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International Journal of Molecular... Sep 2023Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the... (Review)
Review
Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the (), which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR isoform, which lacks exon 3 has recently been related to longevity; individuals carrying this isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the wild type (WT) isoform (flGHR). Further, studies performed in patients with acromegaly, Prader-Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR isoform may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject.
PubMed: 37762211
DOI: 10.3390/ijms241813908 -
Case Reports in Genetics 2023Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS...
Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS critical region contains four paternally expressed protein-coding genes along with small nucleolar RNA (snoRNA) genes under the control of the promoter, including the snoRNA gene cluster that is implicated in the PWS disease etiology. A 5-7 Mb deletion, maternal uniparental disomy, or an imprinting defect of chromosome 15q affect multiple genes in the PWS critical region, causing PWS. However, the individual contributions of these genes to the PWS phenotype remain elusive. Reports of smaller, atypical deletions may refine the boundaries of the PWS critical region or suggest additional disease-causing mechanisms. We describe an adult female with a classic PWS phenotype due to a 78 kb microdeletion that includes only exons 2 and 3 of with apparently preserved expression of .
PubMed: 37736297
DOI: 10.1155/2023/4225092 -
Journal of the Formosan Medical... May 2024This review summarizes the current evidence in systematic reviews, meta-analysis and randomized controlled trials regarding adenotonsillectomy outcomes in pediatric... (Review)
Review
This review summarizes the current evidence in systematic reviews, meta-analysis and randomized controlled trials regarding adenotonsillectomy outcomes in pediatric obstructive sleep apnea (OSA). Adenotonsillectomy is effective in treating OSA in children without co-morbidities, despite postoperative residual OSA remained in roughly half of these children. For children with comorbidities such as Down syndrome, Prader-Willi syndrome, sickle cell disease, or cerebral palsy, adenotonsillectomy is less effective and associated with more postoperative complications than that in children without comorbidities. For other OSA-related outcomes, evidence from meta-analyses and randomized controlled trials confirm adenotonsillectomy results in improvement of subjective OSA-related outcomes (e.g. symptoms, behaviors, and quality of life), but the results in objective OSA-related outcomes (e.g. cardiometabolic parameters or neurocognitive functions) are inconsistent. Future studies should focus on randomized controlled trials comparing objective OSA-related outcomes and the long-term effects of adenotonsillectomy in children with OSA.
Topics: Humans; Tonsillectomy; Sleep Apnea, Obstructive; Adenoidectomy; Child; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome; Postoperative Complications
PubMed: 37718211
DOI: 10.1016/j.jfma.2023.09.004 -
BioRxiv : the Preprint Server For... Aug 2023Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome...
Angelman Syndrome (AS) and Prader-Willi Syndrome (PWS), two distinct neurodevelopmental disorders, result from loss of expression from imprinted genes in the chromosome 15q11-13 locus most commonly caused by a megabase-scale deletion on either the maternal or paternal allele, respectively. Each occurs at an approximate incidence of 1/15,000 to 1/30,000 live births and has a range of debilitating phenotypes. Patient-derived induced pluripotent stem cells (iPSCs) have been valuable tools to understand human-relevant gene regulation at this locus and have contributed to the development of therapeutic approaches for AS. Nonetheless, gaps remain in our understanding of how these deletions contribute to dysregulation and phenotypes of AS and PWS. Variability across cell lines due to donor differences, reprogramming methods, and genetic background make it challenging to fill these gaps in knowledge without substantially increasing the number of cell lines used in the analyses. Isogenic cell lines that differ only by the genetic mutation causing the disease can ease this burden without requiring such a large number of cell lines. Here, we describe the development of isogenic human embryonic stem cell (hESC) lines modeling the most common genetic subtypes of AS and PWS. These lines allow for a facile interrogation of allele-specific gene regulation at the chromosome 15q11-q13 locus. Additionally, these lines are an important resource to identify and test targeted therapeutic approaches for patients with AS and PWS.
PubMed: 37693591
DOI: 10.1101/2023.08.30.555563 -
Nutrients Aug 2023Given the lack of data on dietary quality in young individuals with Prader-Willi syndrome (PWS) in Poland, a multiple case study was conducted in which anthropometric...
