Fragile X Syndrome (Child)
Summary
Fragile X Syndrome (FXS) is the Most Common Inherited Cause of Intellectual Disability and the Most Common Single-Gene Cause of Autism Spectrum Disorder (ASD). It is an X-Linked Dominant Disorder caused by a CGG Trinucleotide Repeat Expansion in the 5' Untranslated Region of the FMR1 Gene on the X chromosome, leading to gene silencing and Loss of Fragile X Mental Retardation Protein (FMRP). FMRP is critical for Synaptic Plasticity and Normal Brain Development. The condition affects approximately 1 in 4,000 males and 1 in 6,000-8,000 females. Males are typically more severely affected than females due to X-inactivation in females. Clinical features include Intellectual Disability (Mild to Severe), Characteristic Physical Features (Long face, Large prominent ears, Macroorchidism post-puberty), Behavioural Abnormalities (ADHD, Anxiety, ASD features, Hand-flapping), And Connective Tissue Abnormalities (Joint hypermobility, Mitral valve prolapse). Diagnosis is by DNA Testing for CGG Repeat Number. Management is Multidisciplinary and Supportive, including educational support, Speech and language therapy, Behavioural interventions, And treatment of comorbidities. There is no cure, But early intervention improves outcomes. Genetic Counselling is essential for families. Related conditions include Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) in older male premutation carriers and Fragile X-Associated Primary Ovarian Insufficiency (FXPOI) in female premutation carriers. [1,2,3]
Key Facts
| Fact | Value |
|---|---|
| Definition | X-linked dominant disorder due to FMR1 CGG expansion |
| Most Common Inherited ID | Yes |
| Most Common Single-Gene ASD | Yes |
| Prevalence (Males) | ~1:4,000 |
| Prevalence (Females) | ~1:6,000-8,000 |
| Premutation Carriers | 1:250 females, 1:800 males |
| Gene | FMR1 (Xq27.3) |
| Protein | FMRP (Fragile X Mental Retardation Protein) |
| Normal Repeats | Less than 45 CGG repeats |
| Premutation | 55-200 CGG repeats |
| Full Mutation | Greater than 200 CGG repeats |
| Mechanism | Methylation silences FMR1, Loss of FMRP |
| Diagnosis | DNA testing (PCR + Southern Blot) |
| ASD Comorbidity | ~50-60% of males |
| ADHD Comorbidity | ~70-90% of males |
| Pathognomonic Sign | Macroorchidism (Post-pubertal males) |
| Key Premutation Conditions | FXTAS (Males Greater than 50), FXPOI (Females) |
Clinical Pearls
"Most Common Inherited Intellectual Disability": Remember FXS first.
"CGG Repeats: Normal Less than 45, Premutation 55-200, Full Greater than 200": Know the ranges.
"Males More Severe, Females Variable": Due to X-inactivation.
"Macroorchidism is POST-Pubertal": Not present in young boys.
"FXTAS and FXPOI": Premutation carriers have their own conditions.
"Southern Blot for Full Mutation": PCR misses Greater than 200 repeats.
"mGluR5 Theory": Explains pathophysiology, Drove drug development.
"Early Intervention is Key": Starting before age 3 improves outcomes.
"Think Family": Cascade testing essential, 50% inheritance risk.
"Anxiety Common": 70-80% have anxiety, Often overlooked.
"Long Face, Large Ears": Classic facial features, More pronounced with age.
"Joint Hypermobility": Connective tissue involvement, Beighton score 4-9/9.
"Hydrate with Knowledge": FMRP regulates ~4% of brain mRNAs.
"Two-Hit Theory Like mGluR": Exaggerated LTD, Immature dendritic spines.
"Anticipation": Repeat expands through maternal transmission.
"Repeat Greater than 100 = High Expansion Risk": Key for counselling premutation carriers.
"Target Less than 45 = Normal": PCR can detect up to ~200 repeats.
"Management is MDT": Coordinated care improves outcomes.
Why This Matters Clinically
Fragile X Syndrome is a paradigm genetic disorder demonstrating trinucleotide repeat expansion, Anticipation, And phenotypic variability. Correct diagnosis has profound implications for the affected individual (Access to services, Prognostic information) and their extended family (Carrier testing, Reproductive options). As the most common monogenic cause of both intellectual disability and ASD, Clinicians must maintain a high index of suspicion. Understanding the premutation spectrum (FXTAS, FXPOI) is increasingly important. FXS is commonly examined due to its genetic mechanism, Classic phenotype, And genetic counselling complexities.
Key Principle
[!NOTE] Fragile X Syndrome is the most common inherited cause of intellectual disability and the most common single-gene cause of autism spectrum disorder. Premutation carriers are much more common than affected individuals.
Incidence & Prevalence
| Measure | Males | Females | Notes |
|---|---|---|---|
| Full Mutation Prevalence | 1:4,000 | 1:6,000-8,000 | Males more commonly and severely affected |
| Premutation Carriers | 1:800 | 1:250 | Much more common than full mutations |
| % of Inherited Intellectual Disability | ~2-3% | ~1-2% | Leading single-gene cause |
| % of ASD with FXS | ~2-5% of males with ASD | ~1-2% of females with ASD | Important differential |
| % of FXS with ASD | 50-60% | ~20% | High comorbidity |
Global Burden
| Region | Estimated Prevalence | Notes |
|---|---|---|
| Worldwide | ~1:4,000-5,000 births | All ethnicities affected |
| Europe | ~1:4,000-5,000 | Well-documented |
| North America | ~1:4,000-5,000 | Similar rates |
| Asia | Limited data | May be underdiagnosed |
| Africa | Limited data | Need for screening programmes |
Demographics
| Factor | Details | Clinical Significance |
|---|---|---|
| Sex | Males more frequent and severe | X-linked; Females have second X for compensation |
| Ethnicity | All ethnicities | No known ethnic predilection |
| Family History | Often present | But may be undiagnosed in relatives |
| Age at Diagnosis | Mean ~36 months (Males), Later (Females) | Early diagnosis improves outcomes |
| Socioeconomic | All levels | Diagnosis may be delayed in underserved areas |
Age-Specific Features
| Age Group | Key Features | Diagnostic Considerations |
|---|---|---|
| Infants (0-12 months) | Hypotonia, Feeding difficulties, Developmental delay | May be subtle |
| Toddlers (1-3 years) | Language delay, Motor delay, Tantrums | Often when diagnosis made |
| Preschool (3-5 years) | ADHD features, Social difficulties, Physical features emerging | Classic presentation |
| School-age (6-12 years) | Learning difficulties, Behavioural problems, Physical features clearer | May still be undiagnosed |
| Adolescence | Macroorchidism appears, Anxiety worsens, Sexuality issues | New challenges |
| Adulthood | Lifelong disability, Transition challenges, Premutation effects in carriers | Long-term management |
Healthcare Burden
| Component | Impact |
|---|---|
| Healthcare Costs | 10-15x higher than general population |
| Educational Costs | Special education, Therapies, Support staff |
| Lifetime Care | Many require lifelong supervision and support |
| Lost Productivity | For affected individuals and caregivers |
| Mental Health Impact | Family stress, Caregiver burnout |
Carrier Prevalence and Impact
| Carrier Type | Prevalence | Associated Conditions |
|---|---|---|
| Female Premutation Carriers | 1:250 | FXPOI (20%), Anxiety, Depression |
| Male Premutation Carriers | 1:800 | FXTAS (40% over 50 yrs), Neuropathology |
| Female Full Mutation | 1:6,000-8,000 | Variable phenotype (50% affected) |
Risk Factors for Expansion
| Factor | Impact |
|---|---|
| Maternal Repeat Size | Larger premutation = Higher expansion risk |
| Greater than 100 Repeats | Very high risk of full mutation in offspring |
| AGG Interruptions | May stabilize repeats (Protective) |
Genetics
| Component | Details |
|---|---|
| Gene | FMR1 (Fragile X Mental Retardation 1) |
| Location | Xq27.3 |
| Protein | FMRP (Fragile X Mental Retardation Protein) |
| Mutation Type | CGG trinucleotide repeat expansion in 5' UTR |
| Inheritance | X-Linked Dominant (With nuances) |
CGG Repeat Classifications
| Category | CGG Repeats | Clinical Significance |
|---|---|---|
| Normal | 5-44 | Normal function |
| Intermediate (Grey Zone) | 45-54 | May expand in transmission. No disease. |
| Premutation | 55-200 | Risk of FXTAS (Males), FXPOI (Females). Risk of expansion to full mutation when transmitted by mother. |
| Full Mutation | >200 | FMR1 gene silenced → No FMRP → Fragile X Syndrome |
Anticipation and Transmission
| Scenario | Risk |
|---|---|
| Mother with Premutation | ~50% chance child inherits expanded allele. Risk of expansion to full mutation increases with maternal repeat size. |
| Father with Premutation | Passes premutation (Unchanged or slight contraction) to ALL daughters. Sons unaffected (Y chromosome). |
| Mother with Full Mutation | 50% affected sons, 50% carrier/Affected daughters. |
Key Concept: Anticipation – Repeat size tends to increase with maternal transmission.
