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International Journal of Molecular... Mar 2021Prader-Labhart-Willi syndrome (PWS) is a rare genetic disorder characterized by intellectual disability, behavioural problems, hypothalamic dysfunction and specific... (Review)
Review
Prader-Labhart-Willi syndrome (PWS) is a rare genetic disorder characterized by intellectual disability, behavioural problems, hypothalamic dysfunction and specific dysmorphisms. Hypothalamic dysfunction causes dysregulation of energy balance and endocrine deficiencies, including hypogonadism. Although hypogonadism is prevalent in males and females with PWS, knowledge about this condition is limited. In this review, we outline the current knowledge on the clinical, biochemical, genetic and histological features of hypogonadism in PWS and its treatment. This was based on current literature and the proceedings and outcomes of the International PWS annual conference held in November 2019. We also present our expert opinion regarding the diagnosis, treatment, care and counselling of children and adults with PWS-associated hypogonadism. Finally, we highlight additional areas of interest related to this topic and make recommendations for future studies.
Topics: Female; Humans; Hypogonadism; Male; Prader-Willi Syndrome; Puberty
PubMed: 33800122
DOI: 10.3390/ijms22052705 -
Missouri Medicine 2024Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder with multisystem impact and a unique behavior profile that evolves over the life span.... (Review)
Review
Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder with multisystem impact and a unique behavior profile that evolves over the life span. Beyond the primary care needs of all children and adults, the unique medical concerns and management needs of those with PWS are best served in a multidisciplinary academic center. Our PWS center has provided care for individuals with PWS and their families since 1981. Our growth hormone studies contributed to growth hormone supplementation becoming standard of care in this country. Here, in collaboration with the primary care provider, early childhood intervention programs, schools and local parent organizations, solid, patient-centered care for affected individuals and their families can be provided across the life-span. The purpose of this article is to provide a brief overview of PWS and the attendant medical and behavior management challenges attendant to the disorder.
Topics: Prader-Willi Syndrome; Humans; Child; Human Growth Hormone
PubMed: 38854617
DOI: No ID Found -
International Journal of Molecular... Jan 2023A high-resolution chromosome microarray analysis was performed on 154 consecutive individuals enrolled in the DESTINY PWS clinical trial for Prader-Willi syndrome (PWS)....
A high-resolution chromosome microarray analysis was performed on 154 consecutive individuals enrolled in the DESTINY PWS clinical trial for Prader-Willi syndrome (PWS). Of these 154 PWS individuals, 87 (56.5%) showed the typical 15q11-q13 deletion subtypes, 62 (40.3%) showed non-deletion maternal disomy 15 and five individuals (3.2%) had separate unexpected microarray findings. For example, one PWS male had Klinefelter syndrome with segmental isodisomy identified in both chromosomes 15 and X. Thirty-five (40.2%) of 87 individuals showed typical larger 15q11-q13 Type I deletion and 52 individuals (59.8%) showed typical smaller Type II deletion. Twenty-four (38.7%) of 62 PWS individuals showed microarray patterns indicating either maternal heterodisomy 15 subclass or a rare non-deletion (epimutation) imprinting center defect. Segmental isodisomy 15 was seen in 34 PWS subjects (54.8%) with 15q26.3, 15q14 and 15q26.1 bands most commonly involved and total isodisomy 15 seen in four individuals (6.5%). In summary, we report on PWS participants consecutively enrolled internationally in a single clinical trial with high-resolution chromosome microarray analysis to determine and describe an unbiased estimate of the frequencies and types of genetic defects and address potential at-risk genetic disorders in those with maternal disomy 15 subclasses in the largest PWS cohort studied to date.
Topics: Humans; Male; Prader-Willi Syndrome; Microarray Analysis; Family; Chromosomes; Chromosomes, Human, Pair 15
PubMed: 36674736
DOI: 10.3390/ijms24021220 -
Andes Pediatrica : Revista Chilena de... Jun 2021Prader-Willi Syndrome (PWS) is the most common cause of genetic obesity. Hyperphagia and obe sity are the most associated concepts with this condition. However,...
INTRODUCTION
Prader-Willi Syndrome (PWS) is the most common cause of genetic obesity. Hyperphagia and obe sity are the most associated concepts with this condition. However, undernutrition secondary to severe hypotonia and feeding difficulties is the predominant initial feature.
OBJECTIVE
to reprodu ce and communicate the nutritional phases on a series of Chilean cases with PWS.
PATIENTS AND METHOD
Cross-sectional study in which clinical records of PWS individuals under nutritional con trol at the Clínica Santa María in Santiago, Chile between 2017 and 2018 were analyzed. The anthro pometric references of the World Health Organization were used to carry out the nutritional as sessment. The classification into nutritional phases was according to the Miller criteria.
