Prader-Willi Syndrome: Understanding the Genetic Disorder

What is Prader-Willi Syndrome?

Prader-Willi syndrome (PWS) is a rare multisystem genetic disorder affecting the metabolic, endocrine, and neurologic systems due to abnormalities on chromosome 15. It is characterized by increased appetite. Patients with this disorder have hormone deficiencies, and infants suffering from this are lethargic and have weak muscle tone. Beginning from age 2, these patients feel the urge to eat constantly, leading to obesity. Many of the complications associated with the disease are due to obesity. PWS patients have distinct facial features like a narrow forehead, almond-shaped eyes, thin upper lip, short stature, triangular face, and small hands and feet.
Additional features include short stature, intellectual disabilities, behavioral issues, and developmental delays. Management focuses on strict dietary control, physical therapy, hormone therapy (like growth hormone), and behavioral interventions to improve quality of life.¹ Candelo E, Feinstein MM, Ramirez-Montaño D, Gomez JF and Pachajoa H (2018) First Case Report of Prader–Willi-Like Syndrome in Colombia. Front. Genet. 9:98. doi: 10.3389/fgene.2018.00098

How common is Prader-Willi Syndrome?

PWS occurs in approximately 1 in every 20,000 to 30,000 births. Globally, it’s estimated that around 400,000 people are living with this condition, with about 20,000 cases in the United States alone. It is recognized as the most common genetic cause of severe obesity.²Pacoricona Alfaro DL, Lemoine P, Ehlinger V, Molinas C, Diene G, Valette M, Pinto G, Coupaye M, Poitou-Bernert C, Thuilleaux D, Arnaud C, Tauber M. Causes of death in Prader-Willi syndrome: lessons from 11 years’ experience of a national reference center. Orphanet J Rare Dis. 2019 Nov 04;14(1):238.³Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016;12(2):136-66.

What Causes Prader-Willi Syndrome?

Prader-Willi Syndrome(PWS) is a rare genetic disorder caused by missing genetic material from chromosome 15 (your body has 23 pairs of chromosomes; think of each of them as a group of genes). PWS occurs when certain genes are absent on chromosome 15 that are inherited from the father. In about 70% of cases, this happens due to a deletion on the paternal chromosome 15 (specifically in the 15q11.2-q13 region). Around 25% of cases are due to maternal uniparental disomy, where two copies of chromosome 15 come from the mother instead of one from each parent. Rarely, PWS results from imprinting defects, which alter the normal expression of genes in this region. These genetic changes disrupt the function of the hypothalamus, leading to issues with hunger, growth, hormone levels, and other vital processes.⁴Heksch R, Kamboj M, Anglin K, Obrynba K. Review of Prader-Willi syndrome: the endocrine approach. Transl Pediatr. 2017 Oct;6(4):274-285.

Though most cases of PWS are sporadic, meaning they occur by chance, there are rare familial instances, particularly when imprinting defects are inherited. This condition affects both males and females across all ethnicities.⁵Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016;12(2):136-66.

Prader-Willi Syndrome Symptoms:

Signs and symptoms of the disease are generally related to obesity.⁶Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J Hum Genet. 2009;17(1):3-13. doi:10.1038/ejhg.2008.165 However, these symptoms may present differently in different age groups.

Infants:

Infants suffering from PWS suffer from distinct physical characteristics such as:

• Poor muscle tone (hypotonia) is a primary symptom for infants. They may feel floppy when held. Babies may keep their legs and elbows loosely. Infants may also have a poor sucking reflex leading to feeding difficulties. This results in failure to thrive.
• Prader-Willi syndrome has distinct facial features like almond-shaped eyes, narrow foreheads, a triangular mouth, and thin upper lips.
• Underdeveloped genitalia is also seen in infants with Prader-Willi. Males may have underdeveloped scrotum and also suffer from cryptorchidism (undescended testes). Female babies may present with smaller labia and clitoris.
• Babies have poor responsiveness and seem unusually tired. Their crying may be weaker and they might have difficulty waking up.

Children & Adults:

Children and adults with Prader-Willi syndrome (PWS) need ongoing care to manage their symptoms, which start in early childhood and last throughout their lives.
In childhood, PWS can cause delayed motor development, meaning children reach milestones like walking later than other kids. Their weak muscles also put them at risk for spinal deformities like scoliosis (an abnormal curve in the spine).
Between ages 1 and 4, children with PWS develop an increased appetite. They have reduced pain sensitivity and can eat larger amounts of food, sometimes even inappropriate items. This puts them at higher risk for complications like food poisoning, stomach problems, and blockages. It’s important to manage their appetite carefully because restricting it can lead to severe behavioral issues.
Speech problems and cognitive impairments affect their learning abilities. They may struggle with articulating words and have intellectual disabilities. Reasoning and problem-solving skills can be impaired as well. These children often need extra support and may attend special schools.
Behavioral problems can occur when they are denied food. It’s crucial to approach these challenges with empathy, understanding, and specialized interventions. PWS patients can be stubborn, controlling, and manipulative. They may also have temper tantrums. Sleep disorders are common and can worsen impulsive behavior. Skin picking is another issue that can lead to open sores and infections.
PWS patients experience slower growth and lower thyroid hormone levels. This results in poor physical development, with adults having below-average height, lower muscle mass, and higher body fat percentages. The development of sex organs may be delayed or limited. Complications such as sterility and osteoporosis (brittle bones) are common. They are also at risk of obesity-related issues like type 2 diabetes, high blood pressure, heart disease, and liver/gallbladder problems. These complications are the main cause of death for people with PWS. For children, death is most likely due to respiratory illness, while for adults, it’s most likely due to obesity.⁷Pacoricona Alfaro, D.L., Lemoine, P., Ehlinger, V. et al. Causes of death in Prader-Willi syndrome: lessons from 11 years experience of a national reference center. Orphanet J Rare Dis 14, 238 (2019). https://doi.org/10.1186/s13023-019-1214-2

Diagnosis:

The diagnosis often begins with observing characteristic signs, such as poor muscle tone (hypotonia), feeding difficulties in infancy, rapid weight gain in early childhood, and developmental delays. If a Physician suspects that his/ her patient suffers from the syndrome, then he/ she may order a genetic test. Prader-Willi Syndrome genetic testing involves taking a sample of your child’s blood to test for chromosomal abnormalities. The preferred method to test is methylation analysis, which can detect PWS almost 99% of the time. This test identifies abnormalities on chromosome 15, such as paternal deletions, maternal uniparental disomy, or other imprinting defects.

Additional tests may include:

• Thyroid Function Tests to rule out hypothyroidism.
• Liver and IGF Levels to assess growth hormone deficiency.
• Diabetes Screening with fasting glucose and hemoglobin A1c tests.
• Sleep Study (Polysomnography) for sleep disorders.
• DXA Scan to check bone density.

Prader-Willi Syndrome Treatment & Management:

Early diagnosis and treatment can massively increase the quality of life for patients of PWS.⁸NHS. Prader-Willi syndrome – Management. Nhs. Uk. Published October 23, 2017. https://www.nhs.uk/conditions/prader-willi-syndrome/living-with/ Prader-Willi Syndrome treatment may require consultation with a dietitian, endocrinologist (a doctor who specializes in hormonal disorders), geneticist, occupational therapist, etc. Though care should be individualized to a patient, most patients should expect the following:

Care for Children:

If your child has Prader-Willi syndrome (PWS), there are specific considerations to keep in mind as they grow:

Difficulty eating

Due to decreased muscle tone, infants with PWS may have trouble eating. Your doctor may prescribe high-calorie formulas or special feeding methods to support your nutrition. Your child’s growth will be closely monitored.

Hormone treatments

Your endocrinologist may discuss HCG (Human Growth Hormone) treatment with you. HCG can promote growth and increase muscle tone. Additionally, when your child reaches puberty, hormone replacement therapy may be recommended. For males, testosterone may be suggested, while for females, estrogen may be recommended. It’s important to note that testosterone may worsen certain behavioral issues. If your child has undescended testes, corrective surgery may be necessary around 6-12 months of age.

Calorie-restricted diet

As your child grows, a calorie-restricted diet may be recommended to manage their weight. Supplemental minerals or vitamins may also be prescribed to ensure a balanced diet.

Other considerations

1. Your child may also need physical, speech, and behavioral therapy. These ensure your child attains maximum learning, age-appropriate social skills, and adequate physical skills.
2. Mental health professionals should be consulted for children suffering from OCD, skin picking, etc. Sleep therapy can reduce daytime drowsiness.
3. If your child shows specific symptoms, other tests will be recommended. These may include eye exams, tests for diabetes or hypothyroidism (low thyroid hormone), etc.

Care for Adults:

Many adults may have to live in specialized care facilities and require supervision throughout their lives. These facilities can provide for their dietary needs and even a safe environment for their leisure activities. They can also benefit greatly from group therapy sessions and family support. This may help in ensuring patient morale is high and they are compliant with the strict limits on their diet, schedule, exercise, and overall medical care.

Can Prader-Willi be Cured?

Prader-Willi syndrome is a genetic disorder. Early diagnosis and careful management can massively improve the quality of life of PWS patients. However, PWS has no cure.

Can Prader-Willi Patients Become Pregnant?

