year, and 2 years after treatment initiation. We also monitored thyroid function, fasting plasma glucose, fasting insulin, and other side effects. Furthermore, we calculated the homeostatic model assessment for insulin resistance. After 1 year of treatment, the GV, HtSDS, IGF-1, BA, and IGFBP-3 in both groups significantly improved compared to the pre-treatment levels (P < 0.05). Moreover, when comparing GV, HtSDS, IGF-1, BA, and IGFBP-3 between the two groups, there were no statistically significant differences either before or after the treatment (P > 0.05). During the treatment intervals of 0-1.0 years and 1.0-2.0 years, both patient groups experienced a slowdown in GV and a decline in HtSDS improvement (P < 0.05). The use of PEG-rhGH in treating GHD patients was confirmed to be effective, with similar outcomes observed in both the high-dose group and low-dose groups, and no significant differences in the main side effects.

THU168 PRMT7 Gene Mutation—A Rare Genetic Syndrome With Novel Endocrine Associations

Abstract Disclosure: K. Nutakki: None. S. Nalla: None. P. Deb: None. A. Vulpala: None. Background: Causes of short stature in children include pathologic causes (genetic diseases, underlying systemic disease, or growth hormone deficiency) and non-pathological variants such as familial and constitutional short stature. Genetic causes include Turner’s syndrome, SHOX mutations, Noonan’s syndrome and Silver- Russel syndrome besides others. Homozygous/compound heterozygous mutations in Protein Arginine Methyltransferase 7 (PRMT7) can result in Short Stature, Brachydactyly, Intellectual Developmental Disability and Seizures syndrome (SBIDDS) . Here, we report a child with SBIDDS syndrome who has associated endocrine manifestations of growth hormone deficiency and primary hypothyroidism. Case report: A 9-year-old male child, twin A of dichorionic diamniotic gestation, presented to the Endocrine OPD with short stature. There was a history of developmental delay, seizure disorder and mild intellectual deficit. Excessive weight gain was observed since 4 years of age. On examination, he was short with abdominal obesity, brachydactyly, simian crease and macroglossia. Height was below 3rd centile and weight at the 97th percentile. SMR was pre-pubertal. Investigations confirmed primary hypothyroidism.GH deficiency (peak GH after clonidine stimulation was less than 4 microgram/L) and reduced IGF-I levels were also found. Twin B was noted to have a normal height percentile. In both, skeletal maturation was consistent with chronological age. Twin A was treated with rGH and levothyroxine and responded well to rGH treatment. Whole exome sequencing revealed homozygosity for PRMT7 mutation in twin A with both parents heterozygous for the same gene mutation. His twin sibling, twin B was also found to be homozygous for the mutation, but he did not display any characteristics of the syndrome. Discussion: To the best of our knowledge, this is only the second reported case of SBIDDS syndrome (PRMT7 mutation) with documented growth hormone deficiency and only case with documented primary hypothyroidism. Height gain observed over the period of rGH treatment is suggestive of a possible role of GH/IGF-I axis alterations as contributors of growth impairment in these children. PRMT7 encodes for an arginine methyltransferase, involved in several biological processes, such as DNA transcription and repairing, RNA splicing, cell differentiation. We would like to propose that children with SBIDDS syndrome may be tested for GH deficiency as part of their overall assessment. Likewise, it should be further explored if PRMT7 gene mutation testing should be recommended in a child presenting with short stature and one or more manifestations of SBIDDS syndrome. Presentation: Thursday, June 15, 2023

Pemberdayaan Kader Kesehatan dalam Upaya Pencegahan Stunting pada Anak di Puskesmas Perumnas II Kota Pontianak

Stunting is a chronic malnutrition problem characterized by short stature in children. The high prevalence of stunting in the long term in children will impact economic losses for Indonesia. Nowadays, nutritional problems are not only seen as health problems but have become a shared responsibility, and they need attention from all sectors, including educational institutions such as the Faculty of Medicine. The leading cause of stunting is malnutrition for a long time. Community Service Activities (PKM) aim to equip the Perumnas II Health Center cadres with information, education, and skills related to information on stunting prevention. This PKM activity consists of several activities, including designing educational methods, stunting educational media, and administering pretests and posttests. The results show an increase in the understanding of cadres with the indicator that the average pretest score is 55 and the average posttest score is 71.75. In conclusion, there has been an increase in the understanding of the Perumnas II Health Center cadres.

