What is Prader-Willi Syndrome?
Prader-Willi syndrome is a rare and complicated genetic condition that affects the body’s metabolism (how the body turns food into energy), endocrine system (the system of glands that produce hormones), and nervous system. It’s mainly recognized as a disease that often causes extreme obesity. People with Prader-Willi syndrome can experience behavioral, developmental, and intellectual challenges that include severe muscle weakness and feeding difficulties during early childhood. Around the age of 3, they often experience slow overall development, extreme hunger, and weight gain.
Prader-Willi syndrome also gives individuals distinct facial features, crossed eyes (strabismus), and issues with their muscles and bones. A lot of people with Prader-Willi syndrome are shorter than average due to a lack of growth hormone. They also may experience issues related to the hypothalamus (a small region at the base of the brain that plays a key role in many critical body functions), which can lead to other hormone disorders such as underactive testes or ovaries (hypogonadism), underactive thyroid gland (hypothyroidism), insufficient stress hormone production (central adrenal insufficiency), and loss of bone density. Because of these, these patients need to see a hormone specialist (endocrinologist) regularly throughout their lives.
What Causes Prader-Willi Syndrome?
Prader-Willi syndrome happens due to the lack of activity of certain genes that are usually inherited from the father. These genes are located on a specific stretch of chromosomal DNA designated as 15q11.2-q13. In about 70% of the cases, the syndrome arises because of a deletion or loss in the father’s genes. This is often due to what’s called ‘genomic imprinting’ errors, a process where the genes are marked in a way to act differently depending on whether they’re inherited from the mother or the father.
Approximately 25% of Prader-Willi syndrome cases occur due to both copies of the gene coming from the mother (also known as maternal uniparental disomy). A small number of remaining cases result from issues with the imprinting center itself, such as tiny deletions or alterations, known as microdeletions or epimutations, on chromosome 15.
Though most cases of Prader-Willi syndrome happen randomly, there are times when the condition can occur in families. This happens when the father’s genes have a microdeletion passed down from the paternal grandmother in the imprinting center. The syndrome has the distinction of being the first genetic disorder discovered to be caused by genomic imprinting, where the action of a gene depends on which parent the affected gene came from.
Risk Factors and Frequency for Prader-Willi Syndrome
Prader-Willi syndrome is a condition affecting 1 in every 20,000 to 30,000 births. It’s estimated that around 400,000 individuals worldwide have this syndrome, including 20,000 people in the United States. This syndrome is notably the leading genetic cause of severe obesity. Remarkably, it affects males and females equally, and there’s no noticeable difference in its occurrence among various races and ethnicities.
Signs and Symptoms of Prader-Willi Syndrome
Prader-Willi syndrome, a genetic disorder, displays a wide array of symptoms and features that often become more noticeable as the patient ages.
During infancy, common signs of Prader-Willi syndrome include weak muscle tone (hypotonia), feeding difficulties due to a poor sucking reflex, and slower than normal growth. This can necessitate the use of special feeding devices or prolonged periods of nutritional support.
The facial features associated with the syndrome might include narrower head at the temples (narrow frontal diameter), almond-shaped eye openings, thin upper lip, and downturned mouth corners. Small hand and feet size may not be visible at birth but can become noticeable later.
Children with Prader-Willi syndrome may undergo slower development in motor skills, achieving early milestones roughly at half the average pace. Notably, they usually start walking independently around 27 months. Other problems can include language impairment, learning difficulties, and behavioral issues such as anxiety, obsessive tendencies, self-harm, and tantrums.
The condition is commonly linked with a deficiency in the growth hormone, leading to stunted growth and rapid weight gain during childhood. By their second decade, affected individuals likely present with short stature and obesity primarily in the upper body.
Food-related issues become apparent as the child grows, progressing through four stages:
- Phase 1a (from birth to 9-15 months): Infants exhibit hypotonia and feed poorly, causing slow weight gain.
- Phase 1b (9-24 months): Steady growth with a typical rate of weight gain.
- Phase 2a (2-4.5 years): Weight gain occurs without consuming extra calories or an increase in appetite.
- Phase 2b (4.5-8 years): Intense food cravings (hyperphagia) begin, along with a heightened interest in food.
- Phase 3 (8 years to adulthood): Hyperphagia intensifies, leading to food-seeking behaviors and a lack of feeling satisfied after eating.
- Phase 4 (adulthood): The previously insatiable appetite settles down.
Excessive eating can lead to potential complications, including choking and sudden death, and behaviors such as consuming non-edible items.