Given the lack of data on dietary quality in young individuals with Prader-Willi syndrome (PWS) in Poland, a multiple case study was conducted in which anthropometric measurements and 7-day dietary records were collected from 20 subjects with PWS. The study group consisted of 8 females and 12 males with a mean age of 14.8 years and a mean BMI of 21.6. Based on BMI analysis, five subjects were overweight, including two subjects who were obese. The study showed that 35% of the subjects had energy intakes above the recommended levels. Protein deficiency was found in one subject in the analyzed diets. However, fat intake was excessive in four subjects, and the majority exceeded the recommended intake of saturated fatty acids. Vitamin E and B deficiencies were found in 40% and 85% of the subjects, respectively. All subjects had inadequate intakes of vitamin D and iodine, while the majority had deficiencies in sodium and copper intakes. Calcium intake was deficient in 35% of the subjects. However, most subjects met recommendations for the intakes of other minerals, vitamins, and fiber. These findings confirm the suboptimal dietary patterns of Polish individuals with PWS, with deficits observed in the intake of certain vitamins and minerals.
Topics: Female; Male; Adolescent; Child; Young Adult; Humans; Poland; Prader-Willi Syndrome; Diet; Nutritional Status; Vitamins; Vitamin A; Vitamin K
PubMed: 37686843
DOI: 10.3390/nu15173811 -
International Journal of Molecular... Aug 2023The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of... (Review)
Review
The hypothalamus regulates fundamental aspects of physiological homeostasis and behavior, including stress response, reproduction, growth, sleep, and feeding, several of which are affected in patients with Prader-Willi (PWS) and Schaaf-Yang syndrome (SYS). PWS is caused by paternal deletion, maternal uniparental disomy, or imprinting defects that lead to loss of expression of a maternally imprinted region of chromosome 15 encompassing non-coding RNAs and five protein-coding genes; SYS patients have a mutation in one of them, . Throughout life, PWS and SYS patients suffer from musculoskeletal deficiencies, intellectual disabilities, and hormonal abnormalities, which lead to compulsive behaviors like hyperphagia and temper outbursts. Management of PWS and SYS is mostly symptomatic and cures for these debilitating disorders do not exist, highlighting a clear, unmet medical need. Research over several decades into the molecular and cellular roles of PWS genes has uncovered that several impinge on the neuroendocrine system. In this review, we will discuss the expression and molecular functions of PWS genes, connecting them with hormonal imbalances in patients and animal models. Besides the observed hormonal imbalances, we will describe the recent findings about how the loss of individual genes, particularly , affects the molecular mechanisms of hormone secretion. These results suggest that evolved as a mammalian-specific regulator of hypothalamic neuroendocrine function.
Topics: Animals; Syndrome; Anxiety; Hypothalamus; Mammals; Neurosecretory Systems
PubMed: 37685915
DOI: 10.3390/ijms241713109 -
Journal of Clinical Medicine Aug 2023This literature review of growth hormone (GH) therapy and sleep-related health outcomes in children diagnosed with Prader-Willi syndrome (PWS) assembles evidence for the... (Review)
Review
This literature review of growth hormone (GH) therapy and sleep-related health outcomes in children diagnosed with Prader-Willi syndrome (PWS) assembles evidence for the consequences of sleep deprivation and poor sleep quality: difficulty concentrating and learning at school, behavioral problems, diminished quality of life, and growth impairment. Sleep-disordered breathing (SDB) is another factor that impacts a child's well-being. We searched the electronic databases Medline PubMed Advanced Search Builder, Scopus, and Web of Science using MeSH terms and text words to retrieve articles on GH deficiency, recombinant human growth hormone (rhGH) therapy, sleep quality, SDB, and PWS in children. The censor date was April 2023. The initial search yielded 351 articles, 23 of which were analyzed for this review. The study findings suggest that while GH may have a role in regulating sleep, the relationship between GH treatment and sleep in patients with PWS is complex and influenced by GH dosage, patient age, and type and severity of respiratory disorders, among other factors. GH therapy can improve lung function, linear growth, and body composition in children with PWS; however, it can also trigger or worsen obstructive sleep apnea or hypoventilation in some. Long-term GH therapy may contribute to adenotonsillar hypertrophy and exacerbate sleep apnea in children with PWS. Finally, GH therapy can improve sleep quality in some patients but it can also cause or worsen SDB in others, leading to diminished sleep quality and overall quality of life. The current evidence suggests that the initial risk of worsening SDB may improve with long-term therapy. In conclusion, rhGH is the standard for managing patients with PWS. Nonetheless, its impact on respiratory function during sleep needs to be thoroughly evaluated. Polysomnography is advisable to assess the need for adenotonsillectomy before initiating rhGH therapy. Close monitoring of sleep disorders in patients with PWS receiving GH therapy is essential to ensure effective and safe treatment.
PubMed: 37685570
DOI: 10.3390/jcm12175504 -
Frontiers in Medicine 2023Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on...
Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation.
Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.
PubMed: 37575996
DOI: 10.3389/fmed.2023.1172565