Prader-Willi syndrome (PWS) is a rare genetic disease caused by the loss of or defects in paternal genes in a particular region of chromosome 15. These genes are known to control sleep, metabolism, appetite, growth, intellectual skills, and social behavior.
This syndrome is characterized by severe hypotonia (weak muscles), slow growth, low levels of sex hormones, and a constant and insatiable appetite.
Causes
One of three main mechanisms result in the loss of the paternal genes in the “PWS locus” — or specific region — of chromosome 15. Each results in the loss of the essential proteins that these genes help to create.
The paternal genes on chromosome 15 are the “active” genes, as the maternal genes are turned off through a natural process called genomic imprinting. The most common way that these paternal genes are lost is through what is called DEL15 — a developmental error in a fetus that causes them to be deleted from chromosome 15’s PWS locus.
A second way these genes go missing is known as maternal uniparental disomy. Here, both copies of chromosome 15 are inherited from the mother — rather than one pair from each parent — but because of genomic imprinting, the mother’s copies are not active.
The third main way, which is the least common, is due to imprinting defects that turn off the paternal genes.
Symptoms
Common symptoms of PWS include floppiness caused by hypotonia, an excessive appetite and overeating (which leads to obesity), shorter stature due to insufficient amounts of growth hormone, developmental delays and learning difficulties, problems with normal sleep patterns and breathing, underdeveloped sex organs, and behavioral problems that include temper outbursts, stubbornness, and obsessive compulsive tendencies.
Other symptoms include unusually light skin and hair, strabismus (improper eye alignment), scoliosis (a sideways curvature of the spine), vision problems like nearsightedness, and distinctive features like a narrow forehead, almond-shaped eyes, and a triangular-shaped mouth.
Some, like weak muscle tone and distinct facial features, are evident in infancy.
Diagnosis
As with many diseases, an early diagnosis for PWS is thought best, as it enables parents to more quickly get a child into interventions and treatment. Consensus diagnostic criteria exist to help guide doctors in identifying this disease.
Genetic testing is generally given to confirm a PWS diagnosis, and to identify the patient’s specific genetic subtype. These tests can usually be done using a small sample of blood.
The current gold standard of genetic testing for PWS is called DNA methylation testing, and examines the methylation status of a gene. Methylation is the addition of methyl groups to the DNA molecule, leading to gene silencing.
While DNA methylation testing cannot distinguish among the major genetic subtypes of PWS, fluorescent in situ hybridization, a method using labeled DNA probes to detect specific genetic sequences, is used to identify PWS patients who have DEL15.
High-resolution microarrays may also be used and can detect both the size of the DEL15 as well as maternal uniparental disomy.
Treatment
Treatment of PWS currently aims to improve quality of life and requires a multidisciplinary team. Specialists on this team are typically an endocrinologist (an expert in hormonal disorders), a geneticist, a behavior specialist, and a dietitian.
Specific therapy depends on a patient’s age and symptoms. The most common treatment options are:
- Nutritional management: For infants, goals are to ensure they get necessary nutrition given difficulties with sucking and feeding due to weak muscle tone. Because excessive appetite begins in childhood, emphasis will switch to managing weight through a more restricted calorie diet, with supplements to ensure proper nutrition, and exercise.
- Sex hormone treatment: Hormone replacement therapy may be given — testosterone for males; estrogen and progesterone for females — to normalize levels of these hormones and reduce the risk of osteoporosis (bone thinning). Surgery may be needed to correct testicles that do not descend.
- Growth hormone treatment: Human growth hormones may be recommended. In addition to promoting growth, these treatments help to improve muscle tone and lower body fat in children with PWS. Parents should discuss both the risks and benefits of hormone treatments with their child’s endocrinologist.
- Sleep disorders, including sleep apnea — in which breathing repeatedly stops and starts during sleep — are treated to ease daytime sleepiness and behavioral issues.
- Behavioral management can help parents in addressing behavior problems in children. Treatment with serotonin uptake inhibitors (common antidepressants) may help teenagers and adults, especially those with obsessive-compulsive issues.
Additional interventions thought to help PWS patients include physiotherapy to improve movement and strength, speech therapy to better develop speaking skills, and occupational therapy for the handling of everyday tasks.
Last updated: April 1, 2021
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