Prader-Willi Syndrome - PWS

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Suspicion based on physical findings

Criteria for Diagnosis

  • Consensus criteria for testing
    • Major criteria
      • Neonatal and infantile central hypotonia with poor suck; improvement with age
      • Feeding problems and/or failure to thrive in infancy, with need for gavage feeding or other special feeding techniques
      • Onset of rapid weight gain between ages 12 months and six years, causing central obesity
      • Hyperphagia
      • Characteristic facial features – narrow bifrontal diameter, almond-shaped palpebral fissures, downturned mouth
      • Hypogonadism manifestations
        • Genital hypoplasia – small labia minora and clitoris in females; hypoplastic scrotum and cryptorchidism in males
        • Incomplete and delayed puberty
      • Infertility
      • Developmental delay (mild to moderate), multiple learning disabilities
    • Minor criteria
      • Decreased fetal movement and infantile lethargy, improving with age
      • Behavior problems, including temper tantrums, obsessive-compulsive behavior, stubbornness, rigidity, stealing, and lying
      • Sleep disturbance or sleep apnea
      • Short stature by age 15 (based on the individual family)
      • Hypopigmentation
      • Hands and feet small for height age
      • Narrow hands with straight ulnar border
      • Esotropia, myopia
      • Thick, viscous saliva
      • Speech articulation defects
      • Skin picking
    • To score, major criteria are weighted at 1 point each, and minor criteria are weighted at 1/2 point each; supportive findings increase the certainty of diagnosis but are not scored
      • For children ≤3 years, 5 points are required, 4 of which should come from major criteria
      • For children >3 years and for adults, 8 points are required with 5 or more points coming from major criteria

Laboratory Testing

  • Absolute diagnosis depends on genetic testing
  • Initial diagnostic testing – methylation PCR
    • Confirms Prader-Willi syndrome (PWS) in 99% of individuals with symptoms meeting consensus criteria
  • Determination of molecular mechanism for PWS
    • Methylation-sensitive PCR detects 99% of affected individuals but will not specify molecular mechanism of PWS; however, current standard of care for PWS patients does not differ based on identified molecular mechanism
    • Cytogenetic testing (FISH metaphase) detects a deletion in the Prader-Willi critical region (PWCR) on chromosome 15 (15q11-q13) in 70% of affected individuals
    • Uniparental disomy testing detects 20-25% of cases
    • Chromosome analysis detects balanced chromosome rearrangements that interrupt the PWCR in <1% of affected individuals
  • Prenatal diagnosis – rarely made but theoretically could use amniocentesis or chorionic villus sampling samples

Differential Diagnosis

  • Craniopharyngioma
  • Growth hormone deficiency
  • Hypotonia in infancy
    • Congenital myotonic dystrophy
    • Spinal muscular atrophy
  • Bardet-Biedl syndrome
  • Developmental delay in childhood
    • Fragile X syndrome
    • Rett syndrome
    • Other rare developmental delay disorders, including Cohen syndrome, Albright hereditary osteodystrophy

Developmental Delay (DD) Testing Algorithm

Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder characterized by severe hypotonia and feeding difficulties in infancy with gradual development of hyperphagia and morbid obesity in early childhood, as well as development of short stature, scoliosis, and maladaptive and compulsive behaviors.


  • Incidence – 1/10,000-25,000
  • Sex – M:F, equal

Recurrence Risk

  • To determine the recurrence risk for parents, the specific genetic mechanism causing PWS in the prior affected child must be determined
    • Recurrence risk for parents whose previous child has an imprinting center mutation – up to 50%
    • Recurrence risk for parents whose affected child has PWS due to any mechanism besides an imprinting center mutation – <1%


