Prader Willi Syndrome: Symptoms, Types, Causes and Treatment

Prader Willi Syndrome (PWS) is a rare, complex genetic disorder that affects multiple body systems, leading to a distinctive pattern of symptoms and health challenges. While it is best known for causing insatiable hunger and obesity, PWS also impacts growth, behavior, hormone production, and cognitive development. Early diagnosis and a multidisciplinary care approach are critical for improving outcomes and quality of life for individuals and families affected by this condition.

Symptoms of Prader Willi Syndrome

Prader Willi Syndrome presents a unique array of symptoms that change as a person grows. Understanding these symptoms is vital for early detection, effective management, and support for individuals living with PWS.

Symptom	Description	Age of Onset	Source(s)
Hypotonia	Low muscle tone, poor suck, feeding difficulties	Infancy	1 6 8 13
Failure to Thrive	Poor weight gain, slow development	Infancy	1 6 8 13
Hyperphagia	Uncontrollable hunger, food seeking	Childhood onwards	1 3 6 8 13
Obesity	Excess weight gain, often severe	Early childhood	1 6 8 17
Short Stature	Below-average height	Childhood	1 6 8 13
Hypogonadism	Underdeveloped sex organs, delayed puberty	Childhood/Adolescence	1 6 8 13
Behavioral Issues	Tantrums, anxiety, obsessive-compulsive behavior	Throughout lifespan	3 4 8 13
Intellectual Disability	Mild to moderate cognitive impairment	Early childhood	1 6 8 13
Distinct Facial Features	Almond-shaped eyes, narrow forehead	Infancy/Childhood	1 6 8 13
Sleep Abnormalities	Sleep apnea, excessive sleepiness, narcolepsy	Childhood/Adulthood	1 4 6 17

Table 1: Key Symptoms

Overview of Symptom Progression

PWS symptoms evolve with age, starting from profound hypotonia and feeding difficulties in infancy to severe hyperphagia and obesity in early childhood. The progression is closely tied to hypothalamic dysfunction, which impacts appetite regulation, growth, and several endocrine functions 1 6 8.

Early Childhood Manifestations

• Hypotonia and Poor Suck: Most newborns with PWS display floppy muscles and struggle to feed, often requiring special feeding techniques or tube feeding 1 6.
• Failure to Thrive: Despite increased appetite later in life, infants typically gain weight slowly, sometimes leading to concerns about malnutrition 1 8.

Transition to Hyperphagia and Obesity

• Onset of Uncontrolled Appetite: Around ages 2–4, children develop intense, insatiable hunger (hyperphagia) and begin to gain weight rapidly if food intake is not strictly controlled 1 3 6 17.
• Obesity: This is a hallmark symptom and a leading cause of morbidity and mortality in PWS, often resulting in complications like type 2 diabetes, sleep apnea, and cardiovascular disease 6 11 17.

Behavioral and Cognitive Features

• Behavioral Challenges: Tantrums, anxiety, compulsivity (such as skin picking), stubbornness, and social cognition deficits are common and can be more disabling than physical symptoms 3 4 13.
• Intellectual Disability: Most individuals have mild to moderate cognitive impairment, with learning difficulties and delayed milestones 1 6 8.

Endocrine and Physical Characteristics

• Short Stature and Hypogonadism: Growth hormone deficiency leads to short stature, while underdeveloped sexual characteristics result from hypogonadism 1 6 8.
• Distinctive Facial Features: Almond-shaped eyes, thin upper lip, and a narrow bifrontal diameter are often noted 1 6 8.
• Other Health Issues: Individuals may experience scoliosis, osteoporosis, high pain threshold, temperature instability, and various sleep disorders 1 4 6 17.

Types of Prader Willi Syndrome

PWS is classified based on the underlying genetic mechanism responsible for the absence of function of certain genes on chromosome 15.

Type	Genetic Mechanism	Prevalence	Source(s)
Paternal Deletion	Loss of paternal 15q11-q13 region	60–75%	1 2 6 8 9 13
Maternal Uniparental Disomy (mUPD)	Two maternal copies of chromosome 15, no paternal copy	20–35%	1 2 6 8 9 13
Imprinting Defect	Error in the imprinting process of paternal chromosome	1–3%	1 2 6 8 9 13

Table 2: Types of Prader Willi Syndrome

Paternal Deletion

• Description: The most common type, caused by a deletion of the paternal segment 15q11-q13. This results in the loss of several paternally-expressed genes crucial for normal development 1 6 8.
• Clinical Features: Classic PWS features are present. Some studies suggest a slightly higher risk of seizures and hypopigmentation in this group 9 10 12.

