Clinical Presentation of Fragile X Syndrome
Fragile X syndrome presents with specific cognitive deficits accompanied by characteristic but nonspecific physical features and behavioral manifestations, with full penetrance in males and variable expression in females. 1
Core Clinical Features
Cognitive and Developmental Manifestations
- Intellectual disability is the hallmark feature, representing the leading inherited cause of cognitive impairment and the second most common identifiable genetic cause after Down syndrome 2, 3
- Learning difficulties range from mild to severe, with males typically more severely affected than females due to X-linked inheritance 1
- Language deficits including delayed speech development and poor language acquisition are prominent features 4, 5
- Autism spectrum disorder (ASD) occurs in approximately 20% of boys with fragile X syndrome when evaluated by objective diagnostic criteria 1
Physical Characteristics
- Macroorchidism (enlarged testicles) is a characteristic finding in males, though not present in early childhood 6
- Long face with prominent ears represents the typical craniofacial dysmorphology 6
- Joint hypermobility is frequently observed on physical examination 6
- Cardiac abnormalities including mitral valve prolapse and aortic root dilation occur in approximately 50-80% of males with fragile X syndrome 6
Behavioral and Psychiatric Features
- Hypersensitivity to stimuli and overarousability are defining behavioral characteristics 2
- Hyperactivity and inattention consistent with ADHD presentation are common 4, 2
- Social anxiety represents the most frequent psychiatric comorbidity, along with other anxiety disorders 2, 7
- Explosive and aggressive behavior toward others or self, particularly in males, requires behavioral and pharmacological management 2
- Impulsivity and poor impulse control contribute to challenging behaviors 2
Associated Medical Complications
- Seizures develop in approximately 10-20% of individuals with fragile X syndrome 6
- Recurrent otitis media and hearing difficulties are frequent complications requiring audiologic assessment 6
- Strabismus and refractive errors necessitate ophthalmologic evaluation 6
- Sleep problems commonly exacerbate behavioral symptoms 5, 7
Premutation Carrier Presentations (55-200 CGG Repeats)
Pediatric Premutation Carriers
- Most individuals with premutations do not show fragile X syndrome-related features, though some with high repeat sizes (>100 repeats) may present with learning difficulties, emotional problems, or even intellectual disability 1
- Anxiety, ADHD, social deficits, or autism spectrum disorders can occur in children carrying premutations 7
Adult Female Premutation Carriers
- Fragile X-associated primary ovarian insufficiency (FXPOI) affects approximately 20% of females with premutations, typically those with >80 CGG repeats 1, 6
- Anxiety and depression are the most common neuropsychiatric problems in adult female carriers 7
- Chronic fatigue, chronic pain, and fibromyalgia frequently accompany neuropsychiatric symptoms 7
Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
- Late-onset progressive intention tremor and ataxia typically manifesting in males over age 50 who carry premutations 1, 6
- Progressive cognitive decline including memory loss, deficits of executive function, and dementia 1
- Behavioral changes including anxiety, reclusive behavior, and mood disturbances 1
- Peripheral neuropathy may accompany the movement disorder 6
- Penetrance increases with age and premutation repeat length, with higher risk in males compared to females 1
Gender-Specific Considerations
Males with Full Mutation
- All males with full mutations are penetrant for intellectual disability and associated features 1
- More severe phenotype compared to females due to hemizygous expression 1
Females with Full Mutation
- Variable expression due to X-inactivation patterns, with many but not all females affected 1
- Milder cognitive deficits on average compared to males, though severity varies considerably 1