Prader-Willi Syndrome

Overview

Prader-Willi syndrome (PWS) is the most common genetically identified cause of life-threatening obesity in humans. There are 3 PWS molecular classes (paternal 15q11-q13, maternal disomy 15, and genomic imprinting center defects). Management of PWS requires early diagnosis and a multidisciplinary approach to achieve the best health outcomes. The primary manifestations of PWS include:

A characteristic appearance with narrow bifrontal diameter, dolichocephaly, distinctive eyes (described as almond-shaped) with strabismus, down-turned corners of the mouth, and small upturned nose
Infantile hypotonia that improves with age, though most remain relatively hypotonic
Infantile hypersomnolence
Feeding difficulties and failure to thrive in the early years
Early onset of childhood obesity initially without hyperphagia
Hyperphasia with food-seeking behaviors in middle childhood
Developmental delay with borderline intellectual disability
Hypogonadism
Behavior problems (temper tantrums, stubbornness, obsessive-compulsive behaviors, skin picking)
Small hands and feet
Endocrine disturbances, including growth hormone deficiency and muted stress response
Sticky saliva Those with PWS and the 15q11-q13 deletion may also have hypopigmentation relative to family background.

Those with PWS and the 15q11-q13 deletion may also have hypopigmentation relative to family background.

Other Names & Coding

Prader-Labhart-Willi syndrome

ICD-10 coding

Q87.11, Congenital malformation syndromes predominantly associated with short stature.

Z82.79, Family history of other congenital malformations, deformations, and chromosomal abnormalities (including Prader-Willi syndrome)

ICD-10 for Congenital Malformation Syndromes Associated with Short Stature (icd10data.com) provides more detail.

Prevalence

The prevalence of PWS is approximately 1:25,000. [Butler: 1990] It affects an estimated 350,000 to 400,000 people worldwide, including 17,000 to 22,000 individuals in the United States. It is present in all ethnic groups but reported disproportionately in Caucasians. [Butler: 2000] [Butler: 2006]

Genetics

PWS is a complex genetic syndrome resulting from the absence of expression of genes found in the region of the paternally inherited 15q11-q13 chromosome region, most commonly due to a paternal 15q11-q13 deletion. Most cases of PWS are sporadic; the odds of familial recurrence are estimated at less than 1%. However, this risk may be as high as 50% in some families due to a microdeletion of the imprinting center in the child with PWS and the unaffected father, which causes defective control of differentially expressed genes that are imprinted (i.e., only active) on the father’s chromosome 15. [Hartin: 2019] Missing issue with id: 8d5909eb.xml provides much more detail about genetics and genetic testing for PWS.

Prognosis

If obesity is avoided and complications well-managed, life expectancy for individuals with PWS is normal or near normal, and most individuals can lead healthy lives. [Butler: 2006] Early education for caregivers and maintenance of a controlled environment are essential for good outcomes.

Practice Guidelines

McCandless SE.
Clinical report—health supervision for children with Prader-Willi syndrome.
Pediatrics. 2011;127(1):195-204. PubMed abstract / Full Text

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. PubMed abstract / Full Text

Roles of the Medical Home

Collaborate with specialized multidisciplinary services when available and coordinate school and other community-based services. When no multidisciplinary clinic is available, the medical home can help the family by coordinating care and accessing needed specialists and appropriate community-based services. Managing the care, particularly the nutrition and behavior of children with PWS, is very challenging - collaborating with and providing support for the family is a key role of the medical home provider.

Clinical Assessment

Overview

PWS is often suspected because of clinical findings and confirmed through genetic testing. The timing of the diagnosis may depend on the severity of the symptoms and access to health care professionals familiar with the diagnosis. Please see [Butler: 2006], and/or [Butler: 2016] for further details.

Pearls & Alerts for Assessment

Ear and other infections with minimal pain

Because children with PWS have decreased pain sensation, the child may not display the discomfort usually associated with otitis media, strep throat, or other infections. The medical home provider should evaluate any child with a fever >101 degrees.

Osteoporosis in children with PWS

Due to poor calcium intake secondary to strict dietary control, decreased exercise, and hormone therapy, children with PWS may develop osteoporosis and scoliosis.

Screening

For the Condition

Infants with severe hypotonia, a poor suck, and feeding difficulties without a clear underlying cause should have DNA-methylation testing and high-resolution microarray analysis to assess for PWS.

Of Family Members

Screening is not indicated for family members unless symptoms associated with PWS are present. Screening with noninvasive prenatal testing (NIPT) with cell-free DNA is now available in pregnancies where concerns about having a child with PWS are raised, such as with decreased fetal movement or abnormal fetal positioning (breech) or amount of amniotic fluid. Risk factors may also include having a previous child with PWS. Yet, NIPT is difficult to utilize with certainty to search for the 15q11-q13 deletion, the most common genetic cause of PWS.

For Complications

Comorbidities, such as diabetes mellitus (type II), hypertension, inflammation, a fatty liver, and orthopedic problems, often depend upon level obesity. Relevant laboratory evaluations (liver function, insulin, glucose, and lipid levels), thyroid function, and inflammatory markers should be monitored during regular health examinations.

Presentations

Clinical findings vary with age; PWS has historically been divided into 2 clinical stages and several nutritional phases. The first stage presents with profound hypotonia (which may lower neonatal Apgar score), feeding difficulties, lack of arousal for feedings, poor weight gain, and developmental delays. Between 1 and 3 years of age without increased caloric intake or hyperphagia, toddlers demonstrate dramatic weight gain even on growth hormone therapy. The second stage begins between ages 2-4 years and is characterized by the onset of hyperphagia that leads to obesity and developmental delays. This leads to a need to reduce calories. Subsequent to this phase, hyperphagia and food-seeking arises, usually between 3 and 6 years of age. Four clinical phases based on nutritional phases, caloric intake, and weight are described below.

Diagnostic Criteria

Clinical criteria, based on the individual's age and clinical presentations, are used to prompt genetic testing (see Genetic Testing, below) to confirm the clinical findings: [Gunay-Aygun: 2001]

Birth to 2 years:
- Any infant born in a hospital should be assessed for severe hypotonia, low arousal, and feeding difficulties. If present, the child should be screened before discharge. Facial features are not consistent, but a child who is breech and undergoes C-section with dolicocephaly should raise suspicion.
2 to 6 years:
- Recognizable facial features, hypotonia with gross motor delays, development of hyperphagia and weight gain, typically shorter stature and smaller OFC
6 to 12 years:
- Development of unusual behaviors, learning disabilities, and cognitive impairments
- Physical features may be more difficult to recognize; hands and feet may become relatively smaller in these years
- Excessive eating with central obesity if uncontrolled
- Scoliosis
13 years to adulthood:
- Cognitive impairment, usually mild-to-borderline intellectual disability
- Excessive eating with central obesity, if uncontrolled
- Hypothalamic hypogonadism and/or typical behavior problems

Clinical Classification

The advent of more accurate and reliable genetic technology has changed data interpretation, reported frequencies, and identification of 3 PWS molecular genetic classes.

A typical de novo paternal deletion of 15q11-q13 (60% of cases) and consists of 2 types based on deletion size (larger Type I and smaller Type II)
Maternal disomy 15 (uni-parental disomy or UPD15) where both chromosomes 15 come from the mother (35% of cases)
An imprinting defect in the remaining PWS subjects (<5%) due to a microdeletion of the imprinting center or from an epimutation controlling the expression of imprinted genes in this region [Hartin: 2019]

Management does not change based on size of deletion unless it is larger than 6 megabases. See Prader-Willi Syndrome Genetics for a detailed discussion of PWS genetics and testing.

Differential Diagnosis

Differential diagnoses will depend on the age of the patient.
During infancy and the failure to thrive stage of PWS:

Neonatal sepsis
Central nervous system anomalies
Inborn errors of metabolism
Microdeletions of 1p36.3, 6q16.2, or 16q12.2 may involve obesity-related genes such as FTO, MC4R, or SIM1, and several features similarly seen in PWS
Infantile botulism
Myotonic Muscular Dystrophy Type 1
Spinal Muscular Atrophy
Zellweger syndrome (peroxisomal disorders)

During childhood and the hyperphagic obesity stage of PWS:

Familial obesity
Fragile X Syndrome
Inborn errors of metabolism
Leptin deficiency (very rare)
SIM 1 gene mutations and 16p deletion
Albright's Hereditary Osteodystrophy
Bardet-Biedl Syndrome, Alström Syndrome, and Cohen Syndrome
Chromosomal abnormalities, including 1p36 deletion, 3p25 duplication, and uniparental disomy 14

See Online Mendelian Inheritance in Man (OMIM) for more information on specific syndromes.

