Prader-Willi Syndrome and Angelman Syndrome

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are both rare autosomal neurodevelopmental genetic disorders mapped to a specific region of chromosome 15 attributed to genomic imprinting. This means that the phenotype depends on the gender of the parent donating the genes. A paternally derived chromosome 15 with this deletion results in 15q11-13 paternal deletion syndrome, or PWS, whereas a maternally derived chromosome 15 with a similar deletion is associated with AS. Diagnosis is established with genetic testing. Management is mostly supportive and is focused on early intervention for developmental, neurologic, and physical abnormalities.

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Prader-Willi syndrome (PWS) is a condition associated with loss of the paternal chromosome 15q11-13 region and is characterized by intellectual disability, short stature, underdevelopment of the sexual organs, and obesity.

Angelman syndrome (AS) is a disorder associated with loss of the maternal chromosome 15q11-13 region and is characterized by severe neurodevelopmental delay.


  • PWS:
    • Prevalence is about 1 in 15,000 to 1 in 30,000 live births in the United States, and affects between 350,000 and 400,000 individuals worldwide.
    • Both sexes are affected equally.
  • AS:
    • Prevalence of AS is about 1 in 10,000 to 1 in 20,000 live births.
    • No gender or racial predominance 
  • Vast majority of cases are sporadic rather than familial.


  • Prader-Willi syndrome: loss of paternal copy of the chromosome 15q11-13 region
  • Angelman syndrome: loss of maternal copy of the chromosome 15q11-13 region


Both PWS and AS are associated with genomic imprinting, which is the differential expression of certain genes based on inheritance from a specific parent.

Angelman syndrome

  • AS is caused by the absence of a maternal copy of the UBE3A gene: 
    • The UBE3A gene encodes E6-associated protein ubiquitin protein ligase 3A.
    • Only the maternally inherited copy of UBE3A is functional in certain areas of the brain; the paternal copy is silent.
  • Most cases (> 70%) are caused by the absence of maternal homologous segment (microdeletion). 
  • A smaller percentage of cases is caused by uniparental disomy (duplication of paternal 15q segment), translocations, or mutations.

Prader-Willi syndrome

  • PWS is caused by:
    • Absence of paternal homologous segment (microdeletion) in 70% of cases 
    • Duplication of maternal chromosome 15q segment (uniparental disomy) in 25% of cases
    • The rest (5%) are caused by translocations or mutations.
  • The end result is an absence of working copies of about 7 genes, as parts of maternal chromosomes are inactive by default; require paternal counterpart to function.

Clinical Presentation

Prader-Willi syndrome

  • At birth:
    • Hypotonia and lethargy
    • Feeding and breathing difficulty
    • Undescended testes in males
  • Childhood:
    • Hyperphagia, insatiable appetite, weight gain, and obesity due to high ghrelin levels
    • Small hands and feet
    • Strabismus
    • Speech delay
    • Mild intellectual disabilities and behavioral issues
  • Adulthood:
    • Borderline intellectual capability
    • Short stature
    • Hypogonadism 
    • Facial features:
      • Almond-shaped eyes
      • Narrow forehead
      • Triangular mouth
Prader-Willi syndrome

Prader-Willi syndrome:
typical facial features and truncal obesity

Image: “Prader-Willi syndrome” by The Prader-Willi Syndrome Center at Winthrop University Hospital, 120 Mineola Blvd,-Suite 210, Mineola, N,Y, 11501, USA. License: CC BY 2.0

Angelman syndrome

  • At birth:
    • Microcephaly
    • Feeding issues
  • Childhood and adulthood:
    • Severe developmental delay
    • Behavioral: inappropriate laughter, seemingly happy demeanor, short attention span (“happy puppet syndrome”)
    • Lack of proper speech, use of nonverbal communication skills
    • Movement disorders such as ataxia, fine tremors, jerky movements
    • Prominent mandible, flat head
    • Strabismus
    • Seizures (onset by 3 years) and abnormal EEG tracings
    • Sleep disturbances
Angelman syndrome

Angelman syndrome: typical craniofacial features, happy demeanor

Image: “Angelman syndrome” by Department of Genetics, Medical School of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil. License: CC BY 2.0