Genetic diagnosis of skeletal dysplasias causing short stature in children

Short stature may often be due to skeletal dysplasias affecting the limbs, spine, or both. A careful clinical evaluation will help in identifying the rhizomelic and mesomelic shortening of the limbs and scoliosis. The mutations in different genes involved in various pathways in skeletal development lead to phenotypes that present from infancy to childhood or adulthood. A systematic clinical evaluation with identification of the limb bowing or deformity, dysmorphic features, radiological findings from skull to toes, and a single gene or multi-gene panel testing will help in making an appropriate diagnosis. The clinical clues to skeletal dysplasia include skeletal disproportion, unexplained limb bowing, recurrent fractures, facial dysmorphism including flat facies and blue sclera in severe cases, and sometimes typical digital or cardiac abnormalities. The following review focuses on the postnatal presentation of skeletal dysplasias mostly referred for evaluation of short stature.

Correlation between Short Stature with Serum Ferritin Levels in Major Beta-Thalassemia Patients at Kediri District General Hospital

In thalassemia, a lifelong sequence of blood transfusions leads to iron overload characterized by increased ferritin levels. Many factors, including iron overload may cause growth delay. High ferritin levels are believed to lead to short stature in children with thalassemia. This study aims to determine the correlation between short stature and ferritin levels in children with major beta thalassemia at Kediri District General Hospital. This research is an observational analytic with a cross-sectional design conducted on 17 subjects of beta thalassemia major patients at Pediatric Health Sciences (IKA) Kediri District General Hospital who met the inclusion and exclusion criteria in December 2022-January 2023. The measuring instrument used in this study was anthropometric status, explained through age stature, while the ferritin levels was obtained from the patient's medical record. Spearman's rank order correlation test was used in the analysis. There were 17 respondents, 82,36% children in short categories and 17,64% in normal categories. The Spearman correlation test has the p-value = 0.000 and r = -0,736. A strong negative correlation exists between short stature and ferritin levels in beta-thalassemia major patients at Kediri District General Hospital that means the higher ferritin levels, the higher incidence rate of short stature.

Causal associations between insulin-like growth factor 1 and vitamin D levels: a two-sample bidirectional Mendelian randomization study.

Insulin-like growth factor 1 (IGF-1) plays a vital role in the attainment and maintenance of bone mass throughout life and is closely related to the stature of children. 25-Hydroxyvitamin D (25-OHD) is an intermediate of vitamin D (Vit D) metabolism and a key indicator of Vit D nutritional status. Multiple studies have revealed that IGF-1 levels undergo a non-significant increase after Vit D supplementation. Here, we analyzed the causal and reverse causal relationships between 25-OHD and IGF-1 levels using Mendelian randomization (MR). Two-sample MR was used to estimate an unconfounded bidirectional causal relationship between the level of IGF-1 and those of Vit D and 25-OHD. Single nucleotide polymorphisms (SNPs) were filtered from genome-wide association studies (GWAS) after a comprehensive search of the Integrative Epidemiology Unit GWAS database. Several MR methods were employed, including inverse-variance weighted (IVW) method, and a sensitivity analysis was undertaken to detect whether pleiotropy or heterogeneity biased the MR results. Genetically predicted IGF-1 was found to have a causal association with Vit D and serum 25-OHD levels, where Vit D and serum 25-OHD levels increased with increasing IGF-1 concentrations (Vit D: IVW β:0.021, 95% CI: 0.005-0.036, p = 7.74 × 10-3; 25-OHD: IVW β: 0.041, 95% CI: 0.026-0.057, p = 2.50 × 10-7). A reverse causal effect was also found, indicating Vit D and serum 25-OHD have a positive causal relationship with IGF-1 (Vit D: IVW β:0.182, 95% CI: 0.061-0.305, p = 3.25 × 10-3; 25-OHD: IVW β: 0.057, 95% CI = 0.017-0.096, p = 4.73 × 10-3). The sensitivity analysis showed that horizontal pleiotropy was unlikely to bias the causality in this study (MR-Egger: Vit D intercept p = 5.1 × 10-5, 25-OHD intercept p = 6.4 × 10-4 in forward analysis; Vit D intercept p = 6.6 × 10-4, 25-OHD intercept p = 1.9 × 10-3 in reverse analysis), and a leave-one-out analysis did not identify evidence of bias in the results. The results of the MR analysis provide evidence that IGF-1 has positive causal and reverse causal relationships with Vit D and serum 25-OHD, respectively, in European populations. Our findings also provide guidance for the prevention and treatment of short stature and other related diseases.

Idiopathic short stature and scoliosis in children treated with growth hormone.

