Prader-Willi Syndrome (PWS)

Prader-Willi syndrome (PWS) is a rare neurodevelopmental condition characterized by hypotonia, poor appetite, and feeding problems in early infancy followed by excessive eating, leading to the gradual development of morbid obesity in childhood.¹

Prader-Willi syndrome results from a lack of gene expression on the paternally inherited chromosome 15q11-q13 due to deleted, missing, or silenced alleles. Around 75% of PWS cases are caused by deletions in the paternal chromosome 15q11-q13, 24% are due to maternal uniparental disomy, and 1% are due to imprinting errors.²

In 2008, experts met to discuss and summarize key diagnostic and treatment clinical practice guidelines for the comprehensive care of patients with PWS. These guidelines were published in the Journal of Clinical Endocrinology and Metabolism.² A more recent clinical practice guideline update was published in 2019 in Current Pediatric Reviews.³

Diagnostic Guidelines for PWS

According to these guideline recommendations, specific clinical presentations during the perinatal and postnatal periods should prompt providers to recommend genetic testing for PWS.^2,3

Perinatal observations of babies with PWS include decreased fetal movement, polyhydramnios, breech positioning, and nonterm delivery.³

Prader-Willi syndrome in infancy manifests with feeding difficulties, poor suck reflex, failure to thrive, hypotonia, poor strength, temperature instability, central sleep apnea, decreased muscle mass, and global developmental delays.³ 

Prader-Willi syndrome in early childhood manifests as hyperphagia, food-seeking behaviors, temper tantrums, and the onset of central obesity if uncontrolled.³

Read more about PWS clinical features

Both the 2008 and 2019 guidelines list the following clinical features by patient age that should lead to a suspicion of PWS and resultant genetic testing for confirmation^2,3:

• Birth to 2 years of age: Hypotonia with poor suck reflex
• Ages 2 to 6 years: Hypotonia with a history of poor suck reflex, global developmental delays, short stature and/or growth failure associated with accelerated weight gain 
• Ages 6 to 12 years: Frequently persistent hypotonia with a history of poor suck reflex, global developmental delay, excessive eating (hyperphagia, obsession with food) with central obesity if uncontrolled
• 13 years of age to adulthood: Mild cognitive impairment, hyperphagia, obsession with food with central obesity if uncontrolled, hypothalamic hypogonadism, and behavioral problems (such as temper tantrums, obsessive-compulsive features)

Read more about PWS diagnosis

Testing Guidelines for PWS

Genetic Testing

The first recommended molecular genetic test for PWS is DNA methylation analysis, as it is the only genetic testing technique that can confirm or rule out a diagnosis of PWS definitively.^2,3 Imprinted genes exhibit differential DNA methylation that is dependent on parental origin. Patients with PWS demonstrate maternal-only imprinting because the paternal contribution is absent.² Most DNA methylation techniques are applied to the SNURF–SNRPN locus.² 

Following DNA methylation studies, a chromosomal analysis using fluorescence in situ hybridization (FISH) should be performed. Chromosomal analysis can detect the typical chromosome 15q11-q13 deletion. This type of testing should preferably include DNA chromosomal microarray analysis, applying copy number variant testing and single nucleotide polymorphism probe testing to detect the size of the 15q11-q13 deletion. It should also assess for the maternal disomy 15 PWS subtype as evidenced by loss of heterozygosity (LOH) of chromosome 15 gene alleles.³

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If methylation testing is positive but chromosomal analysis does not reveal maternal disomy 15 status or deletion on chromosome 15, the next step is to assess for potential imprinting defects. Genotyping with polymorphic chromosome 15 DNA markers can detect normal biallelic inheritance of chromosome 15, suggestive of an imprinting error.³ 

Droplet digital polymerase chain reaction (PCR) testing can detect microdeletions and facilitate gene expression studies to rule out mosaicism in individuals with PWS who exhibit both normal and abnormal methylation or gene expression patterns.³

