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Sökning: L773:1663 2818 OR L773:1663 2826 > (2020-2024)

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1.
  • Backeljauw, Philippe, et al. (författare)
  • Safety and Effectiveness of Recombinant Human Growth Hormone in Children with Turner Syndrome : Data from the PATRO Children Study
  • 2021
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:3-4, s. 133-143
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: PATRO Children is an international, observational, postmarketing surveillance study for a biosimilar recombinant human growth hormone (rhGH; somatropin, Omnitrope (R); Sandoz), approved by the European Medicines Agency in 2006. We report safety and effectiveness data for patients with Turner syndrome (TS).Methods: The study population included infants, children, and adolescents with TS who received Omnitrope (R) treatment according to standard clinical practice. Adverse events (AEs) were monitored for safety evaluation, and height velocity (HV), height standard deviation score (HSDS), and HVSDS were calculated to evaluate treatment effectiveness.Results: As of August 2019, 348 TS patients were enrolled from 130 centers. At baseline, 314 patients (90.2%) were prepubertal and 284 patients (81.6%) were rhGH treatment naive. The mean ( range) age at baseline was 9.0 (0.7-18.5) years, and mean (SD) treatment duration in the study was 38.5 (26.8) months. Overall, 170 patients (48.9%) reported AEs, which were considered treatment related in 25 patients (7.2%). One treatment-related serious AE was reported (intracranial hypertension). Mean.HSDS after 3 years of therapy was +1.17 in treatment-naive prepubertal patients and +0.1 in pretreated prepubertal patients. In total, 51 patients (31.1%) reached adult height (AH), 35 of whom were rhGH treatment naive; in these patients, mean (SD) HSDS was -2.97 (1.03) at the start of Omnitrope (R) treatment, and they achieved a mean (SD) AHSDS of -2.02 (0.9).Conclusion: These data suggest that biosimilar rhGH is well tolerated and effective in TS patients managed in reallife clinical practice. Optimization of rhGH dose may contribute to a higher AH. (C) 2021 S. Karger AG, Basel
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2.
  • Baroncelli, Marta, et al. (författare)
  • Bone, Growth Plate and Mineral Metabolism
  • 2021
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 22-22
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • The skeletal research field develops rapidly and has produced several exciting findings in the last year and includes advances in the treatment of rare skeletal disorders and an ever deeper under-standing into the fundamental molecular mechanisms that control skeletal development, metabolism, growth, and mineralization.The targeting of the C-type natriuretic peptide (CNP) pathway and options to directly antagonize the overactivity of the FGFR3 pathway in achondroplasia continues to be a subject of high inter-est and excitement and in the 2021 yearbook we highlight the dou-ble-blind, randomized placebo-controlled phase 3 study of a CNP analogue (vosoritide) in children with achondroplasia. We also highlight the identification of a novel gene for autosomal domi-nant hypophosphatemic rickets, publication of new growth charts for X-linked hypophosphatemia and two large well-designed pae-diatric vitamin D trials for the prevention of tuberculosis and asthma exacerbation, respectively.Translational highlights include review on the recent advances of mineral metabolism and biomineralization, in vivo data sug-gesting that modification of the synovial microenvironment may allow endogenous skeletal stem cells to form hyalin cartilage and thereby heal articular cartilage injuries, as well as a study using gene targeting in zebra fish to reveal the pathogenic mechanism by which mutations in CRTAP and P3H1 causes osteogenesis imper-fecta type VII and VIII, respectively.Advances in the understanding of skeletal biology a study by McDonald et al. that challenges the current dogma on the origin and fate of osteoclasts as they show evidence that multinucleated osteoclasts can fission into daughter cells, a.k.a. osteomorphs, that subsequently are recycled into bone resorbing osteoclasts via a RANKL-dependent process. Additional articles in this section directly and indirectly highlight the critical role of loading and mechanical stress on the growing skeleton. Several of these excit-ing findings will be highlighted in the presentation.
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3.
  • Bendre, Ameya, et al. (författare)
  • Growth failure in aggrecan haploinsufficiency is due to a decrease in growth plate matrix volume and hypertrophic cell size
  • 2023
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 96:Suppl. 4, s. 40-41
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Heterozygous loss-of-function mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (SSOAOD; OMIM#165800). ACAN mutations is a relatively common finding in idiopathic short stature (ISS) and has been reported to be the cause of growth failure in approximately 2% of children with ISS. However, the underlying cellular and molecular mechanisms by which ACAN mutations cause growth failure in SSOAOD have not been elucidated.Objective: To investigate the underlying cellular and molecular mechanisms of growth failure using a mouse model of SSOAOD.Methods: Cartilage matrix deficiency mouse (Acan cmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth at 1,3,6,12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and distal femoral growth plates. Cell proliferation was assessed by EdU incorporation. Quantification of percentage matrix area was performed using Image J. Single-cell RNA sequencing was carried out on chondro-cytes isolated from 18 day old WT and Acan cmd female mice according to 3’ gene expression protocol (10X Genomics).Results: Heterozygous Acancmd mice were born at a normal size and similar to humans with SSOAOD but showed decreased postnatal growth resulting in a gradually worsening dwarfism with reduced total body length and tibial and femoral lengths (p<0.0001). In the growth plates, chondrocytes were found to be more tightly packed with reduced matrix area (p<0.0001) and increased column density in Acan cmd mice compared to WT mice. Growth plate height (p<0.0001), heights of the individual zones (p<0.001), the number of resting zone chondrocytes (p<0.01), proliferative cells per column (p<0.0001), and the size of terminal hypertrophic chondrocytes (p<0.001) were slightly reduced in both male and female Acan cmd mice, especially at 1 week of age. Interestingly, chondrocyte proliferation was similar in Acan cmd and WT mice at all time-points assessed (p=0.90). Female Acan cmd mice exhibited a more pronounced phenotype than male mice.Conclusions: Similar to children with heterozygous ACAN mutations, heterozygous Acancmd mice exhibit a growth pattern with postnatal growth failure resulting in adult short stature. The growth failure is primarily caused by decreased matrix production and hypertrophic cell size, whereas chondrocyte proliferation is normal. Single-cell RNA sequencing of growth plate chondrocytes is ongoing and will identify the underlying pathogenic mechanisms and might also identify compensatory mechanisms limiting the effects of aggrecan haploinsufficiency.
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4.
  • Bendre, Ameya, et al. (författare)
  • Postnatal growth failure of aggrecan deficient mice is due to impaired growth plate chondrogenesis
  • 2022
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 95:Suppl. 2, s. 294-294
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Heterozygous Aggrecan (Acan) mutations cause autosomal short stature (ISS) with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (OMIM#165800) in humans. Cartilage matrix deficiency mouse (Acancmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd mice develop postnatal dwarfism with progressing age. However, the underlying cellular and molecular mechanisms causing the growth failure have not been characterized in detail.Objective: To investigate the molecular mechanism of proportionate dwarfism in heterozygous Acan cmd mouse.Methods: Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth, at 1, 3, 6, 12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and femoral growth plates. Cell proliferation was assessed by EdU incorpora-tion and assessed by confocal microscopy. Quantification of percentage matrix area was performed using Image J image analysis software.Results: Heterozygous Acancmd mice were born with a normal body size. However, postnatal growth was reduced resulting in a gradually worsening dwarfism with reduced total body length (p <0.0001) as well as shorter tibial length (p<0.0001) and femoral length (p<0.0001) than their wild-type littermates. Histomorphometric analyses revealed that growth plate chondrocytes were more tightly packed with reduced matrix area (p<0.001) and increased proliferative column density in Acancmd mice compared to wild-type mice. Interestingly, the number of resting zone chondrocytes, proliferative cells per column and hypertropic cells per column were reduced at 1 week of age. In contrast, the size of terminal hypertrophic chondrocytes were normal during early postnatal growth, but reduced at 12 and 24 weeks of age. Despite the differences in growth plate morphology, chondrocyte proliferation was similar in Acan cmd and WT mice. Interestingly, female mice exhibited a more pronounced growth phenotype than the males.Conclusions: Heterozygous Acan cmd mice have a growth disorder that is similar to that in children with heterozygous ACAN mutations in terms of progression with age as well as in magnitude (10-15% smaller). Histomorphometric analyses suggest that the growth failure of aggrecan deficient mice is due to a combination of reduced matrix production and decreased size of the terminal hypertrophic chondrocytes. Further studies will elucidate the pathogenic mechanisms as well as the effect of estrogen on growth in aggrecan haploinsufficiency.