Comorbid & Secondary Conditions

Comorbid conditions can include obesity, diabetes, scoliosis, gastric dysmotility, attention deficit – hyperactive disorder (ADHD), autism, velopharyngeal insufficiency, obstructive sleep apnea, and self-injury. These and mortality, survival trends, and causes of death are addressed elsewhere in the module. [Butler: 2018] [Manzardo: 2019]

History & Examination

Current & Past Medical History

Ask about:

Hyperphagia, rumination, and episodes of gastric distention
Problems with feeding and failure to thrive in infants
Hyperphagia in older children and what management is being used (e.g., diet, exercise, or behavior modification)
Use of growth hormone therapy and testosterone or estrogen replacement therapy
Symptoms of diabetes, including frequent urination, acanthosis nigricans, etc.
Energy level, constipation, and growth with consideration of hypothyroidism
Self-injurious behavior, including nose and skin picking or nail-biting
Obsessive-compulsive behaviors
Chronic respiratory infections, reactive airway disease, silent aspiration
Problems while sleeping, including snoring, daytime sleepiness, and frequent arousals, with consideration of sleep apnea (obstructive, central, or mixed) and hypoventilation with hypoxia
Orthopedic issues – scoliosis, hip dysplasia, ankle pronation

Family History

Not likely to be helpful because the majority of cases are sporadic

Pregnancy/Perinatal History

Ask about fetal movement, including breech presentation, which is often limited, of low velocity, and consistent with hypotonia. Depressed Apgar scores at birth may occur due to hypotonia. Infants with PWS are typically born at or near term and have a low but not unusually abnormal birth weight. Ask about post-natal problems, particularly a history of poor feeding, low tone, and self-arousal for feeding.

Developmental & Educational Progress

Ask about:

Learning problems and symptoms of hyperactivity
Speech articulation problems - consider referral to a speech-language therapist for further evaluation
Achievement of developmental milestones and, later, educational progress
Behavior problems and obsessive-compulsive issues

Attention-Deficit/Hyperactivity Disorder (ADHD) is common in individuals with PWS (21%-25.9%), and symptoms should be sought during the history. [Wigren: 2005] [Skokauskas: 2012] In older children and adults with PWS, ask about signs of psychosis such as auditory hallucinations and disordered thinking.

Maturationalprogress

In older children and adolescents with PWS, ask about pubertal progress.

Social & Family Functioning

Ask about the child's social abilities, interactions with other children, family functioning, access to resources, and supports from community groups and extended family.

Physical Exam

General

Hypotonia, poor suck with feeding problems, and low arousability are common in infants in PWS. Look for characteristic appearance, including dolichocephaly, narrow bifrontal diameter, distinctive (almond-shaped) eyes, small up-turned nose, down-turned corners of the mouth, small hands and feet, cryptorchidism, and small external genitalia. [Holm: 1993] [Butler: 1990] [Cassidy: 2012] Assess alertness, activity level, and interactions for age-appropriateness.

Vital Signs

HR | BP | RR, breathing difficulties

Growth Parameters

Measure weight, height, and BMI. Short stature is present in the majority of individuals with PWS. Regular evaluation of growth is important when children receive growth hormone (GH), including head circumference. [McCandless: 2011] Standardized growth charts for PWS for GH-treated and untreated children can be found at:

If uncontrolled, food-seeking (hyperphagia) and decreased energy expenditure will lead to obesity in early childhood. Regular health care examinations and surveillance are required to monitor for health issues related to obesity and its complications.

Skin

Look for areas of excoriation due to skin picking. Check for acanthosis nigricans.

HEENT/Oral

Screen for eye problems, such as strabismus, myopia, and other problems with visual acuity at 1 year of age and as needed every 1 to 2 years.
Monitor the size of tonsils and adenoids, particularly in obese individuals.
Check ears and throat for infection.
Check nares for sores from nose-picking.
Look for sticky saliva. Decreased saliva flow and sticky salivary secretions can impact dental care and hygiene.
Look for dental enamel defects. Enamel hypoplasia is common and can lead to cavities, which is further complicated by rumination seen in a subset of individuals with PWS.
Assess velopharyngeal insufficiency

Chest

Respiratory distress with shallow breathing and central sleep apnea problems may compromise oxygen saturation, pulmonary function, and breathing. Silent aspiration associated with hypotonia and low arousal states in infancy complicates respiratory manifestations.

Heart

Listen for murmurs and gallops that may be a sign of hypertrophy or right-sided heart failure; look for hepatomegaly or peripheral or sacral edema.

Abdomen

Distended abdomen and decreased audible bowel sounds may be related to increased central adiposity. Constipation, decreased gastric motility, and increased colon size are common and require close observation. People with PWS have a high pain threshold, which can impact the reliability of the abdominal exam.

Genitalia

Check for:

Cryptorchidism, Tanner stage, and appearance of external genitalia
Signs of rectal ulcers due to skin picking
Signs of monilial or bacterial infection in deep skin folds

Extremities/Musculoskeletal

Check for:

Scoliosis and kyphosis - monitor closely, particularly if on growth hormone therapy
Dysplastic hips
Edema and skin changes in the legs in obese individuals. Fluid retention is usually noted first as swelling of the lower legs. Fluid retention in persons with PWS is associated with a decreased ability to breathe adequately due to excessive weight.

Neurologic Exam

Look for hypotonia in infants and toddlers. Relative hypotonia may be present in older children. Diminished reflexes and lack of motor activities may be a sign of hypothyroidism.

Testing

Sensory Testing

No specific sensory problems are associated with PWS; however, regular visual and hearing screening are recommended.

Laboratory Testing

Growth hormone deficiency is common in PWS; however, growth hormone supplementation is not dependent on demonstration of growth hormone deficiency. IGF-1 should be monitored regularly during growth hormone treatment. [Deal: 2013] Provoked GH response can be tested in adults to support lifetime growth hormone supplementation.
Thyroid hormone levels should be checked annually and monitored routinely if replacement therapy is needed. [Deal: 2013]
Laboratory evaluation of liver function, insulin, glucose, lipid levels, and inflammatory markers should be monitored routinely, with frequency based on obesity and the presence of comorbid conditions. [Deal: 2013]
Consider performing ACTH stimulation testing to rule out central adrenal insufficiency, which has been reported in PWS. [de: 2008]

Imaging

Consider AP and lateral spine films at 2 years of age and then annually to evaluate for rapid-onset and progressive scoliosis. If there is no evidence of scoliosis, annual spine films are not indicated (but annual physical exams should monitor for spinal curvature). With anticipated changes in height, such as during puberty, closer observation is needed. Spinal deformities (scoliosis and kyphosis) are estimated to occur in 45-86% of children with PWS. [Shim: 2010] The Prader-Willi Syndrome Association (USA) recommends yearly screening because deformities may not be clinically visible.
Bone age testing is part of the assessment prior to starting growth hormone. [Deal: 2013]
Because children with PWS are at risk for osteoporosis/osteopenia, consider a DEXA scan to evaluate for body composition, including bone mineral density, particularly in the setting of a fracture.

Genetic Testing

Genetic testing for PWS is complex and approaches vary among specialists; consulting pediatric genetics in your area is advised. If a diagnosis of PWS is confirmed, identification of the genetic subtype - typical 15q11-q13 Type I or Type II deletion; maternal disomy 15 subclass (maternal heterodisomy 15, segmental isodisomy 15, or total isodisomy 15); and imprinting defect (microdeletion or epimutation) – may be helpful to guide clinical management and advise about recurrence risks. See Flowchart of Recommended Molecular Testing Strategy for PWS (AAP) from [McCandless: 2011] and, for more current information, [Butler: 2019], [Hartin: 2018], and, particularly, [Hartin: 2019] for a recent update and the Proposed PWS Genetic Testing Workflow (Hartin: 2019).
High-resolution SNP microarrays can be used to identify all typical and atypical chromosome 15 deletions in PWS and are informative in 70% of those with PWS UPD15 (i.e., segmental or total isodisomy) and identify about 1/4 of those with imprinting center defects. More than 85% of individuals with PWS using SNP microarray analyses will have a chromosome 15 abnormality. Most recommendations include both methylation study and cytogenomic SNP microarray as necessary to establish the diagnosis of PWS, but if methylation is performed first and the infant is hypotonic, some insurers decline preauthorization for microarray. However, the reverse is not often the case – methylation is usually not declined after a positive microarray result.
See Missing issue with id: 8d5909eb.xml for more information, PWS Genetic Testing (Genetic Testing Registry) for laboratories that offer testing for PWS, and Subspecialist Evaluations, below, for consultation resources.

