Prader-Willi Syndrome

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Prader-Willi Syndrome (PWS) is a genetic condition characterized by chronic hunger, decreased muscle tone, incomplete puberty and developmental delay. This condition affects individuals of both sexes, and all ethnicities equally. [1]

Clinical Features

The following features are common of individuals with PWS. However, PWS exists on a spectrum; symptoms will vary in severity between individuals and not all individuals with PWS will have these signs and symptoms. [1][2]

Infancy:

  • Difficulties feeding
  • Weak muscles
  • Delay in reaching developmental milestones
  • Fatigue
Clinical features of Prader-Willi Syndrome. [2]

Childhood:

  • Constant hunger/excessive appetite
  • Obesity
  • Underdeveloped genitals
  • Delayed and/or incomplete puberty
  • Growth hormone shortage
  • Short stature
  • Decreased muscle tone
  • Learning difficulties
  • Mild to moderate intellectual disability
  • Compulsive tendencies
  • Behavioural challenges
  • Characteristic facial appearance: narrow forehead, almond-shaped eyes

Adulthood:

  • Constant hunger/excessive appetite
  • Obesity
  • Underdeveloped genitals
  • Infertility
  • Growth hormone shortage
  • Short stature
  • Decreased muscle tone
  • Learning difficulties
  • Mild to moderate intellectual disability
  • Compulsive tendencies
  • Behavioural challenges
  • Sleep disorders

Genetics

PWS is a condition that is caused by differences in an individual's genes.

Genes carry instructions that influence what we look like and how we act. Humans have thousands of genes that are packaged into chromosomes. Typically, humans have 23 pairs, or 46 total chromosomes; one copy of each of the 23 chromosomes is inherited from mom and the other copy is inherited from dad. Individuals with PWS are missing genetic information from a specific portion of chromosome 15: region q11.2-q13. [1][3][4][5] This region contains genetic information that is critical for normal development and function. Importantly, the genes in this region are only active in the paternal copy of chromosome 15 (the copy that is inherited from dad). [1][5]

There are three ways in which this can occur:

1. Deletion

In the majority of cases of PWS (65-75%), the affected individual is missing a small piece of the copy of chromosome 15 that they inherited from their dad (paternally-inherited 15q11.2-q13). [1][5] This genetic difference is called a deletion, as there is a segment of information that has been lost from the chromosome. As the genes in this region are only active in the paternal copy of chromosome 15, an individual with a deletion in the chromosome inherited from dad will be missing working copies of genes that are important for development and normal function. [4][5]

The vast majority of people whose PWS is caused by a deletion are the first in their family to have the condition. They are considered to have a de novo (new) change in their genes that was not present in either of their parents. [3]

Prader-Willi Syndrome can be caused by a small deletion in the paternally-inherited copy of chromosome 15. [6]
2. Maternal Uniparental Disomy (UPD)

20-30% of PWS cases occur because an individual has inherited both copies of chromosome 15 from their mother, rather than one copy from each parent. This is known as uniparental disomy; uniparental because the chromosomes came from a single parent, and disomy because there are two copies of the gene present. These individuals do not have any active copies of the important genes found in the q11.2-q13 region of chromosome 15, as they are missing the paternal copy. [4][5]

Prader-Willi Syndrome can be caused by maternal uniparental disomy. [6]
3. Imprinting Defect

Genomic imprinting is a process that turns genes on or off depending on whether the specific gene was inherited from mom or dad. The imprinting control region is like the on/off switch that determines whether certain genes are expressed. [1] A small number (1-3%) of cases of PWS occur as a result of genetic differences that impact the imprinting process. These differences may result in both copies of chromosome 15 being treated as if they were from mom. Consequently, gene expression from both the maternal and paternal copies of chromosome 15 would be turned off. [3][4][5]

Prader-Willi Syndrome can be caused by an imprinting defect. [6]

The genetic change that causes PWS is not a result of something the parents did or did not do before or during the pregnancy.

Prevalence

Prevalence refers to how common or widespread a particular condition is. PWS has an estimated prevalence of 1/10,000–1/30,000 live births, meaning that it is thought to affect around 1 in every 10,000 to 1 in every 30,000 newborns. [7] In other words, in a stadium the size of Rogers Arena in Vancouver, we would expect around 1 person to be affected.

