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Image: “A 9 year, boy with a fragile X mutation and a Prader-Willi phenotype. By: McLennan Y, Polussa J, Tassone F, Hagerman R – Curr. Genomics (2011). License: CC BY 2.5

Definition of Prader-Willi Syndrome (PWS)

PWS is a rare neurodevelopmental genetic disorder in which several genes on chromosome 15 are deleted or unexpressed on the paternal chromosome. The secondary changes that follow affect several organ systems in varying proportions. Conclusive evidence pointing to the cause of hypothalamic dysfunction secondary to genetic changes on chromosome 15 is still lacking.

Obesity, reduced stature, small hands and feet, hypotonia, hypogonadotropic hypogonadism, and mental retardation are symptoms characteristic of PWS.

History of PWS

PWS is variously known as Labhart-Willi syndrome, Prader’s syndrome, and Prader-Labhart-Willi-Fanconi syndrome. It was first reported in 1956 by Andrea Prader, Heinrich Willi, Alexis Labhart, Andrew Ziegler, and Guido Fanconi in Switzerland. Existing evidence points to the description of a similar illness by Langdon Down in 1887.

Epidemiology of PWS

The prevalence of PWS is about 1 in 15,000–30,000 live births and is not gender-specific. It is a genetic disorder that persists throughout life.

Genomic Imprinting and PWS

In genomic imprinting, genes are expressed in a parent-of-origin-specific manner. Chromosome 15 contains a genomically imprinted region. Genes are expressed only on the paternal and maternal chromosomes. Each region is hypermethylated (imprinted/turned-off) on the opposing chromosome.

Patients with PWS have a duplication of the 15q segment (uniparental disomy) in the maternal chromosome or absence of the paternal homologous segment (microdeletion). Non-disjunction in meiosis I leads to heterodisomy and isodisomy. In an attempt to rescue the cell from trisomy, the paternal chromosomal segment is eliminated in heterodisomy and the result is uniparental disomy of the maternally derived segment of chromosome 15.

As a consequence of genomic imprinting, only paternal copies of these genes are expressed; maternal alleles, even if present, are functionally silent. About 70% of cases are a culmination of deletion of the paternal chromosomal segment, while the remaining cases are accounted for by maternal uniparental disomy. The latter has two copies from the mother and none from the father. The end result of both these circumstances is an absence of working copies of about seven genes because parts of the maternal chromosomes are inactive by default and require the paternal counterpart to function.

The loss of paternal copies of SNRPN, necdin genes, and clusters of snoRNAs, namely, SNORD64, DNORD107, SNORD 108, two copies of SNORD116, and 48 copies of SNORD115, results in PWS syndrome. These are the constituents of the “PWS/AS region.” Clinical studies and in vivo experiments have highlighted the deletion of the 29 copies of the C/D box snoRNA SNORD116 (HBII-85) as the predominant cause of PWS. There are different mechanisms by which this functional loss occurs and can be summarized as follows:

  • Chance mutation deletion and microdeletions
  • Uniparental disomy
  • Sporadic mutation
  • Chromosome translocation
  • Gene deletion

This process when reversed (two copies from the father and none from mother), results in Angelman syndrome (AS).

Clinical Features of PWS

The hypothalamus appears to be affected in patients with PWS. The hypothalamus is a minuscule endocrine master gland that regulates essential bodily functions, including hunger and satiety, temperature and pain regulation, fluid balance, puberty, emotions, and fertility.

Previous studies indicate that the normal functioning of the hypothalamus is hampered by abnormalities in chromosome 15. The hypothalamic arcuate nucleus regulates appetite. Additionally, oxytocin-producing cells, which monitor satiety under normal circumstances, are abnormal in these patients. Lastly, high levels of ghrelin are linked to obesity, hyperphagia, and increased appetite.


Image: “t(4;15) Carrier, Prader-Willi Syndrome Phenotype, at 15 Years of Age. Note the absence of typical PWS facial features and presence of mild truncal obesity.” by Schüle B, Albalwi M, Northrop E, Francis DI, Rowell M, Slater HR, Gardner RJ, Francke U. Molecular breakpoint cloning and gene expression studies of a novel translocation t(4;15)(q27;q11.2) associated with Prader-Willi syndrome. BMC Medical Genetics. 6, 18. 2005. PMID 15877813. DOI:10.1186/1471-2350-6-18. License: CC BY 2.0

There are two generally recognized stages of the symptoms associated with PWS as explained below.