Pathophysiology
Step 1: CGG Expansion
- Normal FMR1 has 5-44 CGG repeats
- Premutation (55-200) is unstable – Expands during maternal meiosis
- Full mutation (>200) occurs when premutation expands
Step 2: Gene Silencing (Methylation)
- >200 CGG repeats triggers Hypermethylation of FMR1 promoter
- Chromatin condensation
- Transcriptional Silencing of FMR1 gene
- NO FMRP produced
Step 3: Loss of FMRP Function
- FMRP is an RNA-binding protein
- Essential for Synaptic Plasticity (Regulates translation of ~4% of brain mRNAs)
- Required for normal Dendritic Spine Maturation
- Modulates Metabotropic Glutamate Receptor (mGluR5) signalling
Step 4: Neuronal Consequences
- Excessive mGluR5 signalling → mGluR Theory of Fragile X
- Abnormal dendritic spines (Long, Thin, Immature)
- Dysregulated synaptic protein synthesis
- Impaired Long-Term Depression (LTD) / Long-Term Potentiation (LTP)
Step 5: Clinical Manifestations
- Intellectual Disability (Cognitive deficits)
- Autism Spectrum Features (Social deficits, Repetitive behaviours)
- Behavioural Problems (ADHD, Anxiety)
- Connective Tissue Defects (FMRP role in extracellular matrix?)
- Macroorchidism (Unclear mechanism – Possibly hormonal)
Pathophysiology Diagram
Key Principle
[!NOTE] Fragile X Syndrome presents with a TRIAD of: > 1. Intellectual Disability (Mild to Severe) > 2. Characteristic Physical Features (Long face, Large ears, Macroorchidism) > 3. Behavioural Phenotype (ADHD, Anxiety, Autism features) Physical features may be subtle in young children and become more pronounced with age.
Physical Features
| Feature | Frequency | Males | Females | Notes |
|---|---|---|---|---|
| Long, Narrow Face | 60-80% | Common | Less prominent | May become more apparent with age |
| Large, Prominent Ears | 60-80% | Common | Variable | Often protruding |
| High Arched Palate | 40-60% | Common | Variable | |
| Prominent Jaw (Prognathism) | Variable | More in adults | Less | More apparent in adults |
| Macroorchidism | 80-90% post-puberty | Pathognomonic | N/A | Testicular volume Greater than 25 mL |
| Flat Feet (Pes Planus) | 50-70% | Common | Common | |
| Joint Hypermobility | 50-70% | Common | Common | Connective tissue laxity |
| Soft, Velvety Skin | Variable | Common | Variable | |
| Double-Jointed Thumbs | 40-60% | Common | Variable | Hypermobility sign |
Note: Physical features may be subtle in young children and become more pronounced with age. Some features only appear after puberty (Macroorchidism).
Physical Features by Age
| Age | Key Physical Features |
|---|---|
| Infancy | Hypotonia, Prominent forehead |
| Toddler | Long face beginning, Large ears |
| School-age | Classic facial features clearer |
| Adolescence | Macroorchidism appears (Males) |
| Adulthood | Prognathism, Full phenotype |
Cognitive and Behavioural Features
| Feature | Males | Females | Notes |
|---|---|---|---|
| Intellectual Disability | Moderate-Severe (IQ 20-70) | Mild-Borderline (IQ 70-100) in ~50% | Males more severe |
| Learning Difficulties | Universal | Variable | Specific learning disabilities |
| Speech/Language Delay | Universal | Common | First presenting concern |
| ADHD | 70-90% | ~35% | Inattentive and/or Hyperactive |
| Autism Spectrum Disorder | 50-60% | ~20% | Meets DSM-5 criteria |
| Anxiety | 70-80% | 50-70% | Social and separation anxiety |
| Social Deficits | Common | Variable | Gaze aversion despite social interest |
Severity Grading
| Severity | IQ Range | Adaptive Function | Typical Presentation |
|---|---|---|---|
| Mild | 55-70 | Moderate support | Some independence, Employment possible |
| Moderate | 40-55 | Significant support | Sheltered work, Close supervision |
| Severe | Less than 40 | Extensive support | Full care, Limited communication |
Developmental Trajectory
| Age | Developmental Milestones | FXS Compared to Normal |
|---|---|---|
| 6 months | Sits with support, Babbles | May be delayed, Hypotonic |
| 12 months | First words, Walking | Words delayed, May walk on time |
| 18 months | 10-20 words, Walks well | Limited words, Tantrums appear |
| 2 years | 2-word phrases, Points | Significant language delay |
| 3 years | 3-word sentences | Language delay notable |
| 5 years | School readiness | Special education usually needed |
Behavioural Phenotype - Detailed
| Feature | Description | Frequency |
|---|---|---|
| Hand Flapping | Stereotypic movement, Excitement | 70-80% |
| Hand Biting | Self-stimulatory, When anxious | 60-70% |
| Gaze Aversion | Avoids eye contact (But socially engaged) | 80-90% |
| Tactile Defensiveness | Sensory hypersensitivity to touch | 70-80% |
| Perseverative Speech | Repetitive topics/Phrases | 60-70% |
| Hyperarousal | Easily overstimulated | 80-90% |
| Social Anxiety | Despite being socially motivated | 70-80% |
| Hyperactivity/Impulsivity | ADHD-like features | 70-90% |
| Aggression | When frustrated or overstimulated | 30-40% |
FXS vs Idiopathic Autism Comparison
| Feature | FXS with ASD | Idiopathic ASD |
|---|---|---|
| Social Interest | Often preserved (Socially motivated) | Often diminished |
| Gaze Aversion | Present but with eye contact attempts | Often persistent lack |
| Language | Delayed but often develops | More variable |
| Physical Features | FXS dysmorphism | Usually absent |
| Macroorchidism | Present (Adults) | Absent |