Prader-Willi syndrome also affects sexual development. In males, almost all affected individuals experience undescended testicles, often requiring surgery. The penile size is typically smaller, which may cause difficulties during urination. During puberty, testosterone levels increase but remain low. In females, underdevelopment of external genitalia is common. They usually start puberty at the average age but may experience delayed breast development. Spontaneous onset of menstruation is rare and generally occurs around the age of 20.
Additional symptoms of Prader-Willi syndrome can include sleep disorders, thick saliva, high pain tolerance, decreased vomiting, epilepsy, temperature instability, spinal curvatures, osteoporosis, and skin and hair coloring that’s lighter than the family background. Complications often related to obesity, such as heart disease, liver disease, high cholesterol, diabetes, sleep apnea, and breathing problems, can also occur.
Testing for Prader-Willi Syndrome
When signs point towards Prader-Willi syndrome, a medical condition associated with intellectual difficulties, low muscle tone and continuous feelings of hunger, your doctor may recommend a DNA test called methylation analysis for confirmation. This test detects over 99% of Prader-Willi syndrome cases. If the test comes back positive, additional tests would be done to identify the specific type of genetic issue causing the condition. This could be a deletion (missing piece) in a certain part of the gene, a situation where both copies of the gene are inherited from the mother (instead of one from the mother and one from the father), or an imprinting defect (a problem with turning on or off the gene).
Advanced techniques like fluorescence in situ hybridization can detect the deletion in the 15q11-q13 parts of the gene, and chromosomal microarray can detect if both copies of the gene are from the mother. If you’re in a country with good access to medical care, Prader-Willi syndrome is often diagnosed early, around 2 months of age. However, getting confirmation of the diagnosis can take until around age 4, especially at top-tier specialist medical centers.
Based on your personal health condition, you might need extra tests, like:
* Tests for thyroid function to check if you have an underactive thyroid, especially if you might need growth hormone treatment.
* Liver function tests, serum IGF-1, and insulin-like growth factor binding protein-3 tests to check for problems with growth hormone deficiency (GHD).
* Tests for diabetes, like fasting glucose level, hemoglobin A1c, and oral glucose tolerance test.
* A sleep study (polysomnography) to diagnose potential sleep disorders.
* A special type of x-ray scan (DXA scan) to analyze bone density and composition.
Treatment Options for Prader-Willi Syndrome
Managing Prader-Willi syndrome depends on the patient’s age and involves monitoring various body systems. Babies with this syndrome have weak muscles, feeding difficulties, and may not gain weight as they should. This often requires a team of feeding experts to suggest specialized feeding techniques and high-calorie supplements or formulas.
As the children age, they might develop an excessive desire to eat (hyperphagia), so it becomes crucial to limit their food intake. Most patients with this syndrome don’t require as many calories as kids their age without the syndrome, approximately only 70% of the calories. Therefore, a low-calorie diet may not provide sufficient vitamins and minerals, and they might need to take supplements to meet their daily needs. Parents need to be cautious about using gummy vitamins due to their high caloric content and the risk of overdose as kids may consume them like candy.
To enforce food restrictions, caregivers often use physical barriers such as locking food cupboards and refrigerators and providing close supervision. Individuals with intense eating desires may forget to chew their food well, increasing the risk of choking. So, caregivers are trained to know what to do if choking happens, like performing the Heimlich maneuver. For severe cases of obesity in older children and adults, doctors might consider weight-loss medicines and surgery.
Motor skills delays and weak muscles in people with Prader-Willi syndrome can be improved through physical and occupational therapy. Also, early treatment with a medicine called ‘recombinant human growth hormone’ (rhGH) improves muscle growth and physical function in these patients. This hormone treatment can be introduced as soon as the syndrome is diagnosed, preferably before the first birthday, and continued throughout adolescence to maximize growth.
This treatment may also benefit adults, especially those with ongoing growth hormone deficiencies. Despite the daily or weekly injections involved, the treatment is associated with enhanced growth, reduced obesity, improved bone density, and motor function. Patients treated with this hormone during childhood are more likely to reach their predicted adult height.
Many young boys with this syndrome show undescended testicles (Cryptorchidism), and while a hormone treatment called ‘human chorionic gonadotropin’ may be effective, most of them need a surgical procedure called ‘orchiopexy.’ Hormone replacement therapy may be indicated for delayed puberty, and consultation with an endocrinologist is recommended at puberty. Boys with delayed puberty usually need testosterone treatment, while girls need estrogen replacement in the form of skin patches until they start menstruating.
