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Current Pediatric Reviews 2019Prader-Willi Syndrome (PWS) is a neurodevelopmental genomic imprinting disorder with lack of expression of genes inherited from the paternal chromosome 15q11-q13 region... (Review)
Review
BACKGROUND
Prader-Willi Syndrome (PWS) is a neurodevelopmental genomic imprinting disorder with lack of expression of genes inherited from the paternal chromosome 15q11-q13 region usually from paternal 15q11-q13 deletions (about 60%) or maternal uniparental disomy 15 or both 15s from the mother (about 35%). An imprinting center controls the expression of imprinted genes in the chromosome 15q11-q13 region. Key findings include infantile hypotonia, a poor suck, failure to thrive and hypogonadism/hypogenitalism. Short stature and small hands/feet due to growth and other hormone deficiencies, hyperphagia and marked obesity occur in early childhood, if uncontrolled. Cognitive and behavioral problems (tantrums, compulsions, compulsive skin picking) are common.
OBJECTIVE
Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS. This report will describe an accurate diagnosis with determination of specific genetic subtypes, appropriate medical management and best practice treatment approaches.
METHODS AND RESULTS
An extensive literature review was undertaken related to genetics, clinical findings and laboratory testing, clinical and behavioral assessments and summary of updated health-related information addressing the importance of early PWS diagnosis and treatment. A searchable, bulleted and formatted list of topics is provided utilizing a Table of Contents approach for the clinical practitioner.
CONCLUSION
Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections pertinent in the context of clinical practice. Frequently asked questions by clinicians, families and other interested participants or providers will be addressed.
Topics: Adolescent; Child; Developmental Disabilities; Disease Management; Disease Progression; Evidence-Based Medicine; Feeding Behavior; Genetic Counseling; Genetic Testing; Genomic Imprinting; Guidelines as Topic; Humans; Infant; Interdisciplinary Communication; Morbidity; Obesity; Phenotype; Prader-Willi Syndrome; Problem Behavior
PubMed: 31333129
DOI: 10.2174/1573396315666190716120925 -
Genetics in Medicine : Official Journal... Jan 2012Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal... (Review)
Review
Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy provides improvement in growth, body composition, and physical attributes. Management is otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should be confirmed through genetic testing. Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65-75% of individuals), maternal uniparental disomy 15 (20-30%), or an imprinting defect (1-3%). Parent-specific DNA methylation analysis will detect >99% of individuals. However, additional genetic studies are necessary to identify the molecular class. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Sibling recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal diagnosis is available.
Topics: Diagnosis, Differential; Genetic Association Studies; Genetic Counseling; Genetic Testing; Humans; Morbidity; Prader-Willi Syndrome
PubMed: 22237428
DOI: 10.1038/gim.0b013e31822bead0 -
International Journal of Molecular... Feb 2023Prader-Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive,... (Review)
Review
Prader-Willi syndrome (PWS) is a complex genetic disorder with three PWS molecular genetic classes and presents as severe hypotonia, failure to thrive, hypogonadism/hypogenitalism and developmental delay during infancy. Hyperphagia, obesity, learning and behavioral problems, short stature with growth and other hormone deficiencies are identified during childhood. Those with the larger 15q11-q13 Type I deletion with the absence of four non-imprinted genes () from the 15q11.2 BP1-BP2 region are more severely affected compared with those with PWS having a smaller Type II deletion. and genes encode magnesium and cation transporters, supporting brain and muscle development and function, glucose and insulin metabolism and neurobehavioral outcomes. Lower magnesium levels are reported in those with Type I deletions. The gene encodes a protein associated with fragile X syndrome. The gene is associated with attention-deficit hyperactivity disorder (ADHD) and compulsions, more commonly seen in PWS with the Type I deletion. When the 15q11.2 BP1-BP2 region alone is deleted, neurodevelopment, motor, learning and behavioral problems including seizures, ADHD, obsessive-compulsive disorder (OCD) and autism may occur with other clinical findings recognized as Burnside-Butler syndrome. The genes in the 15q11.2 BP1-BP2 region may contribute to more clinical involvement and comorbidities in those with PWS and Type I deletions.