Other Testing

A sleep evaluation is necessary for any child with PWS who has snoring, frequent awakenings, excessive daytime sleepiness, or other sleep problems. A sleep study is considered mandatory prior to initiation of growth hormone therapy. [Deal: 2013]
Evaluation by speech/language specialists is performed to detect speech delay, articulation problems, velopharyngeal insufficiency, and silent aspiration (swallow study).
Physical therapy evaluation with interventions to help with gross motor skills.
Occupational therapy evaluation and interventions for feeding issues and fine motor skills.
Consider administering questionnaires (e.g., Vanderbilt) for family and school if ADHD is suspected. For more information, see Attention-Deficit/Hyperactivity Disorder (ADHD) for diagnosis and management guidance.

Specialty Collaborations & Other Services

Medical Genetics (see UT providers [7])

Refer for genetic evaluation and diagnosis of children suspected of having PWS and provision of genetic counseling for families. Geneticists will also consider other conditions if the diagnosis is not confirmed. Genetic specialists can help the family access support groups and clinical trials.

Pediatric Endocrinology (see UT providers [7])

Refer for expertise in managing growth and other endocrine problems that are common in children with PWS (e.g., hypothyroidism, delayed secondary sexual characteristics, diabetes).

Developmental - Behavioral Pediatrics (see UT providers [9])

Consultation provides approaches in managing challenging behaviors in children with PWS.

Pediatric Orthopedics (see UT providers [10])

Refer for periodic or as-needed assessments for hip dysplasia, scoliosis, and complications of obesity.

Behavioral Therapies (see UT providers [36])

Refer for evaluation and management of behavior problems, including hyperphagia, tantrums, and obsessive-compulsive behaviors.

Neuropsychological Assessment (see UT providers [43])

Refer as needed for assessment of IQ and achievement testing to allow educational planning, especially with respect to individualized education plans (IEPs).

Pediatric Ophthalmology (see UT providers [4])

Refer for evaluation and management of strabismus, myopia, and other visual problems.

Pediatric Gastroenterology (see UT providers [2])

Consult for assistance with feeding problems, including failure to thrive, constipation, hyperphagia/obesity, rumination, and gastric dilatation.

Pediatric Otolaryngology (ENT) (see UT providers [10])

If indicated, refer to assess the contribution of enlarged tonsils and adenoids to sleep problems and intervention as needed for velopharyngeal insufficiency.

Pediatric Dentistry (see UT providers [50])

Refer for evaluation and treatment of enamel defects and decreased saliva.

Sleep Disorders (see UT providers [1])

Consult for routine sleep studies, silent aspiration, and sleep-related behaviors - include Pulmonary Medicine.

Speech - Language Pathologists (see UT providers [65])

Consult for evaluation of speech and articulation problems.

Early Intervention for Children with Disabilities/Delays (see UT providers [51])

All infants and toddlers need enrollment in early intervention programs to obtain OT, PT, speech, and development assessments on a regular basis through 3 years of age.

Treatment & Management

Overview

The management and special needs of individuals with Prader-Willi syndrome (PWS) should be addressed as soon as the diagnosis is confirmed. A multi-disciplinary approach provided in a PWS Clinic is preferred when available. All PWS individuals, regardless of their age, will require:

Nutritional services by a registered dietitian to help gain, maintain, or lose weight as needed. These services will be required throughout life.
Physical therapy will assist with hypotonia and decreased muscle strength to help keep up with developmental milestones.
Clinical genetics and counseling services may be needed for diagnosis, risk recurrence, referrals, education, resources, and follow-up with psycho-social support.
Endocrine evaluations to evaluate growth and other endocrine problems (e.g., diabetes, hypothyroidism, adrenal issues).
Orthopedic evaluation for scoliosis and joint problems secondary to excessive weight.
Ophthalmology assessment for strabismus and other visual problems.
Dental evaluations for enamel defects and help with dry mouth.
Gastroenterology evaluation and management of hyperphagia, swallowing problems, rumination, gastric dilation, gastroparesis, and inability to vomit.
Assessments by psychologists or psychiatrists and assistance with behavior problems commonly associated with PWS.
Educational and developmental assistance from infancy through adulthood from occupational, physical, and speech therapists to help address cognitive issues and include vocational training.
Social worker involvement for support, identification of resources, and lifelong planning, including arrangements for assisted living and residential group homes in adulthood.

Pearls & Alerts for Treatment & Management

Central adrenal insufficiency

Individuals with PWS may present with central adrenal insufficiency, evident primarily during times of stress (e.g., illness, trauma, or surgery). See [de: 2008] and [Stevenson: 2004]. ACTH stimulation testing can be used to evaluate for central adrenal insufficiency. [de: 2008] Alternatively, one can provide a dose of oral hydrocortisone (cortef) 5-10mg 3x/day during times of illness or IV after surgery.

Water intoxication

Certain medications with antidiuretic effects and excess fluid intake alone have caused water intoxication in individuals with PWS.

High pain tolerance

High pain tolerance or lack of typical pain signals is common and may mask infection or injury. Someone with PWS may not complain of pain until infection is severe or may have difficulty localizing pain. Parent/caregiver reports of subtle changes in condition or behavior should be investigated for medical cause.

Risk of respiratory and sleep problems

Individuals with PWS are at increased risk of respiratory problems. Hypotonia, weak chest muscles, silent aspiration, and sleep apnea are potential complicating factors. Anyone with significant snoring, regardless of age, should have a medical evaluation to look for obstructive sleep apnea. Infants may be at risk for respiratory failure when they are ill due to the increased risk of obstruction. Laboratory evaluation of respiratory function may be necessary.

Risk of complications from anesthesia

Children with PWS have increased risk of complications from anesthesia, including trauma to the airway, oropharynx, or lungs due to physiologic differences (such as narrow airway, underdevelopment of the larynx and trachea, hypotonia, edema, and scoliosis). With increasing numbers of infants and children with PWS undergoing sleep assessments and needing surgical procedures for obstructive sleep apnea, it is important to alert the medical team to potential complications, including an attenuated stress response. See Guidelines for Postoperative Monitoring of Pediatric Patients with Prader-Willi Syndrome (PWSA USA).

No fever despite serious infection

Temperature dysregulation, resulting in high or low body temperatures without evidence of infection or other known cause, has been reported in PWS. However, hyperthermia may occur during minor illnesses and procedures requiring anesthesia. Fever may be absent despite a serious infection.

Skin lesions

Skin lesions in individuals with PWS, including open sores caused by skin picking and bruising, may wrongly lead to suspicion of physical abuse. Skin picking is usually in response to a lesion or itching of the face, arms, legs, or rectum. It is best managed by ignoring the behavior, treating and bandaging sores, and providing substitute activities for the hands. Monitor prolonged bathroom time and other activities to avoid self-injurious behavior. Pharmaceutical intervention for severe skin picking may be beneficial.

Hyperphagia

Hyperphagia due to insatiable appetite may lead to life-threatening weight gain or stomach necrosis and rupture in times of binging. Weight gain may be very rapid and occur even on a low-calorie diet. Individuals with PWS must be supervised at all times in all settings where food is accessible.

Growth hormone deficiency

All individuals with PWS should be considered growth hormone deficient. The FDA has recognized a diagnosis of PWS as an indication for growth hormone therapy. Although currently in the investigational stage, genetic testing for GH receptor gene polymorphism may help guide GH treatment in adulthood and improve the quality of life for those with PWS. [Butler: 2013] [Butler: 2013] [Butler: 2018]

Report death

In the event of death, please contact the Prader-Willi Syndrome Association (USA), which maintains a research database that may eventually help address critical vulnerabilities, such as gender and genetic subtype, in the cause of death in PWS. Although most premature deaths are attributable to morbid obesity, cases unrelated to obesity have recently been noted, leading PWSA to recommend a formal investigation of causes of death. PWSA also provides bereavement support to families who have lost children with PWS. The family may also wish to consider donation of organs for research. PWSA (USA) has established a procedure for Tissue Donation (PWS Association) to support research on PWS. Prompt action is essential for tissue preservation. Families are advised to contact the closest Brain and Tissue Bank (800-847-1539, Maryland) directly.

