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European Journal of Pediatrics Jul 2023Little is known about the global prevalence of congenital hypothyroidism (CH), though it is known to vary across countries and time periods. This meta-analysis aims to... (Meta-Analysis)
Meta-Analysis Review
Little is known about the global prevalence of congenital hypothyroidism (CH), though it is known to vary across countries and time periods. This meta-analysis aims to estimate the global and regional prevalence of CH among births between 1969 and 2020. PubMed, Web of Sciences, and Embase databases were searched for relevant studies between January 1, 1975, and March 2, 2020. Pooled prevalence was calculated using a generalized linear mixed model, and expressed as a rate per 10,000 neonates. The meta-analysis involved 116 studies, which analyzed 330,210,785 neonates, among whom 174,543 were diagnosed with CH. The pooled global prevalence of CH from 1969 to 2020 was 4.25 (95% confidence interval (CI) 3.96-4.57). The geographic region with highest prevalence was the Eastern Mediterranean (7.91, 95% CI 6.09-10.26), where the prevalence was 2.48-fold (95% CI 2.04-3.01) that in Europe. The national income level with the highest prevalence was upper-middle (6.76, 95% CI 5.66-8.06), which was 1.91-fold (95% CI 1.65-2.22) that in high-income countries. Global prevalence of CH was 52% (95% CI 4-122%) higher in 2011-2020 than in 1969-1980, after adjusting for geographic region, national income level, and screening strategy. Conclusion: The global prevalence of CH increased from 1969 to 2020, which may reflect the implementation of national neonatal screening, neonatal testing for thyroid-stimulating hormone, and a lowering of the diagnostic level of this hormone. Additional factors are likely to be driving the increase, which should be identified in future research. What is Known: • Cumulated evidence had suggested that the occurrences of congenital hypothyroidism (CH) among newborns were varied in different countries.. • Up-trends of the birth prevalence of CH were observed in many European and American countries. What is New: • This is the first meta-analysis to estimate global and regional prevalence of CH among newborns. • The global prevalence of CH has increased by 127% since 1969. The Eastern Mediterranean has the highest prevalence and stands out with the most pronounced escalation in the prevalence of CH.
Topics: Humans; Infant, Newborn; Congenital Hypothyroidism; Prevalence; Thyrotropin; Neonatal Screening; Europe
PubMed: 37071175
DOI: 10.1007/s00431-023-04932-2 -
Journal of Clinical Immunology Jul 2023Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is a serious disorder, which may comprise diabetes, thyroid disease, enteropathy,...
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is a serious disorder, which may comprise diabetes, thyroid disease, enteropathy, cytopenias, eczema, and other multi-system autoimmune dysfunction features. IPEX syndrome is caused by mutations in the forkhead box P3 (FOXP3) gene. Here, we report the clinical manifestations of a patient with IPEX syndrome onset in the neonatal period. A de novo mutation at exon 11 of the FOXP3 gene (c.1190G > A, p.R397Q) was found, and its main clinical manifestations included hyperglycemia and hypothyroidism. Subsequently, we comprehensively reviewed the clinical characteristics and FOXP3 mutations of 55 reported neonatal IPEX cases. The most frequent clinical presentation included symptoms of gastrointestinal involvement (n = 51, 92.7%), followed by skin-related symptoms (n = 37, 67.3%), diabetes mellitus (DM) (n = 33, 60.0%), elevated IgE (n = 28, 50.9%), hematological abnormality (n = 23, 41.8%), thyroid dysfunction (n = 18, 32.7%), and kidney-related symptoms (n = 13, 23.6%). In total, 38 variants were observed in the 55 neonatal patients. The most frequent mutation was c.1150G > A (n = 6; 10.9%), followed by c.1189C > T (n = 4; 7.3%), c.816 + 5G > A (n = 3; 5.5%), and C.1015C > G (n = 3; 5.5%), which were reported more than twice. The genotype-phenotype relationship showed that the repressor domain mutations were associated with DM (P = 0.020), and the leucine zipper mutations were associated with nephrotic syndrome (P = 0.020). The survival analysis suggested that treatment with glucocorticoids increased the survival of the neonatal patients. This literature review provides an informative reference for the diagnosis and treatment of IPEX syndrome in the neonatal period.
Topics: Humans; Congenital Hypothyroidism; Diarrhea; Genetic Diseases, X-Linked; Diabetes Mellitus, Type 1; Immune System Diseases; Mutation; Forkhead Transcription Factors; T-Lymphocytes, Regulatory
PubMed: 36867340
DOI: 10.1007/s10875-023-01456-0 -
Frontiers in Endocrinology 2023Growth hormone (GH) affects metabolism and regulates growth in childhood. The most prominent feature of GH deficiency (GHD) in children is diminished height velocity...
