What Is Prader-Willi Syndrome?

Did you know that obesity can be explained by genetics? People suffering from Prader-Willi syndrome have an insatiable appetite, leading to obesity from a young age. This article focuses on the key aspects of the condition, symptoms, diagnosis, treatment, main challenges and a glimpse into possible future treatment options. Proper education, awareness, support and efficient teamwork with the healthcare professionals specialised in Prader-Willi syndrome, are the pillars that will provide the best health outcome and quality of life for both patients and caregivers. 

Definition of prader-willi syndrome (PWS)

Prader-Willi syndrome (PWS) is a genetic disorder which is observed early in childhood because it affects their appearance, development, reaching age-specific milestones, and behaviour.^1,2 Firstly described in 1956, PWS is considered the most common genetic cause of severe obesity in children. The critical signs of PWS are hypotonia (low muscle tone), feeding difficulties in newborns, hypogonadism (low function of sexual glands - testicles and ovaries), short stature (growth hormone deficiency), learning difficulties, insatiable appetite and particular food-focused behaviour leading to early, possible life-threatening obesity.^3,4       

What causes prader-willi syndrome? 

The answer lies in the DNA. The human DNA is folded with proteins into chromosomes. Each chromosome has “regions” called genes, which come in pairs, one from the mother (maternal copy of the gene), and one from the father (paternal copy of the gene). The genetic problem in Prader-Willi syndrome lies with chromosome 15, in the “Prader-Willi critical region”. It plays an important role in the proper function of the hypothalamus, an area deep within the brain that regulates the hormones involved in appetite, growth, reproductive development, temperature regulation, behaviour, and sleep.^1,5,6

The genetic defect can be due to:

• Deletion of the paternal gene copy in chromosome 15

This is the most common cause of the syndrome – about 70% of cases. The deletion of the paternal gene from the “Prader-Willi critical region” leads to a loss of function because the maternal copy of the gene from the pair is naturally inactive and is not able to compensate. Therefore, the lack of “genetic data” causes abnormalities regarding the sense of hunger and fullness in the patients.^1,5,6

• Maternal uniparental disomy

This is the second most common cause of PWS – about 25% of cases. In this scenario, the child has two copies of the gene from the mother and none from the father. This is called “maternal uniparental disomy”, and the syndrome happens because both copies of the gene are inactive (because the maternal copy is always inactive), and this causes a lack of function in the chromosomal “Prader-Willi critical region”.^1,5,6

• Imprinting error on the paternal gene copy 

This happens in about 5% of cases. Normally, in the “Prader-Willi critical region”, the maternal copy of the gene is inactive because of the process called imprinting. The imprinting centre from the maternal copy sets the genetic data as “unreadable” by the cell and becomes inactive. Sometimes, due to a small deletion in the imprinting centre from the paternal copy, the gene from the father also becomes inactive. Even though it is not deleted, there is a loss of function.^1,5,6

How frequent is PWS? 

Prader-Willi syndrome occurs in approximately one in 10,000 to one in 30,000 births. There are around 350,000-400,000 people affected by this disorder, worldwide.^5,7

Early signs: floppiness and failure to thrive

Even before birth (prenatally), hypotonia (low muscle tone) is a sign of this disorder. The foetus is small for the gestational age (how far along the pregnancy is), presents fewer foetal movements, has an abnormal position, and might need additional delivery assistance. Another prenatal sign is polyhydramnios (more amniotic fluid than normal), which shows that the foetus is unable to swallow the amniotic fluid.^2,3,8

After birth, the baby is floppy, lethargic, has a weak cry, poor reflexes, and feeding difficulties caused by the inability to suck and swallow. The baby can’t be breastfed, and this can lead to tube feeding (a tube is installed from mouth to the stomach). 

Other physical signs after birth might be particular facial features like almond-shaped eyes, strabism (misalignment of one or both eyes), thin upper lip, downturned mouth, narrow bridge of the nose, and a disproportionately long head (dolichocephaly). The babies also present fair skin and hair, small hands and feet, and underdeveloped reproductive organs.^2,3,8

Childhood and adult manifestations

As the child grows, the low muscle tone improves, and they overcome feeding difficulties. Around the age of 2, the child usually starts gaining weight because they show an increased interest in food. Between the ages of 4 and 8, their appetite becomes a feeling of extreme hunger, leading them to overeat (hyperphagia) and never feel full (insatiable appetite). Besides becoming obese, children with PWS can endanger themselves while eating because they are unable to feel the sense of stomach fullness, pain, or vomiting reflex. Medical emergencies like stomach rupture or choking can occur. Adults affected by PWS present with health-related complications of obesity, such as hypertension, sleep apnea, and diabetes.^2,3,8

PWS children show delays in motor development. They reach age-specific milestones, such as walking, around the age of 2. These children also present with learning, intellectual disability, and behavioural problems. Although they are friendly and loving children, they can be angry, irritated, stubborn, and manipulative regarding food, show tantrums, obsessive-compulsive behaviour, and skin-picking. Some affected children may have underlying autism, and some affected adults may present various mental disorders, such as psychosis.^2,3,8 

Prader-Willi syndrome causes growth and reproductive hormonal deficiencies. Low growth hormone (GH) production causes short stature. They also have weak bones (osteopenia), small hands and feet, scoliosis (side-to-side curvature of the spine), and hip displacement (hip dysplasia). The underdevelopment of the reproductive system is called hypogonadism and is visible since birth, with babies having small genitals and undescended testicles (cryptorchidism). The deficiency of sexual hormones causes the absence of menstrual cycles (amenorrhoea), or the installation of periods after the age of 30, and infertility.^2,3,8

