Overview
Achondroplasia
1. Clinical Overview
Summary
Achondroplasia is the most common form of skeletal dysplasia (short-limbed dwarfism), affecting approximately 1 in 15,000-40,000 live births. It is caused by a gain-of-function mutation in the FGFR3 (Fibroblast Growth Factor Receptor 3) gene, inherited in an autosomal dominant pattern, though ~80% of cases arise from de novo mutations. The condition results in rhizomelic (proximal) limb shortening with normal trunk length, characteristic facial features (frontal bossing, midface hypoplasia), and potential neurological complications including foramen magnum stenosis and spinal stenosis. Management has evolved significantly with the recent FDA/EMA approval of vosoritide.
Key Facts
- Definition: Autosomal dominant skeletal dysplasia caused by FGFR3 gain-of-function mutation
- Prevalence: 1 in 15,000-40,000 live births worldwide
- Mortality/Morbidity: Increased infant mortality (foramen magnum compression); near-normal life expectancy in adulthood with appropriate care
- Key Management: Monitoring for complications; vosoritide (CNP analogue) for growth; surgical intervention for spinal stenosis
- Critical Finding: Foramen magnum stenosis can cause sudden infant death or central apnoea
- Key Investigation: Clinical diagnosis; genetic testing for FGFR3 mutation (99% sensitivity)
Clinical Pearls
"Rhizomelic Shortening": The proximal limb segments (humerus, femur) are disproportionately shortened compared to forearms and lower legs — a hallmark of achondroplasia.
Foramen Magnum Danger Zone: Infants are at highest risk of foramen magnum stenosis causing central apnoea or sudden death in the first 2 years of life. MRI of craniocervical junction is mandatory.
FGFR3 = Growth Brake: FGFR3 normally inhibits cartilage proliferation. The gain-of-function mutation makes this "brake" overactive, resulting in stunted endochondral ossification.
Why This Matters Clinically
Achondroplasia requires multidisciplinary care to prevent life-threatening complications (foramen magnum compression, spinal stenosis) and optimise quality of life. The recent approval of vosoritide marks a paradigm shift from purely supportive care to disease-modifying therapy.
2. Epidemiology
Incidence & Prevalence
- Incidence: 1 in 15,000-40,000 live births (most common skeletal dysplasia)
- Prevalence: ~250,000 affected individuals worldwide
- Trend: Stable (de novo mutation rate influenced by advanced paternal age)
Demographics
| Factor | Details |
|---|---|
| Age | Lifelong condition; diagnosis typically at birth or prenatally |
| Sex | Male = Female (1:1 ratio) |
| Ethnicity | No significant ethnic variation; affects all populations equally |
| Geography | Worldwide distribution; no geographic predilection |
| Parental Age | Advanced paternal age associated with increased de novo mutation rate |
Risk Factors
Non-Modifiable:
- Affected parent (50% inheritance risk if one parent affected)
- Advanced paternal age (increased de novo mutation risk)
- Parental gonadal mosaicism (rare; recurrence risk in siblings)
Modifiable:
| Risk Factor | Relative Risk |
|---|---|
| None directly modifiable | N/A |
| (Genetic condition; risk is inherited or de novo) | — |
Associated Conditions:
| Associated Finding | Frequency |
|---|---|
| Obstructive sleep apnoea | 50-75% |
| Recurrent otitis media | >0% |
| Conductive hearing loss | 30-40% |
| Spinal stenosis (adults) | 20-30% |
| Foramen magnum stenosis (infants) | 5-10% symptomatic |
| Hydrocephalus | 5-10% |
3. Pathophysiology
Mechanism
Step 1: FGFR3 Gain-of-Function Mutation
- FGFR3 (Fibroblast Growth Factor Receptor 3) is a transmembrane tyrosine kinase receptor
- Normally, FGFR3 activation inhibits chondrocyte proliferation and differentiation in growth plates
- >97% of achondroplasia cases caused by Gly380Arg (G380R) mutation in transmembrane domain
- This gain-of-function mutation causes constitutive (constant) activation of FGFR3
Step 2: Overactive Growth Inhibition
- Constitutively active FGFR3 sends constant inhibitory signals to chondrocytes
- STAT1 and MAPK signalling pathways are over-stimulated
- This suppresses chondrocyte proliferation and matrix production in growth plates
- Results in premature closure and stunted endochondral ossification
Step 3: Skeletal Consequences
- Long bones (which form via endochondral ossification) are shortened
- Proximal segments (humerus, femur) more affected = rhizomelic shortening
- Skull base (also endochondral) is affected → small foramen magnum, midface hypoplasia
- Membranous ossification (calvarium) is NORMAL → frontal bossing (relative prominence)
