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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 -
Advances in Pediatrics Aug 2022Growth hormone (GH) is an injectable medication originally used to replace the deficiency of the hormone, but has expanded to treating conditions that may reduce growth... (Review)
Review
Growth hormone (GH) is an injectable medication originally used to replace the deficiency of the hormone, but has expanded to treating conditions that may reduce growth and adult height even when the body maintains endogenous GH production. In the United States, there are 8 Food and Drug Administration (FDA)-approved indications for pediatric GH therapy: GH deficiency, Prader-Willi Syndrome, small for gestational age (SGA) without catch-up growth, idiopathic short stature, Turner syndrome, SHOX gene haploinsufficiency, Noonan Syndrome, and chronic renal insufficiency. We characterize the growth patterns and effects of GH treatment in each of these indications. We also review patterns of growth that warrant referral to a pediatric endocrinologist, as well as safety updates. This review is intended to guide practitioners on the initial evaluation and management of patients with short stature, and the indications for GH therapy.
Topics: Adult; Child; Dwarfism; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Prader-Willi Syndrome; Turner Syndrome; United States
PubMed: 35985710
DOI: 10.1016/j.yapd.2022.03.005 -
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 -
Pediatric Clinics of North America Jun 2015Three distinct neurodevelopmental disorders arise primarily from deletions or duplications that occur at the 15q11-q13 locus: Prader-Willi syndrome, Angelman syndrome,... (Review)
Review
Three distinct neurodevelopmental disorders arise primarily from deletions or duplications that occur at the 15q11-q13 locus: Prader-Willi syndrome, Angelman syndrome, and 15q11-q13 duplication syndrome. Each of these disorders results from the loss of function or overexpression of at least 1 imprinted gene. This article discusses the clinical background, genetic cause, diagnostic strategy, and management of each of these 3 disorders.
Topics: Angelman Syndrome; Child; Chromosome Aberrations; Chromosomes, Human, Pair 15; DNA Methylation; Epigenesis, Genetic; Gene Dosage; Gene Duplication; Gene Expression; Humans; Intellectual Disability; Prader-Willi Syndrome
PubMed: 26022164
DOI: 10.1016/j.pcl.2015.03.004 -
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 -
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 -
The Journal of Clinical Endocrinology... May 2022Prader-Willi syndrome (PWS) is a rare, multisystemic, genetic disorder involving the hypothalamus. It is caused by loss of expression of paternally inherited genes in...
Prader-Willi syndrome (PWS) is a rare, multisystemic, genetic disorder involving the hypothalamus. It is caused by loss of expression of paternally inherited genes in chromosome 15 q11-13 region. The estimated incidence is around 1 in 20.000 births. PWS is characterized by a complex lifelong trajectory involving neurodevelopmental, nutritional, endocrine, metabolic, and behavioral changes. The major symptoms are hypotonia, short stature, hypogonadism, and eating disorders ranging from anorexia in infancy to hyperphagia, a deficit of satiety, and a high risk of severe obesity. The patients display intellectual disability comprising cognitive deficit, delayed motor and language development, learning deficits, impaired social skills, and emotional regulation. Behavioral features including temper outbursts, anxiety, obsessive-compulsive symptoms and rigidity are common and become more apparent with increasing age. Almost all have hypogonadism and growth hormone deficiency. Central adrenal insufficiency is rare whereas central hypothyroidism occurs in up to 30% of children with PWS. The prevalence of obesity increases with age from almost none in early childhood to more than 90% in adulthood. Up to 25% of adults with obesity have type 2 diabetes. Obesity and its complications are the major causes of comorbidity and mortality in PWS. As there is no specific treatment, care consists of comprehensive management of feeding disorders, a restricted, controlled diet, regular exercise, hormone substitution, and screening and treatment of comorbidities. Here we present the course of PWS from birth to adulthood in 2 patients and discuss their symptoms in relation to the literature.
Topics: Adult; Child; Child, Preschool; Diabetes Mellitus, Type 2; Humans; Hyperphagia; Hypogonadism; Obesity; Prader-Willi Syndrome
PubMed: 35150573
DOI: 10.1210/clinem/dgac082