How should common problems be managed differently in children with Prader-Willi Syndrome?

Growth or Weight Gain

Obesity should be controlled and body composition (% fat or lean mass) measured with DEXA to monitor and lower risks for developing comorbidities, including diabetes mellitus, type 2 (DM2). Standardized growth charts developed for non-GH treated PWS children (0-3 years) are particularly helpful, as are calorie-restricted diets and exercise programs. Non-GH treated PWS growth curves are also available for those between 3 – 18 years. These charts can be found at:

Bacterial Infections

Individuals with PWS are at risk for bacterial and fungal skin infections at sites of skin picking and in skinfold (fat) creases.

Prescription Medications

In general, medications are safe as long as the patient is healthy and has no obesity-related complications, such as a fatty liver or megacolon with an abnormal microflora, delayed gastric emptying, swallowing difficulties (regarding pill administration), or abnormal gut absorption. Pharmacogenetics assay should be performed to determine if they are a slow or rapid metabolizer of prescribed medications, such as stimulants for ADHD, that would interfere with their treatment plan and success.

Common Complaints

Vomiting rarely occurs in individuals with PWS, even when it may be helpful. Emetics may be ineffective, and repeated doses may cause toxicity. This is of particular concern in light of hyperphagia and the possible ingestion of uncooked, spoiled, or otherwise unhealthful food.
Abdominal distention or bloating, pain, and vomiting may be signs of life-threatening gastric inflammation or necrosis, which is more common in PWS than in the general population. Rather than presenting with localized pain, there may be a general feeling of malaise. If an individual with PWS has these symptoms, close observation is needed, including an emergency room assessment. An X-ray and endoscopic exam with biopsy may be necessary to determine the degree of the problem and possible need for emergency surgery.
High pain tolerance or lack of typical pain signals is common and may mask the presence of infection or injury. Someone with PWS may not complain of pain until infection is severe or may have difficulty localizing pain. Parent/caregiver reports of subtle changes in condition or behavior should be investigated for medical cause. Discomfort due to high-fiber or other gas-stimulating foods should also be considered.

Systems

Treatment and management do not vary by genetic subtype or subclass of Prader-Willi syndrome, but the molecular class may impact education or development of an individualized educational plan (IEP). For example, those with UPD15 have greater visual memory skills compared to those with deletion subtypes, while those with a deletion may be better at jigsaw puzzles. [Key: 2017] [Joseph: 2001] [Verdine: 2008] IEP plans should take into account these varying skill strengths. Also, those with UPD15 due to isodisomy may be at greater risk of having a second genetic condition, specifically an autosomal recessive disorder if the mother were a carrier of an autosomal recessive gene allele (e.g., hearing loss).

Endocrine/Metabolism

Growth hormone deficiency
Growth hormone (GH) is typically deficient in PWS, causing short stature, lack of a pubertal growth spurt, and a high body fat ratio (fat/body weight), even in those with normal weight. GH is approved for use in PWS for improvement of body composition, height velocity and linear growth, mobility, behavior, and quality of life. GH therapy may increase muscle mass and function and allow a higher daily calorie intake. Psychosocial development may also be improved. Therapy is initiated at a standard dose of approximately 0.5 mg/kg/wk divided as a daily subcutaneous injection. [Deal: 2013] See the Consensus Guidelines for Recombinant Human Growth Hormone Therapy in PWS and the updated international guidelines for growth hormones at [Deal: 2013] for more information.
Families must be counseled before starting GH therapy about reports of sudden death during initiation of GH, mainly during sleep and possibly related to severe obesity and sleep-disordered breathing. [Deal: 2013] Baseline and follow-up studies and labs include a sleep study, IGF-1, thyroid, metabolic and liver function, lipids, DEXA scan, and possibly adrenal function with AM cortisol level. [Deal: 2013]
Diabetes
Diabetes mellitus type II has been observed in those with PWS, particularly if obesity is present. The risk for diabetes is lowered when weight is reduced. Depending upon the level of obesity and use of growth hormone therapy, blood glucose (fasting glucose, HgbA1c) and fasting insulin levels should be checked periodically. Oral glucose tolerance test can be considered. [Deal: 2013]
Hypothalamic dysfunction
Hypothalamic dysfunction has been implicated in several clinical features in PWS, including hyperphagia, high pain threshold, temperature instability, sleep-disordered breathing, and multiple endocrine abnormalities. These endocrine disturbances include growth hormone deficiency, central adrenal insufficiency, hypogonadism, hypothyroidism, and complications of obesity such as type II diabetes mellitus. Hence, children and adults with PWS are at risk for central adrenal insufficiency (CAI) – the first report in 2008, using overnight testing protocols, indicated a high-frequency (60% of cases). [de: 2008] Several subsequent studies using different methodologies found lower frequencies of CAI, and the risk may be less than 10%. [Angulo: 2015] However, there is no consensus on whether evaluation should be done for CAI and/or glucocorticoid treatment preoperatively or during significant stress, though CAI testing is generally performed prior to GH treatment.
Sex hormones and sexual maturation are addressed in the Maturation/Sexual/Reproductive section, below.

Specialty Collaborations & Other Services

Pediatric Endocrinology (see UT providers [7])

Refer for co-management of growth hormone initiation and treatment, monitoring of diabetes mellitus, and possible sex hormone replacement.

Medical Genetics (see UT providers [7])

Periodic visits are recommended for collaboration on ongoing management.

Prader-Willi Clinics (see UT providers [1])

If available, management at a PWS clinic is recommended.

Gastro-Intestinal & Bowel Function

Failure to thrive
Food intake during the first 2 years of life requires close management to maintain weight-for-height measures between the 25th and 80th percentiles. Failure to thrive may require the use of special nipples or tube feedings. Closely monitor infants with PWS for adequate calorie intake and appropriate weight gain. Nasogastric tube feedings are often needed, but gastrostomies are rarely indicated and may contribute to future gastric rupture. Usually, this improves by 6 months of age; however, increased weight gain in the absence of increased caloric intake may begin as early 12 months of age, and hyperphagia may emerge soon thereafter. Referral to pediatric gastroenterology may be indicated. Published growth standards specifically for use in PWS are available at:

Hyperphagia
In younger toddlers who transition to low caloric utilization there can be weight gain while adhering to low-calorie diet. In older children, hyperphagia due to insatiable appetite may lead to life-threatening weight gain, which can be rapid. Excessive uncontrolled over-eating may lead to stomach necrosis and rupture; a careful food-monitoring program is essential for both children and adults with PWS. [Butler: 1991]
Restricted diet
Restricted caloric intake with vitamin and calcium supplementation, performed under the close supervision of an experienced dietitian, is generally required from age 2-3 years to minimize excessive weight gain and osteoporosis. Successful weight maintenance in children with PWS who have not been treated with growth hormone has been reported with an intake of 8-11 kcal per cm of height per day (children without PWS require 11-14 kcal per cm per day for adequate growth).
Individuals with PWS must be supervised at all times in all settings where food is accessible. Those who have normal weight have only achieved this because of strict external control of their diet and food intake. [Goldberg: 2002] [Butler: 2016] Strictly controlling access to food involves 3 tenants, which relate to “food security” for the individual with PWS (from Prader-Willi Syndrome Food Security (Pittsburgh Partnership) ( PDF Document

478 KB)):

There is no doubt (when meals will occur and what foods will be served).
There is no hope (of getting anything different from what is planned).
There is no disappointment (related to false expectations).