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5.
  • Binder, G, et al. (författare)
  • GHD Diagnostics in Europe and the US: An Audit of National Guidelines and Practice
  • 2020
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 92:3, s. 150-156
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Introduction:</i></b> Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. <b><i>Methods:</i></b> A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. <b><i>Results:</i></b> National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. <b><i>Conclusions:</i></b> GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.
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6.
  • Chaychenko, T, et al. (författare)
  • Difference in Insulin Resistance Assessment between European Union and Non-European Union Obesity Treatment Centers (ESPE Obesity Working Group Insulin Resistance Project)
  • 2021
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 93:11-12, s. 622-633
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Introduction:</i></b> The obesity epidemic has become one of the most important public health issues of modern times. Impaired insulin sensitivity seems to be the cornerstone of multiple obesity related comorbidities. However, there is no accepted definition of impaired insulin sensitivity. <b><i>Objective:</i></b> We hypothesize that assessment of insulin resistance differs between centers. <b><i>Methods:</i></b> The ESPE Obesity Working Group (ESPE ObWG) Scientific Committee developed a questionnaire with a focus on the routine practices of assessment of hyperinsulinemia and insulin resistance, which was distributed through Google Docs platform to the clinicians and researchers from the current ESPE ObWG database (<i>n</i> = 73). Sixty-one complete responses (84% response rate) from clinicians and researchers were analyzed: 32 from European Union (EU) centers (representatives of 14 countries) and 29 from Non-EU centers (representatives from 10 countries). Standard statistics were used for the data analysis. <b><i>Results:</i></b> The majority of respondents considered insulin resistance (IR) as a clinical tool (85.2%) rather than a research instrument. For the purpose of IR assessment EU specialists prefer analysis of the oral glucose tolerance test (OGTT) results, whereas non-EU ones mainly use Homeostatic Model Assessment of Insulin Resistance (HOMA-IR; <i>p</i> = 0.032). There was no exact cutoff for the HOMA-IR in either EU or non-EU centers. A variety of OGTT time points and substances measured per local protocol were reported. Clinicians normally analyzed blood glucose (88.52% of centers) and insulin (67.21%, mainly in EU centers, <i>p</i> = 0.0051). Furthermore, most participants (70.5%) considered OGTT insulin levels as a more sensitive parameter of IR than glucose. Meanwhile, approximately two-thirds (63.9%) of the centers did not use any cutoffs for the insulin response to the glucose load. <b><i>Conclusions:</i></b> Since there is no standard for the IR evaluation and uniform accepted indication of performing, an OGTT the assessment of insulin sensitivity varies between EU and non-EU centers. A widely accepted standardized protocol is needed to allow comparison between centers.
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7.
  • Chen, S. C., et al. (författare)
  • Development of A Minimum Dataset for the Monitoring of Recombinant Human Growth Hormone (rhGH) Therapy Use in Children with Growth Hormone Deficiency (GHD) - A GloBE-Reg Initiative
  • 2023
  • Ingår i: Hormone Research in Paediatrics. - 1663-2818 .- 1663-2826.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction Although there are some recommendations in the literature on the assessments that should be performed in children on recombinant human growth hormone (rhGH) therapy, the level of consensus on these measurements is not clear. The objective of the current study was to identify the minimum dataset (MDS) that could be measured in a routine clinical setting across the world, aiming to minimise burden on clinicians and improve quality of data collection. Methods This study was undertaken by the GH Scientific Study Group (SSG) in GloBE-Reg, a new project that has developed a common registry platform that can support long-term safety and effectiveness studies of drugs. Twelve clinical experts from 7 international endocrine organisations identified by the GloBE-Reg Steering Committee, 2 patient representatives and representatives from 2 pharmaceutical companies with previous GH registry expertise collaborated to develop this recommendation. A comprehensive list of data fields routinely collected by each of the clinical and industry experts for children with GHD was compiled. Each member was asked to determine the: (1) Importance of the data field and (2) Ease of data collection. Data fields that achieved 70% consensus in terms of importance qualified for the MDS, provided <50% deemed the item difficult to collect.Results A total of 246 items were compiled and 27 removed due to redundancies, with 219 items subjected to the grading system. Of the 219 items, 111 achieved at least 70% consensus as important data to collect when monitoring children with GH deficiency (GHD) on rhGH treatment. Sixty-nine of the 219 items were deemed easy to collect. Combining the criteria of importance and ease of data collection, 63 met the criteria for the MDS. Several anomalies to the MDS rule were identified and highlighted for discussion, including whether the patients were involved in current or previous clinical trials, need for HbA1c monitoring, other past medical history, and adherence, enabling formulation of the final MDS recommendation of 43 items; 20 to be completed once, 14 every 6 months and 9 every 12 months.Conclusion In summary, this exercise performed through the GloBE-Reg initiative provides a recommendation of the minimum dataset requirement, collected through real-world data, for the monitoring of safety and effectiveness of rhGH in children with GHD, both for the current daily preparations and the newer long-acting growth hormone.
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8.
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9.
  • Cianfarani, S, et al. (författare)
  • The Impact of Stress on Health in Childhood and Adolescence in the Era of the COVID-19 Pandemic
  • 2023
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 96:1, s. 83-87
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background:</i></b> The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is posing many challenges to global health. Efforts from the whole scientific community have shed light on the pathogenetic mechanisms and the clinical features of SARS-CoV-2 infection as well as on potential therapeutic strategies. <b><i>Summary:</i></b> The consequences of stress related to social isolation and anxiety generated by the pandemic on mental and physical health are collateral effects that are yet poorly investigated.
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10.
  • Deodati, A, et al. (författare)
  • Crk Haploinsufficiency Is Associated with Intrauterine Growth Retardation and Severe Postnatal Growth Failure
  • 2022
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 94:11-12, s. 456-466
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • <b><i>Background:</i></b> Children with 17p13.3 microdeletions including the YWHAE gene show intrauterine growth restriction, craniofacial dysmorphisms, postnatal growth failure, and cognitive impairment. This region is characterized by genomic instability and has been associated with isolated lissencephaly sequence and Miller-Dieker syndrome characterized by facial dysmorphisms, microcephaly, short stature, seizures, cardiac malformations, and agyria. Whilst brain abnormalities are secondary to YWHAE deficiency, the cause of pre- and postnatal growth failure has not been identified yet. <b><i>Case Presentation:</i></b> We describe 2 patients (patient 1 15 years and patient 2 11 years and 10 months) referred to our Center of Pediatric Endocrinology for intrauterine growth retardation with de novo 17p13.3 deletion. In vitro assays showed a defect in CRK expression and GH/IGF1 signaling. rhGH therapy was effective in partially reducing the deficit in height in patient 1 and induced catch-up growth in patient 2. <b><i>Conclusion:</i></b> Our results suggest that 17p13.3 microdeletion involving CRK affects both GH and IGF1 signaling ultimately leading to pre- and postnatal growth retardation, secondary to partial insensitivity to GH/IGF1. rhGH therapy may be considered to reduce the height deficit in these patients, though data on adult height are lacking.