| Family History | Often positive for ID/Learning difficulties | Variable |
| Genetic Test | FMR1 mutation | Usually negative |
Medical Comorbidities - Detailed
| Comorbidity | Frequency | Mechanism | Management |
|---|---|---|---|
| Epilepsy | 10-20% | Neuronal excitability | Antiepileptics |
| Mitral Valve Prolapse | 50% adults | Connective tissue defect | Echo monitoring |
| Recurrent Otitis Media | Common | Eustachian tube dysfunction | Grommets if recurrent |
| Strabismus | 8-30% | Unclear | Ophthalmology referral |
| Sleep Disorders | Common | Multiple factors | Sleep hygiene, Melatonin |
| Gastroesophageal Reflux | Common | Hypotonia | PPI if needed |
| Obesity | Increases with age | Medication, Lifestyle | Diet and exercise |
| Scoliosis | 10-20% | Hypotonia | Monitoring, Orthopaedics |
Red Flags for FXS Diagnosis
[!CAUTION] Consider Fragile X Testing if:
- Unexplained intellectual disability (Especially males)
- Autism spectrum disorder (Especially with physical features)
- Family history of intellectual disability or autism
- Characteristic physical features (Long face, Large ears, Macro-orchidism)
- ADHD with learning difficulties
- Premature ovarian insufficiency (Less than 40 years) in female relatives (FXPOI)
- Late-onset tremor/ataxia in older male relatives (FXTAS)
- Maternal history of "grey zone" or premutation carriers
Key Principle
[!NOTE] The clinical examination in Fragile X Syndrome focuses on:
- Characteristic dysmorphic features
- Behavioural observation
- Connective tissue abnormalities
- Post-pubertal macroorchidism (Males) Remember: Physical features may be SUBTLE in young children.
Structured OSCE/Clinical Approach
Introduction:
- Wash hands, Introduce yourself
- Consent from parent/guardian
- Note the child's age and sex
1. General Inspection:
| What to Observe | Findings in FXS |
|---|---|
| Overall appearance | May appear normal in young children |
| Behaviour | Hyperactivity, Hand-flapping, Gaze aversion |
| Interaction | May be shy but socially motivated |
| Speech | Delayed, Perseverative, Cluttered |
| Dysmorphism | May be subtle – Look carefully |
2. Head and Face Examination:
| Feature | What to Look For | How to Examine |
|---|---|---|
| Face Shape | Long, Narrow | Look from front |
| Forehead | Prominent, High | Side view |
| Ears | Large, Protruding, Low-set | Side view, Measure if available |
| Eyes | Strabismus | Cover test, Corneal reflections |
| Palate | High-arched | Ask child to open mouth, Use torch |
| Jaw | Prognathism (Adults) | Side view - Prominent chin |
3. Hands and Musculoskeletal:
| Feature | What to Look For | How to Examine |
|---|---|---|
| Joints | Hypermobility | Beighton score (See below) |
| Thumbs | Double-jointed | Appose to forearm |
| Fingers | Hyperextensible | Extend past 90 degrees |
| Skin | Soft, Velvety | Feel dorsum of hands |
Beighton Hypermobility Score:
| Test | Positive if | Points |
|---|---|---|
| Passive 5th finger hyperextension Greater than 90° | Greater than 90° | 1 per side (2) |
| Appose thumb to forearm | Thumb touches forearm | 1 per side (2) |
| Elbow hyperextension Greater than 10° | Greater than 10° | 1 per side (2) |
| Knee hyperextension Greater than 10° | Greater than 10° | 1 per side (2) |
| Palms flat on floor (Knees straight) | Achieves | 1 |
Score 4-9/9 common in FXS. Score ≥4 = Hypermobility.
4. Feet:
| Feature | Findings |
|---|---|
| Pes Planus | Flat feet (Loss of arch) |
| Hypermobility | Flexible flat foot |
5. Cardiovascular:
| What to Check | Findings |
|---|---|
| Auscultation | Mid-systolic click (MVP) |
| Blood Pressure | Usually normal |
6. Genitalia (Males – Post-Pubertal ONLY):
| Feature | Findings | Notes |
|---|---|---|
| Testicular Volume | Greater than 25 mL (Use orchidometer) | Pathognomonic |
| Normal Adult | 15-25 mL |
Macroorchidism is NOT present in prepubertal boys.
7. Neurological:
| What to Check | Findings in FXS |
|---|---|
| Tone | Hypotonia (May persist) |
| Coordination | Motor clumsiness |
| Reflexes | Usually normal |
Developmental and Behavioural Assessment
| Assessment | Tool | Purpose |
|---|---|---|
| Cognitive | Wechsler, Stanford-Binet | IQ assessment |
| Adaptive Function | Vineland, ABAS | Daily living skills |
| ASD Screening | ADOS-2, ADI-R | Autism diagnosis |
| ADHD | Conners, SNAP-IV | ADHD symptoms |
| Anxiety | SCARED, RCADS | Anxiety symptoms |
Documentation Checklist
| Item | Findings |
|---|---|
| Long face | Present / Absent |
| Large ears | Present / Absent |
| High palate | Present / Absent |
| Prognathism | Present / Absent |
| Hypermobility (Beighton) | Score /9 |
| Pes planus | Present / Absent |
| Soft skin | Present / Absent |
| Macroorchidism (If post-pubertal) | Volume L/R |
| MVP (Murmur) | Present / Absent |
| Behaviour (Gaze aversion, Flapping) | Observed |
What to Present in OSCE/Viva
"On examination, This [age] male child demonstrates subtle dysmorphic features consistent with Fragile X Syndrome including [Long face, Large protruding ears, High-arched palate]. He has joint hypermobility with a Beighton score of [X/9] and flat feet. Behaviourally, He demonstrates [Gaze aversion, Hand-flapping, Hyperactivity]. [If post-pubertal: He has macroorchidism with testicular volumes of [X] mL.] I would like to confirm the diagnosis with FMR1 CGG repeat analysis and arrange multidisciplinary assessment."
