Prader-Willi syndrome, also known as PWS is an uncommon genetic disorder (present at birth) in which seven genes (or subsets) on chromosome 15 are deleted or unexpressed. Patients with PWS may have physical, mental and behavioral problems - the main one being an unrelenting feeling of hunger.

Individual with Prader-Willi syndrome have serious problems controlling their body weight, because they spend much longer eating than other people do - there is a very strong food compulsion. PWS is the most common genetic cause of morbid obesity in children.

According to the Prader-Willi Association, USA, between 1 in 8,000 and 1 in 25,000 people live with the condition. PWS affects both sexes equally.

Patients with Prader-Willis syndrome often have low muscle tone, incomplete sexual development, and chronic (long-term) hunger. They also tend to have a metabolism that utilizes fewer calories, compared to other people. Many individuals with PWS have short stature if they do not receive growth hormone therapy.

A newborn with PWS tends to weigh less than normal, has weak muscles (hypotonia), and may find sucking difficult. Between the ages of 2 and 5 years individuals start developing a voracious appetite. Some, however, may start later. When hyperphagia begins it tends to persist for life. Hyperphagia (polyphagia) is an abnormally high appetite for food, and eating much more food than normal.

Prader-Willi syndrome was first described in 1956 by Andrea Prader (Switzerland, 1919-2001, pediatrician and endocrinologist), Heinrich Willi (Switzerland, 1900-1971, pediatrician), Alexis Labhart (Switzerland, 1916 Prof. Internal Medicine), and Guido Fanconi (Switzerland, 1892-1979, Pediatrician).

According to Medilexicon’s medical dictionary:

Prader-Willi syndrome is ‘a congenital syndrome characterized by short stature, mental retardation, polyphagia with marked obesity, and sexual infantilism; severe muscular hypotonia and poor responsiveness to external stimuli decrease with age; a small deletion is demonstrable in the paternal-derived chromosome 15q11-13 in many cases; some cases are due to maternal uniparental disomy (both chromosomes 15 are derived from the mother).’

What are the signs and symptoms of Prader-Willi Syndrome?

A symptom is something the patient senses and describes, while a sign is something other people, such as the doctor notice. For example, drowsiness may be a symptom while dilated pupils may be a sign.

Prader-Willi signs and symptoms tend to occur in two stages, with the first becoming evident during the first year of an infant’s life, and others occurring between the ages of 1 and 6 years.

Signs and symptoms in infants (babies under 1 year of age):

• Hypotonia - poor muscle tone; a primary sign. The baby may feel floppy when held. Their elbows and knees may be loosely extended instead of being firmly in position. Hypotonia improves with age.

• The face - eyes may have an almond shape. The head may narrow at the temples. The infant’s mouth may be turned down, with a thin upper lip. The mouth often appears to be small.

• Failure to thrive - this term refers to babies and children whose physical growth is less than their peers’. Poor muscle tone may undermine the infant’s ability to suck properly, making feeding difficult. Babies with Prader-Willi syndrome commonly gain weight more slowly than other babies.

• Strabismus - the eyes may not move in unison. It may appear that an eye wanders, or that the eyes cross.

• Cry - the infant may have a weak cry.

• Responsiveness - the infant may not respond as he/she should to simulation. He/she may seem tired.

Between 1 and 6 years of age - the signs and symptoms that emerge will tend to persist for the rest of the child’s life:

• Food craving, body weight - the child craves for food constantly, and eats lots and often. Consequently they gain weight. Sometimes the child may hoard food, or eat things most people would not, such as frozen food before it is thawed or cooked, or food that has gone off.

• Hypogonadism - the testes or ovaries do not produce enough sex hormones, resulting in underdeveloped sex organs. In most cases adults with Prader-Willi syndrome are infertile. There is poor sexual development during puberty. The testes of males may not descend, while females may never have menstrual periods (or very scant ones).

• Growth and strength - individuals with Prader-Willi syndrome tend to have poor muscle mass, small hands and feet. Hands may be narrow with straight ulnar border. Adults with the PWS are usually shorter than average.

• Cognitive abilities - a significant percentage of people with PWS have mild to moderate mental retardation. Learning disabilities are common, even among those without mental retardation.

• Motor skills - coordination milestones, such being able to sit up or walking are usually reached later. A baby with PWS may not be able to walk until he/she is 24 months old. Motor skills refers to movement and motion.

• Verbal skills - a child with PWS will start speaking later than other children. Good diction may be challenging throughout life.

• Behavior and mental disorders - the child may have temper tantrums, especially when the issue is food. There is a tendency to be argumentative, oppositional, rigid, manipulative, possessive and stubborn. Some may develop OCD (obsessive compulsive disorder), repetitive behaviors, recurring thoughts, and some other mental disorders.

• Sleep disorders - a higher percentage of people with PWS have sleep apnea, compared to the rest of the population. This may be linked to obesity. There may also be disturbances of the normal sleep cycle.

• Scoliosis (curvature of the spine) - a significantly higher proportion of children with PWS develop scoliosis, compared to the rest of the population.