Topics: Humans; Carrier Proteins; Chromosomes; Chromosomes, Human, Pair 15; Magnesium; Prader-Willi Syndrome
PubMed: 36901699
DOI: 10.3390/ijms24054271 -
Nutrients May 2022Prader-Willi syndrome (PWS) is a complex genetic disorder which involves the endocrine and neurologic systems, metabolism, and behavior. The aim of this paper is to... (Review)
Review
Prader-Willi syndrome (PWS) is a complex genetic disorder which involves the endocrine and neurologic systems, metabolism, and behavior. The aim of this paper is to summarize current knowledge on dietary management and treatment of PWS and, in particular, to prevent excessive weight gain. Growth hormone (GH) therapy is the recommended standard treatment for PWS children, because it improves body composition (by changing the proportion of body fat and lean body mass specifically by increasing muscle mass and energy expenditure), linear growth, and in infants, it promotes psychomotor and IQ development. In early childhood, the predominant symptom is hyperphagia which can lead to early onset, severe obesity with different obesity-related comorbidities. There are several studies on anti-obesity medications (metformin, topiramate, liraglutide, setmelanotide). However, these are still limited, and no widely accepted consensus guideline exists concerning these drugs in children with PWS. Until there is a specific treatment for hyperphagia and weight gain, weight must be controlled with the help of diet and exercise. Below the age of one year, children with PWS have no desire to eat and will often fail to thrive, despite adequate calories. After the age of two years, weight begins to increase without a change in calorie intake. Appetite increases later, gradually, and becomes insatiable. Managing the progression of different nutritional phases (0-4) is really important and can delay the early onset of severe obesity. Multidisciplinary approaches are crucial in the diagnosis and lifelong follow-up, which will determine the quality of life of these patients.
Topics: Child; Child, Preschool; Humans; Hyperphagia; Infant; Obesity, Morbid; Prader-Willi Syndrome; Quality of Life; Weight Gain
PubMed: 35565916
DOI: 10.3390/nu14091950 -
Journal of Endocrinological... Oct 2021Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The three main... (Review)
Review
Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. The three main genetic subtypes are represented by paternal 15q11-q13 deletion, maternal uniparental disomy 15, and imprinting defect. Clinical picture of PWS changes across life stages. The main clinical characteristics are represented by short stature, developmental delay, cognitive disability and behavioral diseases. Hypotonia and poor suck resulting in failure to thrive are typical of infancy. As the subjects with PWS age, clinical manifestations such as hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency due to hypothalamic dysfunction occur. Obesity and its complications are the most common causes of morbidity and mortality in PWS. Several mechanisms for the aetiology of obesity in PWS have been hypothesized, which include aberration in hypothalamic pathways of satiety control resulting in hyperphagia, disruption in hormones regulating appetite and satiety and reduced energy expenditure. However, despite the advancement in the research field of the genetic basis of obesity in PWS, there are contradictory data on the management. Although it is mandatory to adopt obesity strategy prevention from infancy, there is promising evidence regarding the management of obesity in adulthood with current obesity drugs along with lifestyle interventions, although the data are limited. Therefore, the current manuscript provides a review of the current evidence on obesity and PWS, covering physiopathological aspects, obesity-related complications and conservative management.
Topics: Animals; Humans; Obesity; Phenotype; Prader-Willi Syndrome
PubMed: 33891302
DOI: 10.1007/s40618-021-01574-9 -
Journal of Endocrinological... Dec 2015Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region.... (Review)
Review
INTRODUCTION
Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65-75 % of cases), maternal uniparental disomy 15 (20-30 % of cases), and imprinting defect (1-3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS.
METHODS
An extensive review of the literature was performed and interpreted within the context of clinical practice and frequently asked questions from referring physicians and families to include the current status of the cause and diagnosis of the clinical, genetics and endocrine findings in PWS.
CONCLUSIONS
Updated information regarding the early diagnosis and management of individuals with Prader-Willi syndrome is important for all physicians and will be helpful in anticipating and managing or modifying complications associated with this rare obesity-related disorder.
Topics: Humans; Prader-Willi Syndrome
PubMed: 26062517
DOI: 10.1007/s40618-015-0312-9 -
Genes Sep 2021This Special Issue includes 15 peer-reviewed articles for publication by experts in Prader-Willi syndrome (PWS) and their reflective area of interest impacting this rare...
