Approach

Prader-Willi syndrome (PWS) is a rare (present in approximately 1 in 10,000 to 1 in 25,000 live births) multisystem neurologic disorder and is caused by paternally inherited genetic defects on chromosome 15q11-q13 due to any of three genotypes: deletion, maternal uniparental disomy of chromosome 15, or imprinting defect.[1][2][3]​​​[26]

It is usually diagnosed in infants and young children by identification of characteristic features with confirmation using genetic testing.[1][2][3]​​​[26]​ The clinical features of PWS may be extensive and wide ranging; in general, however, genetic testing in an infant or young child should be prompted by the presence of hypotonia, difficulty feeding, and/or hypogonadism.[2]

Complications of PWS include type 2 diabetes and gastrointestinal and respiratory issues.[2][3]​​ See Complications.

History

Consider PWS in an infant or young child with:[1][2][3]​​​

  • Features of hypotonia (e.g., weak cry, poor suck, gross motor delay)

  • Difficulty feeding

    • In practice, if a baby has not required a feeding tube or assisted feeding in the neonatal period it is very unlikely that they have PWS.

Prenatally, there may be a history of polyhydramnios and decreased fetal movements.[2][26]

Although PWS is usually diagnosed in infants and young children, patients may also present in adolescence or early adulthood.[1][2][3]​​​ Depending on the age of the patient, other features from the history include:[1][2][3]​​​

  • Weight gain (which usually begins around 18 to 26 months of age) and hyperphagia (which usually begins around 6 to 12 years of age)[26]

  • Developmental delay

  • Cognitive disability

  • Sleep abnormalities

  • Characteristic behaviors (e.g., temper tantrums, skin picking, other compulsive and autistic spectrum behaviors)[1][26]

  • Psychiatric disorders (e.g., psychosis, mood disorders).[26]

Less common features include:[1][2][3]​​​

  • Seizures

  • Premature adrenarche.

The diagnosis is unlikely in patients with obesity who do not have a history of neonatal feeding problems, hypotonia, or developmental delay.[17]

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Physical exam

Examine the patient for the key physical features of PWS:[1][2][3]​​

  • Central hypotonia, which is common in infants and tends to improve with age but is present throughout life[26]

  • Hypogonadism[26]

    • Other endocrine disorders such as growth hormone deficiency, diabetes mellitus, and hypothyroidism may also be present.

Other physical features include:

  • Short stature[1][2][3]​​[26]

  • Small hands and feet[1][2][3]​​

  • Hypopigmentation[2]

  • Ocular problems (e.g., strabismus, myopia)[1][2][3]​​

  • Spinal deformities[1][2][3]​​

  • Developmental dysplasia of the hip in neonates (although this is uncommon).[1][3]​​

Genetic testing

Organize DNA methylation testing if PWS is suspected, which will confirm the diagnosis in >99% of patients with PWS.[1][3]​​​ In general, key features that should prompt DNA methylation testing include one or more of the following: hypotonia, difficulty feeding, and/or hypogonadism.[2] A full list of clinical features by age that can help guide which patients should undergo DNA methylation testing has been proposed. See Criteria.

Refer the patient to a medical geneticist for further genetic testing if PWS is confirmed to determine the specific genotype (deletion, maternal uniparental disomy of chromosome 15, or imprinting defect).[3][25]

If there are existing genetic test results, repeat testing is not recommended unless there is uncertainty about the existing result, e.g., the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[27]

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