Read more about PWS genetics

Clinical Testing

Clinical tests may include those for adrenal reserves, thyroid function, serum insulin-like growth factor 1 (IGF-1), serum fasting glucose, oral glucose tolerance, dual X-ray absorptiometry (DEXA) for bone mineral density, polysomnography, and spinal radiography for scoliosis. Other workups may rule out other obesity-related disorders.³

Read more about PWS differential diagnosis

Treatment Guidelines for PWS

Although no curative treatment exists for PWS, there are recommendations for the management of PWS-related comorbidities and symptoms that develop throughout a patient’s lifespan.³

Nutrition

Neonates and infants with PWS are typically tube fed for over 2 months due to failure to thrive.² During infancy, maintaining a weight between the 25th and 75th percentiles is the goal, following a recommended diet consisting of 25% to 30% protein, 25% to 30% fat, and 30% to 40% carbohydrate.³ 

In early childhood, as body weight increases and aggressive food seeking and reduced satiety become apparent, obesity management is recommended. Obesity management involves early institution of a low-calorie, well-balanced diet with regular exercise, food restriction, and rigorous supervision of the food environment and physical activity levels. Psychological and behavioral counseling — both for the patient and the family — is encouraged.² 

Read more about PWS diet and nutrition

Growth

Slowed growth and short stature is common among infants with PWS due to growth hormone insufficiency worsened by the absence of pubertal growth spurts. Growth hormone treatments aim to improve childhood growth, body composition, and adult height.²

The 2008 guidelines recommend specific monitoring prior to, during, and after growth hormone treatment.² 

Before initiating growth hormone treatment, the following steps should be performed²:

• Genetic confirmation of PWS
• Evaluation of growth hormone status and serum IGF-1 levels
• Oral glucose tolerance testing, especially in patients over 2 years of age with obesity or a family history of diabetes
• Assessment of body composition via DEXA scans and nutritional evaluation
• Control of the food environment
• Sleep and breathing studies
• Scoliosis evaluation via X-rays
• Assessment for hypothyroidism, including thyroid stimulating hormone (TSH), free T₄, and free T₃ measurements, and initiation of thyroid hormone replacement if needed

 During growth hormone treatment, the following steps and measures are recommended²:

• Routine clinical assessment of height, weight, body mass index, body composition, pubertal status, scoliosis, IGF-1, and any treatment side effects every 3 to 6 months
• Oral glucose tolerance testing
• Polysomnography and ear, nose, and throat (ENT) testing within the first 6 months of initiating growth hormone treatment with mandatory assessment if sleep-disordered breathing, snoring, or tonsillar or adenoid enlargement worsens
• X-ray with orthopedic assessment if there are concerns about scoliosis
• Continued monitoring for hypothyroidism
• Routine bone age determination, especially during puberty

After growth hormone treatment has ended, recommended monitoring for the following is advised²:

• Uncontrolled progression of obesity
• Worsening of glycemic control despite weight control, medication for diabetes, and normal IGF-1 levels
• Worsening of sleep-disordered breathing despite weight control, removal of the tonsils and adenoids, and normal IGF-1 levels
• Assessment of final height

Read more about PWS therapies

Updated 2013 clinical care consensus guidelines for recombinant human growth hormone (rhGH) therapy in PWS stipulated the following with the highest level of recommendation based on evidence supporting benefit in patients with PWS:⁴