The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study. A total of 2,053 children with idiopathic short stature and 4,106 age- and sex-matched (1:2) children without short stature with available whole-spine radiographs were enrolled in the cross-sectional study. Among them, 1,056 with idiopathic short stature and 790 controls who had radiographs more than twice were recruited to assess the development and progression of scoliosis, and the need for bracing and surgery. In the cross-sectional study, there was an unexpectedly higher prevalence of scoliosis (33.1% (681/2,053) vs 8.52% (350/4,106)) in children with idiopathic short stature compared with controls (odds ratio 3.722; p < 0.001), although most cases were mild. In the longitudinal study, children with idiopathic short stature had a higher risk of the development and progression of scoliosis than the controls. Among children with idiopathic short stature without scoliosis at baseline, treatment with growth hormone significantly increased the risk of developing scoliosis (p = 0.015) and the need for bracing (p < 0.001). Among those with idiopathic short stature and scoliosis at baseline, treatment with growth hormone did not increase the risk of progression of the scoliosis, the need for bracing, or surgery. The impact of treatment with growth hormone on scoliosis in children with idiopathic short stature was considered controllable. However, physicians should pay close attention to the assessment of spinal curves in these children.

Cost-effectiveness analysis of herbal medicines in children with idiopathic short stature.

Herbal medicines have been used for a long time to treat idiopathic short stature (ISS) in children in East Asian countries. The aim of this study was to analyze the cost-effectiveness of 5 herbal medicines frequently used in clinical settings for children with ISS based on medical records. Patients with ISS who had been prescribed a 60-day supply of herbal medicines in 1 Korean medicine hospital were included in this analysis. Their height and height percentile were measured before and after treatment within 6-months. The average cost-effectiveness ratios (ACERs) of 5 herbal medicines for height (cm) and height percentile were calculated for boys and girls, respectively. The ACERs per 1 cm height growth were USD 56.2 (Naesohwajung-Tang), USD 74.8 (Ogapi-Growth decoction), USD 86.6 (Gamcho-Growth decoction), USD 94.6 (Gwakhyangjeonggi-San plus Yukmijihwang-Tang), and USD 113.8 (Boyang-Growth decoction). The ACERs per 1 percentile height growth were USD 205 (Naesohwajung-Tang), USD 293 (Ogapi-Growth decoction), USD 470 (Gamcho-Growth decoction), USD 949 (Boyang-Growth decoction), and USD 1051 (Gwakhyangjeonggi-San plus Yukmijihwang-Tang). Herbal medicine might be a potential economical alternative treatment for ISS.

Etiological study of short stature in children and role of insulin like growth factor-1 and insulin like growth factor binding protein-3 as screening markers for growth hormone deficiency.

To determine aetiological factors in children with short stature, and to evaluate the role of insulin like growth factor-1 and insulin like growth factor binding protein-3 as screening markers for growth hormone deficiency. The cross-sectional study was conducted at the Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from August 2020 to July 2021, and comprised children with short stature. Evaluation protocol included complete history and examination, baseline laboratory investigations, X-ray for bone age and karyotyping. Growth hormone status was assessed using growth hormone stimulation tests, and serum insulin like growth factor-1 and insulin like growth factor binding protein-3 levels were also assessed. Data was analysed using SPSS 25. Of the 649 children, 422(65.9%) were boys and 227(34.9%) were girls. The overall median age was 11 years (interquartile range: 11 years). Of the total, 116(17.9%) children had growth hormone deficiency. Familial short stature was present in 130(20%) children and constitutional delay in growth and puberty in 104(16.1%). There was no significant difference in levels of serum insulin like growth factor-1 and insulin like growth factor binding protein-3 in children who had growth hormone deficiency and those who had other causes of short stature (p>0.05). Physiological variants of short stature were found to be more common in the population followed by growth hormone deficiency. Serum insulin like growth factor-1 and insulin like growth factor binding protein-3 levels alone should not be used to screen children with short stature for growth hormone deficiency.

Relationship between short stature at 3 years old and height, weight, and body mass index changes for 6 years after birth: a retrospective, nationwide, population-based study of children born 2011-2014 in Korea.

Height at 3 years of age, when catch-up growth based on birth history is completed, is considered a major prognostic factor for predicting short stature, underweight, and growth faltering. However, too few large-scale studies have followed and analyzed height, weight, and body mass index (BMI) changes in children whose stature was short at 3 years of age. This study followed and compared the growth parameters (height, weight, and BMI) of children with short stature at 3 years of age and children with nonshort stature at 3 years of age for 6 years after birth using nationwide, population-based data. We retrospectively analyzed physical measurement data from the National Health Screening Program for Infants and Children for people born in 2011-2014 in Korea and followed to 2020. The data were provided by the National Health Insurance Service's customized data service. Growth parameters were compared using chi-square tests, Student t-tests, analyses of variance, and linear regressions. Among 210,902 enrolled participants, 759 (0.4%) and 210,143 (99.6%) were in the short stature at 3 years group and the nonshort stature at 3 years group, respectively. In both sexes, height, weight, and BMI for 6 years after birth were significantly higher in the nonshort stature at 3 years group than in the short stature at 3 years group (P<0.0001). The BMI rebound was observed later than the standard period in the short stature at 3 years group. Early intervention and close follow-up are necessary to prevent persistent short stature and growth faltering in children with short stature at 3 years of age.