BACKGROUND
Growth hormone (GH) affects metabolism and regulates growth in childhood. The most prominent feature of GH deficiency (GHD) in children is diminished height velocity that eventually leads to short stature. In adult-onset GHD, lean body mass (LBM) is reduced, and visceral fat mass (FM) increased. Beneficial effects of GH treatment on body composition in adults with GHD, including an increase in muscle mass and a decrease in FM, are well established. Relatively few studies have investigated the effects of GH treatment on the body composition of pediatric patients with idiopathic or hypothalamic-pituitary disease-associated GH deficiency. This systematic review aimed to summarize available evidence relating to the effects of GH treatment on body composition in children with GHD.
METHODS
The PubMed, Science Direct, Cochrane Trials, and Embase databases, were searched with keywords including "GH", "body composition", "children", and "growth hormone" for English-language articles, published between January 1999 and March 2021. Two reviewers independently evaluated the search results and identified studies for inclusion based on the following criteria: participants had a confirmed diagnosis of GHD (as defined in each study); participants were pediatric patients who were receiving GH or had stopped GH treatment, regardless of whether they were pre- or post-pubertal; the intervention was recombinant human GH (rhGH; somatropin); and outcomes included changes in body composition during or after stopping GH therapy. Data extracted from each study included study quality, study sample characteristics, study interventions, and body composition. Data on fat-free mass and LBM were combined into a single category of LBM.
RESULTS
Sixteen studies reporting changes in body composition (i.e., FM and LBM) associated with GH treatment in children with GHD were identified and included in the review. Collectively, these studies demonstrated that FM decreased, and LBM increased in response to GH replacement therapy.
CONCLUSION
Despite study limitations (i.e., potential effects of diet and physical activity were not considered), we concluded that a periodic body composition assessment is required to ensure that a satisfactory body composition is achieved during GH replacement therapy in children with GHD.
Topics: Child; Humans; Body Composition; Dwarfism, Pituitary; Growth Hormone; Human Growth Hormone; Hypopituitarism
PubMed: 36843617
DOI: 10.3389/fendo.2023.1093691 -
The Plant Journal : For Cell and... Mar 2023High yield and stress resistance are the major prerequisites for successful crop cultivation, and can be achieved by modifying plant architecture. Evolutionarily... (Review)
Review
High yield and stress resistance are the major prerequisites for successful crop cultivation, and can be achieved by modifying plant architecture. Evolutionarily conserved growth-regulating factors (GRFs) control the growth of different tissues and organs of plants. Here, we provide a systematic overview of the expression patterns of GRF genes and the structural features of GRF proteins in different plant species. Moreover, we illustrate the conserved and divergent roles of GRFs, microRNA396 (miR396), and GRF-interacting factors (GIFs) in leaf, root, and flower development. We also describe the molecular networks involving the miR396-GRF-GIF module, and illustrate how this module coordinates with different signaling molecules and transcriptional regulators to control development of different plant species. GRFs promote leaf growth, accelerate grain filling, and increase grain size and weight. We also provide some molecular insight into how coordination between GRFs and other signaling modules enhances crop productivity; for instance, how the GRF-DELLA interaction confers yield-enhancing dwarfism while increasing grain yield. Finally, we discuss how the GRF-GIF chimera substantially improves plant transformation efficiency by accelerating shoot formation. Overall, we systematically review the conserved and divergent roles of GRFs and the miR396-GRF-GIF module in growth regulation, and also provide insights into how GRFs can be utilized to improve the productivity and nutrient content of crop plants.
Topics: Plants, Genetically Modified; Gene Expression Regulation, Plant; MicroRNAs; Plant Development; Plant Leaves; Intercellular Signaling Peptides and Proteins
PubMed: 36582168
DOI: 10.1111/tpj.16090 -
Clinical Endocrinology Apr 2023Growth hormone stimulation testing (GHST) is used to diagnose growth hormone deficiency (GHD) in children. As sex steroids impact on anterior pituitary function, there...
OBJECTIVE
Growth hormone stimulation testing (GHST) is used to diagnose growth hormone deficiency (GHD) in children. As sex steroids impact on anterior pituitary function, there is concern around the efficacy of GHST in peripubertal children, where endogenous sex steroid levels are low. Sex steroid priming before GHST is thought to improve test efficacy in these children, however evidence to support its use in clinical practice is limited. In this systematic review, we addressed the following research questions: Does priming increase GH stimulation test efficacy in peripubertal children? Does priming identify those who would benefit most from treatment in terms of final height? Is there evidence for an optimal sex-steroid priming regimen?