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11.
  • Gawlik-Starzyk, Aneta M., et al. (författare)
  • Availability, usage, and preferences of estradiol and progestogen preparations for puberty induction from a multicentral perspective
  • 2024
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Natural oestrogen administration as oral or transdermal 17β-estradiol is recommended for pubertal induction in girls with hypogonadism. However, suitable low-dose formulations are not consistently available globally. This questionnaire study aimed to identify the current availability of oestrogen and progesterone preparations worldwide.Methods: Endorsed by the ESPE Turner Syndrome Working Group, the questionnaire targeted paediatric endocrinologists. Questions focused on accessibility of oral/transdermal 17β-estradiol and progestogen preparations. Responses were collected through a SurveyMonkey survey disseminated via ESPE channels, direct outreach, and conferences from June 2020 to December 2022.Results: Participation included 229 healthcare professionals from 45 countries. Oral and transdermal 17β-estradiol in adult dosage was highly accessible (86.5% and 84.3%), with transdermal administration the preferred form (62.8%). Most commonly available estradiol preparations included 50 μg patches (32 countries) and 1 or 2 mg tablets (65.8% and 71.1% countries). However, 0.5 mg 17β-estradiol tablets were available in only 20% of respondents from 8 countries. Patches delivering 14 or 25 μg/day of 17β-estradiol were available in 3 and 20 countries, respectively. Oral progestogen had widespread availability (96.0%) and preference (87.0%), while transdermal usage was limited to 15.2% of respondents.Conclusion: This study highlights global challenges in accessing suitable hormone preparations for female pubertal induction. In most countries, the lowest dose of the estradiol is 50 μg for patches and 2 mg for tablets. Appropriate low-dose 17β-estradiol tablets are much less available than low-dose patches. Our survey underscores the importance of adapting guidelines to local availability, and the need for improved accessibility to address these global disparities.
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12.
  • Gerver, Willem J. M., et al. (författare)
  • Arm Span and Its Relation to Height in a 2- to 17-Year-Old Reference Population and Heterozygous Carriers of ACAN Variants
  • 2020
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 93:3, s. 164-172
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND/OBJECTIVES: In the clinical assessment of a short or tall child, estimating body disproportion is useful to assess the likelihood of a primary growth disorder, e.g., skeletal dysplasia. Our objectives were (1) to use data from the Maastricht study on healthy children (2-17 years) to calculate relative arm span (AS) for height (H) to serve as age references for clinical purposes; (2) to assess its age and sex dependency; and (3) to investigate relative AS adjustment for age and sex in individuals with ACAN haploinsufficiency.METHODS: The Maastricht study data (2,595 Caucasian children, 52% boys, 48% girls) were re-analysed to produce reference tables and graphs for age and sex of AS - H and AS/H. Published information on AS/H in Europeans was used as reference data for adults. Relative AS from 33 patients with ACAN haploinsufficiency were plotted against reference data and expressed as standard deviation score (SDS) for age and sex.RESULTS: Mean AS - H from 2 to 17 years increased from -1.2 to +1.5 cm in boys and from -4.8 to +1.6 cm in girls. Mean AS/H increased from 0.9848 to 1.0155 in boys and from 0.9468 to 1.0028 in girls. Mean AS/H in patients with ACAN haploinsufficiency was approximately 1.0, 1.5 and 0.5 SDS in young children, adolescents and 20- to 50-year-olds, respectively, and normal thereafter.CONCLUSIONS: These reference charts can be used for 2- to 17-year-old children/adolescents. Carriers of ACAN haploinsufficiency have an elevated mean AS/H in childhood and adolescence and a slightly elevated ratio till 50 years.
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13.
  • Hallgrimsdottir, Sigrun, et al. (författare)
  • Premature epiphyseal fusion induced by a retinoic acid agonist in a young girl with fibrodysplasia ossificans progressiva
  • 2021
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 95-95
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Retinoic acid receptor agonists can have dramatic negative effects on growth and even induce premature growth cessation and epiphyseal fusion (1, 2).An 11 5/12-year-old, prepubertal girl with fibrodysplasia ossificans progressiva presented in our pediatric skeletal disorders clinic with the concern of early growth cessation. She had participated in a clinical trial of Palovarotene (“MOVE”, NCT03312634), a retinoic acid receptor-gamma agonist, since the age of 9 10/12 years. At the visit, she had recently discontinued her participation in the study. During the 19 months since starting on Palovarotene, her height had only increased 1.9 cm to 136.4 cm. A skeletal survey detected fusion of several growth plates that normally remain open until the end of puberty including the growth plates of proximal humerus, distal ulna and distal radius. One year after stopping Palovarotene, she was in early puberty and her height had increased another 3.9 cm to 140.3 cm (-2.6 SDS). Measurements of height, sitting height, and arm span confirmed that growth of arms and legs had ceased, whereas growth of the spine continued.This report supports previous findings indicating that highdose retinoic acid receptor agonists can induce premature epiphyseal fusion even before puberty and may therefore cause significant, disproportionate short stature if used in young children. The finding that growth of the spine, but not legs and arms, resumed after the treatment was discontinued suggests that long bones are more susceptible than vertebrae to retinoic acid-induced epiphyseal fusion.1. De Luca F, Uyeda JA, Mericq V, Mancilla EE, Yanovski JA, Barnes KM, et al. Retinoic acid is a potent regulator of growth plate chondrogenesis. Endocrinology. 2000;141(1):346–53.2. Pease CN. Focal retardation and arrestment of growth of bones due to vitamin A intoxication. JAMA. 1962;182:980–5.
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14.
  • Hallgrimsdottir, Sigrun, et al. (författare)
  • Premature epiphyseal fusion induced by Palovarotene in a young girl with fibrodysplasia ossificans progressiva
  • 2021
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 213-213
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Retinoic acid receptor agonists can have dramatic negative effects on growth and even induce premature growth cessation and epiphyseal fusion (1, 2).An 11 5/12-year-old, prepubertal girl with fibrodysplasia ossificans progressiva presented in our pediatric skeletal disorders clinic with the concern of early growth cessation. She had participated in a clinical trial of Palovarotene (“MOVE”, NCT03312634), a retinoic acid receptor-gamma agonist, since the age of 9 10/12 years. At the visit, she had recently discontinued her participation in the study. During the 19 months since starting on Palovarotene, her height had only increased 1.9 cm to 136.4 cm. A skeletal survey detected fusion of several growth plates that normally remain open until the end of puberty including the growth plates of proximal humerus, distal ulna and distal radius. One year after stopping Palovarotene, she was in early puberty and her height had increased another 3.9 cm to 140.3 cm (-2.6 SDS). Measurements of height, sitting height, and arm span confirmed that growth of arms and legs had ceased, whereas growth of the spine continued.This report supports previous findings indicating that high-dose retinoic acid receptor agonists can induce premature epiphy-seal fusion even before puberty and may thus cause significant, disproportionate short stature if used in young children. The finding that growth of the spine, but not legs and arms, resumed after the treatment was discontinued suggests that long bones are more susceptible than vertebrae to retinoic acid-induced epiphyseal fusion.References1. De Luca F, Uyeda JA, Mericq V, Mancilla EE, Yanovski JA, Barnes KM, et al. Retinoic acid is a potent regulator of growth plate chondrogenesis. Endocrinology. 2000;141(1):346–53.2. Pease CN. Focal retardation and arrestment of growth of bones due to vitamin A intoxication. JAMA. 1962;182:980–5.
