Could a 3-year-old with cognitive dysfunction, long ears, and hand flapping/shaking be diagnosed with Angelman syndrome or Fragile X syndrome?

Differential Diagnosis: Fragile X Syndrome vs Angelman Syndrome

Based on the clinical presentation of long ears and hand flapping/shaking in a 3-year-old with cognitive dysfunction, Fragile X syndrome is the more likely diagnosis, and molecular testing for FMR1 gene should be performed first. 1

Clinical Feature Analysis

The combination of long ears (a characteristic dysmorphic feature) and stereotypic hand movements (flapping/shaking) points more strongly toward Fragile X syndrome than Angelman syndrome. Here's why:

Features Favoring Fragile X Syndrome:

• Long, prominent ears are a classic dysmorphic feature of Fragile X syndrome 1
• Hand flapping is commonly seen in Fragile X syndrome, which is the leading monogenetic cause of autism spectrum behaviors 1
• Cognitive dysfunction and developmental delay are universal in Fragile X syndrome 1

Features of Angelman Syndrome (Less Consistent with This Case):

• Angelman syndrome typically presents with ataxic gait and tremulousness of limbs rather than hand flapping 2
• The behavioral profile in Angelman syndrome is characterized by a happy demeanor and hypermotoric behavior, not primarily stereotypic hand movements 2, 3
• Angelman syndrome patients have severe to profound mental retardation with a characteristic happy/sociable disposition 3
• Microcephaly is present in >80% of Angelman syndrome cases, which should be assessed 2

Diagnostic Testing Algorithm

Step 1: Initial Molecular Testing

• For suspected Fragile X syndrome: Order FMR1 gene testing by polymerase chain reaction (PCR) to detect CGG triplet repeats (>200 repeats confirms diagnosis) 1
• The American Academy of Pediatrics recommends testing individuals with intellectual disability, global developmental delay, autism, or family history of the mutation 4, 1

Step 2: If Fragile X Testing is Negative

• Consider Angelman syndrome testing: Perform DNA methylation analysis using SNRPN or PW71B probes as the first-line test, which detects approximately 99% of Angelman syndrome cases 5, 4
• If only paternal methylation pattern is present, Angelman syndrome is confirmed 6
• If biparental inheritance is identified, Angelman syndrome is ruled out 6

Step 3: Additional Considerations

• Approximately 70% of Angelman syndrome cases have a deletion of 15q11-q13 on the maternal chromosome 6, 2
• About 3% show paternal uniparental disomy, 1% have imprinting center mutations, and 6% have UBE3A gene mutations 2
• Important caveat: 20% of Angelman syndrome cases have no detectable genetic abnormality, so clinical diagnosis may still be considered if testing is negative 2, 7

Key Distinguishing Clinical Features to Assess

Examine for Fragile X-Specific Features:

• Long, prominent ears (already noted) 1
• Macroorchidism (in post-pubertal males)
• Autism spectrum behaviors including hand flapping 1

Examine for Angelman-Specific Features:

• Happy demeanor with frequent laughter (highly characteristic) 2, 3
• Ataxic, wide-based gait 2
• Tremulousness of limbs (not just hand movements) 2
• Microcephaly (measure head circumference) 2
• History of seizures or abnormal EEG (present in >80% of cases) 2

Common Pitfalls to Avoid

• Do not rely solely on hand movements to differentiate these conditions—the quality and context matter. Hand flapping with autism features suggests Fragile X, while tremulousness with happy affect suggests Angelman 2, 1
• Do not overlook other mimicking conditions including Rett syndrome, chromosome 22q13 deletion, and other developmental disorders if initial testing is negative 7
• If Angelman syndrome testing is pursued and negative, consider that 15-20% of cases may be missed by standard methylation testing and may require UBE3A gene sequencing 6