Stage Explanation
Stage 1 Infants are hypotonic or “floppy” with very low muscle tone. A weak cry and poor suck reflex are typical. Babies with PWS are usually unable to breastfeed and require frequent tube feeding. Failure to thrive if feeding difficulties are not monitored and treated. Strength and muscle tone generally improve over time. Motor milestones are achieved but are usually delayed.
Stage 2 It is characterized by a voracious appetite. The absence of normal satiety and hunger cues is a characteristic of this stage and encountered between 2–6 years of age. Obesity, overeating, and food-seeking behavior are prevalent. If left untreated, obesity and subsequent complications, including type 2 diabetes mellitus, often set in. The basal metabolic rate is low.

Other characteristics of patients with PWS are as follows:

  • Reduced fertility and reduction in the levels of sex hormones
  • Delayed musculoskeletal development and motor skills
  • Narrow forehead; small/short limbs
  • Delayed puberty
  • Behavioral issues and frequent temper tantrums
  • Skin picking
  • Learning disabilities
  • Delayed speech and repetition
  • Mental retardation and low IQ; some children may display normal intelligence
  • Abnormal behavioral traits (collecting items)
  • Sleep disorders including obstructive sleep apnea

Some patients with PWS have some remarkable cognitive skills like jigsaw-puzzle solving.

PWS has a diverse range of signs and symptoms that change as the patient matures. In 1993, Holm et al defined a specified set of symptoms and signs that could be used as a pretest indicator of PWS. They are segregated based on age and can be described in short as follows:

Age cohort Symptoms and signs
In utero Diminished fetal movement, aberrant fetal presentation, and prevalent polyhydramnios
At birth Hypotonia and feeding difficulty; breathing difficulty, lethargy, and hypogonadism
Children Hyperphagia, insatiable craving for food, scoliosis, strabismus, speech delay, cryptorchidism, delayed puberty, intellectual retardation, obesity and its complications, including obstructive sleep apnea and type II diabetes mellitus
Adults Borderline intellectual capability, extreme flexibility secondary to diminished but persistent hypotonia, hypogonadism, and infertility

PWS affects multiple organs in magnitudes of varying severity.

Based on the organ system that is affected, symptoms can be classified as follows:

Affected organ system
Clinical features
Physical morphology and musculoskeletal system Almond-shaped eyes, striae, bruised picked skin, central adiposity, dysmorphism, skin depigmentation, small limbs, a conspicuous absence of sexual development
Neurocognitive system Impairment in auditory data retrieval, cognition and response formulation, visual attention span, writing skills, and executive task management

Based on their research in the neuropsychological development of individuals with PWS, Curfs and Fryns in 1992 concluded that about 39% of patients had a mild intellectual disability with an IQ score ranging from 50–70, while 5% of patients displayed high/low intelligence. About 2% of patients had IQ scores < 35.

Endocrine system Short stature, obesity, hypogonadism, undescended testes, benign premature adrenarche (in women)
Ophthalmologic involvement Strabismus and esotropia

Diagnosis of PWS

Previously, medical personnel relied on clinical features for the diagnosis of PWS. The current trend focuses on recognizing the presenting symptoms to make an initial diagnosis of PWS, especially in patients with hypotonia. Genetic testing is indicated to confirm this diagnosis. Molecular cytogenetic techniques can be used to diagnose PWS. Early detection can help in the treatment and also help prevent the occurrence of some symptoms.

The commonly used techniques are summarized in the table below.

Technique Explanation
FISH (fluorescence in situ hybridization) Using fluorescence microscopy and fluorescent probes, FISH determines the presence or absence of specific DNA sequences on the chromosomes of interest. It is instrumental in defining the specific spatiotemporal gene profile in cells and tissues in patients with PWS. FISH can be used prenatally to detect deletion in the 15q region after amniocentesis or chronic villus sampling.
MethylCollector Ultra magnetic assay for specific isolation of CpG-methylated DNA DNA methylation is crucial in the regulation of gene expression. This assay, albeit expensive, isolates methylated CpG segments from mammalian DNA. In patients with PWS, the assay indicates the absence of paternally derived 15q11–q13 segments in about 97% of cases. This test is indicated in infants with marked hypotonia.