Generally, experts believed that these patients were sterile. However, it is possible to become pregnant with PWS.⁹Åkefeldt, A., Törnhage, C.-J. and Gillberg, C. (1999), ‘A woman with Prader-Willi syndrome gives birth to a healthy baby girl.’ Developmental Medicine & Child Neurology, 41: 789a-790. https://doi.org/10.1111/j.1469-8749.1999.tb00542.x Hence, birth control may be needed for women with PWS.

What is the Life Expectancy of Prader-Willi?

PWS patients suffer from a reduced life expectancy of about 30 years.¹⁰Prader-Willi syndrome. Livi. https://www.livi.co.uk/medical-advice/general-health/prader-willi-syndrome/ Some cases with long-term care management have survived well into their 60s. The oldest living individual was 84 years old. The most frequent causes of death include GI urinary tract problems, infections, and cardio-respiratory issues.

Does Prader-Willi Run in Families?

Prader-Willi Syndrome (PWS) usually occurs due to random genetic mutations and is not typically inherited. Most cases are sporadic, meaning they happen by chance and are not passed down from parents to children. However, in rare instances, if a parent carries a genetic mutation affecting the imprinting center on chromosome 15, there is a small risk of recurrence in siblings. This form of PWS can be inherited, but such cases are uncommon.

Is There Any Condition Similar to Prader-Willi?

Schaaf-Yang Syndrome (SYS) shares many clinical features with Prader-Willi. However, SYS is primarily a neurodevelopmental disorder. It arises from the disruption of the MAGEL2 gene on chromosome 15. PWS, however, occurs from an abnormality in more than one gene.

 Angelman Syndrome Vs. Prader-Willi

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are both genetic disorders linked to the same region on chromosome 15, but they differ in which parent’s gene is affected. In PWS, genes on the paternal chromosome 15 are missing or not expressed, while in AS, the maternal genes are absent or inactive. Both syndromes can lead to developmental delays and intellectual disabilities, but different genetic mechanisms cause them.
Angelman syndrome typically involves mutations in the UBE3A gene. This gene is located on chromosome 15, and it plays a crucial role in brain development and function. In Angelman syndrome, the maternal copy of the UBE3A gene is either missing or mutated, leading to the disorder’s characteristic symptoms, such as severe developmental delays, speech impairments, movement and balance issues, and a typically happy demeanor with frequent laughter. In contrast, PWS results from the absence of several other paternally expressed genes in the 15q11.2-q13 region.

Wrap-up

Prader-Willi syndrome is a complex genetic disorder affecting multiple body systems, particularly metabolism and growth. Although the condition presents various challenges, early diagnosis, tailored interventions, and ongoing management can significantly improve the quality of life for individuals with PWS.

Refrences

• 1
  Candelo E, Feinstein MM, Ramirez-Montaño D, Gomez JF and Pachajoa H (2018) First Case Report of Prader–Willi-Like Syndrome in Colombia. Front. Genet. 9:98. doi: 10.3389/fgene.2018.00098
• 2
  Pacoricona Alfaro DL, Lemoine P, Ehlinger V, Molinas C, Diene G, Valette M, Pinto G, Coupaye M, Poitou-Bernert C, Thuilleaux D, Arnaud C, Tauber M. Causes of death in Prader-Willi syndrome: lessons from 11 years’ experience of a national reference center. Orphanet J Rare Dis. 2019 Nov 04;14(1):238.
• 3
  Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016;12(2):136-66.
• 4
  Heksch R, Kamboj M, Anglin K, Obrynba K. Review of Prader-Willi syndrome: the endocrine approach. Transl Pediatr. 2017 Oct;6(4):274-285.
• 5
  Butler MG, Manzardo AM, Forster JL. Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches. Curr Pediatr Rev. 2016;12(2):136-66.
• 6
  Cassidy SB, Driscoll DJ. Prader-Willi syndrome. Eur J Hum Genet. 2009;17(1):3-13. doi:10.1038/ejhg.2008.165
• 7
  Pacoricona Alfaro, D.L., Lemoine, P., Ehlinger, V. et al. Causes of death in Prader-Willi syndrome: lessons from 11 years experience of a national reference center. Orphanet J Rare Dis 14, 238 (2019). https://doi.org/10.1186/s13023-019-1214-2
• 8
  NHS. Prader-Willi syndrome – Management. Nhs. Uk. Published October 23, 2017. https://www.nhs.uk/conditions/prader-willi-syndrome/living-with/
• 9
  Åkefeldt, A., Törnhage, C.-J. and Gillberg, C. (1999), ‘A woman with Prader-Willi syndrome gives birth to a healthy baby girl.’ Developmental Medicine & Child Neurology, 41: 789a-790. https://doi.org/10.1111/j.1469-8749.1999.tb00542.x
• 10
  Prader-Willi syndrome. Livi. https://www.livi.co.uk/medical-advice/general-health/prader-willi-syndrome/