Key Principle
[!NOTE] Diagnosis of Fragile X Syndrome is made by genetic testing for FMR1 CGG repeat expansion. Clinical suspicion should be HIGH in:
- Unexplained intellectual disability (Especially males)
- Autism spectrum disorder (Especially with physical features)
- Family history of ID, ASD, or premutation conditions
Genetic Testing (Diagnostic)
| Test | Method | What It Detects | When to Use |
|---|---|---|---|
| FMR1 CGG Repeat Analysis | PCR ± Southern Blot | CGG repeat number | First-line |
| PCR Only | Polymerase chain reaction | Up to ~200 repeats | Screens for premutation |
| Southern Blot | Methylation-sensitive | Greater than 200 repeats + Methylation status | Confirms full mutation |
| Methylation PCR | Alternative to Southern | Methylation status | May replace Southern |
Testing Algorithm:
| Step | Action |
|---|---|
| 1. | Order FMR1 CGG repeat analysis (PCR ± Southern Blot) |
| 2. | If Normal (Less than 45): FXS excluded |
| 3. | If Intermediate (45-54): May expand in offspring, Monitor |
| 4. | If Premutation (55-200): Carrier, Risk of expansion, FXTAS/FXPOI risk |
| 5. | If Full Mutation (Greater than 200): Diagnosis confirmed |
| 6. | Check methylation status (Full mutation usually methylated) |
Interpreting Results:
| Result | CGG Repeats | Methylation | Clinical Significance |
|---|---|---|---|
| Normal | Less than 45 | N/A | No FXS |
| Intermediate | 45-54 | N/A | May expand in offspring |
| Premutation | 55-200 | Unmethylated | Carrier, FXTAS/FXPOI risk |
| Full Mutation | Greater than 200 | Usually methylated | FXS confirmed |
| Mosaic | Mixed | Variable | Variable phenotype |
Mosaicism:
| Type | Explanation | Significance |
|---|---|---|
| Size Mosaic | Mix of premutation and full mutation alleles | May have milder phenotype |
| Methylation Mosaic | Some cells unmethylated | Some FMRP produced, Milder |
Screening Indications
| Who to Test | Reason |
|---|---|
| Unexplained ID/DD | FXS is most common inherited cause |
| ASD (Especially with ID or dysmorphism) | FXS is most common single-gene cause |
| Family history of ID/ASD/FXS | Cascade testing |
| ADHD with ID | May be FXS |
| Family history of FXPOI | Mother/Relatives may be carriers |
| Family history of FXTAS | Relatives may be carriers |
| Atypical physical features | Long face, Large ears, Hypermobility |
Additional Investigations
For Diagnosis/Baseline:
| Investigation | Indication | Notes |
|---|---|---|
| Developmental Assessment | All patients | IQ, Adaptive function (Vineland, Bayley) |
| Autism Assessment (ADOS-2, ADI-R) | If ASD features | Diagnose comorbid ASD |
| Speech Assessment | All patients | Language delay |
For Complications:
| Investigation | Indication | Notes |
|---|---|---|
| Echocardiogram | Murmur or adolescence | MVP screening |
| EEG | Seizures suspected | 10-20% have epilepsy |
| Audiometry | Recurrent OM, Hearing concern | |
| Ophthalmology | Strabismus, Refractive errors | |
| Sleep Study | Sleep apnoea suspected | If obese or severe hypotonia |
Cascade Testing - Detailed
| Family Member | When to Test | What Test |
|---|---|---|
| Siblings of Affected | At diagnosis | FMR1 CGG repeat |
| Mother of Affected | At diagnosis | Confirm carrier status |
| Mother's Siblings (Aunts/Uncles) | If mother is carrier | May be carriers |
| Maternal Grandmother | If relevant history | May be carrier |
| Father of Affected | If no maternal transmission | Check for mosaicism (Rare) |
| Carrier's Children | Pre-symptom or family planning | May be affected or carriers |
Prenatal Testing Options:
| Option | When | Notes |
|---|---|---|
| CVS | 10-13 weeks | Earlier result, Slightly higher miscarriage risk |
| Amniocentesis | 15-18 weeks | Later result, Lower risk |
| Preimplantation Genetic Diagnosis (PGD) | IVF cycle | Avoids affected pregnancy |
| Maternal blood cell-free DNA | Research only | Not standard |
Key Principle
[!IMPORTANT] Management of Fragile X Syndrome is:
- Multidisciplinary - Requires coordinated care
- Symptom-Targeted - No cure, But symptoms treatable
- Lifelong - Needs evolve over time
- Family-Centred - Support for entire family
- Early Intervention - Earlier treatment = Better outcomes
Management Algorithm
Multidisciplinary Team - Detailed
| Specialist | Role | When to Involve |
|---|---|---|
| Developmental Paediatrician | Diagnosis, Coordination, Developmental monitoring | At diagnosis and ongoing |
| Clinical Geneticist | Diagnosis confirmation, Family counselling | At diagnosis, Family planning |
| Speech and Language Therapist | Communication support, Feeding | From diagnosis, Ongoing |
| Educational Psychologist | Learning support, IQ assessment | Pre-school onwards |
| Special Education Coordinator | Appropriate educational placement, IEP | From school age |
| Behavioural Therapist | Behavioural management, ABA if ASD | If behavioural problems |
| Occupational Therapist | Sensory integration, Fine motor, Self-care | From diagnosis, Ongoing |
| Physiotherapist | Gross motor, Hypotonia management | Infancy if hypotonic |
| Child Psychiatrist | ADHD, Anxiety, ASD medication | If significant symptoms |
| Cardiologist | MVP monitoring | Adolescence/Adulthood |
| Neurologist | Epilepsy management | If seizures |
| Audiologist | Hearing assessment | If recurrent OM |
| Ophthalmologist | Strabismus, Visual assessment | Routine screening |
| Social Worker | Family support, Benefits, Services | As needed |
Pharmacological Management - Detailed Protocols
ADHD Management:
| Agent | Starting Dose | Target Dose | Notes |
|---|---|---|---|
| Methylphenidate IR | 2.5-5 mg BD | 0.3-1 mg/kg/day | Short-acting, Titrate slowly |
| Methylphenidate MR | 10-18 mg OD | Up to 54 mg/day | Once daily |
| Lisdexamfetamine | 20-30 mg OD | 30-70 mg/day | Prodrug, Smooth effect |
| Guanfacine XR | 0.5-1 mg OD | 1-4 mg/day | Good if anxiety comorbid |
| Clonidine | 25-50 mcg nocte | 2-5 mcg/kg/day | Helps sleep and hyperarousal |
Anxiety Management:
| Agent | Starting Dose | Target Dose | Notes |
|---|---|---|---|
| Fluoxetine | 2.5-5 mg OD | 10-20 mg/day | Start very low, Slow titration |
| Sertraline | 12.5-25 mg OD | 50-100 mg/day | Alternative SSRI |
| Guanfacine | 0.5-1 mg OD | 1-4 mg/day | For hyperarousal-related anxiety |
| Buspirone | 2.5 mg BD | 5-10 mg BD | Alternative |
Aggression/Irritability Management:
| Agent | Starting Dose | Notes | Monitoring |
|---|---|---|---|
| Risperidone | 0.25 mg OD | Effective but metabolic effects | Weight, Lipids, Glucose |
| Aripiprazole | 2-5 mg OD | May have fewer metabolic effects | Weight |
| N-Acetylcysteine | 600 mg TDS | May help irritability | Safe |
Seizure Management:
| Agent | Indication | Notes |
|---|---|---|
| Levetiracetam | First-line for partial/Generalized | Well-tolerated |