DESIGN, PATIENTS, MEASUREMENTS
The study was registered with PROSPERO and conducted according to PRISMA guidelines. We searched Medline, Cochrane-Library, Scopus, EMBASE and Web-of-Science and included all studies that included GHST in both primed and unprimed children. A GH cut-off of 7 µg/L was used as a threshold for GHD. Study quality was assessed using the Risk-Of-Bias in Non- Randomized Studies (ROBINS-I) tool or the revised Cochrane risk-of-bias tool for Randomised trials.
RESULTS
Fifteen studies met our inclusion criteria, of which 4/15 (27%) were randomised control trials. The majority (9/15) of the studies indicated that priming increases growth hormone response upon GHST in peripubertal children, increasing test specificity. Two studies investigated final height after treatment based on the results of primed versus unprimed GHST. These results indicate that growth hormone treatment based on results of a primed GHST improve outcomes compared with treatment based on an unprimed test.
CONCLUSION
Sex-steroid priming increases the growth hormone response during GHST, resulting in fewer patients meeting the threshold required for a diagnosis of GHD. Unnecessary GH treatment may be avoided in some patients without a detrimental effect on final height. Numerous sex-steroid priming regimens have been used in clinical practice and the majority appear to be effective, but an optimal regimen has not been determined.
Topics: Humans; Child; Adolescent; Growth Hormone; Human Growth Hormone; Gonadal Steroid Hormones; Dwarfism, Pituitary; Growth Disorders; Body Height; Steroids
PubMed: 36515075
DOI: 10.1111/cen.14862 -
International Journal of Molecular... Nov 2022Spinal stenosis (SS) is a multifactorial polyetiological condition characterized by the narrowing of the spinal canal. This condition is a common source of pain among... (Review)
Review
Spinal stenosis (SS) is a multifactorial polyetiological condition characterized by the narrowing of the spinal canal. This condition is a common source of pain among people over 50 years old. We perform a systematic review of molecular and genetic mechanisms that cause SS. The five main mechanisms of SS were found to be ossification of the posterior longitudinal ligament (OPLL), hypertrophy and ossification of the ligamentum flavum (HLF/OLF), facet joint (FJ) osteoarthritis, herniation of the intervertebral disc (IVD), and achondroplasia. FJ osteoarthritis, OPLL, and HLF/OLFLF/OLF have all been associated with an over-abundance of transforming growth factor beta and genes related to this phenomenon. OPLL has also been associated with increased bone morphogenetic protein 2. FJ osteoarthritis is additionally associated with Wnt/β-catenin signaling and genes. IVD herniation is associated with collagen type I alpha 1 and 2 gene mutations and subsequent protein dysregulation. Finally, achondroplasia is associated with fibroblast growth factor receptor 3 gene mutations and fibroblast growth factor signaling. Although most publications lack data on a direct relationship between the mutation and SS formation, it is clear that genetics has a direct impact on the formation of any pathology, including SS. Further studies are necessary to understand the genetic and molecular changes associated with SS.
Topics: Humans; Middle Aged; Spinal Stenosis; Ossification of Posterior Longitudinal Ligament; Ligamentum Flavum; Achondroplasia; Osteoarthritis
PubMed: 36362274
DOI: 10.3390/ijms232113479 -
Hormone Research in Paediatrics 2023The link between the effects of recombinant human growth hormone (rhGH) therapy in patients with growth hormone deficiency (GHD) and Chiari malformation type I (CM-1) is...
BACKGROUND
The link between the effects of recombinant human growth hormone (rhGH) therapy in patients with growth hormone deficiency (GHD) and Chiari malformation type I (CM-1) is controversial.
SUMMARY
We report the case of a patient with an unusual association of GHD due to ectopic posterior pituitary and CM-1. Our patient developed a headache and worsening of CM-1 after the initiation of rhGH therapy. Following an atlo-occipital decompression surgery, the patient was able to resume therapy with a marked growth improvement. Based on this observation, we provide a systematic review of the current literature about these two pathologies.
KEY MESSAGES
A careful follow-up of all patients with CM-1 treated with GH is mandatory, paying particular attention to the appearance of any neurological signs and symptoms.
Topics: Humans; Arnold-Chiari Malformation; Human Growth Hormone; Dwarfism, Pituitary; Recombinant Proteins
PubMed: 36001954
DOI: 10.1159/000526617 -
European Journal of Endocrinology Aug 2022Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result of 'GHD reversal'. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD aetiology, GH cut-off and retesting time point, with heterogeneous results. We aimed to systematically analyse the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points.
METHODS
PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating the reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models.
RESULTS
Of the 29 studies initially identified, 25 provided sufficient detail for IGHD analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (P = 0.0013). Pooled (95% CI) reversal rates were 80% (59-92%, n = 227), 73% (62-81%, n = 516) and 55% (41-68%, n = 1287) for cohorts using retesting GH cut-offs of 3-4 ng/mL, 5-6 ng/mL and 7.7-10 ng/mL, respectively. Individuals retested at FH (n = 674) showed a pooled reversal rate of 74% (64-82%) compared to 48% (25-71%) when retested before FH (n = 653).