Maternal Uniparental Disomy (mUPD)

• Description: Occurs when both copies of chromosome 15 are inherited from the mother, with no paternal contribution 1 2 6 8.
• Clinical Features: Individuals may have a higher risk of neuropsychiatric problems, including autism spectrum traits and psychotic illness, as well as slightly higher cognitive abilities compared to those with deletions 2 4 9.

Imprinting Defect

• Description: This rare form arises from a defect in the genomic imprinting process that controls gene expression on paternal chromosome 15 1 6 8.
• Clinical Features: Phenotype is similar to other forms, but the recurrence risk in siblings can be higher if the defect is inherited 1 7 8.

Genotype-Phenotype Correlations

• Behavioral and Cognitive Differences: mUPD is associated with increased rates of psychosis and autistic features, while deletion cases may have more pronounced physical features and a higher frequency of seizures 2 4 9.
• Diagnosis: Molecular genetic testing, particularly DNA methylation analysis, can distinguish between these types and is essential for accurate diagnosis and management 1 6 7 8.

Causes of Prader Willi Syndrome

The root cause of PWS lies in the loss of function of specific genes on chromosome 15, which are normally only expressed from the paternal copy due to genomic imprinting.

Cause	Underlying Mechanism	Key Genes Affected	Source(s)
Paternal Deletion	Deletion of 15q11-q13 from father's chromosome	Multiple imprinted genes	1 6 7 8 9
Maternal Uniparental Disomy	Two maternal, no paternal chromosome 15	Same genes not expressed	1 2 6 7 8 9
Imprinting Defect	Failure of paternal gene expression	Imprinting center, snoRNAs	1 6 7 8 9
Hypothalamic Dysfunction	Result of gene loss	SNORD116, SNRPN, others	1 6 7

Table 3: Causes of Prader Willi Syndrome

Genomic Imprinting and Chromosome 15

• Imprinting Mechanism: Normally, some genes on chromosome 15q11-q13 are only active on the chromosome inherited from the father. If these genes are missing or inactive, PWS develops 1 6 7.
• Key Genes: Several genes are implicated, including SNRPN, MKRN3, MAGEL2, NDN, and snoRNAs such as SNORD116. Loss of SNORD116 alone can reproduce many core features of PWS 1 7.

Three Genetic Pathways

• Paternal Deletion: Physical loss of the DNA segment means the genes are simply not present 1 6 7.
• Maternal Uniparental Disomy: Both chromosome 15s come from the mother, so the paternally-expressed genes are absent 1 2 6 7.
• Imprinting Defect: The genetic material is present, but the regulatory signal that "marks" the paternal chromosome for gene expression is missing or faulty 1 6 7.

Additional Insights

• Hypothalamic Dysfunction: The hypothalamus is central to appetite, hormone regulation, and temperature control. PWS features arise primarily from hypothalamic dysfunction due to the loss of these key genes 6 8.
• Recurrence Risk: Most cases are sporadic, with a recurrence risk in siblings of less than 1%, except in certain imprinting defect cases 1 8.
• Related Syndromes: Prader-Willi-Like Syndrome can resemble PWS but results from different genetic causes, underscoring the importance of precise molecular diagnosis 7.

Treatment of Prader Willi Syndrome

While there is currently no cure for PWS, a combination of medical, behavioral, and supportive interventions can dramatically improve quality of life and reduce health risks.

