• Definition: an X-linked dominant disease caused by a CGG trinucleotide repeat expansion in the FMR1 gene (fragile X mental retardation 1 gene) during oogenesis. This leads to its hypermethylation, which silences the gene and renders it unable to express its physiological gene product.
• Epidemiology
  • Second most common genetic cause of intellectual disability (after trisomy 21)
  • Most common inherited cause of intellectual disability, as trisomy 21 mostly occurs sporadically
• Clinical features: The clinical presentation varies depending on the number of trinucleotide repeats.
  • 50–200 repeats (premutation): ataxia, primary ovarian insufficiency, tremor
  • 200 repeats (full mutation):
    • Intellectual disability of varying severity
    • Delayed language development
    • Behavioral features: autistic behavior, hyperactivity, anxiety
    • Characteristic facial anomalies
      • Long and narrow face
      • Prominent forehead and jaw
      • Large everted ears
    • Hypermobile joints
    • In men: postpubertal macroorchidism (enlarged testes; rarely occurs prior to puberty)
    • Mitral valve prolapse: can lead to mitral regurgitation
    • Above-average head circumference

Mnemonic

Fragile X: “X-tra large” ears, testes, and face in these patients.