Isolated growth hormone deficiency in children with vertically transmitted short stature: What do the genes tell us?

The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far. To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature. Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines. The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (GHSR and OTX2). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (ACAN, COL1A2, COL11A1, COL2A1, EXT2, FGFR3, NF1, NPR2, PTPN11 [2x]), in one (7%) a genetic variant impairing IGF-1 action (IGFALS) and in two (12%) a variant in miscellaneous genes (SALL4, MBTPS2). In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.

Long-acting PEGylated growth hormone in children with idiopathic short stature: time to reconsider our diagnostic and treatment policy?

Idiopathic short stature (ISS) is a diagnosis of exclusion, and therefore each child with short stature or slow growth referred to a paediatrician deserves a full medical history and physical examination, as well as radiological and laboratory screening tests. In patients with an increased likelihood of a genetic cause, genetic testing is indicated. Idiopathic short stature is an approved indication for recombinant human growth hormone (rhGH) in the USA but not in most other parts of the world. In a recent article published in this journal, Luo et al reported on the 1-year's results of a multicentre randomized controlled trial (n = 360) on the efficacy and safety of two dosages of long-acting PEGylated rhGH (PEG-rhGH, Jintrolong®) (0.1 or 0.2 mg/kg body weight per week, respectively) in children with ISS compared with an untreated control group. The growth response to the higher dosage was similar to reported data on daily rhGH. In this commentary, we discuss whether the recent data on genetic causes of short stature in children who initially were labelled ISS, and data on the long-term safety of daily rhGH, may influence the balance between risks and benefits of rhGH treatment in children with ISS. We further discuss the pharmacokinetic and -dynamic profile of PEG-rhGH and its potential consequences for long-term safety.

Short Stature in children: Review Article

Short Stature in children: Review Article

Retracted: Analysis of Prevalence, Influencing Factors, and Countermeasures of Short Stature in Children and Adolescents Aged 6∼14 in Furong District, Changsha City, in 2020.

[This retracts the article DOI: 10.1155/2021/3933854.].

Insufficient weight gain under 3 years of age correlates with short stature in school-aged children

Insufficient weight gain under 3 years of age correlates with short stature in school-aged children

Distal tibial trabecular morphometry in a Sprague Dawley rat model of fetal alcohol syndrome: a micro focus X-ray computed tomography case-control study.

intrauterine alcohol exposure has adverse health effects on the offspring, which may result in fetal Alcohol Spectrum Disorders (FASD). The neurological and craniofacial aspects have been well studied; however, long bones have received limited attention despite the short stature reported in FASD children. time-mated (n=13) pregnant Sprague Dawley dams were assigned to either the ethanol (n=5), saline control (n=5) or untreated group (n=3) which received no treatment. The ethanol and saline control dams were treated with 0.015ml/g of 25.2% ethanol or 0.9% saline, respectively. Treatment was for the first 19 days of gestation. Two pups from each dam were used and terminated at 21 days of age. Paired tibiae were harvested. Each bone was scanned using a Nikon XTH 225L 3D-μCT to investigate trabeculae morphometry. the ethanol group had less bone to total volume (BT/TV), thinnest trabeculae (TbTh) which were less spaced (TbSp) compared to the controls. However, number of trabecular (TbN) remained unaffected in all three groups. Tibial length was similar in all three groups; however, the distal metaphysis volume was smallest in the ethanol group. Logistic regression showed that the distal medullary canal area and trabecular separation were the main parameters affected the most in gestational alcohol. The negative correlation of trabecular thickness and spacing in the ethanol group may be a contributor to bone weakness. gestational alcohol exposure affects bone internal morphology in addition to the bone size. Overall, this study supports the findings of clinical observation of small stature in FAS children.

Growth plate extracellular matrix defects and short stature in children.

Many etiological factors causing short stature have already been identified in humans. In the last few years, the advent of new techniques for the detection of chromosomal and molecular abnormalities has made it possible to better identify patients with genetic causes of growth failure. Some of these factors directly affect the development and growth of the skeleton, since they damage the epiphyseal growth plate, where linear growth occurs, influencing chondrogenesis. In particular, defects in genes involved in the organization and function of the growth plate are responsible for several well-known conditions with short stature. These genes play a pivotal role in various mechanisms involving the extracellular matrix, intracellular signaling, paracrine signaling, endocrine signaling, and epigenetic regulation. In this review, we will discuss the genes involved in extracellular matrix disorders. The identification of genetic defects in linear growth failure is important for clinicians and researchers in order to improve the care of children affected by growth disorders.

Etiological Classification of Short Stature in Children over 5 Years Old

Short stature is a common problem in childhood, which may be a normal variant of growth or the result of pathologic conditions. Determination of the etiological factors would lead to more appropriate assessment and clinical approach for patients.