Fragile X Syndrome

Background

• Fragile X syndrome is a genetic disorder characterized by intellectual disability and other neurodevelopmental disorders, especially attention deficit hyperactivity disorder and features of autism spectrum disorder.
• It is caused by X-linked dominant inheritance of a mutation on the fragile X intellectual disability (FMR1) gene.
• Clinical features are similar in males and females, but females may have milder phenotype, which includes:
  • developmental delay and cognitive impairment - almost all males and about 25% of females have intellectual disability (IQ < 70)
  • behavior problems, especially autistic behaviors including hand flapping and biting, difficulty with eye contact and shyness, and hyperactivity
  • characteristic craniofacies (long face, prominent forehead and jaw, large protuberant ears) and other physical features such as flexible fingers, flat feet, and rapid growth in childhood
  • macroorchidism in adolescent and adult males
• Common complications include seizures, ophthalmologic, orthopedic, and dental abnormalities, feeding problems in infants, and mitral valve prolapse in adults.

Evaluation

• Suspect fragile X syndrome in patients with intellectual disability, developmental delay, or autism, especially in those with any of:
  • characteristic physical or behavioral features
  • family history of fragile X syndrome
  • relatives with intellectual disability of unknown etiology
• Perform molecular genetic testing.
  • FMR1 loss-of-function mutation confirms the diagnosis.
    • Full mutation consisting of > 200 cytosine-guanine-guanine (CGG) nucleotide repeats and associated hypermethylation is present in > 99%.
    • Deletion or other alteration is present in < 1%.
  • Premutation consisting of 55-200 CGG repeats indicates increased risk for other FMR1 gene disorders, and offspring of female premutation carriers are at increased risk for fragile X syndrome.
• After diagnosis, perform additional evaluations directed toward establishing disease severity and identifying comorbidities.
  • Include developmental, behavioral, and psychological assessments.
  • Perform additional testing based on clinical findings.

Management

• Provide supportive, symptom-based treatment such as:
  • early developmental and educational interventions
  • behavioral intervention to address autistic behaviors, anxiety, and attention deficit hyperactivity disorder symptoms
  • pharmacologic - for behavioral problems such as hyperactivity and symptoms like anxiety
  • monitoring and treatment for complications and comorbid conditions