  • 15q11-q13 region harbors several genes regulated by genomic imprinting
    • Genes are expressed from one parental allele – gene is functionally haploid
  • Three disorders occur from deletion/duplications at this locus – PWS, Angelman syndrome, dup 15q syndrome
    • 70% have a deletion on one number 15 chromosome involving bands 15q11-q13, known as the PWS/Angelman syndrome (AS) critical region
    • 25% have maternal uniparental disomy of chromosome 15
    • <5% have an imprinting center defect 

Clinical Presentation

  • Severe hypotonia and feeding difficulties in infancy
  • Delayed motor and language milestones (developmental delay)
  • Behavioral problems – temper tantrums, stubbornness, obsessive-compulsive traits
    • Autism reported in patients with maternal uniparental disomy
  • Hypogonadism, cryptorchidism
  • Short stature, small hands and feet
  • Facial features – narrow bifrontal diameter, downturned mouth, almond-shaped palpebral fissures
  • Hyperphagia and morbid obesity (begins between ages 1-6 years)
  • Complications of obesity are the main cause of morbidity and mortality


  • Multidisciplinary approach – physical, speech, occupational and behavioral therapies
  • Consider growth hormone treatment
  • Orthopedic treatment for scoliosis
  • Screen for causes of possible morbidity, including central adrenal insufficiency due to stressful conditions and obstructive/central sleep apnea
  • Weight management programs
  • Consider sex steroid replacement based on individual assessment and bone mineral density
  • Discourage pregnancy in females because of cognitive dysfunction and the risk of Angelman syndrome in offspring of mothers with 15q11-q13 deletion
  • Alert medical team performing surgical procedures to potential increased risk of complications from anesthesia

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Angelman Syndrome and Prader-Willi Syndrome by Methylation 2005077
Method: Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring


Specific molecular mechanism responsible for abnormal methylation results cannot be determined

AS resulting from molecular mechanisms that do not affect methylation patterns will not be identified

Diagnostic errors can occur due to rare sequence variations

Chromosome FISH, Metaphase 2002299
Method: Fluorescence in situ Hybridization


PWS caused by uniparental disomy or imprinting center defects will not be detected; therefore, it is recommended that the methylation sensitive polymerase chain reaction/fluorescent monitoring test be performed instead of the FISH assay

Additional Tests Available

Angelman Syndrome (UBE3A) Sequencing 2005564
Method: Polymerase Chain Reaction/Sequencing


Second-tier test for the diagnosis of AS

Order if suspicion for AS remains after normal methylation analysis

For first-tier testing, refer to methylation test

Regulatory mutations, deep intronic mutations, and large deletions/duplications will not be detected

Diagnostic errors may occur due to rare sequence variations

Clinical sensitivity – 11% (Lossie, 2001)

Analytical sensitivity – 99%

Angelman Syndrome and Prader-Willi Syndrome by Methylation, Fetal 2012232
Method: Methylation Sensitive Polymerase Chain Reaction/Fluorescence Monitoring


Prenatal testing for AS or PWS

Identifies cases resulting from molecular mechanisms that produce abnormal methylation patterns

General References

Buiting K. Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C Semin Med Genet. 2010; 154C(3): 365-76. PubMed

Chen C, Visootsak J, Dills S, Graham J. Prader-Willi syndrome: an update and review for the primary pediatrician. Clin Pediatr (Phila). 2007; 46(7): 580-91. PubMed

Driscoll D, Miller J, Schwartz S, Cassidy S. Prader-Willi Syndrome. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jan 2014; Accessed: Nov 2015]

Goldstone A, Holland A, Hauffa B, Hokken-Koelega A, Tauber M, speakers contributors at the Second Expert Meeting of the Comprehensive Care of Patients with PWS. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008; 93(11): 4183-97. PubMed

Kalsner L, Chamberlain S. Prader-Willi, Angelman, and 15q11-q13 Duplication Syndromes. Pediatr Clin North Am. 2015; 62(3): 587-606. PubMed

Wattendorf D, Muenke M. Prader-Willi syndrome. Am Fam Physician. 2005; 72(5): 827-30. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Medical Reviewers

Last Update: December 2015