- Spine: Narrow spinal canal, short pedicles → predisposition to stenosis
Classification
| Classification | Basis | Features |
|---|---|---|
| Achondroplasia | Heterozygous FGFR3 mutation | Classic phenotype; most common |
| Homozygous Achondroplasia | Homozygous FGFR3 (both parents affected) | Lethal perinatal; severe thoracic/pulmonary hypoplasia |
| Hypochondroplasia | Different FGFR3 mutation (milder) | Milder phenotype; proportions less abnormal |
| Thanatophoric Dysplasia | Different FGFR3 mutation (severe) | Lethal; extremely short limbs, narrow thorax |
Anatomical/Physiological Considerations
The FGFR3 mutation primarily affects endochondral ossification, which is responsible for long bone growth and skull base development. This explains:
- Long bone shortening: Growth plates in humerus/femur most affected (rhizomelic)
- Narrow foramen magnum: Skull base forms via endochondral ossification; can compress brainstem/cervical cord
- Frontal bossing: Calvarium (skull vault) forms via membranous ossification (NOT affected), so appears relatively prominent
- Narrow spinal canal: Pedicles are short due to affected endochondral growth → stenosis risk
- Trident hand: Characteristic due to differential growth of metacarpals
4. Clinical Presentation
Symptoms
Typical Presentation:
Atypical Presentations:
Signs
Red Flags
[!CAUTION] Red Flags — Seek immediate assessment if:
- Apnoea, central breathing pauses, or cyanotic episodes (foramen magnum compression)
- Rapidly increasing head circumference (hydrocephalus)
- Progressive weakness in legs or change in bladder/bowel function (cord compression)
- Severe headache, vomiting (raised intracranial pressure)
- Worsening thoracolumbar kyphosis despite bracing (may need surgery)
- Severe or worsening tibial bowing (may need surgical correction)
Short stature with disproportionate body segments (100% of cases)
Common presentation.
Short arms and legs (rhizomelic shortening) (100%)
Common presentation.
Large head with frontal bossing (>90%)
Common presentation.
Delayed motor milestones (hypotonia in infancy) (60-70%)
Common presentation.
Recurrent ear infections (50%)
Common presentation.
Snoring/sleep disturbance (obstructive sleep apnoea) (50-75%)
Common presentation.
5. Clinical Examination
Structured Approach
General:
- Plot height/weight/head circumference on achondroplasia-specific growth charts
- Assess body proportions (arm span vs height; upper:lower segment ratio)
- Observe gait and posture
Specific System Examination:
- Head: Frontal bossing, midface hypoplasia, macrocephaly
- Spine: Thoracolumbar kyphosis (infant), exaggerated lumbar lordosis (toddler/child), scoliosis
- Upper limb: Rhizomelic shortening, limited elbow extension, trident hand
- Lower limb: Rhizomelic shortening, genu varum (bowed legs), tibial bowing
- Neurological: Tone (hypotonia in infancy), reflexes (hyperreflexia if cord compression), clonus
Special Tests
| Test | Technique | Positive Finding | Sensitivity/Specificity |
|---|---|---|---|
| Arm span measurement | Measure fingertip to fingertip with arms extended | Arm span significantly < height (vs. equal in normal) | Clinical screening |
| Upper/lower segment ratio | Measure crown-pubis vs pubis-floor | Increased U:L ratio (short limbs relative to trunk) | Clinical screening |
| Polysomnography | Overnight sleep study | Central apnoeas, obstructive events, desaturation | Gold standard for sleep apnoea |
| MRI craniocervical junction | Imaging of foramen magnum/cervical cord | Foramen magnum stenosis, cervicomedullary compression | 95%/99% for stenosis |
| Neurological examination | Full spinal cord assessment | Hyperreflexia, clonus, myelopathic signs | Indicates cord compression |
6. Investigations
First-Line (Bedside)
- Growth charts (achondroplasia-specific) — monitor height velocity
- Head circumference chart — monitor for hydrocephalus
- Pulse oximetry — screen for desaturation/apnoea
Laboratory Tests
| Test | Expected Finding | Purpose |
|---|---|---|
| FGFR3 genetic testing | G380R mutation in >7% | Confirmatory diagnosis |
| Routine bloods (FBC, U&E) | Usually normal | Baseline pre-surgery |
| Sleep study (polysomnography) | Central or obstructive apnoeas | Screen for sleep apnoea |
Imaging
| Modality | Findings | Indication |
|---|---|---|
| Skeletal survey (X-ray) | Short long bones (rhizomelic), narrow foramen magnum, champagne-glass pelvis, bullet-shaped vertebrae, short pedicles | Diagnosis; characterise skeletal features |
| MRI craniocervical junction | Foramen magnum stenosis, cord signal changes, cervicomedullary compression | All infants; screen for critical stenosis |