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15.
  • Inzaghi, E, et al. (författare)
  • The Challenge of Defining and Investigating the Causes of Idiopathic Short Stature and Finding an Effective Therapy
  • 2020
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 92:2, s. 71-83
  • Tidskriftsartikel (refereegranskat)abstract
    • Idiopathic short stature (ISS) comprises a wide range of conditions associated with short stature that elude the conventional diagnostic work-up and are often caused by still largely unknown genetic variants. In the last decade, the improvement of diagnostic techniques has led to the discovery of causal mutations in genes involved in the function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis as well as in growth plate physiology. However, many cases of ISS remain idiopathic. In the future, the more frequent identification of the underlying causes will allow a better stratification of subjects and offer a tailored management. GH therapy has been proposed and approved in some countries for the treatment of children with ISS. To improve the efficacy of GH therapy, trials with GH combined with GnRH agonists, aromatase inhibitors, and even IGF-I have been conducted. This review aims to revise the current definition of ISS and discuss the management of children with ISS on the basis of the most recent evidence.
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16.
  • Jacobs, An, et al. (författare)
  • Pigmented Hypertrichosis with Insulin-Dependent Diabetes Mellitus Syndrome: A Case Series
  • 2024
  • Ingår i: HORMONE RESEARCH IN PAEDIATRICS. - 1663-2818 .- 1663-2826.
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) syndrome is a rare disease, and part of the cluster histiocytosis-lymphadenopathy plus syndrome (H syndrome), which is associated with mutations in the SLC29A3 gene. Patients with PHID show clinical features of H syndrome but also have insulin-dependent diabetes mellitus. The PHID has previously been described as predominantly in absence of pancreatic autoantibodies. Case Series Presentation: Through an open call in two international diabetes registers, clinical and genetic characteristics of 7 PHID patients in 6 treatment centres were collected after informed consent. All of them had consanguinity in their families, and their origins were located in North-African and Middle Eastern regions. Four out of 7 patients had at least one positive pancreatic autoantibody. Discussion and Conclusion: Our case series reveals that PHID exhibits a wide range of clinical symptoms and signs. When consanguinity is present in a patient with newly diagnosed diabetes, and/or if other atypical symptoms such as dysmorphic features, skin lesions, haematological abnormalities, and developmental delay are present, threshold for genetic analysis should be low. Moreover, the presence of autoantibodies should not withhold genetic testing as our case series contradicts the previous observation of predominant autoantibody absence in PHID. Established FactsHistiocytosis-lymphadenopathy plus syndrome (H syndrome) comprises a cluster of diseases associated with gene mutations.SLC29A3Pigmented hypertrichosis with insulin-dependent diabetes mellitus (PHID) syndrome is a rare disease and part of the H syndrome cluster.Patients with PHID syndrome have clinical features of H syndrome and predominantly autoantibody-negative diabetes, as it has previously been described.
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17.
  • Janson, Annika, et al. (författare)
  • Metabolic and Bariatric Surgery in Adolescents: For Whom, When, and How?
  • 2023
  • Ingår i: HORMONE RESEARCH IN PAEDIATRICS. - : S. Karger AG. - 1663-2818 .- 1663-2826. ; 96:6, s. 609-619
  • Forskningsöversikt (refereegranskat)abstract
    • Severe obesity in adolescence profoundly impacts health and social well-being. Lifestyle modifications are seldom successful in maintaining sufficient weight loss to mitigate the risk of complications. Metabolic and bariatric surgery (MBS) is a standard treatment for adult patients and has emerged as an option for adolescent patients. Several high-quality studies of adolescent MBS show substantial and sustained improvements both in weight and cardiometabolic parameters, as well as a safety profile similar to that seen in adult patients. Patients report improvements in health- and weight-related quality of life. Concerns around adolescent MBS can be attributed to a fear of side effects on growth and puberty, risk of nutritional deficiencies and osteoporosis, alcohol abuse, psychosocial vulnerability, and the ability to consent in the decision process. Guidelines give somewhat different recommendations, but the most comprehensive guidelines from the American Society for Metabolic and Bariatric Surgery recommend MBS for class III obesity or class II obesity with comorbidity. This mini-review aimed to pre-sent published data on MBS in adolescents. We discuss indications for MBS and the optimal timing in the young person's life, the choice of surgical method, and MBS in relation to the new anti-obesity medications. Based on data primarily from the USA and Sweden, we conclude that MBS is a valuable treatment option for adolescents with severe obesity that appears underutilized against the backdrop of the poor prognosis of severe obesity. We argue for continued research, development of guidelines, multi-professional teamwork, long-term follow-up, and centralization of adolescent MBS.
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18.
  • Jorgensen, A, et al. (författare)
  • Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models
  • 2023
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 96:2, s. 190-206
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background:</i></b> Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. <b><i>Summary:</i></b> In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. <b><i>Key Messages:</i></b> Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.
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19.
  • Jorgensen, A, et al. (författare)
  • Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models
  • 2023
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 96:2, s. 190-206
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background:</i></b> Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. <b><i>Summary:</i></b> In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. <b><i>Key Messages:</i></b> Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.
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20.
  • Kiss, Eszter, et al. (författare)
  • Granulosa cell tumors in girls : Preliminary results of a meta-analysis of new and published cases
  • 2023
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 96:Suppl. 4, s. 126-127
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Granulosa cell tumors (GCT) originate from sex cord/stromal tissue in the gonad. They are typically located in an ovary, but extra-gonadal localisation exists. These tumors are extremely rare in children and no systematic review has been published. The objective of this systematic review is to examine the following questions: What is the clinical picture of girls with a GCT? How are these patients treated and what is their prognosis?Methods: To be included in the review, the article had to present a new case with GCT fulfilling the following criteria: female human fetus or a girl aged < 19 years with clinical information included a tumor containing granulosa cells.The databases MEDLINE, Embase, Web of Science, and CINAHL were searched in November 2021. To find new cases, we asked pediatric endocrinologists in Sweden to report patients after informed consent had been secured. We also collected data from a Swedish paediatric reference pathology laboratory.Results: The search identified 1,894 published references of which 35 were duplicates. We have screened 1,859 abstracts. We are in the process of reading 824 selected articles in full text to check for eligibility. Individual participant data has been extractedfrom 20 of the published reports for preliminary results. Nineteen new Swedish cases with a GCT were identified.The preliminary analysis of 39 patients’ data shows an average age of 7.3 years at the time of diagnosis (range: antenatal diagnosis up to 18 years of age). Symptoms at presentation were: prepubertal breast enlargement, vaginal discharge/bleeding, abdominal distension or pain, pubic hair growth, fever, constipation, swelling of vulva or cliteromegaly, hyperpigmentation of the skin, primary/secondary amenorrhea, headache, hirsutism and advanced linear growth.The histopathological diagnosis was juvenile GCT in 76.9%, adult GCT in 12.8%, a mixed type of juvenile and adult GCT in 7.7% and another type of tumor containing granulosa cell component in 2.6% of the cases.All patients received surgical treatment except one with a post-mortem GCT diagnoses. Adjuvant chemotherapy was administered in two cases.Three patients (7.7%) died, two of them due to late discovery of the primary tumor and one secondary to local recurrence of the tumor with metastases 4 years after the primary diagnosis.Conclusion: GCT can present in all pediatric ages and often, but far from always, with endocrine symptoms such as peripheral precautious puberty. Data from this systematic review will hopefully promote early recognition of this malignant disease.