Diagnosis

Genetic testing

Doctors recommend genetic tests for newborns with hypotony and feeding difficulties. Although clinical features are representative of the diagnosis, taking a blood test confirms the diagnosis and shows which type of mutation the patient has. DNA methylation analysis and a high-resolution type of microarray genetic test called oligo-small nucleotide polymorphism (SNP) combination array (OSA) are the first choices to determine the diagnosis. Other useful genetic tests are methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), DNA sequence analysis, and fluorescent in situ hybridization (FISH).^3,9,10

Importance of early diagnosis

An early diagnosis enables parents to provide the appropriate care for their child. Meeting the particular needs and building the right, healthy environment offers the chance to become a functional, independent adult.^9,11

Genetic counselling and prenatal genetic testing 

Prader-Willi syndrome usually affects one member of a family because the genetic mutation occurs “de novo” (was not inherited from the parents). If a family wishes to have more children, they can be counselled by a geneticist and discover the risk of having another affected child. The exact genetic diagnosis is very important because, based on the particular mutation the affected child has, the risk for future pregnancy varies from 1% to 50% or even 100% in a very rare scenario. Prenatal genetic testing is also possible for a future baby by testing their blood through amniocentesis.¹⁰ 

Treatment

Multidisciplinary approach

Each Prader-Willi case is unique and requires the teamwork of healthcare specialists to ensure the best outcome for the patients and their families. As soon as a baby presents hypotonia and feeding difficulties, the neonatologist has to be on alert for Prader-Willi and team up with the clinical geneticist. Later, the “players” usually are the paediatrician, the endocrinologist, the nutritionist, the psychologist, the psychiatrist, the sleep specialist, the orthopedist, the ophthalmologist, the dentist, the surgeon, and more.^3,11

Hormone replacement therapy

The endocrinologist is a “key player”. Prader-Willi patients present a dysfunction of the hypothalamus. This affects the hormones involved in essential processes for the human body. Hormone replacement therapy with growth hormone (GH) is needed for affected children. This will assist with the increase in height,  improve muscle tone and mobility, lower body fat and even benefit development and behaviour. Endocrinologists may prescribe other hormonal therapies like testosterone or human chorionic gonadotropin (hCG) to help testicles descend in case the child has cryptorchidism and testosterone or oestrogen and progesterone to aid puberty and sexual development. Patients can also have problems with their thyroid and adrenal glands; therefore, the patient needs to be monitored closely by an endocrinologist,^1,3,11

Surgical interventions 

Cryptorchidism

Around 80-90% of children assigned male at birth (AMAB) and diagnosed with Prader-Willi syndrome present with undescended testicles (cryptorchidism) and require urologic surgery called orchidopexy (corrects the testicle position).^10,12

Bariatric surgery for morbid obesity

Fighting obesity is a challenge for Prader-Willi patients and their families. Nutritional advice, food access control, physical activity, behavioural therapy and other “non-invasive” solutions often fail, and patients become severely obese (BMI>35kg/mp). Bariatric surgery is recommended in selected cases as a weight loss option when patients are exposed to life-threatening complications related to obesity. e.g. diabetes, heart and lung problems. Although more studies are needed to fully understand the long-term effects of bariatric surgery in Prader-Willi cases, this is a valid weight-loss option and directly improves health and quality of life.^13,14,15

Challenges 

Obesity-related risks

Severe obesity can lead to life-threatening complications such as diabetes, heart failure, heart attack, blood clots in the lungs, sleep apnea, hypertension (high blood pressure), fatty liver disease (steatohepatitis), and more.^2,3,13

Mental health issues

PWS patients have a particular behaviour focused on food, which is fueled by their insatiable appetite. They need strict food limitations, a structured, predictable everyday life routine, good sleep hygiene and a minimum exposure to stress. Their caregivers need to be educated and aware of possible mental health problems such as anxiety, depression, obsessive-compulsive disorder (OCD), bipolar disorder, psychosis, aggression and even suicidal thoughts. Families should reach out to healthcare professionals such as psychiatrists and psychotherapists for help and support.^1,12,16,17

Impact on families

Families and caregivers of PWS patients need support and specific education to improve their quality of life and their children's lives. There are many PWS associations and foundations for research that help families find support, specific health centres, professionals, and treatments.^17,18

Research and future

Scientists are still searching for an effective treatment to fight the insatiable appetite and obesity in PWS patients. Various medications, such as Beloranib, Oxytocin, Setmelanotide, Livoletide, cannabinoids and non-invasive techniques, such as transcranial direct-current stimulation (tDCS); and bariatric surgery options still require more studies.¹⁹

Summary

Prader-Willi syndrome is the genetic explanation for potentially severe, life-threatening obesity in children, teenagers and young adults. Nowadays, these patients can have better health outcomes, access to treatment, support, and overall improved quality of life due to the available knowledge and increased awareness. Scientists are still fighting to improve the lives of these patients by studying medications, techniques, devices, and surgeries, hoping the future will bring more clarity, along with technological advancements. 

FAQs

What is Prader-Willi Syndrome?

A: People suffering from Prader-Willi syndrome have an insatiable appetite, leading to obesity from a young age.

What are the signs of Prader-Willi Syndrome?

A: The critical signs of PWS are hypotonia (low muscle tone), feeding difficulties in newborns, hypogonadism (low function of sexual glands - testicles and ovaries), short stature (growth hormone deficiency), learning difficulties, insatiable appetite and particular food-focused behaviour leading to early, possible life-threatening obesity.

What causes Prader-Willi Syndrome?

A: Prader-Willi Syndrome is caused by a genetic defect on chromosome 15, in the “Prader-Willi critical region”. It plays an important role in the proper function of the hypothalamus, an area deep within the brain that, regulates the hormones involved in appetite, growth, reproductive development, temperature regulation, behaviour, and sleep.