| MRI spine | Spinal stenosis, disc disease, canal narrowing | Symptoms of leg weakness, claudication |
| CT head | Ventriculomegaly (hydrocephalus) | If head circumference crossing centiles |
| AP/lateral spine X-ray | Kyphosis angle, vertebral changes | Monitor thoracolumbar kyphosis |
Diagnostic Criteria
Clinical Diagnosis (Typical Cases):
- Rhizomelic limb shortening
- Frontal bossing and midface hypoplasia
- Trident hands
- Characteristic radiographic features (skeletal survey)
Genetic Confirmation:
- FGFR3 mutation testing (sequencing)
- G380R mutation found in >97% of cases
- Useful for atypical cases, prenatal diagnosis, and differentiating from other skeletal dysplasias
7. Management
Management Algorithm
Acute/Emergency Management (if applicable)
Immediate Actions (for suspected foramen magnum compression):
- Stabilise airway — careful cervical spine handling
- Avoid neck flexion/extension (can worsen compression)
- Urgent MRI craniocervical junction
- Neurosurgical consultation for foramen magnum decompression
Conservative Management
- Monitoring: Regular multidisciplinary follow-up (genetics, orthopaedics, paediatrics, ENT)
- Growth charts: Use achondroplasia-specific charts (AAP-endorsed)
- Thoracolumbar kyphosis: Back bracing in infancy; avoid unsupported sitting
- Obesity prevention: Dietary counselling (important for spine/joint health)
- Physiotherapy: Core strengthening, postural support
- Occupational therapy: Adaptive equipment, environmental modifications
Medical Management
| Drug Class | Drug | Dose | Duration |
|---|---|---|---|
| CNP Analogue (Growth Therapy) | Vosoritide (Voxzogo) | 15 mcg/kg SC daily | Until growth plate closure; ongoing |
| Analgesics (if pain) | Paracetamol/NSAIDs | Age-appropriate dosing | As needed |
Vosoritide Details:
- First disease-modifying therapy for achondroplasia (FDA/EMA approved 2021)
- Acts as C-type natriuretic peptide (CNP) analogue
- Counteracts overactive FGFR3 signalling
- Improves annualised growth velocity (~1.5 cm/year gain)
- Side effects: Transient hypotension (monitor BP after injection), injection site reactions
Surgical Management
Indications:
| Indication | Procedure |
|---|---|
| Symptomatic foramen magnum stenosis (apnoea, cord compression) | Foramen magnum decompression (suboccipital craniectomy ± C1 laminectomy) |
| Symptomatic hydrocephalus | VP shunt insertion |
| Spinal stenosis with neurogenic claudication/myelopathy | Lumbar spinal decompression (laminectomy) |
| Severe progressive kyphosis | Spinal fusion |
| Severe genu varum (bowed legs) | Tibial osteotomy (guided growth or corrective surgery) |
| Short stature (patient choice) | Limb lengthening (Ilizarov or motorised nail) — controversial |
Procedure Notes:
- Foramen magnum decompression is potentially life-saving in infants with cervicomedullary compression
- Limb lengthening: Cosmetic/functional; significant commitment (months/years); risk of complications
Disposition
- Admit if: Apnoea, neurological symptoms, surgical intervention required
- Discharge if: Stable, no red flags, routine monitoring
- Follow-up: Regular MDT review (initially every 3-6 months in infancy, then annually)
8. Complications
Immediate (Minutes-Hours)
| Complication | Incidence | Presentation | Management |
|---|---|---|---|
| Foramen magnum compression (infant) | 5-10% symptomatic | Apnoea, cyanosis, hypotonia | Urgent MRI; neurosurgical decompression |
| Sudden infant death | <1% | Found unresponsive | Prevention via MRI screening; decompression if stenosis |
Early (Days-Months)
- Recurrent otitis media: Due to Eustachian tube dysfunction; may require grommets
- Obstructive sleep apnoea: Adenotonsillectomy, CPAP, or tracheostomy in severe cases
- Thoracolumbar kyphosis: Usually resolves; bracing if progressive
- Developmental delay: Gross motor delay due to hypotonia; normal intelligence expected
Late (Years)
- Spinal stenosis (lumbar/thoracic): Progressive neurogenic claudication, myelopathy — surgery often required
- Lumbar hyperlordosis: Chronic back pain
- Genu varum: May require surgical correction
- Obesity: Common; exacerbates joint and spine problems
- Psychosocial challenges: Short stature, societal attitudes — support essential
- Joint problems: Premature osteoarthritis
9. Prognosis & Outcomes
Natural History
Without intervention, achondroplasia carries increased mortality in the first years of life primarily due to foramen magnum stenosis causing central apnoea or sudden death. Those who survive infancy generally have near-normal life expectancy but may develop progressive spinal stenosis in adulthood requiring surgical intervention. Intellectual development is typically normal.