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21.
  • Lennartsson, Otto, 1993-, et al. (författare)
  • Sex steroid priming decreases the frequency of divergent results between spontaneous and stimulated GH tests
  • 2023
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 96:Suppl. 4, s. 287-287
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: The diagnosis of growth hormone (GH) deficiency (GHD) is complicated by the low specificity of GH testing, especially in children before and during early pubertal stages. Sex steroid priming reduces false positive results in pre- and early pubertal children. However, only a small number of studies have assessed its efficacy in improving the diagnostic accuracy of GHD investigations.Aim: To evaluate the effect of sex steroid priming in GH testing on the prevalence of divergent results of spontaneous nocturnal secretion and arginine-insulin-tolerance test (AITT).Methods and Materials: This is a retrospective chart review of all 196 children investigated for GHD from January 1, 1993 until February 28, 2023 at the Department of Paediatrics, Örebro University Hospital, Örebro, Sweden. Of them 173 (89%) children had undergone both overnight GH sampling and AITT and 28 of 173 children (16%) had received estrogen priming prior to their tests. A GH peak concentration of ≥ 7.0 μg/L or more was considered normal for both tests.Results: Children receiving priming (36% girls) had a median age of 12.1 years (6.2–15.0) vs. 8.4 years (1.5 – 15.9) in children not primed (43% girls). Of the 173 children that had undergone both tests, 31 (18%) tested positive (<7.0 μg/L) on both tests, 22 (13%) tested positive on overnight sampling only, and 13 (8%) tested positive on AITT only. Of the 28 children who had received priming ,only one child had divergent results, with a positive result solely from AITT. Amongst non-primed children, 34 of 145 had divergent results with 21 (14.6%) testing positive on AITT, and 13 (9%) exhibiting a positive result on the spontaneous GH test. The frequency of divergent tests was significantly lower (p = 0.016) amongst primed children (3.6%) compared to non-primed children (23.6%).Conclusion: Our results show that sex steroid priming prio rto GHD testing with overnight sampling and AITT decreases the frequency of divergent results between the two tests and thus suggest that sex steroid priming decreases the risk of false positive results.
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22.
  • Mantovani, G, et al. (författare)
  • Recommendations for Diagnosis and Treatment of Pseudohypoparathyroidism and Related Disorders: An Updated Practical Tool for Physicians and Patients
  • 2020
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 93:3, s. 182-196
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients affected by pseudohypoparathyroidism (PHP) or related disorders are characterized by physical findings that may include brachydactyly, a short stature, a stocky build, early-onset obesity, ectopic ossifications, and neurodevelopmental deficits, as well as hormonal resistance most prominently to parathyroid hormone (PTH). In addition to these alterations, patients may develop other hormonal resistances, leading to overt or subclinical hypothyroidism, hypogonadism and growth hormone (GH) deficiency, impaired growth without measurable evidence for hormonal abnormalities, type 2 diabetes, and skeletal issues with potentially severe limitation of mobility. PHP and related disorders are primarily clinical diagnoses. Given the variability of the clinical, radiological, and biochemical presentation, establishment of the molecular diagnosis is of critical importance for patients. It facilitates management, including prevention of complications, screening and treatment of endocrine deficits, supportive measures, and appropriate genetic counselling. Based on the first international consensus statement for these disorders, this article provides an updated and ready-to-use tool to help physicians and patients outlining relevant interventions and their timing. A life-long coordinated and multidisciplinary approach is recommended, starting as far as possible in early infancy and continuing throughout adulthood with an appropriate and timely transition from pediatric to adult care.
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23.
  • McClenaghan, C, et al. (författare)
  • Sulfonylurea-Insensitive Permanent Neonatal Diabetes Caused by a Severe Gain-of-Function Tyr330His Substitution in Kir6.2
  • 2022
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 95:3, s. 215-223
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background/Aims:</i></b> Mutations in <i>KCNJ11</i>, the gene encoding the Kir6.2 subunit of pancreatic and neuronal K<sub>ATP</sub> channels, are associated with a spectrum of neonatal diabetes diseases. <b><i>Methods:</i></b> Variant screening was used to identify the cause of neonatal diabetes, and continuous glucose monitoring was used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant K<sub>ATP</sub> channel function was used to determine molecular basis. <b><i>Results:</i></b> We identified a previously uncharacterized <i>KCNJ11</i> mutation, c.988T&#x3e;C [p.Tyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (intermediate DEND). Functional analysis of recombinant K<sub>ATP</sub> channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. <b><i>Conclusions:</i></b> In this subject, the <i>KCNJ11</i> (c.988T&#x3e;C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution and highlights the need for molecular analysis of such mutations.
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24.
  • Nordenstrom, A, et al. (författare)
  • Current and Novel Treatment Strategies in Children with Congenital Adrenal Hyperplasia
  • 2023
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 96:6, s. 560-572
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background:</i></b> The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the dose per square meter body surface area used in children of different ages and developmental phases have improved the situation and outcome for the patients. Neonatal screening enables an earlier diagnosis and initiation of treatment, prevents from adrenal crisis, and improves growth and development also for children with the less severe forms of CAH. <b><i>Summary:</i></b> This review describes the current treatment strategies for children with CAH and discusses some potential treatment options that have been developed with the primary aim to decrease the adrenal androgen production. Novel modified release glucocorticoid therapies are also discussed. <b><i>Key Messages:</i></b> The long-term effects of the new adjunct therapies are unknown, and some are not suitable for use in children and adolescents. The effects of the new therapies on bone mineral density, gonadal functions, and long-term cognitive development are yet to be assessed. It is not known what levels of adrenal androgens are optimal for normal growth, puberty, and bone health. The basis of using glucocorticoids and mineralocorticoids in the treatment of CAH remains, and in some individuals, it may be beneficial to add therapies to reduce the androgen load during certain life stages.
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25.
  • Nordenström, A, et al. (författare)
  • Current and Novel Treatment Strategies in Children with Congenital Adrenal Hyperplasia
  • 2023
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 96:6, s. 560-572
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background:</i></b> The standard treatment for congenital adrenal hyperplasia (CAH) in children is still hydrocortisone. Improved strategies for timing of the dose during the day and the dose per square meter body surface area used in children of different ages and developmental phases have improved the situation and outcome for the patients. Neonatal screening enables an earlier diagnosis and initiation of treatment, prevents from adrenal crisis, and improves growth and development also for children with the less severe forms of CAH. <b><i>Summary:</i></b> This review describes the current treatment strategies for children with CAH and discusses some potential treatment options that have been developed with the primary aim to decrease the adrenal androgen production. Novel modified release glucocorticoid therapies are also discussed. <b><i>Key Messages:</i></b> The long-term effects of the new adjunct therapies are unknown, and some are not suitable for use in children and adolescents. The effects of the new therapies on bone mineral density, gonadal functions, and long-term cognitive development are yet to be assessed. It is not known what levels of adrenal androgens are optimal for normal growth, puberty, and bone health. The basis of using glucocorticoids and mineralocorticoids in the treatment of CAH remains, and in some individuals, it may be beneficial to add therapies to reduce the androgen load during certain life stages.
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26.