| Valproate | Alternative | Avoid in females of childbearing age |
| Carbamazepine | Focal seizures | Drug interactions |
Sleep Disturbance:
| Agent | Dose | Notes |
|---|---|---|
| Melatonin | 1-5 mg nocte | First-line, Very safe |
| Clonidine | 25-100 mcg nocte | For sleep and hyperarousal |
| Trazodone | 25-50 mg nocte | Alternative |
Non-Pharmacological Management - Detailed
Early Intervention (0-3 Years):
| Intervention | Details | Goal |
|---|---|---|
| Developmental Stimulation | Play-based learning, Responsive parenting | Maximise developmental potential |
| Speech Therapy | Early language development | Improve communication |
| Physical Therapy | For hypotonia | Improve motor skills |
| Parent Coaching | Teach strategies | Empower parents |
Educational Interventions:
| Age | Intervention | Key Components |
|---|---|---|
| Preschool (3-5) | Special education preschool, IEP | Language focus, Social skills |
| Primary (5-11) | Mainstream with support OR Special school | Modified curriculum, 1:1 support |
| Secondary (11-16) | Continued support, Life skills | Vocational preparation |
| Post-16 | Transition planning, Vocational training | Independent living skills |
Behavioural Interventions:
| Approach | Description | When to Use |
|---|---|---|
| Applied Behaviour Analysis (ABA) | Structured learning, Reinforcement | ASD features, Behavioural problems |
| Visual Supports | Schedules, Picture cards | All children with FXS |
| Sensory Strategies | Sensory diet, Calming techniques | Sensory hypersensitivity |
| Social Stories | Teach social expectations | Social difficulties |
| Cognitive Behavioural Therapy | Adapted for ID | Anxiety (Higher functioning) |
Monitoring Schedule
| Component | Frequency | Details |
|---|---|---|
| Developmental Review | 6-12 monthly | Monitor progress, Update goals |
| Growth | Each visit | Height, Weight, BMI (Especially if on antipsychotics) |
| Cardiac | Adolescence then periodic | Echo if murmur or suspected MVP |
| Hearing | Annually in early childhood | ENT referral if recurrent OM |
| Vision | Annually in early childhood | Ophthalmology if strabismus |
| Mental Health | Each visit | Screen for anxiety, Depression |
| Medication Review | Every 6-12 months | Efficacy, Side effects |
Transitioning to Adulthood
| Aspect | Planning |
|---|---|
| Education | Post-16 options, Vocational training |
| Employment | Supported employment, Day services |
| Living | Supported living, Residential care, Family |
| Healthcare | Transition to adult services |
| Sexuality/Relationships | Education, Safeguarding |
| Legal | Capacity assessment, Guardianship if needed |
Experimental/Emerging Therapies
| Therapy | Mechanism | Status | Notes |
|---|---|---|---|
| mGluR5 Antagonists (Mavoglurant) | Based on mGluR theory | Failed phase 3 trials | Did not meet primary endpoints |
| GABA-B Agonists (Arbaclofen) | Excitatory/Inhibitory balance | Mixed results | Some positive signals |
| CRISPR Gene Editing | FMR1 reactivation | Preclinical | Future potential |
| Antisense Oligonucleotides | Target repeat expansion | Preclinical | Early research |
| BPN14770 (PDE4D Inhibitor) | cAMP signalling | Phase 2 | Positive early results |
Genetic Counselling - Expanded
| Topic | Key Points | Resources |
|---|---|---|
| Recurrence Risk | 50% for carrier mother | Risk tables available |
| Expansion Risk | Maternal premutation → Full mutation (Higher with larger premutation Greater than 100) | Correlates with repeat size |
| Reproductive Options | PGD, Prenatal diagnosis (CVS/Amnio), Donor gametes, Adoption | Genetic counsellor |
| Cascade Testing | Offer to at-risk relatives | Family tree analysis |
| Psychological Support | Implications for family, Guilt, Anxiety | Counselling services |
| Carrier Testing | For siblings, Relatives | PCR-based testing |
Overview
| Category | Key Complications |
|---|---|
| Medical | Epilepsy, MVP, Otitis media, Obesity, Sleep disorders |
| Behavioural | Depression, Aggression, Social isolation |
| Premutation | FXTAS (Males), FXPOI (Females) |
Medical Complications - Detailed
Epilepsy:
| Aspect | Details |
|---|---|
| Incidence | 10-20% |
| Seizure Types | Partial (Most common), Generalized |
| Onset | Usually childhood |
| EEG Features | May show focal slowing |
| Treatment | Levetiracetam, Valproate (Avoid in females of childbearing age) |
| Prognosis | Often well-controlled, May remit in adolescence |
Mitral Valve Prolapse:
| Aspect | Details |
|---|---|
| Incidence | ~50% adults (25% children) |
| Mechanism | Connective tissue abnormality |
| Clinical Finding | Mid-systolic click, Late systolic murmur |
| Screening | Echo in adolescence/adulthood |
| Management | Usually asymptomatic, Endocarditis prophylaxis rarely needed |
Recurrent Otitis Media:
| Aspect | Details |
|---|---|
| Incidence | Common in childhood |
| Cause | Eustachian tube dysfunction |
| Consequences | Potential hearing loss, Language delay |
| Management | Antibiotics for acute OM, Grommets if recurrent |
| Screening | Audiometry |
Obesity:
| Aspect | Details |
|---|---|
| Incidence | Increases with age |
| Risk Factors | Medications (Antipsychotics), Reduced activity, Hyperphagia |
| Consequences | Sleep apnoea, Metabolic syndrome |
| Prevention | Diet, Exercise, Medication review |
Sleep Disorders:
| Type | Management |
|---|---|
| Insomnia | Melatonin, Sleep hygiene |
| Sleep Apnoea | Weight management, CPAP if obese |
| Restless Legs | Iron, Clonidine |
Behavioural/Psychiatric Complications - Detailed
| Complication | Incidence | Management |
|---|---|---|
| Anxiety | 70-80% | SSRIs, CBT (Adapted), Environmental modification |
| Depression | Common (Adults) | SSRIs, Psychology |
| Aggressive Behaviour | 30-40% | Behavioural strategies, Risperidone if severe |
| Self-Injurious Behaviour | 10-20% | Behavioural intervention, Protective measures |
| Social Isolation | Common | Social skills training, Supported activities |
Complications for Premutation Carriers - Detailed
FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome):
| Aspect | Details |
|---|---|
| Who | Male premutation carriers Greater than 50 years |
| Incidence | ~40% of male carriers over 50 |
| Features | Intention tremor, Cerebellar ataxia, Parkinsonism, Cognitive decline, Neuropathy |
| Imaging | MRI: T2 hyperintensities in middle cerebellar peduncles (MCP sign) |
| Management | Symptomatic (Tremor, Parkinsonism medications), Supportive |
| Prognosis | Progressive |
FXPOI (Fragile X-Associated Primary Ovarian Insufficiency):
| Aspect | Details |
|---|---|
| Who | Female premutation carriers |
| Incidence | ~20% of female carriers |
| Definition | Cessation of ovarian function before age 40 |