When food access is restricted, individuals with PWS should have no doubt about their meals and snacks. Menus are planned and posted; calories are controlled, but the amount of food presented can still be generous. Although the timing of the meals and snacks remains fixed, it is not usually focused on the clock; it is set by the sequence of activities across the day. It is important to keep strict mealtime regimens and ensure unwavering consistency by parents and care providers, both inside and outside of the home. See Prader-Willi Syndrome Educational Downloads (Pittsburgh Partnership) for more information.
Other tactics include:

Locking away food
Keeping limited amounts of food in the home
Continual close supervision of the patient around food or food-related events
Providing non-food-related rewards
Reduction of portion sizes using small plates and bowls
Allowing participation in menu planning and preparation
Counting calories
Having access to food with fewer calories
Maintaining secure trash that harbors any edible morsels

To date, no medication or surgical intervention has been found that would eliminate the need for strict dieting and supervision around food. Bariatric surgery has generally been unsuccessful and is not recommended in PWS in the United States. [Scheimann: 2008] See also Prader-Willi Syndrome and Complications from Obesity and Clinical Trials related to hyperphagia in Prader-Willi (ClinicalTrials.gov).
Nutrition
Many nutritional issues arise in children with PWS. Guidance on nutrition can be obtained by working with a dietician, particularly one familiar with PWS. Healthy diet information can be found at Red-Yellow-Green Weight Control System (Children's Institute), and Anytime, Sometimes, Rarely Food List (East Carolina University) ( PDF Document

140 KB). Other ideas may be found in Missing link with id: 99e6f817.xml and Prader-Willi Syndrome Nutrition & Diet.
Exercise
Individually tailored exercise programs are encouraged - 30 minutes of sustained activity 3-5 times per week are generally recommended. [Butler: 2006]
Gastroesophageal reflux
Reflux is common in children with PWS and may be particularly problematic in infants due to their hypotonia. The Medical Home Portal’s page on Gastroesophageal Reflux Disease provides treatment information.
Vomiting and rumination
Commonly reported features of PWS include a decreased ability to vomit and a high prevalence of rumination. [Alexander: 1987] Dental enamel defects due to rumination should be looked for routinely. Rumination may increase in children with strict behavioral food intake programs. See Decreased sensitivity to gastric fullness and pain, below.
Decreased sensitivity to gastric fullness and pain
Although they have no known congenital defects involving the gastrointestinal system, children with PWS have decreased sensitivity to gastric fullness and pain. A decreased pain response may mask the symptoms of gastrointestinal problems such as gastric distention, gastroparesis, and necrosis, which are common in individuals with PWS. In addition, because vomiting is reduced in children with PWS, they may not respond to eating spoiled or contaminated foods. Children with PWS may present with behavior changes and vague feelings of unwellness that might represent medically urgent gastrointestinal disease. These complaints should be taken seriously by providers.
Constipation
Constipation occurs in over 20% of children with PWS. Rectal ulcers, which may occur due to skin picking, can be exacerbated by large stools and constipation. Treatment of bowel disorders in individuals with PWS often requires ongoing specialized treatment and monitoring with a multi-disciplinary approach to optimize therapy. The UCanPoopToo Program (BeHealth Solutions) is an online program that helps solve the physical, emotional, and behavioral issues of encopresis. The Medical Home Portal’s Constipation provides treatment details.
Fatty liver (hepatic steatosis)
Monitor ALT and AST and consider liver ultrasound or biopsy in obese individuals. [Deal: 2013]

Specialty Collaborations & Other Services

Pediatric Gastroenterology (see UT providers [2])

Referral may be helpful for management of failure to thrive, hyperphagia, severe reflux, constipation, and fatty liver.

Dieticians and Nutritionists (see UT providers [6])

It is important to involve nutritionists familiar with this disorder for both failure to thrive and the restricted diet necessary for children and adolescents with PWS.

Medical Genetics (see UT providers [7])

Periodic visits are helpful for overall management of pediatric issues specific to PWS.

Prader-Willi Clinics (see UT providers [1])

When available, management at a PWS clinic is preferred.

Skin & Appearance

Skin picking
A common problem that may become a habit in children with PWS is scratching and picking at the skin or mucosal areas of the face, arms, legs, or rectum. Insect bites or other skin lesions sometimes trigger the problem. Skin picking behavior may vary in severity and duration; anxiety, stress, or boredom seems to increase the severity of the picking behavior. Over half of adolescents and adults with PWS exhibit this self-injurious behavior. Frequent nose bleeds or rectal bleeds should prompt further examination for sores from picking. Rectal ulcers may occur as a result of rectal itching or “digging.”
Treatment includes keeping the fingernails short, behavior modification, limiting time spent in the bathroom to reduce opportunities for rectal picking, and providing substitute activities for the hands. Skin and mucosal infections can be managed with topical antibiotics, bandaging, and, if necessary, oral antibiotics. Oral topiramate has been shown to reduce skin picking in some cases, and N-acetylcysteine may be effective in others. [Shapira: 2002] [Miller: 2014]
Infections
The very obese individual is also more prone to fungal and bacterial infections, severe ulceration, and cellulitis due to the inability to cleanse the skin in deep fat folds. Management includes daily cleansing in these folds, air drying with a heat lamp or hairdryer, and the use of medications for infections.

Specialty Collaborations & Other Services

Pediatric Dermatology (see UT providers [2])

May be helpful for those with more severe skin problems.

Pediatric Gastroenterology (see UT providers [2])

If rectal picking continues, gastroenterology may be helpful to treat underlying conditions, such as constipation.

Psychiatry > … (see UT providers [72])

Psychotherapeutic assessments may be helpful for severe skin picking.

Cardiology

Cardiovascular risk is higher in individuals with PWS for a variety of reasons, including:

Overeating and obesity
Poor dietary habits
Diabetes
Excess work of breathing
Unexplained elevations of C-reactive protein
Severe obstructive sleep apnea
Thrombophilia

In older individuals, these factors can result in hypertension, left ventricular hypertrophy, right-sided heart failure, and pulmonary embolism, particularly in morbidly obese individuals. See (Butler et al., 2018). Relevant studies include fasting lipid panel (total cholesterol, triglycerides, LDL, and HDL). Although these are not generally present in young children with PWS, older individuals should be referred to a cardiologist for management as needed.

Specialty Collaborations & Other Services

Pediatric Cardiology (see UT providers [4])

Older individuals should be referred for evaluation and management of cardiac risks as needed.

Sleep

Apnea
Up to 90% of children and adults with PWS will have apnea (obstructive and central) and profound hypoventilation during sleep. [Butler: 2006] This may be due to extrinsic factors such as large tonsils and/or an intrinsic sleep disorder, probably related to hypothalamic dysfunction. Symptoms may include:

Hypoventilation
Oxygen desaturation during REM sleep
Sleep apnea
Nocturnal enuresis
Excessive daytime sleepiness and snoring

If a sleep evaluation finds apnea, consider referral to otolaryngology for evaluation of tonsils and adenoids and/or to a pulmonologist or sleep specialist to consider options such as BIPAP or CPAP. A sleep study should be performed before starting GH treatment, with a follow-up study 3-6 months later. [Deal: 2013] Surgical management of the obstructive airway should be performed prior to starting GH, though early initiation of GH therapy may preclude this approach. [Deal: 2013] In most individuals with sleep-disordered breathing due to PWS, GH can actually improve (or at least not worsen) the apnea. [Haqq: 2003] [Miller: 2006] [Festen: 2006]
Nocturnal enuresis
This may occur secondary to other underlying sleep problems or as an independent problem. If medical treatment is being considered, for example with DDAVP, start with smaller doses than those used in the general population and gradually increase the dose as needed.

Specialty Collaborations & Other Services

Pediatric Pulmonology (see UT providers [3])

For help in evaluating and managing persistent sleep-related problems.

Pediatric Otolaryngology (ENT) (see UT providers [10])

For evaluation and surgery for large adenoids or tonsils in those with obstructive sleep apnea.

Sleep Study/Polysomnography (see UT providers [4])

For help in evaluating and managing persistent sleep problems

Respiratory

Individuals with PWS may be at increased risk for respiratory problems, especially as infants. Problems at birth due to hypotonia, weak chest muscles, and poor swallowing reflexes may include asphyxia, apnea, respiratory failure, and hypoventilation.

Specialty Collaborations & Other Services

Pediatric Pulmonology (see UT providers [3])

For routine evaluation and management of respiratory issues.

