What is the diagnostic approach for Prader-Willi Syndrome?

Diagnostic Approach for Prader-Willi Syndrome

DNA methylation analysis should be the first-line diagnostic test for Prader-Willi Syndrome (PWS), as it can detect approximately 99% of cases regardless of the underlying genetic mechanism. 1

Clinical Suspicion and Indications for Testing

The clinical presentation of PWS varies by age, with different features prompting suspicion at different life stages:

Neonates and Infants

• Unexplained hypotonia with poor suck requires immediate PWS testing 1, 2
• Feeding difficulties requiring assisted feeding methods 1
• Characteristic facial features (almond-shaped eyes, thin upper lip, downturned mouth) may be present but are less reliable (sensitivity only 49%) 2

Children (2-6 years)

• History of hypotonia with poor suck in infancy plus global developmental delay warrants testing 2
• Delayed motor and speech milestones 3
• Short stature (present in 53% of cases) 3

School-Age Children (6-12 years)

• Hypotonia history plus developmental delay plus excessive eating with central obesity 2
• Food-seeking behaviors and hyperphagia (reported in 67% of cases) 3
• Small hands and feet relative to body size 4

Adolescents and Adults (13+ years)

• Cognitive impairment with excessive eating and central obesity 2
• Hypogonadotropic hypogonadism (underdeveloped external genitalia present in 100% of cases) 3
• Behavioral problems including temper tantrums and obsessive-compulsive features 2

Diagnostic Testing Algorithm

Step 1: DNA Methylation Analysis

• Conduct methylation analysis using Southern hybridization with methylation-sensitive SNRPN or PW71B probes 1
• If only maternal methylation pattern is present, PWS is confirmed 1
• If biparental inheritance is identified, PWS is ruled out 1

Step 2: Determine Specific Genetic Mechanism (after positive methylation test)

• Perform FISH analysis with SNRPN probe and chromosome 15 centromeric probe 1, 4

  • Deletion of 15q11-q13 (accounts for >70% of PWS cases) 1
  • FISH can detect most deletions that high-resolution chromosome analysis might miss 4

• If no deletion is found by FISH, perform microsatellite analysis to detect maternal UPD 1

  • Maternal uniparental disomy accounts for approximately 28% of cases 1
  • Uses PCR with informative markers to trace chromosome 15 inheritance 1

• If neither deletion nor UPD is found, suspect imprinting center defect (rare, <2% of cases) 1

  • May require referral to specialized research laboratory 1

Important Considerations

• Chromosome analysis should be performed routinely to rule out other abnormalities or rare translocations 1

• Recurrence risk varies by genetic mechanism: 1

  • Deletions and UPD have low recurrence risk (approximately 1%)
  • Imprinting mutations can have up to 50% recurrence risk
  • Important for genetic counseling purposes

• If clinical suspicion remains high despite negative testing, consider: 1

  • Consultation with a clinician experienced in PWS
  • Evaluation for conditions with overlapping features (Williams syndrome, Smith-Magenis syndrome, fragile X) 1
  • Referral to a research laboratory for further molecular investigation 1

Prenatal Diagnosis

• Prenatal testing is possible in specific circumstances: 1
  • When cytogenetic deletion is suspected on CVS or amniocentesis
  • When trisomy 15 mosaicism is detected
  • When there is prenatal identification of a translocation involving chromosome 15
  • For reassurance in families with previous PWS cases, even though recurrence risk is low for most cases 1

Common Pitfalls to Avoid

• Relying solely on high-resolution chromosome analysis, which is insufficient for diagnosis 1
• Waiting for all clinical features to appear before testing, as many evolve over time 2
• Missing the diagnosis in infants who are still in the failure-to-thrive phase before hyperphagia develops 2
• Failing to test hypotonic infants with feeding difficulties, as these are the earliest and most consistent signs (present in >97% of cases) 2