| Features | Irregular periods, Infertility, Premature menopause |
| Management | HRT, Fertility counselling, Egg donation |
| Implications | Fertility may be preserved if carriers diagnosed early |
Complication Monitoring Schedule
| Complication | Screening/Monitoring |
|---|---|
| Epilepsy | EEG if seizures, Regular review |
| MVP | Echo in adolescence/adulthood |
| Hearing | Audiometry annually in early childhood |
| Vision | Ophthalmology in early childhood |
| Obesity | Weight at each visit |
| Mental Health | Screen at each visit |
| FXTAS/FXPOI | Counsel premutation carriers |
Overview
| Factor | Impact on Prognosis |
|---|---|
| Sex | Females generally milder than males |
| Mutation Type | Full mutation worse than mosaic |
| Methylation | Complete methylation = No FMRP = Worse |
| Early Intervention | Improves outcomes |
| Comorbidities | ASD, Epilepsy may worsen outcomes |
Prognosis by Sex
| Outcome | Males | Females |
|---|---|---|
| Life Expectancy | Near normal (Slightly reduced if severe ID) | Near normal |
| Independence | Most require lifelong support | Many live independently |
| Employment | Supported employment for some (10-20%) | Regular employment possible (30-50%) |
| Relationships | May have relationships with support | Many have relationships/Marry |
| Living Situation | Supported living or family | Many independent |
Prognosis by Cognitive Level
| IQ Range | Classification | Typical Outcome |
|---|---|---|
| Less than 40 | Severe ID | Full care, Limited communication |
| 40-55 | Moderate ID | Sheltered work, Close supervision |
| 55-70 | Mild ID | Some independence possible |
| Greater than 70 | Borderline/Normal (Some females) | Regular employment/Marriage |
Life Stage Outcomes
| Life Stage | Key Outcomes | Challenges |
|---|---|---|
| Childhood | Development with support | Behavioural difficulties, Education |
| Adolescence | Puberty (Macroorchidism), Anxiety peaks | Sexuality, Transition planning |
| Adulthood | Stable cognitive function | Employment, Living, Relationships |
| Middle Age | Generally stable | Increased medical comorbidities |
| Older Age | Possible cognitive decline | Premutation: FXTAS risk |
Factors Affecting Outcome
Positive Prognostic Factors:
| Factor | How It Helps |
|---|---|
| Female Sex | X-inactivation compensation, Often milder |
| Early Diagnosis | Enables early intervention |
| Early Intervention (Less than 3 years) | Maximizes developmental potential |
| Higher Baseline IQ | Better adaptive function |
| Supportive Environment | Family, Educational, Community |
| Mosaicism | Some FMRP production = Milder phenotype |
| No Comorbid ASD | Better social outcomes |
Negative Prognostic Factors:
| Factor | How It Worsens Outcome |
|---|---|
| Male Sex | Hemizygous, No compensation |
| Full Mutation (Completely Methylated) | No FMRP |
| Comorbid ASD | Additional social/Behavioural challenges |
| Severe ID | Limits independence |
| Lack of Early Intervention | Missed developmental window |
| Poor Support Systems | Less access to services |
Long-Term Management Considerations
| Aspect | Key Points |
|---|---|
| Healthcare | Lifelong monitoring, Multi-specialty |
| Employment | Supported employment programmes |
| Living | Range from independent to full care |
| Relationships | Support for sexuality, Safeguarding |
| Legal | Capacity assessment, Guardianship if needed |
| End of Life | Familial planning, Palliative care |
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Fragile X Syndrome Consensus Statement | ACMG (2005, Updated 2019) | Testing indications, Diagnostic algorithm |
| Practice Guidelines for FXS | NFXF (National Fragile X Foundation) | Comprehensive management |
Key Evidence
FMR1 Gene Discovery (1991)
- Verkerk et al. identified FMR1 gene and CGG expansion
- PMID: 1675488
- Established molecular basis
mGluR Theory (Bear et al., 2004)
- FMRP regulates mGluR signalling
- Basis for drug development
- PMID: 15364714
Natural History Studies
- Longitudinal cohort studies informing prognosis
- Variable expressivity documented
AAP Health Supervision Guidelines (2011)
- Hersh et al.
- PMID: 21518720
- Comprehensive surveillance recommendations
Mavoglurant Trials (2014-2016)
- mGluR5 antagonist
- Did not meet primary endpoints in Phase 3
- mGluR theory validated but clinical translation challenging
What is Fragile X Syndrome?
Fragile X Syndrome is an inherited genetic condition that causes learning difficulties and often affects behaviour. It is the most common inherited cause of learning difficulties and intellectual disability. It is caused by a change in a gene called FMR1 on the X chromosome.
Key Points to Understand
| Fact | Explanation |
|---|---|
| Inherited | It runs in families, Passed through generations |
| Genetic | Caused by a change in the FMR1 gene |
| No Cure | But lots can be done to help |
| More Severe in Boys | Boys have one X, Girls have two |
| Affects the Brain | The missing protein (FMRP) helps the brain develop |
Why Does it Happen?
Everyone has a section of DNA in the FMR1 gene that repeats (like a stutter). In Fragile X, this section repeats too many times (Greater than 200 repeats). This switches off the gene, so the body can't make an important protein called FMRP that helps the brain develop normally.
| Number of Repeats | What It Means |
|---|---|
| Less than 45 | Normal – No problems |
| 55-200 | Premutation – Carrier, Might have other issues |
| Greater than 200 | Full Mutation – Fragile X Syndrome |
Who Gets It?
- It's more common and more severe in boys because boys only have one X chromosome
- Girls have two X chromosomes, so they often have a "backup" that works (Called X-inactivation)
- It's passed down through families
- About 1 in 4,000 boys are affected
- About 1 in 6,000-8,000 girls are affected (Often milder)
What are the Signs?
Learning and Development:
| Sign | What It Looks Like |
|---|---|
| Learning difficulties | Mild to severe – May need special school |
| Delayed speech | Often the first thing parents notice |
| Slow to walk | May be delayed but usually achieved |
Behaviour:
| Sign | What It Looks Like |
|---|---|
| ADHD-like behaviour | Hyperactive, Can't sit still, Difficulty concentrating |
| Anxiety | Worries a lot, Doesn't like change, Social anxiety |
| Autism features | Some children (About half of boys) have features of autism |
| Hand flapping/Biting | Common, Especially when excited or anxious |
| Avoids eye contact | But often still wants to be social (Unlike typical autism) |
Physical Features:
| Feature | Notes |
|---|---|
| Long face | Becomes clearer with age |
| Large ears | Stick out |
| Flexible joints | Double-jointed, Flat feet |
| Large testicles | In males AFTER puberty (Not in young boys) |
Can it Be Treated?