Treatment	Main Goal	Key Considerations	Source(s)
Growth Hormone Therapy	Improve growth, body composition, strength	Start early, monitor side effects	1 6 8 13 16
Dietary Management	Prevent obesity	Strict food supervision, low-calorie diet	6 15 17
Physical Activity	Enhance muscle tone, control weight	Needs supervision	6 15 17
Behavioral Therapy	Manage tantrums, compulsions, anxiety	Multidisciplinary approach	3 6 14
Psychotropic Medication	Treat behavioral and psychiatric symptoms	Antipsychotics, antidepressants, topiramate	2 14
Experimental Therapies	Address hyperphagia, behavior, weight	Neuromodulation, clinical trials	5 15
Surgical Approaches	Severe, life-threatening obesity	Bariatric surgery, still controversial	15 17
Endocrine Replacement	Address hormone deficiencies	Sex hormones, thyroid hormone	6 9 13
Supportive Care	Sleep apnea, scoliosis, osteoporosis, etc.	Multisystem monitoring	6 8 13 17

Table 4: Treatment Approaches in Prader Willi Syndrome

Growth Hormone Therapy

• Benefits: Growth hormone (GH) therapy is widely recommended for most children with PWS, regardless of actual GH deficiency. It improves height, reduces body fat, increases muscle mass, and may aid cognition and motor skills 1 6 8 13 16.
• Timing: Early initiation, often in infancy or early childhood, yields the best results 16.

Dietary and Lifestyle Management

• Strict Food Supervision: Because of relentless hunger and lack of satiety, tightly controlled access to food is crucial. Families often need to lock food storage and maintain strict meal routines 6 15 17.
• Dietary Restriction: A low-calorie, well-balanced diet tailored to the individual's needs helps prevent obesity, but lifelong vigilance is necessary 15 17.
• Exercise: Regular, supervised physical activity is encouraged to improve muscle tone, help with weight management, and support overall health 6 15 17.

Behavioral and Psychiatric Interventions

• Behavioral Therapy: Addressing behavioral challenges—tantrums, rigidity, compulsivity, anxiety—requires experienced therapists and a structured environment 3 14.
• Psychotropic Medications: Antipsychotics (such as risperidone), antidepressants, and newer agents like topiramate or N-acetylcysteine may help manage severe behavioral symptoms, psychosis, or skin picking. However, they must be used cautiously due to side effects like weight gain 2 14.

Endocrine and Medical Support

• Hormone Replacement: Sex hormone therapy for hypogonadism, thyroid hormone for hypothyroidism, and sometimes hydrocortisone for adrenal insufficiency are often needed 6 9 13.
• Sleep and Orthopedic Care: Treatment for sleep apnea (CPAP, surgery), scoliosis (bracing, surgery), and osteoporosis (calcium, vitamin D, bisphosphonates) are important adjuncts 6 8 13 17.

Emerging and Experimental Therapies

• Pharmacological Agents: Clinical trials are underway for drugs targeting appetite regulation and weight loss, with some promising early results 15.
• Neuromodulation: Device-based therapies such as vagus nerve stimulation or deep brain stimulation are being explored in small studies to address hyperphagia and behavioral issues 5.
• Surgery: Bariatric surgery is considered for extreme, life-threatening obesity but remains controversial due to unpredictable outcomes and high risks in PWS 15 17.

Multidisciplinary, Lifelong Care

• Team Approach: Management requires input from endocrinologists, geneticists, dietitians, psychologists, physical therapists, and social workers 6 8 13.
• Family and Social Support: Education, counseling, and support groups are invaluable for families coping with the daily challenges of PWS 6 8 13.

Conclusion

Prader Willi Syndrome is a rare yet profoundly impactful genetic disorder that requires early, accurate diagnosis and a comprehensive, multidisciplinary care approach. Understanding its symptoms, genetic types, causes, and treatment options empowers families and healthcare providers to optimize outcomes and quality of life.

Key Takeaways:

• PWS is characterized by a unique progression of symptoms, including hypotonia in infancy, hyperphagia and obesity in childhood, and behavioral and endocrine challenges throughout life 1 3 6 8 13.
• There are three main genetic types—paternal deletion, maternal uniparental disomy, and imprinting defects—each with subtle clinical differences and implications for management 1 2 6 8 9 13.
• The root cause is the absence of function of critical paternally-expressed genes on chromosome 15, leading to hypothalamic dysfunction 1 6 7 8.
• Treatment focuses on growth hormone therapy, dietary and behavioral management, hormone replacement, and support for associated medical conditions. New therapies are being explored, but strict food and behavioral oversight remain fundamental 1 6 8 13 15 16 17.
• Lifelong, multidisciplinary support and education are essential for individuals with PWS and their families 6 8 13.

With ongoing research and advances in care, the outlook for people with PWS continues to improve, offering hope for better management and quality of life.