Diagnosis

PWS is rarely diagnosed before birth. After birth, a suspected diagnosis of PWS may be made by a doctor based on a baby's physical characteristics. Diagnoses are confirmed by a blood test that looks for specific genetic differences in the q11.2-q13 region of chromosome 15 that are seen in individuals with PWS. Additional genetic testing may be needed to determine the specific type of genetic difference that is causing PWS. [1][8]

Recurrence

The likelihood that a couple with PWS will have another affected child depends on the type of genetic difference that caused the condition. If the child with PWS has a de novo deletion in the copy of chromosome 15 that they inherited from their dad or maternal UPD, the chance of recurrence in a subsequent pregnancy is < 1%. However, if the affected child has a genetic difference in the imprinting control region - the genes' on/off switch - the likelihood of recurrence in a future pregnancy is up to 50%. [1]

Genetic counselling is recommended for individuals or couples with a child affected by Prader-Willi Syndrome, to help them navigate the medical, emotional, and practical outcomes of a diagnosis, and understand their specific risks for future pregnancies.

Management and Treatment

There is currently no cure for this condition. However, there are treatments and interventions that may be implemented by health care professionals to manage the symptoms of PWS. Depending on the individual's unique symptoms and needs, health care professionals may recommend the following:

Interventions to restrict excessive food consumption

Individuals with PWS have a difference in the part of the brain called the hypothalamus, which typically detects sensations of hunger or fullness. While the mechanism is not entirely understood, individuals with this difference are unable to feel completely full and experience chronic feelings of hunger. People with this condition also tend to have lower muscle tone, and require less calories than someone without the condition. These symptoms can lead to excessive eating and obesity if not well managed. Individuals may work with professions to identify caloric needs, or design environments that limit access to food. No medications have been shown to minimize or eliminate food-seeking behaviours. [9][10]

Growth hormone (GH) replacement therapy

A common characteristic of PWS is decreased levels of growth hormones (GH), which are necessary for growth, development and metabolism. Several studies have found that GH replacement therapy can positively affect growth and activity level, increase lean body mass and decrease fat mass in individuals with PWS. [9][11] In Canada and the United States, there are approved GH that can be prescribed to individuals with a diagnosis of PWS. [12][13]

Special Feeding Techniques/Tubes

Newborns and infants with PWS are often unable to feed properly, as their low muscle tone makes it challenging for them to suckle. Infants with this difficulty may require special nipples or tubes in order to get the nourishment that they need. [3]

Depending on the individual's unique symptoms, other specialists such as physiotherapists, occupational therapists, endocrinologists, opthamologists, speech language pathologists, sleep specialists, social workers and behavioural interventionists may also be a part of the health care team.

Resources

PWS is a rare genetic condition, and most people are unfamiliar with it. Awareness and understanding of this genetic condition are crucial to promote early diagnosis, effective management, advocacy for and support for individuals and their families affected by PWS. Several resources exist for families, caregivers, medical professionals, educators and supports of individuals with PWS. These include:

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Cassidy, Suzanne B., et al. "Prader-willi syndrome." Genetics in medicine 14.1 (2012): 10-26.
  2. ↑ 2.0 2.1 Bellman, Val, et al. "Suicidality and self-harming behaviors in patients with Prader-Willi syndrome (PWS): case report and literature review." Case reports in psychiatry 2021 (2021).
  3. ↑ 3.0 3.1 3.2 3.3 Driscoll DJ, Miller JL, Cassidy SB. "Prader-Willi Syndrome." (1998) [Updated 2023]. Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1330/
  4. ↑ 4.0 4.1 4.2 4.3 Butler, Merlin G. "Prader-Willi Syndrome." Neuroscience in the 21st Century: From Basic to Clinical. Cham: Springer International Publishing, 2022. 3563-3603.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 Angulo, M. A., M. G. Butler, and M. E. Cataletto. "Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings." Journal of endocrinological investigation 38 (2015): 1249-1263.
  6. ↑ 6.0 6.1 6.2 "What is Prader-Willi Syndrome?". Foundation for Prader-Willi Research.
  7. ↑ Bohonowych, Jessica, et al. "The global Prader–Willi syndrome registry: development, launch, and early demographics." Genes 10.9 (2019): 713.
  8. ↑ Gunay-Aygun, Meral, et al. "The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria." Pediatrics 108.5 (2001): e92-e92.
  9. ↑ 9.0 9.1 Tauber, Maithé, and Charlotte Hoybye. "Endocrine disorders in Prader-Willi syndrome: a model to understand and treat hypothalamic dysfunction." The Lancet Diabetes & Endocrinology 9.4 (2021): 235-246.
  10. ↑ Höybye, Charlotte, and Maithé Tauber. "Approach to the Patient With Prader–Willi Syndrome." The Journal of Clinical Endocrinology & Metabolism 107.6 (2022): 1698-1705.
  11. ↑ Burman, Pia, E. Martin Ritzen, and Ann Christin Lindgren. "Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH." Endocrine reviews 22.6 (2001): 787-799.
  12. ↑ "Regulatory Decision Summary for Genotropin". Government of Canada. June 22, 2020.
  13. ↑ McCandless, Shawn E., and Committee on Genetics. "Health supervision for children with Prader-Willi syndrome." Pediatrics 127.1 (2011): 195-204.
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