• Skin and hair - the individual’s skin and/or hair may be fairer compared to parents’ and siblings’.

• Pain tolerance - people with PWS tend to have a high tolerance for pain.

• Eyesight - the individual may have myopia (short-sightedness).

• Skin picking - repetitive picking of one’s own skin.

You should see a doctor if your baby:

• Has feeding difficulties
• Does not wake up easily
• Does not respond to normal stimulation, such as touch
• Feels floppy when held

See a doctor is your child:

• Is always hungry
• Is constantly foraging for food
• Has rapid weight gain

What are the causes of Prader-Willis Syndrome?

What are genes? Every living organism has genes. Genes are a set of instructions that decide what the organism is like, how it survives, and how it behaves in its environment. The genes lie in long strands of DNA (deoxyribonucleic acid) called chromosomes. Humans have 23 pairs of chromosomes - or a total of 46. A donkey has 31 pairs of chromosomes, a hedgehog has 44, and a fruit fly has just 4.

Prader-Willi syndrome is caused by an error in a gene (or genes). We are not sure which genes are involved, but we know the abnormality is in a region of chromosome 15.

All human genes come in pairs, except for those related to sex characteristics. We get one copy from our father (paternal gene) and one copy form our mother (maternal gene). In most types of gene, if one copy is active so is the other one. Sometimes, however, genes are active on their own - this is usually normal. A paternal gene may be active while the maternal one is not (silent). If that paternal active gene is faulty, genetic information will be missing.

Prader-Willi syndrome may have three possible causes:

• The paternal genes on chromosome 15 are not present (they are missing)

• The paternal genes on chromosome 15 are faulty

• The offspring has inherited no chromosome 15 from the father, and two copies form the mother (and they are both inactive)

This genetic fault results in a disruption of the normal functions of the hypothalamus. The hypothalamus is a part of the brain which controls thirst and hunger. It also releases hormones that trigger the release of chemicals involved in sexual development and growth.

Put simply - a genetic fault causes a part of the brain to malfunction, which undermines the person’s ability to regulate hunger, growth, sexual development, as well as other functions which result in PWS signs and symptoms.

Acquired Prader-Willi Syndrome - if there is damage to the hypothalamus during a person’s life, PSW-like signs and symptoms may develop - may be acquired. This could be caused by a Head injury, a tumor, or surgery to remove a tumor. In such cases the patient does not have the genetic faults or physical characteristics of PWS, but may acquire some of the behavioral problems linked to the syndrome, such as a constant craving for food.

Treatment used for patients with congenital PSW can be effective for those with acquired PSW.

Diagnosing Prader-Willi Syndrome

Prader-Willi syndrome used to be diagnosed by clinical presentation - if the signs and symptoms were present. Today diagnosis is done through genetic testing.

Genetic testing is recommended: (Source: Prader-Willi Syndrome Assoc. USA)

• Infants - if an infant has pronounced hypotonia (poor muscle tone) with poor suck.

• Children aged 2 to 6 years - if the child has a history of poor suck, as well as general developmental delays.

• Children aged 6 to 12 years - if the child has a history of poor muscle tone, poor suck, general developmental delays, constant hunger and overeating (with central obesity if uncontrolled).

• Everybody aged 13 years or more - if there are signs of mild mental retardation, constant hunger and overeating (with central obesity if uncontrolled), hypogonadism, temper tantrums, and obsessive compulsive behaviors.

Genetic testing involves a DNA-based methylation test to detect the absence of the paternally contributed PSQ region on chromosome 15q11-q13. This test will detect 97% of patients with PSW. The test is important to confirm the diagnosis of PWS in all patients, but especially those who are too young to have enough evident signs and symptoms. Early diagnosis of PWS allows for early intervention as well as the early prescription of growth hormone.

A significant number of patients with PWS are undiagnosed, or misdiagnosed as Down syndrome. Experts say this is mainly because many in the medical community are unfamiliar with Prader-Willi syndrome.

What are the treatment options for Prader-Willi Syndrome?

There is no cure for Prader-Willi syndrome, however, several treatments are available which help to lessen the signs and symptoms of the condition, including infant/child nutrition, growth hormone therapy, sex hormone therapy, physical therapy, speech therapy, occupational therapy, and developmental therapy . The best treatment involves a team of different health care professionals who will be involved in the care of the patient for most of his/her life.

• Infant/child nutrition - if the infant has feeding difficulties a high-calorie formula may be recommended. Doctors will carefully monitor the child’s weight and growth. Later on a nutritionist may help the child develop a healthy, low-calorie diet to keep his/her weight under control.

• Growth hormone treatment - growth hormone treatment has been shown in studies to help increase growth and lower body fat in children with Prader-Willi syndrome. However, we do not know what the long-term effects might be. An endocrinologist will help determine whether the child is suitable for growth hormone treatment.

• Sex hormone treatment - HRT (hormone replacement therapy) may be recommended for children with Prader-Willi syndrome. HRT would involve testosterone for boys and progesterone for girls to top up low levels of sex hormones. Apart from helping their sexual development, HRT may also reduce the risk of osteoporosis (thinning of bones).