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| Infant Mortality | Reduced with MRI screening and timely foramen magnum decompression |
| Adult Life Expectancy | Near normal (~10 years shorter than general population without optimal care) |
| Final Height | Males: ~130 cm; Females: ~125 cm (without growth therapy) |
| Vosoritide Impact | +1.5 cm/year height velocity gain; long-term effects under study |
Prognostic Factors
Good Prognosis:
- Early diagnosis and multidisciplinary monitoring
- Timely intervention for foramen magnum stenosis
- Access to vosoritide therapy
- Obesity prevention
Poor Prognosis:
- Unrecognised foramen magnum stenosis in infancy
- Delayed diagnosis of spinal cord compression
- Severe thoracolumbar kyphosis requiring surgery
- Comorbid obesity worsening mobility and spine health
10. Evidence & Guidelines
Key Guidelines
- AAP Health Supervision for Children with Achondroplasia (2020) — Recommends MRI craniocervical junction by 6 months, polysomnography screening, achondroplasia-specific growth charts. American Academy of Pediatrics
- ESPE/PES Consensus on Management of Achondroplasia (2021) — Endorses vosoritide for growth therapy; outlines comprehensive care pathways. European Society for Paediatric Endocrinology
Landmark Trials
ACcomplisH Trial (Savarirayan et al., 2020) — Phase 3 RCT of vosoritide in children with achondroplasia.
- 121 children aged 5-18 randomised
- Key finding: Vosoritide increased annualised growth velocity by 1.57 cm/year vs placebo
- Clinical Impact: Led to FDA/EMA approval of vosoritide as first disease-modifying therapy
Natural History Study (Hoover-Fong et al., 2021) — Largest prospective cohort of achondroplasia.
- 1,400+ patients followed
- Key finding: Documented high rate of foramen magnum stenosis in infancy; established need for MRI screening
- Clinical Impact: Reinforced AAP screening recommendations
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Vosoritide for growth | 1b | ACcomplisH RCT; phase 3 |
| MRI screening for foramen magnum stenosis | 2a | Cohort studies; AAP guideline |
| Foramen magnum decompression for symptomatic stenosis | 2b | Case series; expert consensus |
| Limb lengthening | 3 | Case series; controversial; patient-specific |
11. Patient/Layperson Explanation
What is Achondroplasia?
Achondroplasia is a genetic condition that affects how bones grow. It's the most common form of dwarfism. People with achondroplasia have shorter arms and legs (especially the upper parts) compared to their body, and often have a larger head with a prominent forehead. It happens because of a change (mutation) in a gene called FGFR3, which normally controls bone growth.
Why does it matter?
Most children with achondroplasia grow up to lead full, active lives. However, there are some important health issues to watch for:
- In babies: A narrow opening at the base of the skull (foramen magnum) can sometimes press on the spinal cord, which can affect breathing — this is why early scans are important
- In children and adults: Narrowing of the spinal canal can cause leg pain or weakness
- Ear infections: More common due to differences in ear tube anatomy
- Sleep problems: Snoring and breathing pauses during sleep are common
How is it treated?
- Regular check-ups: With a team of specialists (genetics, bone doctors, ear-nose-throat, paediatrics)
- Vosoritide (Voxzogo): A new medicine given as a daily injection that helps bones grow faster. It's the first treatment that actually targets the underlying cause.
- Surgery if needed: For spine problems, leg bowing, or if the opening at the skull base is too narrow
- Support: Physiotherapy, occupational therapy, and adaptations to help with everyday life
What to expect
- Children with achondroplasia typically have normal intelligence and can attend mainstream schools
- Average adult height is around 125-130 cm
- With monitoring and treatment, most people live full, healthy lives
- Regular follow-up continues into adulthood (for spine checks)
When to seek help
- Urgent: If your baby has breathing pauses, turns blue, becomes floppy, or is unusually irritable
- Soon: If you notice worsening leg bowing, changes in walking, or numbness/weakness in the legs
- Routine: Keep all clinic appointments for monitoring
12. References
Primary Guidelines
- Trotter TL, et al. Health Supervision for Children With Achondroplasia. Pediatrics. 2020;145(6):e20201010. PMID: 32457214
- Hoover-Fong J, et al. Consensus Statement on the Management of Children with Achondroplasia. Nat Rev Endocrinol. 2021;17(3):173-189. PMID: 33456007
Key Trials
- Savarirayan R, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet. 2020;396(10252):684-692. PMID: 32866435
- Hoover-Fong JE, et al. Natural history of foramen magnum stenosis in achondroplasia: A multicenter study. Am J Med Genet A. 2017;173(3):779-787. PMID: 28162374
Further Resources
- Little People of America: Information and support
- Radiopaedia: Achondroplasia Imaging
- Restricted Growth Association (UK): RGA
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists. This content does not constitute medical advice for individual patients.