There is no cure yet, but lots can be done to help your child:
| Treatment | What It Does |
|---|---|
| Speech and language therapy | Helps with talking and understanding |
| Educational support | Special teachers, Smaller classes |
| Behaviour strategies | Helps manage behaviour, Reduce anxiety |
| Medications | For specific symptoms (ADHD, Anxiety, Seizures, Sleep) |
| Occupational therapy | Helps with writing, Self-care, Sensory issues |
| Early intervention | Starting help early makes a BIG difference |
What About Carriers (Premutation)?
Carriers have 55-200 repeats and usually don't have Fragile X Syndrome, but may have:
| In Women | In Men |
|---|---|
| FXPOI – Early menopause (Before 40) in about 20% | FXTAS – Tremor, Balance problems, Memory issues (Over 50 years) |
| Anxiety, Depression more common | Tremor may start in 50s-60s |
What About the Family?
If a child is diagnosed, other family members should be tested because they might be carriers.
| Who Should Be Tested | Why |
|---|---|
| Brothers and Sisters | They might be affected or carriers |
| Mother | To confirm she's a carrier (Almost always is) |
| Mother's relatives | Aunts, Cousins, Grandmother might be carriers |
| Father | Rarely affected (If son has it, Usually from mother) |
Genetic Counselling
Genetic counselling helps families understand:
| Topic | What It Covers |
|---|---|
| Who might be affected | Testing other family members |
| Risks for future pregnancies | 50% chance for carrier mothers |
| Options | Prenatal testing, PGD, Donor eggs/Sperm |
| Feelings | Support for guilt, Worry, Decisions |
Frequently Asked Questions (FAQs)
| Question | Answer |
|---|---|
| Will my child get worse? | No – They don't "get worse". But needs change as they grow. |
| Can they go to normal school? | Many can with support. Some need special school. Depends on severity. |
| Will they live independently? | Boys often need lifelong support. Many girls can be independent. |
| Can they have children? | Women usually can (50% risk of passing it on). Men usually can't due to severity. |
| Is there a cure coming? | Research is ongoing. No cure yet but treatments improving. |
| Can I prevent it in my next child? | Options include prenatal testing, PGD (Testing embryos), Donor gametes. |
When to Worry / See a Doctor
[!CAUTION] Seek help if your child:
- Has seizures (Fits)
- Becomes very aggressive or self-harms
- Seems very unwell
- You are struggling to cope
Psychological Impact and Support
Living with Fragile X affects the whole family:
| Challenge | Support |
|---|---|
| Diagnosis shock | Genetic counsellor, Family support groups |
| Guilt (For passing it on) | Counselling, Peer support |
| Sibling impact | Support for brothers/Sisters |
| Parent stress/Burnout | Respite care, Support groups |
| Financial strain | Benefits advice, Social worker |
Support Resources
| Organisation | Website | What They Offer |
|---|---|---|
| Fragile X Society (UK) | www.fragilex.org.uk | Information, Family support, Advocacy |
| National Fragile X Foundation (US) | www.fragilex.org | Research, Education, Conferences |
| Genetic Alliance UK | www.geneticalliance.org.uk | Genetic condition support |
| Contact | www.contact.org.uk | Families with disabled children |
| FRAXA Research Foundation | www.fraxa.org | Research funding |
Primary Guidelines
-
Sherman S, et al. ACMG Practice Guideline: Fragile X syndrome diagnostic testing. Genet Med. 2005;7(8):584-587. PMID: 16247293
-
Hagerman RJ, et al. Fragile X syndrome. Nat Rev Dis Primers. 2017;3:17065. PMID: 28960184
-
National Fragile X Foundation. Consensus Guidelines. www.fragilex.org
Genetics and Pathophysiology
-
Verkerk AJ, et al. Identification of a gene (FMR-1) containing a CGG repeat. Cell. 1991;65(5):905-914. PMID: 1675488
-
Bear MF, et al. The mGluR theory of fragile X mental retardation. Trends Neurosci. 2004;27(7):370-377. PMID: 15364714
-
Darnell JC, et al. FMRP stalls ribosomal translocation on mRNAs. Cell. 2011;146(2):247-261. PMID: 21784246
Clinical Features and Management
-
Kidd SA, et al. Fragile X syndrome: A review of associated medical problems. Pediatrics. 2014;134(5):995-1005. PMID: 25287460
-
Farzin F, et al. Autism spectrum disorders and attention-deficit/hyperactivity disorder in fragile X syndrome. Am J Med Genet A. 2006;140A(17):1804-1813. PMID: 16906549
Premutation Disorders
-
Hagerman RJ, Hagerman PJ. Fragile X-associated tremor/ataxia syndrome (FXTAS). Mov Disord. 2007;22(7):931-942. PMID: 17393549
-
Sullivan AK, et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod. 2005;20(2):402-412. PMID: 15608041
Additional References
-
Hessl D, et al. Cognitive and behavioral phenotype in fragile X. Am J Med Genet A. 2009;149A(4):764-772. PMID: 19206177
-
Berry-Kravis E, et al. Drug development for neurodevelopmental disorders. Nat Rev Drug Discov. 2018;17(4):280-299. PMID: 29217836
-
Garber KB, et al. Fragile X syndrome. Eur J Hum Genet. 2008;16(6):666-672. PMID: 18398441
-
Lozano R, et al. Advances in treatment of fragile X syndrome. J Neurodev Disord. 2014;6(1):24. PMID: 25075212
-
Hersh JH, et al. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127(5):994-1006. PMID: 21518720
High-Yield Facts for Exams
| Fact | Value | Exam Importance |
|---|---|---|
| Definition | X-linked dominant, FMR1 CGG expansion | Core knowledge |
| Most Common Inherited ID | Yes | Must know |
| Most Common Single-Gene ASD | Yes | Must know |
| Prevalence (Males) | 1:4,000 | Commonly asked |
| Prevalence (Females) | 1:6,000-8,000 | Commonly asked |
| Gene | FMR1 (Xq27.3) | Must know |
| Protein | FMRP | Must know |
| Normal CGG Repeats | Less than 45 | Must know |
| Premutation | 55-200 repeats | Must know |
| Full Mutation | Greater than 200 repeats | Must know |
| Pathognomonic Finding | Macroorchidism (Post-pubertal) | Classic exam point |
| FXTAS | Tremor/Ataxia in premutation males | Commonly tested |
| FXPOI | POI in premutation females | Commonly tested |
Common Exam Questions - Detailed
Genetics Questions:
-
"What is the inheritance pattern of Fragile X Syndrome and why are males more severely affected?"
- Model Answer: "Fragile X Syndrome follows X-linked dominant inheritance. Males are more severely affected because they have only one X chromosome (Hemizygous), so if they inherit the mutated allele, they have no backup. Females have two X chromosomes, so even if one carries the mutation, the other (Through X-inactivation) can provide partial compensation, resulting in milder or no symptoms in about 50% of carrier females."
-
"What CGG repeat numbers define normal, Premutation, and full mutation in FXS?"