Prader-Willi syndrome

  • Genetic testing:
    • DNA methylation testing: detects parent-specific imprinting of the specific chromosome 15 region
    • Establishes diagnosis in > 99% of patients
  • Clinical criteria for genetic testing:
    • Birth to 2 years:
      • Hypotonia with poor suck and poor weight gain
      • Cryptorchidism in boys
    • 2–6 years:
      • Hypotonia with history of poor suck
      • Global developmental delay
      • Short stature and/or growth failure associated with accelerated weight gain
    • 6–12 years:
      • History of hypotonia with poor suck (hypotonia often persists)
      • Global developmental delay
      • Excessive eating (hyperphagia (obsession with food)), with obesity if food intake is uncontrolled
    • 13 years through adulthood:
      • Cognitive impairment (usually mild intellectual disability)
      • Excessive eating (hyperphagia), with central obesity if uncontrolled
      • Hypogonadism (e.g., delayed puberty)
      • Typical behavior problems (including temper tantrums and obsessive-compulsive features)

Angelman syndrome

  • Genetic testing:
    • DNA methylation study is the 1st test.
    • This test is followed by genomic hybridization technique to detect specific deletion (class 1 (more severe) or class 2).
    • If negative, perform uniparental disomy studies
  • Clinical diagnostic criteria:
    • History of neurodevelopmental, cognitive, and speech development delay
    • History of seizures
    • General happy demeanor, inappropriate laughter
    • Characteristic facies
    • Odd limb movements, such as hand flapping
    • Fine tremors, jerky joint dispositions, seemingly spastic wide-based gait


Prader-Willi syndrome management

  • Diet modification for obesity
  • Behavioral therapy, possible selective serotonin reuptake inhibitors (SSRIs) for obsessive-compulsive behaviors
  • Speech therapy
  • Physical therapy
  • Human growth hormone may improve stamina and muscle mass, but is associated with tonsillar hypertrophy, which can cause early demise.
  • Prognosis:
    • Usually reach adulthood
    • Able to function in a group setting and do vocational work
    • Some patients can attend community colleges.

Angelman syndrome management

  • EEG, analysis, and treatment of seizure disorder with anticonvulsant drugs
  • Address feeding problems.
  • Physical therapy to help with ataxia
  • Speech and occupational therapy
  • Clonidine and melatonin to help with sleep disturbances
  • Prognosis:
    • Can have a normal life span with appropriate interventions
    • Severe intellectual disability

Differential Diagnosis

  • Fragile X syndrome: a genetic abnormality on the X chromosome that leads to intellectual disability and behavioral disorders. Diagnosis is with molecular DNA analysis. Treatment is supportive.
  • Craniopharyngioma: a slow-growing, noncancerous brain tumor that develops near the pituitary gland and the hypothalamus. The tumor most commonly affects children between 5 and 10 years of age; however, adults can sometimes be affected.
  • Cohen syndrome: a congenital condition manifesting with obesity, hypotonia, intellectual disabilities, distinctive facial features with prominent upper central teeth, and abnormalities of the hands and feet.
  • Albright hereditary osteodystrophy: a rare disorder with a wide range of signs and symptoms, including short stature, obesity, round face, subcutaneous ossifications, and brachydactyly. When the disorder is inherited from the mother, resistance to parathyroid hormone is found. When inherited from the father, this resistance is not seen. 
  • Spinal muscular atrophy: is a neuromuscular disorder with a genetic etiology that causes degenerative changes in the spinal cord and brainstem, resulting in progressive muscle weakness and loss of movement due to muscle atrophy. The age of onset, severity of symptoms, and clinical presentation vary by type. It can affect the arm and leg muscles resulting in difficulty walking, as well as difficulty with breathing and swallowing.
  • Alström syndrome: a rare genetic disorder that affects many body systems including vision and hearing abnormalities, childhood obesity, and cardiomyopathy. Alström syndrome is caused by mutations in the ALMS1 gene and is of autosomal recessive inheritance.


  1. Bacino, C. Microdeletion Syndromes (chromosomes 12 to 22). UpToDate. Retrieved March 22, 2021, from
  2. Scheimann, A.O. (2021) Epidemiology and genetics of Prader-Willi syndrome. UpToDate. Retrieved March 22, 2021, from
  3. Diseases | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. Retrieved March 23, 2021, from
  4. Driscoll DJ, Miller JL, Schwartz S, and Cassidy SB. (2016). Prader-Willi Syndrome. GeneReviews.

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