This Special Issue includes 15 peer-reviewed articles for publication by experts in Prader-Willi syndrome (PWS) and their reflective area of interest impacting this rare disorder [...].
Topics: Databases, Genetic; Genetic Association Studies; Humans; Pharmacogenomic Testing; Phenotype; Prader-Willi Syndrome; Rare Diseases
PubMed: 34573411
DOI: 10.3390/genes12091429 -
The Journal of Clinical Endocrinology... Dec 2022Prader-Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed. (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Prader-Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed.
OBJECTIVE
To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS.
METHODS
This was a multicenter, 52-week, placebo-controlled trial with a 16-week double-blinded period. Adolescents (n = 31, aged 12-17 years; Tanner stage 2-5) and children (n = 24, aged 6-11 years; Tanner stage <2) with PWS and obesity were included. Patients were randomized 2:1 to liraglutide 3.0 mg (or maximum-tolerated dose) or placebo for 16 weeks, after which placebo was stopped. Liraglutide was continued for 52 weeks. All patients followed a structured diet and exercise program throughout the trial. The coprimary endpoints were change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 and 52 weeks. Secondary endpoints included other weight-related parameters, hyperphagia, and safety.
RESULTS
Change in BMI SDS from baseline to weeks 16 and 52 was not significantly different between treatments in adolescents (estimated treatment difference: -0.07 at week 16 and -0.14 at week 52) and children (-0.06 and -0.07, respectively). Changes in other weight-related parameters between treatments were not significant. At week 52, hyperphagia total and drive scores were lower in adolescents treated with liraglutide vs no treatment. The most common adverse events with liraglutide were gastrointestinal disorders.
CONCLUSION
Although the coprimary endpoints were not met, changes in hyperphagia total and drive scores in adolescents warrant further studies on liraglutide in this population.
Topics: Child; Adolescent; Humans; Liraglutide; Prader-Willi Syndrome; Obesity; Hyperphagia; Body Mass Index
PubMed: 36181471
DOI: 10.1210/clinem/dgac549 -
International Journal of Molecular... Jan 2023Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal... (Review)
Review
Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clinical trials with existing results for the management of obesity and hyperphagia in PWS will be discussed in this review, including treatments such as beloranib, setmelanotide, a diazoxide choline controlled-release tablet (DCCR), an unacylated ghrelin analogue, oxytocin and related compounds, glucagon-like peptide 1 receptor agonists, surgical intervention, and transcranial direct-current stimulation.
Topics: Female; Humans; Prader-Willi Syndrome; Transcranial Direct Current Stimulation; Hyperphagia; Anxiety; Mothers
PubMed: 36768472
DOI: 10.3390/ijms24032150 -
Archives of Endocrinology and Metabolism 2020Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of gene expression in the 15q11.2-q13 paternal chromosome. Patients with PWS develop hypothalamic... (Review)
Review
Prader-Willi syndrome (PWS) is a genetic disorder caused by the absence of gene expression in the 15q11.2-q13 paternal chromosome. Patients with PWS develop hypothalamic dysfunction that can lead to various endocrine changes such as: obesity, growth hormone deficiency, hypogonadism, hypothyroidism, adrenal insufficiency and low bone mineral density. In addition, individuals with PWS have increased risk of developing type 2 diabetes mellitus. This review summarizes and updates the current knowledge about the prevention, diagnosis and treatment of endocrine manifestations associated with Prader Willi syndrome, especially diagnosis of growth hormone deficiency, management and monitoring of adverse effects; diagnosis of central adrenal insufficiency and management in stressful situations; screening for central hypothyroidism; research and treatment of hypogonadism; prevention and treatment of disorders of glucose metabolism. Careful attention to the endocrine aspects of PWS contributes significantly to the health of these individuals. Arch Endocrinol Metab. 2020;64(3):223-34.
Topics: Diabetes Mellitus; Humans; Hypogonadism; Hypothyroidism; Obesity; Prader-Willi Syndrome
PubMed: 32555988
DOI: 10.20945/2359-3997000000248