CONCLUSION
Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.
Topics: Body Height; Child; Dwarfism, Pituitary; Growth Hormone; Human Growth Hormone; Humans
PubMed: 35670597
DOI: 10.1530/EJE-21-1179 -
Journal of Pediatric Endocrinology &... Jun 2022Registries are considered valuable data sources for identification of pediatric conditions treated with growth hormone (GH), and their follow-up. Currently, there is no... (Review)
Review
BACKGROUND
Registries are considered valuable data sources for identification of pediatric conditions treated with growth hormone (GH), and their follow-up. Currently, there is no systematic literature review on the scope and characteristics of pediatric GH registries. Therefore, the purpose of this systematic review is to identify worldwide registries reported on pediatric GH treatment and to provide a summary of their main characteristics.
CONTENT
Pediatric GH registries were identified through a systematic literature review. The search was performed on all related literature published up to January 30th, 2021. Basic information on pediatric GH registries, their type and scope, purpose, sources of data, target conditions, reported outcomes, and important variables were analyzed and presented.
SUMMARY
Twenty two articles, reporting on 20 pediatric GH registries, were included in this review. Industrial funding was the most common funding source. The main target conditions included in the pediatric GH registries were: growth hormone deficiency, Turner syndrome, Prader Willi syndrome, small for gestational age, idiopathic short stature, and chronic renal insufficiency. The main objectives in establishing and running pediatric GH registries were assessing the safety and effectiveness of the treatment, describing the epidemiological aspects of target growth conditions and populations, serving public health surveillance, predicting and measuring treatment outcomes, exploring new and useful aspects of GH treatment, and improving the quality of patient care.
OUTLOOK
This systematic review provides a global perspective on pediatric GH registries which can be used as a basis for the design and development of new GH registry systems at both national and international levels.
Topics: Child; Dwarfism, Pituitary; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Registries
PubMed: 35567286
DOI: 10.1515/jpem-2022-0045 -
Frontiers in Endocrinology 2022Pediatric patients with growth hormone deficiency (GHD) are currently treated with daily injections of recombinant human growth hormone (rhGH) to promote linear growth...
Treatment Adherence to Injectable Treatments in Pediatric Growth Hormone Deficiency Compared With Injectable Treatments in Other Chronic Pediatric Conditions: A Systematic Literature Review.
BACKGROUND
Pediatric patients with growth hormone deficiency (GHD) are currently treated with daily injections of recombinant human growth hormone (rhGH) to promote linear growth and enable attainment of normal adult height. One of the main reasons for suboptimal growth during rhGH therapy is non-adherence to treatment. The objective of this systematic literature review was to examine the recent literature on pediatric adherence to injectable treatments for chronic conditions (focusing on rhGH) to characterize levels of adherence and identify the factors/barriers associated with adherence.
METHODS
The Embase and MEDLINE databases (January 2015-October 2020) were searched to identify publications describing studies of pediatric patients (aged ≤17 years) with GHD and other chronic conditions requiring daily or weekly injectable treatments; a similar targeted search of Chinese literature was also performed. Adherence data were extracted from the included studies and summarized. Risk of bias was determined using the Cochrane Risk of Bias tool 2 or the Newcastle-Ottawa Scale.
RESULTS
A total of 23 publications were included, with all publications except for one (multiple sclerosis) focused on pediatric GHD studies: there were two clinical trials, 18 observational studies and three survey studies. Study sample sizes ranged from 30 to 13,553 patients (median: 95 patients). The definition of adherence varied between studies and included mean adherence rate, median adherence rate, and the percentage of patients within pre-specified adherence categories. Of the publications assessing adherence to daily rhGH, 11 studies reported 12-month mean adherence rate (range: 73.3%- 95.3%) and eight studies reported median adherence (range: 91%- 99.2%). The barriers to treatment adherence identified included self-administration, increased administration frequency, age (adolescence), longer treatment duration, device design, and insufficient family education, awareness, and/or engagement. Recommendations for increasing adherence included using adherence reminder tools, increasing patient engagement/education, and improving injection device design and drug product.
CONCLUSIONS
Adherence to rhGH treatment was high (>80%) for many studies, though comparability between studies was limited given the substantial heterogeneity in the way adherence was defined, measured, and reported. To address this heterogeneity, we recommend standardizing how adherence is defined and reported and encourage the use of standardized study designs and outcome measures.
Topics: Adolescent; Adult; Child; Dwarfism, Pituitary; Human Growth Hormone; Humans; Recombinant Proteins; Surveys and Questionnaires; Treatment Adherence and Compliance
PubMed: 35299969
DOI: 10.3389/fendo.2022.795224