Imaging studies include magnetic resonance imaging, X-rays, and scoliosis X-rays to study the impact of this condition on bones.

Management of PWS

A well-planned and integrated approach is essential in the management of PWS. To ensure patient independence, the following aspects should be focused on:

  • Speech therapy
  • Exercise
  • Management of physical activity
  • Behavioral therapy
  • Hormone replacement therapy
  • Drug therapy

Parental counseling and education are equally important as it is essential for parents to understand the disease and their offspring, and then decide on a suitable management plan. Simple measures, such as securing the refrigerator and monitoring food intake, can go a long way.

Currently, human growth hormone (HGH) is the only FDA-approved hormonal supplement that is available in the management of PWS.

HGH therapy brings about the following changes:

  • Increase in bone mineral density
  • Improvement in stamina
  • Increase in height
  • Generalized improvement in body ratio and weight distribution
  • A decrease in body fat with simultaneous improvement in muscle mass

Current research in PWS are focused on the following areas:

  • Psychiatric and behavioral issues (temper tantrums)
  • Regulation of appetite
  • Control of food intake
  • Learning disabilities
  • Mental development

Prognosis of PWS

Active care to prevent obesity and its related complications can increase life expectancy. Cognitive problems are common and no cure is currently available. Behavioral counseling and education can be offered to the parents of the affected child. Group homes serve as an effective strategy in adults.

Recent Advances in the Management of PWS

The following therapies show promise in the management of PWS:

  • Bariatric surgeries, including gastric bypass, in the management of obesity and its related complications
  • Surgical treatment of cryptorchidism and scoliosis
  • Tonsillectomy, adenoidectomy, or tracheostomy for the management of obstructive sleep apnea
  • Serotonin agonists to improve impulsive behavior
  • Use of a positive airway pressure machine in the management of obstructive sleep apnea

Genetic Testing and Counseling in PWS

Prenatal genetic testing should be offered to families of children diagnosed with PWS to determine the risk to the future offspring. Although the roots of PWS appear to be of chromosomal origin, strictly speaking, this is not a genetic disease, as it is not hereditary. Genetic damage occurs during meiosis, the formation of the haploid gametes, or during early development. Genetic mutations are often spontaneous and sporadic. Thus, the risk level depends on the involved genetic aberration and can vary significantly.

When the aberration occurs in the imprinting control region and is likely to be replicated in the offspring, PWS often presents as an autosomal dominant disease. In such cases, the risk to the subsequent sibling is almost 50%. The offspring is prone to the risk of developing PWS if an affected parent has uniparental disomy or gene deletion. This risk escalates to about 25% when the cause is attributed to parental chromosomal translocation. This probability can be confirmed after prenatal testing to determine the genetic mechanism underlying PWS.


PWS is a rare autosomal disease in which the loss of paternal alleles or duplication of maternal copies of chromosome 15 q11.2-q13 segment leads to loss of function secondary to genomic imprinting function in this region. A converse loss-duplication pattern leads to Angelman syndrome.

PWS involves multiple organs as it progresses. Although this condition cannot be reversed, it can be managed medically or surgically.

Hypothalamus is the organ that is primarily affected in PWS. The subsequent implications of hypothalamic dysfunction are evident in almost every organ system of the affected individual. The key concerns are feeding difficulties and hypotonia in infancy and hypogonadism in children and adults. Compulsive eating disorders and behavioral issues are common presentations.

Until recently, the clinical diagnosis of PWS was based on symptomatic evaluation of the presenting patient. Currently, FISH and hypermethylation assays can accurately diagnose PWS.

There are many ways to improve the quality of life of patients with PWS and enable independent living. A complete cure, unfortunately, is yet to be discovered.

Genetic testing and counseling can be offered to families of children with PWS to assess the potential risk of this condition in the offspring.

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