Overview
Definition:
Fragile X syndrome (FXS) is an inherited genetic disorder that causes intellectual disability, developmental delays, and behavioral and learning challenges
It is the most common inherited cause of intellectual disability and a leading genetic cause of autism spectrum disorder.
Epidemiology:
FXS affects approximately 1 in 4,000 to 5,000 males and 1 in 8,000 to 10,000 females
The prevalence is consistent across different ethnic groups
Carrier rates for premutation alleles are higher, with about 1 in 250 females and 1 in 500 males carrying a premutation allele.
Clinical Significance:
Understanding FXS is crucial for pediatricians to ensure early diagnosis, implement appropriate developmental support services, manage associated comorbidities, and provide genetic counseling to affected families
Early intervention significantly improves long-term outcomes.
Clinical Presentation
Symptoms:
Developmental delays in reaching milestones like sitting and walking
Intellectual disability, ranging from mild to severe
Speech and language problems, including delayed speech, difficulties with articulation, and stuttering
Attention deficit hyperactivity disorder (ADHD)
Autistic behaviors, such as poor eye contact, repetitive movements, and social interaction challenges
Physical features, which can become more apparent with age: long face, prominent jaw, large ears, broad forehead, and postpubertal macroorchidism in males
Seizures occur in approximately 10-15% of individuals with FXS.
Signs:
Long face with prominent jaw and large ears
Large testicles (macroorchidism) in postpubertal males
Hypotonia
Hypermobile joints
Flat feet
Sometimes, mitral valve prolapse.
Diagnostic Criteria:
There are no formal diagnostic criteria in the sense of symptom thresholds, as FXS is a genetic disorder
Diagnosis is confirmed by genetic testing that identifies mutations in the FMR1 gene
Clinical suspicion should be high in individuals presenting with developmental delays, intellectual disability, and/or autism spectrum disorder, especially with a family history suggestive of X-linked inheritance.
Diagnostic Approach
History Taking:
Detailed developmental history, including age of milestones
Family history of intellectual disability, autism, or similar features, especially on the maternal side
History of behavioral issues, including attention problems and social interaction difficulties
Previous genetic testing results or known genetic conditions in the family
Presence of seizures.
Physical Examination:
Assess for characteristic facial features (long face, prominent jaw, large ears)
Evaluate for hypotonia and joint hypermobility
Check for macroorchidism in males
Assess growth parameters
Perform a thorough neurological examination
Screen for cardiac murmurs suggesting mitral valve prolapse.
Investigations:
Molecular genetic testing for the FMR1 gene is the gold standard
This typically involves Southern blot analysis or repeat-primed PCR to detect the expanded CGG trinucleotide repeat in the promoter region of the FMR1 gene
Analysis of repeat size distinguishes between normal, intermediate, premutation, and full mutation alleles
Cytogenetic testing (karyotype) may be considered if other genetic abnormalities are suspected
Electrophysiology (EEG) if seizures are present
Echocardiography if mitral valve prolapse is suspected.
Differential Diagnosis:
Other causes of intellectual disability: Down syndrome, Prader-Willi syndrome, Angelman syndrome, other chromosomal abnormalities
Autism spectrum disorder: Idiopathic autism, Rett syndrome, other genetic causes of autism
ADHD
Other genetic syndromes with developmental delay and distinctive features.
Developmental Support And Management
Early Intervention:
Multidisciplinary approach focusing on speech therapy, occupational therapy, and physical therapy
Early intervention programs (Birth to Three) are critical for infants and toddlers with developmental delays
Behavioral therapy and applied behavior analysis (ABA) for autistic features and behavior management
Special education services tailored to individual learning needs.
Educational Support:
Individualized Education Programs (IEPs) in school settings
Support with academic learning, social skills development, and behavioral strategies
Vocational training and life skills development for adolescents and adults.
Medical Management:
Management of associated medical conditions: ADHD (stimulants or non-stimulants), anxiety (SSRIs), seizures (antiepileptic drugs like levetiracetam or valproate)
Cardiac management for mitral valve prolapse if symptomatic
No specific pharmacologic treatment exists for the core symptoms of FXS itself, but medications can manage comorbidities.
Family Support And Counseling:
Genetic counseling for families to understand inheritance patterns, recurrence risks, and implications
Support groups and resources for families of individuals with FXS
Psychological support for parents and siblings to cope with the diagnosis and challenges.
Complications
Common Comorbidities:
Autism spectrum disorder features are present in up to 60% of individuals with FXS
ADHD is common, affecting a large proportion of affected individuals
Anxiety disorders and mood disorders are prevalent in adolescents and adults
Seizures occur in about 10-15%
Mitral valve prolapse is a cardiac complication that may require management.
Behavioral Challenges:
Aggression, self-injury, hyperactivity, social withdrawal, and sensory sensitivities can be significant challenges requiring tailored behavioral interventions.
Long Term Sequelae:
Ongoing intellectual disability, persistent learning difficulties, and potential for chronic mental health issues require lifelong support and management
Premutation carriers are at risk for Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI).
Prognosis
Factors Affecting Prognosis:
Severity of intellectual disability, presence and severity of associated comorbidities (autism, ADHD, seizures), and access to early and consistent therapeutic interventions
Family support and resources also play a role.
Outcomes:
With comprehensive developmental support and management of comorbidities, individuals with FXS can achieve varying degrees of independence
Many can learn to read, write, and perform daily living skills
Social engagement and vocational potential vary widely
Lifelong support is often necessary.
Follow Up:
Regular developmental assessments throughout childhood and adolescence
Annual check-ups with pediatrician to monitor growth, development, and manage comorbidities
Specialist follow-up as needed for cardiology, neurology, psychiatry, and genetics
Transition to adult healthcare services.
Key Points
Exam Focus:
FXS is the most common inherited cause of intellectual disability and a leading genetic cause of ASD
Caused by CGG repeat expansion in the FMR1 gene on the X chromosome
Full mutation (>200 CGG repeats) leads to gene silencing
Diagnosis is by molecular genetic testing (FMR1 gene analysis)
Key features include intellectual disability, developmental delay, behavioral issues (ADHD, ASD traits), and characteristic physical features
Management is supportive and multidisciplinary.
Clinical Pearls:
Always consider FXS in children with unexplained intellectual disability or ASD, particularly with a suggestive family history
Early intervention is paramount for improving developmental outcomes
Be vigilant for associated medical comorbidities like seizures and mitral valve prolapse
Remember premutation carriers are at risk for FXTAS and FXPOI.
Common Mistakes:
Delayed diagnosis due to not considering genetic causes of developmental delay
Inadequate multidisciplinary support
Underestimating the importance of family genetic counseling
Failing to screen for associated medical conditions
Confusing FXS with idiopathic autism or ADHD without genetic workup.