Musculoskeletal

Decreased muscle mass, strength, and tone
Individuals with PWS commonly have decreased muscle mass and strength. The few histologic and ultrastructural studies of muscle fibers performed in individuals with PWS have found only minimal abnormalities. A disuse or minimal myopathy may accompany central hypotonia in individuals with PWS. [Sone: 1994] Physical therapy and regular participation in exercise programs are essential to improve muscle strength and decrease fat mass. See Missing issue with id: c509f8ec.xml. Growth hormone therapy and appropriate testosterone replacement in adolescent and adult males also improve muscle strength in individuals with PWS.
Scoliosis, kyphosis, and lordosis
Up to 86% of individuals with PWS may have scoliosis, kyphosis, and/or lordosis. [Shim: 2010] Progression may occur with the increased linear growth during late childhood and adolescence, and can be rapid. Treatment with growth hormone or anabolic steroids may exacerbate scoliosis. Severe kyphoscoliosis may lead to restrictive lung disease. Children with PWS should be screened regularly for scoliosis and, if scoliosis is present, referred to a pediatric orthopedic surgeon for management. Surgery to correct the scoliosis is sometimes necessary.
Hip dysplasia
The medical home provider should screen for hip dysplasia, which occurs in about 13% of individuals; refer to an orthopedic surgeon if suspected. Hip ultrasound studies during infancy should be considered.
Osteoporosis
Approximately 50% of adolescents and adults with PWS have osteopenia/osteoporosis. Consider osteoporosis in individuals with any fracture that is not consistent with the force of injury. [Kroonen: 2006]
A lack of bone mineral deposition during growth (e.g., adolescence) may cause the osteoporosis. [Butler: 2011] Low calcium and vitamin D intake within a calorie-restricted diet, lack of sun exposure, and a decreased production of sex or growth hormones may also play a role. [Lee: 2000] [Allen: 2004] If osteoporosis is present, calcium and vitamin D intake should be maximized, and the provider should consider a referral to endocrinology. A program of physical activity may help prevent the development of osteoporosis by providing neuromuscular stimulation necessary for bone mineral deposition.
Growth hormone therapy, which is recommended for use in children with PWS, is associated with more normal bone mineral density. Gonadal steroid replacement to achieve normal serum levels may also help prevent osteoporosis [Lee: 2000] [Allen: 2004] For more information, please see Osteoporosis and Pathologic Fractures.

Specialty Collaborations & Other Services

Pediatric Orthopedics (see UT providers [10])

Regular visits are recommended to supervise conditioning, manage exercise in children adolescents with PWS, and handle bracing as needed.

Physical Therapy (see UT providers [40])

Regular visits are recommended to supervise conditioning and manage exercise and, if needed, bracing in children and adolescents with PWS.

Pediatric Endocrinology (see UT providers [7])

Guides evaluation and treatment of osteopenia/osteoporosis.

Prader-Willi Clinics (see UT providers [1])

When available, management at a PWS clinic is preferred.

Eyes/Vision

Strabismus
Strabismus includes both esotropia, which is more common, and exotropia beginning in early childhood. Treatment may involve correction of refractive errors, patching of the better eye, and/or surgical correction of unbalanced eye muscles. Generally, treatment is more successful if started in the first few years of life. Amblyopia, or reduced vision due to disuse of an eye during development (commonly called "lazy eye"), results from inadequately treated strabismus.
Oculo-cutaneous albinism type 2 has been linked to a pigment gene in the 15q11-q13 region - individuals with PWS due to a deletion in this area may also exhibit signs of hypopigmentation. Strabismus and impaired visual acuity may also be features of oculo-cutaneous albinism type 2. [Saadeh: 2007]
Myopia and Hyperopia
Myopia (near-sightedness) and hyperopia (far-sightedness) are common findings in children with PWS. Periodic screenings with a pediatric ophthalmologist are recommended throughout childhood.

Specialty Collaborations & Other Services

Pediatric Ophthalmology (see UT providers [4])

Referrals to ophthalmology may be needed for management of strabismus and acuity problems beginning in early childhood.

Maturation/Sexual/Reproductive

Hypogonadotropic hypogonadism
Individuals with PWS typically have hypogonadotropic hypogonadism, resulting in decreased estrogen levels in females and decreased testosterone levels in males. In the newborn period, most males have small testes and scrotum. Undescended testes are common in PWS. If the testes are not palpable, referral for a testicular ultrasound and evaluation by a pediatric urologist should be made by about 6 months of age. In newborn females, labial hypoplasia has been reported.
Over 80% of adolescents and adults with PWS will experience incomplete sexual maturation. Some children show early growth of underarm and pubic hair, but then do not progress through puberty normally. Both sexes have good responses to treatment for hormone deficiencies, although side effects to treatment have been reported. Males with PWS typically do not progress past mid-puberty and make no mature sperm. Testosterone levels are usually low; testosterone replacement beginning early in adolescence may be helpful. [Kido: 2013] Normal levels of testosterone are beneficial to preserve bone mass and prevent osteoporosis. Testosterone replacement also increases muscle mass and strength. In older males with a small penis, a short course of testosterone can be given to improve appearance and size.
Most females with PWS do not have regular menstrual cycles, and if they do menstruate, they may have early menopause. Hypoplasia of the labia and/or clitoris in teenage females is common. The use of estrogen replacement therapy for women with PWS is not well established but may help preserve bone mass and reduce osteoporosis.
Fertility has only been documented in a few rare cases. Sexually active individuals should be counseled regarding the risk of pregnancy and the risk of having a child with PWS (50%, except when the mutation is due to maternal disomy).
Sexuality needs to be discussed with adolescents with disabilities and their parents in an effort to address common issues that may include:

The assumption that teens with disabilities do not need this information
The lack of sex education specific to people with disabilities
Motor impairments that may make sexual function difficult (e.g., condom use)
The presence of intellectual impairment that might complicate the imparting and understanding of sex education material
Concerns about sexual exploitation in this population
Body image concerns on the part of the adolescents

See Sexuality and People with Disabilities ( PDF Document

257 KB).

Specialty Collaborations & Other Services

Pediatric Endocrinology (see UT providers [7])

Refer for consideration, initiation, and management of sex hormone therapy and hypogonadism in those with delayed puberty.

Gynecology: Pediatric/Adolescent; Special Needs (see UT providers [9])

Consider referral for female patients with delayed puberty.

Pediatric Urology (see UT providers [3])

Refer for evaluation and management of males with cryptorchidism and/or a small penis.

Dental

An initial visit and regular follow-up with a dentist should be part of the treatment plan; however, preventive dental care may be difficult for the following reasons:

Cognitive and fine motor skills may limit the child's ability to perform brushing and flossing. Early emphasis on brushing and flossing is important.
Behavioral and health issues (e.g., sleep apnea, congenital heart disease) may increase the difficulty of dental visits and increase the risks of using sedation in the dental setting.

Children with PWS are prone to dental problems:

Soft dental enamel makes it easier for caries to develop. Special toothbrushes can be used that are less abrasive and help maintain enamel and improve oral hygiene.
There is a tendency to grind teeth and sugar intake may be large.
Overproduction of thickened saliva results in thick, crusted deposits in the corners of the mouth and difficulty with the saliva coating protecting the teeth. Products to increase and thin the saliva are available.

The primary care provider's role should include:

Discussing the need for routine dental care with families and ensuring that the child and family have been instructed on dental hygiene and fluoride supplementation. The CDC's page My Water's Fluoride (CDC) provides information about fluoride levels in local water sources.
Helping families identify an appropriate dentist and/or funding for dental care. Dental checkups are recommended by age 1 and then every 6 months.
Offering the family information about dental care specific to PWS. Ensure that families and dental care providers are aware of medical issues that may impact care (e.g., need for bacterial prophylaxis and sedation risks).
Monitoring general oral hygiene and dental health at well-child visits and discussing issues with families as they arise. If signs of periodontal disease are evident, refer to a dental provider as soon as possible; periodontal disease can be rapidly progressive.
Helping the child, teen, and family manage halitosis, which may result in societal exclusion. Halitosis may improve with simple interventions such as tongue brushing, mouthwashes, breath fresheners, and better dental hygiene or may require evaluation for medical issues, including chronic sinusitis, gastroesophageal reflux, drooling, and periodontal disease.

See Dental and Oral Health Screening.

Specialty Collaborations & Other Services

General Dentistry (see UT providers [93])

Particularly helpful when pediatric dentists are not available.

Pediatric Dentistry (see UT providers [50])

Often have special interest and skill in the care of children with special health care needs.

Development (general)

Speech and language skills of individuals with PWS range from nonverbal to normal. The development of speech and language is often delayed; sometimes, children do not learn to combine words until they are 6 years old. Problems are seen with speech rate, voice quality, and coordinating movements of the tongue, lips, jaws, and palate, which can lead to slow, slurred, and/or nasal speech. Most individuals will have more delays in expressive language than in receptive language. Difficulties with auditory short-term memory, order processing, and auditory-verbal processing skills may affect vocabulary, grammar, and conversational abilities. Despite oral difficulties, children with PWS may show strengths in written language skills and reading, although reading comprehension may be poor. Speech and language difficulties continue into adolescence and adulthood. In these stages, emphasis should be placed on functional language skills and life-skills training.
Sign language, picture communication boards, and augmentative communication devices should be considered for individuals with verbal communication problems. Referrals should be made as early as possible to speech and language pathologists. Aiding communication may help with behavior problems.