  • Padidela, Raja, et al. (författare)
  • BUR-CL207 : An Open-label, Multicenter, Non-randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of Burosumab in Pediatric Patients from Birth to Less than 1 Year of Age with XLH
  • 2021
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 226-226
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Background: X-linked hypophosphatemia (XLH) is caused by mutations in PHEX which increases serum Fibroblast Growth Factor 23 (FGF23) concentrations leading to phosphate wast-ing and osteomalacia. Burosumab is a recombinant fully human IgG1 monoclonal antibody which selectively inhibits the activity of FGF23. In clinical trials burosumab demonstrated significant clinical improvements in radiological rickets severity, growth, and biochemistry among XLH children aged 1-12 years compared to those continuing on conventional therapy (Imel 2019). Buro-sumab is licensed by the European Medicines Agency for manage-ment of XLH in children >1 year. Early initiation of treatment in XLH improves height (Makitie 2003) and effective and sustained treatment improves dental and musculoskeletal outcomes. Study BUR-CL207 has been designed to evaluate the safety, tolerability, pharmacology and efficacy of burosumab in pediatric patients <12 months.Methods: This study is enrolling and will include approxi-mately 20 XLH infants (<12 months old) with a confirmed PHEXmutation. Baseline fasted serum phosphate below the age-adjusted normal range is required for inclusion. Infants receiving conven-tional therapy will discontinue medications >1 week before com-mencing burosumab treatment and for the duration of study. This study comprises three cohorts with a total treatment period of up to 48 weeks. Subjects will be enrolled into a cohort dependent on their age. Cohorts 1 and 2 for subjects aged: ≥6 months to <12 months, and cohort 3 for subjects <6 months. Burosumab starting doses of 0.4 mg/kg (Cohorts 1 and 3) and 0.8 mg/kg (Cohort 2), administered every two weeks, will be studied in each subgroup in a staggered manner with up to 3 subjects per cohort (final num-ber per cohort will depend on age of eligible patients as enrolled). Burosumab dose adjustments will be determined by serum phos-phate levels. A Data Safety Monitoring Board will review data accrued in each cohort.Outcome Measurements: The primary endpoint is the safety of burosumab in pediatric patients <12 months. The secondary endpoints include: PK assessments and change from baseline in serum phosphate and 1,25(OH)2D, the clinical effects of buro-sumab on growth and prevention and/or healing of rickets and skeletal deformities. Exploratory endpoints include presence and appearance of bone and skeletal XLH related abnormalities in pediatric subjects starting treatment <12 months, anthropometric and motor development in pediatric subjects with XLH and char-acterizing the immunogenicity of burosumab following adminis-tration to pediatric subjects with XLH.BUR-CL207 is conducted in Austria, France, Germany, Italy, Spain, Sweden, UK.
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27.
  • Padidela, Raja, et al. (författare)
  • Patient-reported outcomes from a randomized open-label phase 3 trial comparing burosumab versus conventional therapy in children with X-linked hypophosphatemia : results from the 24-week treatment extension period
  • 2022
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 95:Suppl. 2, s. 29-30
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • In a randomized open-label phase 3 trial in 62 children (1–12 years) with X-linked hypophosphatemia (XLH) (NCT 02915705), switching from conventional therapy (oral phosphate plus active vitamin D) to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved serum phosphate concentration, rickets, lower-extremity deformities, growth, mobility, and patient-reported outcomes (PROs) at 64 weeks. Children in Europe, USA, Canada, and Australia who completed 64 weeks’ treatment could continue to receive burosumab in the extension period (burosumab continuation group) or cross over from conventional therapy to burosumab (crossover group) to 124 weeks. A Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire was used in children aged ≥5 years to measure Pain Interference, Physical Function Mobility, and Fatigue; health-related quality of life was measured using the SF-10 Health Survey for Children (n=35). Here, we describe changes in PROs from baseline to weeks 64 and 88, and report whether the 3-point minimal important difference (MID) was reached for PROMIS domains (Thissen et al., 2016; PMID 26118768). The mean change from baseline exceeded the MID for Pain Interference at weeks 64 and 88 and for Fatigue at week 64 in the burosumab continuation group, and for Pain Interference and Fatigue at week 88 in the crossover group. Similar improvements in SF-10 Physical Health were seen baseline to week 64 in the burosumab continuation group, and week 64 to 88 in the cross-over group. SF-10 Psychosocial Health changed little in either group at the two timepoints.Treatment with burosumab improved Pain Interference and Fatigue beyond the MID in children with XLH who switched from conventional therapy to receive 24 weeks of burosumab. Improvements were also maintained in children who received an additional 24 weeks’ burosumab treatment.
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28.
  • Pampanini, V, et al. (författare)
  • Fertility Preservation for Prepubertal Patients at Risk of Infertility: Present Status and Future Perspectives
  • 2021
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 93:11-12, s. 599-608
  • Tidskriftsartikel (refereegranskat)abstract
    • The increasing cure rate of cancer has led to a vast population of survivors having to face the late adverse effects of oncological treatments, with fertility impairment being one of the most sensitive issues for patients. Different options to preserve the fertility of adult patients are routinely used in clinical practice. However, fertility preservation strategies for prepubertal patients at risk of infertility are limited to the cryopreservation of immature gonadal tissue. In recent decades, many research efforts have been focused on the future use of cryopreserved gonadal tissue. This review discusses the common status of fertility preservation measures for pediatric patients undergoing gonadotoxic treatment, focusing especially on the challenges that remain to be solved in order to implement this fundamental service.
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29.
  • Pampanini, V, et al. (författare)
  • Long-Acting Growth Hormone Preparations and Their Use in Children with Growth Hormone Deficiency
  • 2023
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 96:6, s. 553-559
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background:</i></b> Daily recombinant human growth hormone (rhGH) is approved and marketed worldwide to treat children and adults with GH deficiency and other conditions. Efficacy of rhGH therapy is influenced by several variables. Drop of treatment adherence over time has been recognized as a cause of reduced rhGH efficacy and has driven considerable efforts from pharmaceutical companies and scientists to develop long-acting rhGH (LAGH) formulations in order to relieve patients and their families from the burden of daily injections. <b><i>Summary:</i></b> Different technologies to manipulate drug release have been produced allowing weekly, biweekly, or monthly rhGH administration. The LAGH formulations developed at present have demonstrated a comparable or even higher efficacy as compared with daily rhGH in most of the cases and no major safety issues in phase 3 studies. A greater incidence of injection-site reactions has been reported but mainly of mild and transient nature. <b><i>Key Messages:</i></b> Despite LAGH analogs appearing promising, potential drawbacks still need to be addressed. Long-term consequences of nonphysiological GH profile and its consequences on metabolism and risk of cancer, optimal therapeutic monitoring, immunogenicity of LAGH molecules, and potential novel side effects related to the technologies used to develop these molecules are among the major concerns that require answers from long-term surveillance. Finally, increased acceptance of LAGH formulations from patients and their caregivers is yet to be demonstrated and cost-effectiveness evaluated consequently.
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30.