• Prior to rhGH initiation, patients must demonstrate a genetically confirmed diagnosis of PWS following expert multidisciplinary assessment.
• Following genetic testing that confirms PWS diagnosis, rhGH treatment should be immediately considered, and if initiated, continued for as long as demonstrated benefits outweigh risks.
• GH stimulation testing should not be required for therapeutic decision-making in infants and children with PWS.
• The GH/IGF axis should be evaluated in adults with PWS prior to initiation of rhGH therapy.
• Contraindications for rhGH initiation in patients with PWS include severe obesity, uncontrolled diabetes, untreated severe obstructive sleep apnea, active cancer, and active psychosis.
• Scoliosis is not a contraindication for rhGH initiation in patients with PWS.
• Cognitive impairment is not a barrier to rhGH treatment in patients with PWS.
• Infants and children with PWS should begin rhGH therapy with a starting daily dose of 0.5 mg/m² · d sc with adjustments of 1.0 mg/m² · d every 3 to 6 months according to clinical response and IGF-1 levels.
• Adults with PWS should begin rhGH therapy with a starting dose of 0.1 to 0.2 mg/d based on age, presence of edema, previous exposure and sensitivity to rhGH, and concurrent use of oral estrogen. Subsequent dosage titrations should be based on clinical response and sex-appropriate IGF-1 levels in the 0 to 2+ SDS range.
• IGF-1 levels should be maintained within the upper part of normal range for patients with PWS undergoing rhGH therapy.
• Dosing strategy and selection of patients with PWS for rhGH therapy is not dependent on the molecular genetic subtype of PWS.
• Clinical outcome priorities should vary depending on patient age and physical, mental, and/social disabilities.
• Patients with PWS receiving rhGH therapy must be continually monitored for potential adverse effects during GH treatment.
• Patient monitoring during rhGH treatment should address specific benefits and risks of treatment in the PWS population as well as potential influence on other hormonal deficiencies.
• Therapy with RhGH should occur in the context of appropriate dietary, environmental, and lifestyle interventions that are necessary for effective care of all individuals with PWS.

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Hypogonadism/Hypogenitalism

Hypogonadism/hypogenitalism consistently occurs in both male and female patients with PWS. Most individuals with PWS experience delayed, absent, or incomplete puberty, requiring hormonal treatment with sex steroids (testosterone and estrogen) to induce, promote, and/or maintain puberty. Sex steroid replacement may continue into adulthood to improve mental, emotional, and physical well-being, promote bone health, and protect muscle mass.^2,3

Read more about PWS treatment

Behavioral/Psychiatric Management

Behavioral management and counseling are recommended for overeating, anxiety related to food insecurity, obsessive-compulsive behaviors, and mood disorders. Behavioral management consists of positive reinforcement of desired behaviors, giving little attention to undesired behaviors, detailing the consequences of undesired behaviors, and providing incentives to avoid inappropriate behaviors.^2,3 

Maintenance of a low-stress, predictable, safe environment is also recommended for all individuals with PWS. Individuals with anger management problems or anxiety may benefit from cognitive behavioral therapy, applied behavioral analysis, social skills training, and the development of coping strategies.^2,3

Antidepressants, mood stabilizers, beta blockers, stimulants, alpha-adrenergic agonists, and typical or atypical antipsychotic medications may be indicated depending on the mood disorder diagnosis or diagnoses.³ These medications must be started with lower than normal dosing and careful monitoring for adverse side effects.² 

Catatonia may occur in young adults with PWS associated with psychosis, seizures, mood disorders, or medical illnesses. Symptoms of muscular rigidity, echolalia or mutism, negativism, or excited delirium progress rapidly over 1 to 3 days, necessitating emergency medical evaluation and treatment. The most effective treatments involve lorazepam or electroconvulsive therapy (ECT) when symptoms persist.³ 

Read more about PWS care team

References

1. Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2023. October 6, 1998. Updated March 9, 2023. Accessed July 8, 2023.
2. Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93(11):4183-4197. doi:10.1210/jc.2008-0649
3. Butler MG, Miller JL, Forster JL. Prader-Willi syndrome – clinical genetics, diagnosis and treatment approaches: an update. Curr Pediatr Rev. 2019;15(4):207-244. doi:10.2174/1573396315666190716120925
4. Deal CL, Tony M, Höybye C, et al. Growth Hormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. 2013;98(6):E1072-E1087. doi:10.1210/jc.2012-3888

Reviewed by Kyle Habet, MD, on 7/20/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.