Put simply - HRT hormone therapy can increase stature, decrease obesity, and increase muscle mass.

• General development - a range of therapies may help the child, including:

o Developmental therapy - to acquire social and interpersonal skills appropriate for the child’s age.

o Occupational therapy - to help with everyday tasks.

o Physical therapy - to improve strength and movement.

o Speech therapy - to help with diction and oral communication.

• Mental health - if the child has symptoms of obsessive-compulsive disorder, a mood disorder or some behavioral problems, a psychologist or psychiatrist may help provide the appropriate therapies.

• Adulthood - the majority of individuals with Prader-Willi syndrome require supervision and specialized care for the rest of their lives.

If obesity can be prevented and complications controlled properly, the life expectancy for a person with PWS is normal or near-normal.

Non-stop food restriction and behavior management is often demanding and stressful for family members. Various Prader-Willi organizations around the world can provide information and support for families as well as health care providers. Sometimes, family counseling may help.

Experts say that teenagers and adults with Prader-Willi syndrome can function well in group and supported living programs if there is proper nutritional control and a structured environment.

Reactions to medications - individuals with Prader-Willi syndrome may react differently to standard dosages of medications. Doctors are advised to be extremely cautious when administering sedatives, as prolonged and exaggerated responses are possible.

Pain tolerance - people with PWS tend to have a high tolerance for pain. A patient may not complain about discomfort or pain until an infection or condition is severe.

Vomiting - people with PWS rarely vomit. If an individual with PWS vomits he/she may have something much more serious than others may think. Hyperphagia (abnormally increased appetite for and consumption of food) may result in the consumption of unhealthy foods, such as uncooked or spoiled foods. A gastrointestinal complication, such as a stomach infection would result in vomiting much earlier in people who don’t have PWS.

Anesthesia - children with PWS are at higher risk of developing a complication from anesthesia, compared to other children. Many infants and children undergo surgical procedures for obstructive sleep apnea - the medical team should be aware of the possible complications.

What are the possible complications of Prader-Willi syndrome?

Obesity - individuals with PWS have a significantly higher risk of becoming obese for two main reasons:

• Hyperphagia - there is an abnormally high appetite for food, and an abnormally high consumption of food.

• Muscle mass - muscle mass is usually lower than other people’s, so a person with PWS generally requires fewer calories than other people of the same weight.

Hyperphagia combined with low muscle mass make the patient much more likely to become obese. Medical complications related to obesity include:

• Type II diabetes - the body either does not produce enough insulin or the insulin is not working properly (insulin resistance). In the case of insulin resistance, the body is producing the insulin, but insulin sensitivity is reduced and it does not do the job as well as it should do. The glucose is not entering the body’s cells properly, causing two problems: 1. A build-up of glucose in the blood. 2. The cells are not getting the glucose they need for energy and growth.

In the early stages of Type 2 insulin sensitivity is the main abnormality - also there are elevated levels of insulin in the blood. There are medications which can improve insulin sensitivity and reduce glucose production by the liver. As the disease progresses the production of insulin is undermined, and the patient will often need to be given replacement insulin.

• Heart disease/stroke - obese individuals are at significantly higher risk of developing hypertension (high blood pressure), hardened arteries, and elevated blood cholesterol levels - all of which contribute to a higher risk of stroke or heart disease.

• Osteoarthritis - cartilage loses its elasticity. If the cartilage is stiff it becomes damaged more easily. The cartilage, which acts as a shock absorber, will gradually wear away in some areas. As the cartilage becomes damaged tendons and ligaments become stretched, causing pain. Eventually the bones may rub against each other causing very severe pain.

• Obstructive sleep apnea (OSA) - a condition which causes interruptions in breathing during sleep. It is a potentially serious sleep disorder in which breathing repeatedly stops and starts during sleep as the throat muscles intermittently relax and block the airway. In obstructive sleep apnea, breathing is interrupted by a physical block to airflow, despite the effort to breathe. The most noticeable sign of obstructive sleep apnea is snoring. However, not everyone who has OSA snores.

Hypogonadism - sexual growth and development is poor because the gonads (ovaries or testes) are not producing enough hormones (estrogen, progesterone, and testosterone). This can lead to:

• Infertility - most people with PWS cannot have children. Cases of females with PWS who became mothers are extremely rare.

• Osteoporosis - bones become thin and weak (brittle).

Observations

And to think that many, so-called ‘experts’, treating obesity do not know what PWS is…

PWS

Felix Larocca

Medico psiquiatra de adultos y de ninos. Psicoanalista de adultos y de ninos. Ex oficial medico de la US Navy. Especialista en las enfermedades del comer (disorexias). Ex miembro de las facultades de Washington University y de Saint Louis University en Saint Louis, MO. Ex miembro de la Facultad de Educacion Extensiva del Saint Louis Psychoanalytical Institute.

Santiago de los Caballeros, Provincia de Santiago, República Dominicana