Specialty Collaborations & Other Services

Speech - Language Pathologists (see UT providers [65])

In addition to speech/language therapy, speech therapists can initiate augmentative communication when needed.

Mental Health/Behavior

Behavior
Behavioral issues often impact the child with PWS and their family more than any other aspect of the condition. Family support and anticipatory guidance for developmental delays and medical problems should be provided. Transitions and life changes are easier if the person with PWS is prepared for them, for example, by allowing the child with PWS to visit a new school and meet his/her prospective teachers. Children with PWS should have a clear idea of expectations and the limits set for them, including those related to participation in social activities and interactions with other children.
To avoid secondary behavioral issues, hyperphagia needs to be managed consistently by family, teachers, health care providers, and anyone who interacts with the child. Controlling both the quantity and types of food that are available is essential. Attempts to suppress appetite with medication have been unsuccessful; active research continues in this area. Conflicts related to food may lead to other behavioral problems. Aggressive behaviors or acting out can also be problematic.
Co-management with psychology and/or psychiatry may be important if simple measures are ineffective. The choice of psychotropic medication is the same as in typical patients with psychiatric diagnoses, but dosing should start low and be titrated upward based upon response since many individuals with PWS respond unusually to medication.
Mood stabilizers have been used successfully for treating mood disorders and severe impulse control. Valproate and lithium are well tolerated at typical doses. Carbamazepine and oxcarbazepine should be used with care because of the increased risk for hyponatremia. Individuals with PWS will sometimes ingest large quantities of flavored beverages or water making them more susceptible to hyponatremia than non-PWS subjects.
Serotonin reuptake inhibitors have worsened behavioral problems and led to psychosis in some individuals with PWS. The worsening behavior after an initial favorable response to medication may cause some physicians to increase the dose, which further complicates treatment. However, when monitored closely, this class of medications can effectively treat OCD and depression in individuals with PWS.
Monitor all medications that may affect eating behavior and weight gain. In well-controlled environments, neuroleptics, atypical neuroleptics, valproic acid, and lithium have effectively been used without a noticeable change in food-seeking behavior. [Forster: 2008] In severe cases, the child may need to be admitted to a facility that has experience in dealing with behavioral issues secondary to underlying medical problems.
Attention deficit hyperactivity disorder (ADHD)
ADHD should be treated if present. Co-management with a child psychiatrist may be indicated if medication is required. The Portal's diagnosis and management module can be found at Attention-Deficit/Hyperactivity Disorder (ADHD).

Specialty Collaborations & Other Services

General Counseling Services (see UT providers [298])

Refer for help in managing the behavior problems of children with PWS and for family counseling, include School-based Mental Health Care (see UT providers [3])

Psychiatry/Medication Management (see UT providers [53])

Refer for help with severe behavior problems requiring medical treatment.

Behavioral Therapies (see UT providers [36])

Refer for help with behavior problems requiring treatment.

Learning/Education/Schools

Individuals with PWS typically have impaired cognitive functioning. IQ scores are generally in the range of mild to moderate intellectual disability, although scores may range from normal to profound disability. The Medical Home Portal's Intellectual Disability & Global Developmental Delay module provides diagnoses and management information; Missing issue with id: 15179e9f.xml provides further relevant details.
The type of gene alteration causing the PWS plays a role in IQ score results; individuals with PWS due to uniparental disomy (UPD) have higher verbal than performance scores, while children with PWS due to deletions have higher performance scores. Children with UPD generally perform better than children with deletions, and the size of the deletion correlates inversely with performance. Areas primarily affected include reading, spelling, and math. Short-term visual memory is often a weak area, whereas visual perception, organization, and puzzle-solving are relative strengths. Children with PWS should have full psychological evaluations, including IQ and achievement, so that school and future planning can be optimized. An Individual Education Plan (IEP) should be initiated as early as possible. For more information, please see School Accommodations: IEPs & 504s and Missing issue with id: e7725abc.xml.

Specialty Collaborations & Other Services

General Counseling Services (see UT providers [298])

Refer for help with educational programming and behavior management programs.

Neuropsychiatry/Neuropsychology (see UT providers [6])

Refer for evaluation and help with educational programming.

Psychiatry/Medication Management (see UT providers [53])

Refer for medication management of ADHD, if needed.

Family

There are many demands on families of children and adults with PWS. Siblings are significantly impacted by care of children with PWS, often due to walking on pins and needles while awaiting temper tantrums and behavior outbursts, as well as family food regulation. The medical home, in addition to providing support for the child, can help families access emotional, financial, and informational resources. Referral to the Prader-Willi Syndrome Association (USA) for local information and support by other families may be invaluable. Family Support (PWSA USA) and Funding Your Child's Special Needs may also be helpful.

Transitions

Transitioning to adult life and health care systems is challenging for individuals with PWS, their families, and their care providers. An important goal in transition planning is to find a medical home provider who recognizes the special needs of individuals with PWS and will communicate with the pediatric team. Other important goals of transition planning are to identify where the person will live and what the educational and vocational training needs are. Transition should include the following:

Begin planning well before the patient will be transitioned.
Take medical problems and learning disabilities into account.
Center the planning on the person and their family; take into account cultural, ethnic, and spiritual values, and economic resources.
Consider the goals of the youth – they should include measurable outcomes. Transitions should be presented as positive changes in the person's life.
Obtain agreement from all members of the health care team, current and future, on the overall plan and how to achieve the outcomes desired.
Plan medical management so there is no interruption in care and so that the patient and family are aware of potential changes in available resources. Medicaid support typically ends at age 19 and Social Security financial support after age 18.
There needs to be continued oversight of dietary restrictions and access to food, even if hyperphagia is less problematic.

Specialty Collaborations & Other Services

Adolescent Health Transition Programs (see UT providers [6])

Provides lists of funding sources.

No Related Issues were found for this diagnosis.

Ask the Specialist

What are the most common features seen in patients with Prader-Willi syndrome?

The cardinal features are infantile hypotonia, poor suck with feeding problems with failure to thrive, lack of infantile arousal, growth hormone deficiency with short stature and small hands and feet, hypogonadism/hypogenitalism, onset of obesity in early childhood if not controlled, childhood hyperphagia, and learning/behavioral problems.

What is the suggested treatment once the diagnosis is confirmed?

Growth hormone therapy is indicated to treat the deficiency and to improve stature, decrease fat mass, and increase muscle and strength. Diet intervention with reduced caloric intake and exercise programs to avoid obesity are recommended throughout the lifespan. Pulmonary care for hypoxia, obstructive sleep apnea, aspiration, and central sleep apnea.

What is the risk for other family members or future babies?

Most cases of PWS are sporadic; however, at least 20 families have been reported with more than 1 affected member, including reports in twins. The chance for familial recurrence is estimated to be less than 1%. However, this risk may be as high as 50% in some families where an imprinting defect causes defective control of differentially expressed genes in both the PWS child and the unaffected father. [Hartin: 2018] [Hartin: 2019]

Resources for Clinicians

On the Web

Prader-Willi Syndrome (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Prader-Willi Syndrome (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine

Consensus Guidelines for Recombinant Human Growth Hormone Therapy in PWS
Recommendations for the use of rhGH in children and adult patients with PWS; International Growth Hormone Research Society Workshop Summary 2011.

PWS Genetic Testing (Genetic Testing Registry)
List of laboratories providing testing for PWS; Genetic Testing Registry.

Helpful Articles

PubMed search on Prader-Willi syndrome: pertinent articles over the last 2 years

Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS.
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):E1072-87. PubMed abstract / Full Text
Workshop summary with expert opinion on the use of growth hormone therapy in Prader-Willi syndrome.

Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V, Dykens E, Butler MG, Shuster JJ, Driscoll DJ.
Nutritional phases in Prader-Willi syndrome.
Am J Med Genet A. 2011;155A(5):1040-9. PubMed abstract / Full Text
Description and discussion of nutritional phases in Prader-Willi syndrome.

