Prader-Willi syndrome (PWS) is a genetic disorder caused by the loss of function of genes located in a specific region of chromosome 15 that controls metabolism, appetite, growth, intellectual abilities, and social behavior. As a result, people with PWS experience symptoms such as metabolic abnormalities, obesity, behavioral problems, and bone damage.
When achieved early, diagnosis enables patients to begin a quick intervention and treatment. There are consensus diagnostic criteria that are effective for identifying potential cases of PWS. However, genetic testing confirms the diagnosis of PWS in 99% of patients, and identifies the patient’s specific genetic subtype.
These subtypes include: 15q11-q13 deletion (when genes on the chromosome 15 that the patient inherited from their father are missing); maternal uniparental disomy, (when a child inherits two copies of chromosome 15 from their mother and none from their father); or imprinting defects (when a genetic mutation turns off the paternal genes on chromosome 15).
Criteria for diagnosis
According to the National Institutes of Health, children younger than 3 must have at least four major criteria and at least one minor criterion to receive a diagnosis of PWS.
Those older than 3 must have at least five major criteria and at least three minor criteria for a PWS diagnosis.
Major clinical criteria for diagnosis
The major clinical criteria of PWS are:
- floppiness and weak muscles
- difficulty sucking, which improves after the first few months
- feeding problems and/or failure to grow during the first year of life
- rapid weight gain in children ages 1 to 6, resulting in severe obesity
- uncontrollable overeating
- characteristic facial features, including a narrow forehead and triangular mouth
- underdevelopment of the genital organs resulting in incomplete and late puberty or infertility
- physical development delays
- multiple learning difficulties
Minor clinical criteria for diagnosis
The minor clinical criteria for a diagnosis of PWS are:
- reduced movement and fatigue during infancy
- behavioral problems, such as tempermental outbursts, obsessive-compulsive tendency, and stubbornness
- sleep disturbances, including sleep apnea and daytime sleepiness,
- short stature
- unusually light hair, skin, and eye color
- small hands and feet
- nearsightedness and/or trouble focusing both eyes at the same time
- thick and sticky saliva
- poor pronunciation of words and sounds
- frequent skin picking
Genetic testing confirms the PWS diagnosis, as almost all individuals with this syndrome have genetic alterations within chromosome 15.
Prenatal diagnosis also is available for those with a family history of PWS, to confirm the likelihood of having a child with PWS.
DNA methylation testing
The current genetic tool used to confirm PWS is called DNA methylation testing. It examines the methylation status of a gene. Methylation is the addition of methyl groups to the DNA molecule, leading to gene silencing.
This test determines whether the paternal copy of genes located in a specific region of chromosome 15 is absent or inactive.
DNA methylation testing is particularly important in patients who do not have typical symptoms or are too young to show enough features to make a symptom-based diagnosis.
Fluorescent in situ hybridization
DNA methylation testing cannot distinguish among the major genetic subtypes of PWS. Therefore, additional tests are necessary to determine the underlying cause of the disease.
One of those tests is fluorescent in situ hybridization in which labeled DNA probes can detect specific genetic sequences. This test allows physicians to identify PWS patients who have a deletion in chromosome 15. However, it is not able to identify those who have uniparental disomy or an imprinting error.
Another test that can detect both the size of the 15q11-q13 deletion, the most common genetic cause of PWS, as well as maternal disomy 15, is high-resolution microarrays.
Last updated: March 29, 2021
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