- Model Answer: "Normal is Less than 45 repeats (Some say Less than 55). Premutation is 55-200 repeats – These individuals are usually unaffected but at risk for FXTAS (Males) or FXPOI (Females). Full Mutation is Greater than 200 repeats – This causes hypermethylation and silencing of the FMR1 gene, resulting in Fragile X Syndrome."
-
"Explain the concept of anticipation in Fragile X Syndrome."
- Model Answer: "Anticipation refers to the tendency for the CGG repeat expansion to increase in size when transmitted from one generation to the next, particularly through maternal transmission. A mother with a premutation (55-200) can have offspring with a full mutation (Greater than 200), causing earlier onset or more severe disease in subsequent generations. The risk of expansion increases with larger maternal repeat sizes."
Pathophysiology Questions:
- "What is the mGluR theory of Fragile X?"
- Model Answer: "The mGluR (Metabotropic Glutamate Receptor) theory proposes that loss of FMRP leads to excessive mGluR5 signalling at synapses. FMRP normally acts as a translational repressor. Without it, There is unregulated protein synthesis leading to exaggerated Long-Term Depression (LTD) and immature dendritic spines with elongated, Thin morphology. This underlies the cognitive and behavioural abnormalities. This theory has driven drug development (mGluR5 antagonists), Though clinical trials have had mixed results."
Clinical Questions:
-
"What is the pathognomonic physical finding in adult males with FXS?"
- Model Answer: "Macroorchidism – Testicular enlargement with volumes Greater than 25 mL (Normal adult 15-25 mL), measured using an orchidometer. Important: This is only present post-pubertally, not in prepubertal boys."
-
"What conditions affect premutation carriers?"
- Model Answer: "FXTAS (Fragile X-Associated Tremor/Ataxia Syndrome): Affects approximately 40% of male premutation carriers over 50. Features include intention tremor, Cerebellar ataxia, Parkinsonism, And cognitive decline. FXPOI (Fragile X-Associated Primary Ovarian Insufficiency): Affects approximately 20% of female premutation carriers, Causing premature menopause before age 40."
OSCE Stations
Station 1: Explaining Diagnosis to Parents
| Component | Expected Points |
|---|---|
| Introduces self | Name, Role |
| Establishes rapport | Kind, Empathic tone |
| Explains condition | "Fragile X is a genetic condition causing learning difficulties" |
| Causes | "Caused by a change in a gene called FMR1" |
| Severity | "Boys usually more affected. Girls often milder." |
| Support | "There's no cure, But lots can help – Therapy, Education, Medications" |
| Family implications | "Other family members should be tested" |
| Resources | "I'll give you information about Fragile X Society" |
| Questions | "Do you have any questions?" |
| Follow-up | "We'll see you again soon" |
Station 2: Dysmorphology Examination
| Task | Expected Findings |
|---|---|
| General observation | May comment on hyperactivity, Gaze aversion |
| Face | Long face, Prominent forehead |
| Ears | Large, Protruding |
| Palate | High arched (If examined) |
| Joints | Hypermobility (Beighton score) |
| Feet | Flat |
| Skin | Soft, Velvety |
| System summary | "Dysmorphic features consistent with FXS" |
| Differential | "Would confirm with FMR1 genetic testing" |
Station 3: Counselling for Genetic Testing
| Component | Expected Points |
|---|---|
| Why testing | "To confirm if your child has Fragile X" |
| What the test involves | "A blood sample to look at the FMR1 gene" |
| Implications of positive result | "Confirms diagnosis, Helps with support and planning" |
| Family implications | "Other relatives may need testing" |
| Emotional support | "This can be a lot to take in" |
| Consent | "Do you understand and agree to proceed?" |
Viva Points - Expanded
Opening Statement:
"Fragile X Syndrome is the most common inherited cause of intellectual disability and the most common single-gene cause of autism. It is an X-linked dominant condition caused by CGG trinucleotide repeat expansion in the FMR1 gene, leading to loss of FMRP, a protein essential for synaptic plasticity and brain development."
Key Facts Table:
| Category | Key Facts |
|---|---|
| Prevalence | ~1:4,000 males, 1:6,000 females |
| Genetics | FMR1 gene, Xq27.3, CGG expansion |
| Repeat Ranges | Normal Less than 45, Premutation 55-200, Full Greater than 200 |
| Mechanism | Methylation silences FMR1, Loss of FMRP |
| Physical | Long face, Large ears, Macroorchidism (Adult males) |
| Behavioural | ID, ASD (50-60%), ADHD (70-90%), Anxiety |
| Pathophysiology | mGluR5 theory |
| Premutation | FXTAS (Males), FXPOI (Females) |
Evidence to Cite:
| Study | What It Showed |
|---|---|
| Verkerk et al. (1991) | Discovered FMR1 gene and CGG expansion |
| Bear et al. (2004) | Proposed mGluR theory |
| HALT-PKD Trial | N/A (Different condition) |
Common Mistakes
What Fails Candidates:
| Mistake | Correct Information |
|---|---|
| ❌ Confusing X-linked dominant with X-linked recessive | FXS is X-linked dominant |
| ❌ Not knowing CGG repeat ranges | Normal Less than 45, Premutation 55-200, Full Greater than 200 |
| ❌ Forgetting premutation-related conditions | FXTAS (Males), FXPOI (Females) |
| ❌ Missing that macroorchidism is POST-pubertal | Not present in young boys |
| ❌ Not mentioning genetic counselling importance | Essential for families |
| ❌ Saying "X-linked recessive" | Incorrect |
| ❌ Forgetting about mosaic forms | Some patients have mosaicism |
Dangerous Clinical Errors:
| Error | Why It Matters |
|---|---|
| ⚠️ Not offering cascade testing to family members | Misses carriers who may have affected children |
| ⚠️ Missing FXS diagnosis in child with unexplained ID/ASD | Delayed diagnosis, Missed interventions |
| ⚠️ Saying there are no treatments | There are symptomatic treatments |
Examiner Follow-Up Questions
| Question | Expected Answer |
|---|---|
| "Why do we use Southern Blot?" | Detects expansions Greater than 200 repeats and methylation status |
| "Can females be affected?" | Yes, ~50% of females with full mutation have some symptoms |
| "What is the role of FMRP?" | RNA-binding protein regulating synaptic plasticity |
| "Why did mGluR5 antagonist trials fail?" | Complex reasons – May need earlier treatment, Different endpoints |
Differential Diagnosis
| Condition | Key Distinguishing Features |
|---|---|
| Autism Spectrum Disorder (Idiopathic) | No dysmorphism, FMR1 negative |
| Angelman Syndrome | Happy affect, EEG changes, UBE3A mutation |
| Prader-Willi Syndrome | Hyperphagia, Obesity, Hypogonadism |
| Sotos Syndrome | Overgrowth, NSD1 mutation |
| ADHD | No ID, No dysmorphism |
| Other trinucleotide repeat disorders | Different genes (e.g., Huntington's, Myotonic dystrophy) |
Last Reviewed: 2025-12-25 | MedVellum Editorial Team
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists and current guidelines.