  • Reyes, TME, et al. (författare)
  • Bone Mass in Young Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency
  • 2021
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 94:1-2, s. 1-8
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Background:</i></b> The effects of hyperandrogenism and steroid treatment on bone mineral density (BMD) in patients with congenital adrenal hyperplasia (CAH) are controversial. <b><i>Objectives:</i></b> The objectives of this study were to characterize BMD and fractures in patients with CAH and to identify whether there is an association between alterations in BMD, nutritional status, and variables related to the disease. <b><i>Methods:</i></b> A cross-sectional descriptive study was conducted to explore clinical, hormonal, dairy consumption, physical activity, and BMD variables in patients with CAH due to 21-hydroxylase deficiency and controls matched by age, gender, skin color, body mass index, and Tanner scale. <b><i>Results:</i></b> Fifty subjects (CAH <i>n</i> = 25; females <i>n</i> = 42 [84%]) with a mean age of 15.9 ± 5.8 years were included in the study. White skin color predominated in 34 subjects (68%), mestizo in 11 (22%), and black in 5 (10%). In patients with CAH, BMD lumbar spine was decreased compared to that in controls (0.83 ± 0.23 vs. 0.98 ± 0.26 g/cm<sup>3</sup>, <i>p</i> = 0.004). BMD femur was also decreased in patients with CAH; however, this was not significant (0.95 ± 0.20 vs. 1.04 ± 0.24 g/cm<sup>3</sup>, <i>p</i> = 0.17). There was a positive relationship between age at diagnosis, age of initiation of glucocorticoid treatment, and testosterone levels with all measurements of BMD. The daily glucocorticoid dose was negatively related to BMD. No fractures were found. <b><i>Conclusions:</i></b> Patients with CAH had decreased BMD, especially in lumbar spine. Increased androgen exposure seemed to improve, while increased glucocorticoid dose impaired BMD.
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31.
  • Rodanaki, Maria, 1987-, et al. (författare)
  • A Randomized Trial of the Effect of a GnRH Analogue Injection on Ghrelin Levels in Girls
  • 2022
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 95:5, s. 442-451
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Ghrelin concentrations decline during puberty by an unclear mechanism. Acylated ghrelin (AG) is unstable in sampling tubes, but no standardized sampling protocol exists. We hypothesized that ghrelin levels decrease as a consequence of increased gonadotropin-releasing hormone (GnRH) signalling and that the addition of a protease inhibitor to sampling tubes preserves the AG levels.Methods: In this randomized, placebo-controlled, cross-over study, 13 girls with suspected central precocious puberty were included. They performed an adjusted GnRH stimulation test twice and were given Relefact LHRH (R)(100 mu g/m(2)) or saline in a randomized order. Blood was sampled repeatedly for 150 min for the analysis of hormone concentrations. Oestradiol levels were only measured at baseline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes. Specific ELISA kits were used for the analysis of AG and desacylated ghrelin (DAG) levels.Results: Neither AG nor DAG levels changed after GnRH analogue injection in comparison to saline. The addition of AEBSF preserved AG levels (650.1 +/- 257.1 vs. 247.6 +/- 123.4 pg/mL, p < 0.001) and decreased DAG levels (51.9 [12.5-115.7] vs. 143.5 [71.4-285.7] pg/mL, p < 0.001). Both AG and DAG levels were inversely associated with insulin levels (r = -0.73, p = 0.005, and r = -0.78, p = 0.002, respectively). AG levels were inversely associated with oestradiol levels (rho = -0.57, p = 0.041).Conclusion: Ghrelin levels do not decrease following a pharmacological dose of a GnRH analogue in the short term in girls. Addition of a protease inhibitor to the sampling tubes decreases AG degradation, resulting in preserved AG and decreased DAG levels. (C) 2022 The Author(s). Published by S. Karger AG, Basel
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32.
  • Rodanaki, Maria, 1987-, et al. (författare)
  • Adding a protease inhibitor to sampling tubes increases the acylated ghrelin and decreases the desacylated ghrelin levels in girls
  • 2021
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 94:Suppl. 1, s. 111-112
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: Ghrelin is a growth hormone-releasing acylated peptide stimulating the appetite, mainly produced in the stomach, and with an important role in pubertal development (1). Two ghrelin forms have been described, acylated (AG) and desacylated (DAG), but it is debated whether DAG is an active hormone or a degradation product of AG (2). Our aim was to evaluate the effects of adding the protease inhibitor 4-(2-aminoethyl) benzenesufonyl fluoride hydrochloride (AEBSF) to sampling tubes and acidification of plasma on levels of AG and DAG in girls with suspected central precocious puberty (CPP).Methods: 13 girls aged 6.6 to 10.1 years with suspected CPP undergoing a gonadotropin-releasing hormone stimulation test during 2015-2017 at the Departments of Paediatrics, at Örebro or Uppsala University Hospital were included. Blood samples were collected at 0 min in precooled EDTA tubes with or without AEBSF at a final concentration of 2mg/ml. After cold centrifugation, HCl at a final concentration of 50 μmol/l, was added to 50% of the plasma tubes containing AEBSF. The AG and DAG concentrations were measured by ELISA kits. Comparison was performed using one-way ANOVA for repeated measurements.Results: The mean plasma AG levels were significantly higher after the addition of AEBSF only (650.9 +/- 257.1 pg/ml) or AEBSF+HCl (681.2 +/- 299 pg/ml) compared to the concentrations without additives (247.6 +/- 123.4 pg/ml, p<0.01 for both comparisons). There was no significant difference between the AG levels after AEBSF and AEBSF+HCl addition. The plasma levels of DAG were significantly lower after the addition of AEBSF+HCl (69.3 +/- 30.6 pg/ml) and even further lowered after the addition of AEBSF only (56.3+/- 30.9 pg/ml) compared to the concentrations of DAG in tubes without any additives (149.9 +/- 73.7 pg/ml, p < 0.01 for both comparisons).Discussion: Due to the unstable nature of AG, special procedures are required for accurate measurement of its plasma levels in children, including the use of a protease inhibitor like AEBSF. However, DAG was still measurable indicating that it may not only be a degradation product of AG. 1. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85(2):495-522.2. Blatnik M, Soderstrom CI, Dysinger M, Fraser SA. Prandial ghrelin attenuation provides evidence that des-acyl ghrelin may be an artifact of sample handling in human plasma. Bio-analysis. 2012;4(20):2447-55.
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33.
  • Rodanaki, Maria, 1987-, et al. (författare)
  • The effect of a GnRH analogue injection on the circulating levels of kisspeptin-1 in girls with suspected central precocious puberty
  • 2022
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 95:Suppl. 2, s. 341-341
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: Kisspeptin stimulates the gonadotropin releasing hormone (GnRH) neurons in hypothalamus initiating puberty. However, it is not known whether GnRH inhibits kisspeptin secretion by negative feedback and whether there are any associations between circulating levels of kisspeptin and other hormones, like ghrelin, important for the onset of puberty.Methods: Thirteen girls with suspected central precocious puberty performed an adjusted GnRH stimulation test twice, placebo-controlled in a randomized order, at Örebro or Uppsala University Hospital, Sweden. Blood was sampled 0, 30, 60, 90, 120 and 150 min after the iv injection of either Relefact LHRH® or saline. The protease inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) was added to the sampling tubes to a final concentration of 2 mg/ml. An ELISA kit from LifeSpan BioSciences, Inc. (No LS-F8231) was used for the analyses of Kisspeptin-1 levels. The levels of acylated ghrelin were analyzed with Millipore® Human Ghrelin (Active) ELISA kit (#EZGRA-88K). Serum ultrasensitive estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), insulin and glucose levels were analyzed using the usual clinical methods.Results: The median Kisspeptin-1 level at baseline was 39 pg/ml (min–max: 0.1–221.3 pg/ml). The area-under-the curve for Kisspeptin-1 levels was not significantly lower after the GnRH injection as compared to the placebo injection. We did not find any significant correlations between the levels of kisspeptin-1 and acylated ghrelin, estradiol, LH, FSH, or insulin. However, we could see a positive correlation between kisspeptin-1 and glucose levels at baseline (Spearman’s rank test, rho = 0.63, p=0.021).Discussion: We did not find evidence of a negative feedback mechanism between GnRH and kisspeptin in girls with suspected central precocious puberty since the circulating levels of kisspeptin-1 were unaffected by an intravenous injection of a GnRH analogue. However, paracrine actions in the hypothalamus cannot be ruled out by this study. The positive correlation found between kisspeptin-1 and glucose levels is in accordance with previous findings in both adults and children, suggesting a possible role for kisspeptin signaling in glucose metabolism.