About a quarter of children with this syndrome meet the diagnostic criteria for autism spectrum disorder. In case of mood disorders or psychoses, medication and therapy may be required for teenagers and adults. Strategies to help understand rules, schedules, expectations, and verbal pointers can decrease symptoms of compulsion and actions of aggression. Skin picking is common, and a study has shown that oral medication called ‘guanfacine’ can help. Many individuals are also observed to have cognitive impairment, which might worsen with age. Schoolchildren should have an individualized educational plan, while adults often thrive in a supervised job setting.
Bone weakness is common, and regular scans to assess bone density every 2 to 3 years, starting from age 5, is recommended. Scoliosis (spine curvature) is also prevalent. For suspected cases, the children should be referred for a detailed orthopedic evaluation.
Hypothyroidism (underactive thyroid gland) is another manifestation of this syndrome which; routine testing should start within the first year. Because of severe obesity, type 2 diabetes can occur, and screening should be done as needed. Breathing difficulties during sleep is a common problem, affecting most children and young adults. Individuals showing daytime sleepiness and behavior issues should be checked for obstructive sleep apnea (a sleep disorder causing difficulty in breathing). In some cases, a tonsil removal surgery might be necessary.
What else can Prader-Willi Syndrome be?
There are various disorders that can show similar symptoms to Prader-Willi syndrome. These should be considered when diagnosing someone with this syndrome. One such condition is neonatal hypotonia, which is often caused by certain nerve and muscle conditions such as spinal myotonic dystrophy. This condition often results in poor respiratory effort early in life.
There’s also a condition called “Prader-Willi-like syndrome.” Despite sharing many similar symptoms with Prader-Willi syndrome like muscle weakness, short stature, obesity, and developmental delays, it actually has different genetic causes.
Children with craniopharyngioma, a rare type of tumor, may also show symptoms that resemble Prader-Willi syndrome. This is often due to the effects treatment can have on an area of the brain known as the hypothalamus.
Despite these similarities, what makes Prader-Willi syndrome unique is how its symptoms progress. It usually starts with muscle weakness and poor feeding leading to slow weight gain early in life. It then evolves into excessive eating, followed by severe obesity. This sequence sets it apart from other conditions.
What to expect with Prader-Willi Syndrome
The future rate of recovery and survival for patients with Prader-Willi syndrome can change depending on when it was detected and how severe the condition is. Starting treatment earlier and stopping extreme obesity make it more possible for these patients to achieve a normal lifespan. However, due to learning difficulties, many affected will often need extra help and support and are less likely to live completely on their own when they become adults.
Complications like obesity, diabetes, and heart failure can decrease life expectancy in Prader-Willi syndrome. Usually, death can occur in their 40s when accompanying health conditions are not properly managed. However, individuals with Prader-Willi syndrome can potentially live until their 70s if they maintain a healthy weight.
Possible Complications When Diagnosed with Prader-Willi Syndrome
Complications associated with Prader-Willi syndrome are numerous. Many of these complications are tied to severe obesity, but they can also be related to various issues in the muscular, neurological, behavioral, and developmental areas, affecting different bodily systems. The problems related to Prader-Willi syndrome include:
- Respiratory problems such as sleep apnea, reduced breathing during sleep, aspiration pneumonia or respiratory failure due to obesity.
- Heart problems like high blood pressure and failure of the right side of the heart.
- Digestive issues like stomach paralysis, delayed stomach emptying, increase in liver fat, reduced saliva production, increased hunger hormone secretion, stomach rupture or blockages due to eating excessively.
- Musculoskeletal issues like weakened bones (osteoporosis), bone fractures, abnormal spine curvature (scoliosis, kyphosis) and hip malformation (dysplasia)
- Skin conditions like ulcers from blood pooling in the legs and skin infections (cellulitis).
- Behavioral problems like tantrums, outbursts, self-harming behavior, stealing and hoarding food, delayed brain development, intellectual impairment, and learning disabilities.
- Neurological issues like reduced muscle tone (hypotonia), body temperature instability, and seizures.
- Endocrine or hormonal problems like short stature, growth hormone deficiency, adrenal gland insufficiency, low thyroid hormone levels, sexual development problems, and type 2 diabete
Preventing Prader-Willi Syndrome
Doctors looking after children need to be vigilant and watchful, especially when caring for infants who show signs of low muscle tone (hypotonia), difficulty with sucking, slow weight gain, or undescended testicles (cryptorchidism). These could be symptoms of a condition called Prader-Willi syndrome. Recognizing and treating this syndrome early can effectively address these issues during a baby’s growth.
It’s crucial that families of these babies are taught about what to expect as their child grows and develops with this condition. Children diagnosed with Prader-Willi syndrome need to follow a careful diet plan to avoid serious weight gain and obesity. The support they need goes beyond diet and includes both medical care and educational services. This comprehensive care usually involves a team of specialists working together for the child’s best health outcomes.