Butler MG, Hartin SN, Hossain WA, Manzardo AM, Kimonis V, Dykens E, Gold JA, Kim SJ, Weisensel N, Tamura R, Miller JL, Driscoll DJ.
Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study.
J Med Genet. 2019;56(3):149-153. PubMed abstract
Largest study to date on molecular genetic classification and frequency of PWS genetic subtypes in 510 individuals with Prader-Willi syndrome using advanced genetic technology.

Butler MG, Manzardo AM, Heinemann J, Loker C, Loker J.
Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey.
Genet Med. 2017;19(6):635-642. PubMed abstract / Full Text
Description of causes of death and their frequencies in Prader-Willi syndrome using a 40-year dataset.

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. PubMed abstract
Description of clinical findings and genetic causes in Prader-Willi syndrome with diagnostic aspects, genetic testing, and treatment approaches.

Clinical Tools

Care Processes & Protocols

Flowchart of Recommended Molecular Testing Strategy for PWS (AAP)
One-page flowchart from Health Supervision for Children With Prader-Willi Syndrome (Figure 1).

Growth/BMI Charts

Growth Standards for Non-Growth Hormone Treated PWS (0-36 months)
Curves for weight, length, head circumference, weight/length, and BMI for white infants (boys and girls) with PWS between 0 and 36 months of age. Link leads to free article by Butler et al. published in Pediatrics (2011). Scroll for charts, PowerPoint slide can be downloaded.

Growth Charts for Non-Growth Hormone Treated PWS (3-18 years)
Curves for weight, height, head circumference, and BMI for white male and female U.S. subjects with PWS between 3 and 18 years of age. Link leads to article by Butler et al. published in Pediatrics (2015). Scroll for charts; PowerPoint slide can be downloaded. Accessible with subscription.

Growth Charts for PWS During Growth Hormone Treatment (0-18 years)
Curves for weight, height, head circumference, and BMI for white male and female U.S. subjects with PWS between 0 and 18 years of age treated with growth hormone and published in Clin Pediatr (Phila). 2016;55(10):957-974.

Toolkits

Health Care for Adults with Intellectual & Developmental Disabilities - Toolkit for Clinicians (Vanderbilt)
Health Watch Tables and checklists for autism, Down syndrome, fragile X, Prader-Willi, Williams syndrome, and 22q11.2 deletion syndrome. Developed for primary care providers of adults with developmental and intellectual disabilities; Kennedy Center for Excellence in Developmental Disabilities.

Resources for Patients & Families

Excellent resources, including those listed below, are available from the Prader-Willi Syndrome Association (USA)Medical home providers and families of children with PWS are encouraged to visit their website and see the numerous resources available.
For a list of answers to questions frequently asked by parents, see Prader-Willi Syndrome (FAQ).

Information on the Web

Medical Issues A-Z (PWSA)
Key points about medical issues related to PWS, such as adrenal insufficiency, edema, intestinal issues, growth hormone, high pain threshold, hyperphagia, hypogonadism, hypothyroidism, nutrition, orthopedic issues, post-operative issues, psychotropic medications, medical alerts, respiratory issues, seizures, skin picking, and sleep problems; Prader-Willi Syndrome Association.

Prader-Willi Syndrome (MedlinePlus)
Information about PWS and links to other reliable sources of information; National Library of Medicine and National Institutes of Health.

Prader-Willi Syndrome Food Security (Pittsburgh Partnership) ( PDF Document 478 KB)
Basic concepts of food security and checklist for those caring for individuals with Prader-Willi syndrome; from the Pittsburgh Partnership, providing education and consultation.

National Organization of Rare Disorders (NORD)
Information for families that includes synonyms, signs & symptoms, causes, affected populations, related disorders, diagnosis, therapies (both standard and investigational), and support organizations; National Organization of Rare Disorders.

Utah Prader-Willi Syndrome Association
Provides families and professionals with a network of support, resources, and information. Promotes awareness of PWS and raises funds that will directly benefit affected individuals in Utah.

Prader-Willi Syndrome Educational Downloads (Pittsburgh Partnership)
Information for providers and families regarding food security, behavioral management, nutrition/weight management, and other issues in individuals with PWS; from the Pittsburgh Partnership, which provides education and consultation.

Genetic Conditions: Prader-Willi Syndrome (MedlinePlus)
Excellent, detailed review of condition for patients and families; National Library of Medicine and National Institutes of Health.

National & Local Support

Prader-Willi Syndrome Association (USA)
A strong national organization of families and professionals, PSWA offers a toll-free helpline, a bimonthly newsletter and numerous publications about PWS, an annual family conference and scientific meeting, and chapters throughout the country to provide local family support and advocacy.

International Prader-Willi Syndrome Organization
Work toward a world where people with PWS and their families receive the services and support they need to fulfil their potential and achieve their goals.

Foundation of Prader-Willi Syndrome Research
Focused on research and developing new therapies.

Heartland Genetic Services Network
Region 5 of the Genetic Service Networks; provides information for families and providers including listings of local resources.

Studies/Registries

Prader-Willi Syndrome Studies (ClinicalTrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families in Utah (UT)

Service Categories	UT	NW		NM	NV
Adolescent Health Transition Programs	6	2	6	2	2
Behavioral Therapies	36	1	17	19	32
Developmental - Behavioral Pediatrics	9	1	2	3	12
Dieticians and Nutritionists	6	1	1	4	3
Early Intervention for Children with Disabilities/Delays	51	3	34	30	13
Educational Testing/Assessment	5		3	1	2
General Counseling Services	298	1	10	210	30
General Dentistry	93	1	12	13	47
Genetic Testing and Counseling	11	6	6	12	8
Gynecology: Pediatric/Adolescent; Special Needs	9				3
Medical Genetics	7	1	2	5	4
Neuropsychiatry/Neuropsychology	6		1	3	9
Neuropsychological Assessment	43		7	3	28
Occupational Therapy	37	1	17	22	21
Pediatric Cardiology	4		3	4	17
Pediatric Dentistry	50	2	6	28	54
Pediatric Dermatology	2	1	3	1	3
Pediatric Endocrinology	7	1	4	6	12
Pediatric Gastroenterology	2		2	5	18
Pediatric Ophthalmology	4	1	6	6	8
Pediatric Orthopedics	10	4	7	8	16
Pediatric Otolaryngology (ENT)	10	1	11	5	7
Pediatric Pulmonology	3		4	4	6
Pediatric Urology	3			13	1
Physical Therapy	40		12	9	6
Prader-Willi Clinics	1
Psychiatry	72		5	101	90
Psychiatry/Medication Management	53		3	37	80
School-based Mental Health Care	3				6
Sleep Disorders	1				2
Sleep Study/Polysomnography	4		2		1
Speech - Language Pathologists	65	4	23	11	33
SSI/SSDI	11	4	17	14	10
Supportive Housing & Residential Care Homes	32		14	3	6
Vocational Education	75	1	11	41	10

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: September 2008; last update/revision: March 2020

Current Authors and Reviewers:

Author:	Merlin G. Butler, MD, PhD
Reviewer:	David Viskochil, MD, PhD

Funding: This original version of this module was developed in 2008 in partnership with the Heartland Regional Genetics and Newborn Screening Collaborative Heartland Genetic Services Network (now the Heartland Regional Genetics Network) and was funded in part by a Health Resources Services Administration (HRSA) cooperative agreement (U22MC03962).
We appreciate the Prader-Willi Syndrome Association (USA) for their outstanding support of individuals with PWS and their families and for the information they provide on their website – www.pwsausa.org – to which we have provided several links within the Diagnosis Module.

Authoring history

2015: revision: Jennifer Goldman, MD, MRP, FAAP^R

2014: update: Merlin G. Butler, MD, PhD^A

2010: revision: Debbie Mason^CA

2008: revision: Kyna Byerly, MS, CGC^R

2008: first version: Merlin G. Butler, MD, PhD^A; Judy L. Welch, RN, BSN^CA

^AAuthor; ^CAContributing Author; ^SASenior Author; ^RReviewer

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Standardized growth curves for weight, length, head circumference, weight/length, and BMI for non–growth hormone–treated white infants (boys and girls) with Prader-Willi syndrome (PWS) between 0 and 36 months of age.

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Prader-Willi Syndrome: Clinical and Genetic Findings.
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Investigates whether PWS patients suffer from central adrenal insufficiency (CAI) during stressful conditions. Based data, recommends considering treatment with hydrocortisone during acute illness in PWS patients unless CAI has recently been ruled out with a metyrapone test.

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