RESULTS
24 patients from infants to adults were included. All children aged under 9 months were in phase I and had malnutrition or were eutrophic; those between 9 and 25 months were classified in phase 2a; pa tients between 2.1 and 4.5 years were distributed between phases 1 and 2 and 66% were eutrophic; those between 4.5 to 8 years, 80% were in phase 2a and 2b and obesity begins to appear, and patients over 8 years of age, 75% were in phase 3 and all are overweight or obese. There was an association bet ween nutritional phase and age but not between it and nutritional status.
CONCLUSIONS
In our series, the nutritional phases described according to age were reproduced according to those internationally described. There was no association between nutritional status and age.
Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Cross-Sectional Studies; Disease Progression; Female; Humans; Hyperphagia; Infant; Infant, Newborn; Male; Malnutrition; Pediatric Obesity; Prader-Willi Syndrome; Young Adult
PubMed: 34479241
DOI: 10.32641/andespediatr.v92i3.2400 -
Frontiers in Endocrinology 2024Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the... (Review)
Review
Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.
Topics: Prader-Willi Syndrome; Humans; Genetic Association Studies; Endocrine System Diseases; Phenotype
PubMed: 38737552
DOI: 10.3389/fendo.2024.1382583 -
Journal of Clinical Medicine Aug 2021Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioural challenges,...
Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioural challenges, cognitive dysfunction, and hypogonadism. Psychotic illness is common, particularly in patients with maternal uniparental disomy (mUPD), and antipsychotic medications can result in hyperprolactinemia. Information about hyperprolactinemia and its potential clinical consequences in PWS is sparse. Here, we present data from an international, observational study of 45 adults with PWS and hyperprolactinemia. Estimated prevalence of hyperprolactinemia in a subset of centres with available data was 22%, with 66% of those related to medication and 55% due to antipsychotics. Thirty-three patients were men, 12 women. Median age was 29 years, median BMI 29.8 kg/m, 13 had mUPD. Median prolactin was 680 mIU/L (range 329-5702). Prolactin levels were higher in women and patients with mUPD, with only 3 patients having severe hyperprolactinemia. Thyroid function tests were normal, 24 were treated with growth hormone, 29 with sex steroids, and 20 with antipsychotic medications. One patient had kidney insufficiency, and one a microprolactinoma. In conclusion, severe hyperprolactinemia was rare, and the most common aetiology of hyperprolactinemia was treatment with antipsychotic medications. Although significant clinical consequences could not be determined, potential negative long-term effects of moderate or severe hyperprolactinemia cannot be excluded. Our results suggest including measurements of prolactin in the follow-up of adults with PWS, especially in those on treatment with antipsychotics.
PubMed: 34441908
DOI: 10.3390/jcm10163613 -
Endocrine Connections Jun 2024Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000.... (Review)
Review
Prader Willi syndrome (PWS) is a rare orphan disease and complex genetic neurodevelopmental disorder, with a birth incidence of approximately 1 in 10,000-30,000. Management of people with PWS requires a multi-disciplinary approach, ideally through a multi-disciplinary team (MDT) clinic with community support. Hypotonia, poor feeding and faltering growth are characteristic features in the neonatal period, followed by hyperphagia and risk of rapid weight gain later in childhood. Children and adolescents (CA) with PWS usually display developmental delay and mild learning disability, and can develop endocrinopathies, scoliosis, respiratory difficulties (both central and obstructive sleep apnoea), challenging behaviours, skin picking, and mental health issues especially into adulthood. This consensus statement is intended to be a reference document for clinicians managing children and adolescents (up to 18 years of age) with PWS. It considers the bio-psycho-social domains of diagnosis, clinical assessment, and management in the paediatric setting as well as during and after transition to adult services. The guidance has been developed from information gathered from peer-reviewed scientific reports and from the expertise of a range of experienced clinicians in the United Kingdom and Ireland involved in the care of patients with PWS.
PubMed: 38838713
DOI: 10.1530/EC-24-0091 -
European Journal of Medical Genetics Feb 2023The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and...