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35.
  • Rohrer, TR, et al. (författare)
  • Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome
  • 2021
  • Ingår i: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 93:6, s. 380-395
  • Tidskriftsartikel (refereegranskat)abstract
    • <b><i>Introduction:</i></b> Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). <b><i>Objective:</i></b> To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. <b><i>Methods:</i></b> Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, <i>n</i> = 67) with ≥4 years’ height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. <b><i>Results:</i></b> The mean (SD) baseline age was 8.38 (3.57) years; HSDS, −2.76 (1.03); GH dose, 41.6 (11.1) µg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was −1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was −1.51 (0.60) (154.90 [3.21] cm) in females and −1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ −2. Adverse drug reactions and GH-unrelated serious adverse events (<i>n</i> = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. <b><i>Conclusions:</i></b> GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ –2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.
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36.
  • Serapio, Solveig, et al. (författare)
  • Second Trimester Maternal Leptin Levels Are Associated with Body Mass Index and Gestational Weight Gain but not Birth Weight of the Infant
  • 2020
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 92:2, s. 106-114
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Obesity is increasing among the pregnant population. Leptin has an important role in the regulation of energy balance and hunger. The aim of this study was to investigate the association between maternal leptin levels with maternal obesity, gestational weight gain (GWG), single nucleotide polymorphisms (SNPs) within the leptin gene, and the age-adjusted birth weight of the child.MATERIAL AND METHODS: Maternal leptin levels (n = 740) and SNPs (n = 504) were analyzed in blood samples taken within the Uppsala Biobank of Pregnant women at pregnancy weeks 16-19.RESULTS: Maternal leptin levels differed significantly between body mass index (BMI) groups. Normal weight women had the lowest median leptin levels and levels increased with each BMI group. Leptin SNP genotype was not associated with leptin levels or BMI. There was also no association between maternal leptin levels and age-adjusted birth weight of the child except for a negative association between leptin levels and birth weight in the morbid obese group.DISCUSSION/CONCLUSION: Maternal BMI was identified as the best positive explanatory factor for maternal leptin levels. Leptin was a strong positive explanatory factor for GWG. Birth weight of children of uncomplicated pregnancies was, however, dependent on maternal height, BMI, GWG, and parity but not leptin levels, except for in morbid obese women where a negative association between maternal leptin levels and birth weight was found. We speculate that this indicates altered placental function, not manifested in pregnancy complication. We conclude that maternal leptin levels do not affect the birth weight of the child more than BMI, GWG, and parity.
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37.
  • Tidblad, Anders, et al. (författare)
  • Metabolic Effects of Growth Hormone Treatment in Short Prepubertal Children : A Double-Blinded Randomized Clinical Trial
  • 2021
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 93:9-10, s. 519-528
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Growth hormone (GH) is a central hormone for regulating linear growth during childhood and also highly involved in the metabolism of lipids, carbohydrates, and protein. However, few studies report on how treatment with GH during childhood influences metabolic parameters. Our aim was to investigate metabolic effects of different doses of GH in short children with GH peak levels in the low to normal range. Design: Thirty-five prepubertal short children (<-2.5 SDS), aged 7-10 years, with peak levels of GH between 7 and 14 mu g/L during an arginine-insulin tolerance test, were randomized to 3 different doses (11/33/100 mu g/kg/day) of GH treatment for 2 years. Auxological and metabolic investigations were performed. These included metabolites in blood and interstitial microdialysis fluid, dual-energy X-ray absorptiometry, frequently sampled intravenous glucose tolerance test (FSIVGTT), and stable isotope examinations of rates of glucose production and lipolysis. Results: At 24 months, the high-dose group (HD) had higher fasting insulin compared with the standard-dose (SD) and low-dose (LD) groups (HD: 111.7 vs. SD: 61.2 and LD: 46.0 pmol/L [p < 0.001]) and showed signs of insulin resistance (HOMA-IR, HD: 4.20 vs. SD: 2.17 and LD: 1.71 (LD) [p < 0.001]). The FSIVGTT also demonstrated higher acute insulin response (p < 0.05). Few other metabolic differences were found at 24 months, but a decreased insulin sensitivity index (Si) could already be seen at 12 months for both SD and HD compared with the LD group (p < 0.05). Conclusion: Treatment with GH resulted in a dose-dependent decrease in insulin sensitivity, demonstrated by higher levels of fasting insulin and signs of insulin resistance in both HOMA indices and FSIVGTT examinations.
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38.
  • Östling, Hanna, 1976-, et al. (författare)
  • Global microRNA and protein expression in human term placenta may improve our understanding of fetal growth
  • 2022
  • Ingår i: Hormone Research in Paediatrics. - : S. Karger. - 1663-2818 .- 1663-2826. ; 95:Suppl. 2, s. 247-247
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Introduction: The placenta is an endocrine organ vital to fetal growth. It has multiple functions: pregnancy maintenance, nutrient and oxygen transport to the fetus, and removal of waste products among other functions. MicroRNAs (miRNAs) and proteins are significant mediators of these functions. A description of their global expression in healthy placenta may increase our understanding of the molecular biological pathways that are important for normal fetal growth and development. The aims of this study were to explore the global expression of both miRNAs and proteins in the same samples of human term healthy placenta and to describe involved pathways.Methods: Nineteen term placenta samples from healthy women with uncomplicated pregnancies were identified in a local sample collection. The samples were derived from uncomplicated vaginal deliveries with healthy normal weight new-borns (5 females). Next generation sequencing and nano-scale liquid chromatographic tandem mass spectrometry were used for the analyses of miRNA and protein expression, respectively. Ingenuity Pathway Analysis was used for functional bioinformatics analyses.Results: A total of 895 mature miRNAs and 6,523 proteins were detected in the placenta samples, whereof 123 miRNAs and 346 proteins were highly abundant. The miRNAs were in high degree mapped to chromosomes 19, 14 and X. The most abundant proteins served as enzymes (23%), transporters (10%) or transcription regulators (8%). Of the 20 most significant downstream functions for the highly expressed miRNAs and proteins, respectively, eight shared functions were found, namely Cellular function and maintenance, Cell death and survival, Cell-to-cell signaling and interaction, Cellular assembly and organization, Organismal development, Digestive system development and function, Hepatic system development and function, and Inflammatory response.Discussion: As far as we know, this is the first study presenting both global miRNA and protein expression in the same placenta sample set from healthy term pregnancies. Two of the chromosomes found to have high presence of miRNA genes in the present study are known to contain placenta-specific miRNA clusters (chromosomes 14 and 19), while chromosome X might have been identified here since it has a higher density of miRNA genes than autosomes. The biological functions for the miRNAs and proteins point at basic cellular actions and clearly illustrate that development is an important task during fetal life. Profound knowledge of miRNA and protein expression in healthy placenta can improve the management of aberrant fetal growth and development.
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45.
  • Baroncelli, M, et al. (författare)
  • Bone, Growth Plate and Mineral Metabolism
  • 2021
  • Ingår i: HORMONE RESEARCH IN PAEDIATRICS. - 1663-2818. ; 94:SUPPL 1, s. 22-22
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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