The CpG island flanking the promoter region of SNRPN on chromosome 15q11.2 contains CpG sites that are completely methylated in the maternally derived allele and unmethylated in the paternally derived allele. Both unmethylated and methylated alleles are observed in normal individuals. Only the methylated allele is observed in patients with Prader-Willi syndrome, whereas only the unmethylated allele is observed in those with Angelman syndrome. Hence, detection of aberrant methylation at the differentially methylated region is fundamental to the molecular diagnosis of Prader-Willi syndrome and Angelman syndromes. Traditionally, bisulfite treatment and methylation-sensitive restriction enzyme treatment or methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) have been used. We here developed a long-read sequencing assay that can distinguish methylated and unmethylated CpG sites at 15q11.2 by the difference in current intensity generated from nanopore reads. We successfully diagnosed 4 Prader-Willi syndrome patients and 3 Angelman syndrome patients by targeting differentially methylated regions. Concurrent copy number analysis, homozygosity analysis, and structural variant analysis also allowed us to precisely delineate the underlying pathogenic mechanisms, including gross deletion, uniparental heterodisomy, uniparental isodisomy, or imprinting defect. Furthermore, we showed allele-specific methylation in imprinting-related differentially methylated regions on chromosomes 6, 7, 11, 14, and 20 in a normal individual together with 4 Prader-Willi patients and 3 Angelman syndrome patients. Hence, presently reported method is likely to be applicable to the diagnosis of imprinting disorders other than Prader-Willi syndrome and Angelman syndrome as well.
Topics: Humans; Prader-Willi Syndrome; Angelman Syndrome; DNA Methylation; Nanopores; Uniparental Disomy; Chromosomes, Human, Pair 15; Genomic Imprinting
PubMed: 36587803
DOI: 10.1016/j.ejmg.2022.104690 -
Intractable & Rare Diseases Research Feb 2023Prader-Willi syndrome (PWS) is a rare genetic disorder due to lack of genes expression inherited from the paternal chromosome 15q11-q13 region usually from paternal... (Review)
Review
Prader-Willi syndrome (PWS) is a rare genetic disorder due to lack of genes expression inherited from the paternal chromosome 15q11-q13 region usually from paternal deletions, maternal uniparental disomy 15 or imprinting defect. There are two different nutritional stages reported in an individual with PWS; first stage during infancy marked by feeding and growth difficulties and second stage where hyperphagia starts and leads to development of obesity. However, the exact mechanism of hyperphagia development, from having difficulties in feeding during early years to insatiable appetite after they grow is still unknown and is the focused in this review. The keywords used for literature search such as "Prader-Willi syndrome", "hyperphagia", "obesity", and "treatment" were used to create the search strings by using synonyms in order to retrieve the relevant records from PubMed, Scopus and Science Direct. The possible mechanism of hyperphagia can be classed into hormonal abnormalities such as increase in ghrelin and leptin from infancy to adulthood. Low level of hormones was observed in the thyroid, insulin and peptide YY at certain ages. Neuronal abnormalities contributed by Orexin A and brain structure alteration was documented at 4-30 years old. Treatment in the form of drugs such as livoletide, topiramate, and diazoxide could potentially alleviate these abnormalities and make hyperphagia less prominent in PWS. The approaches are important to regulate the hormonal changes and neuronal involvement as potentially controlling hyperphagia and obesity.
PubMed: 36873672
DOI: 10.5582/irdr.2022.01127 -
Frontiers in Endocrinology 2022The generalized dysfunction of the hypothalamic-pituitary axis in patients with Prader-Willi syndrome (PWS) is the most likely cause of hypogonadism, inadequate growth... (Review)
Review
The generalized dysfunction of the hypothalamic-pituitary axis in patients with Prader-Willi syndrome (PWS) is the most likely cause of hypogonadism, inadequate growth hormone secretion, excessive appetite and associated obesity, impaired body temperature regulation, and hypothyroidism. The syndrome is also related to an increased risk of central adrenal insufficiency, although its prevalence remains unknown. The results of the studies in which different methods of pharmacological stimulation were used do not provide conclusive outcomes. As a result, there are no clear guidelines with regard to diagnosis, prevention, or long-term care when adrenal insufficiency is suspected in patients with PWS. Currently, most patients with PWS are treated with recombinant human growth hormone (rhGH). It has been confirmed that rhGH therapy has a positive effect on growth, body composition, body mass index (BMI), and potentially on psychomotor development in children with PWS. Additionally, rhGH may reduce the conversion of cortisone to cortisol through inhibition of 11β-hydroxysteroid dehydrogenase type 1. However, its influence on basal adrenal function and adrenal stress response remains unexplained in children with PWS. This paper reviews the literature related to the hypothalamic-pituitary-adrenal axis dysfunction in the PWS patient population with a focus on children.
Topics: Child; Humans; Prader-Willi Syndrome; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Hydrocortisone; Human Growth Hormone; Adrenal Insufficiency
PubMed: 36465638
DOI: 10.3389/fendo.2022.1021704