Achondroplasia

Question 1

What is the inheritance pattern for achondroplasia?

Answer 1

Autosomal dominant

Usually sporadic

Question 2

What is the recurrence risk for achondroplasia?

Answer 2

normal parents <1%
Parent with achondroplasia 50%
Two parents with achondroplasia: 50% achondroplasia, 25% unaffected child, 25% homozygous achondroplasia (severe, lethal)

Question 3

What is the genetic defect in achondroplasia?

Answer 3

Unique single base pair substitution mutation involving fibroblast growth factor receptor 3 gene (FGFR3) at chromosome 4p16.3

Question 4

What are the associated medical findings with achondroplasia?

Answer 4

1. Disproportionate limbs, rhizomelic shortening, “trident” fingers
2. Short stature (mean height 49-51in)
3. Macrocephaly, frontal bossing, depressed nasal bridge, malar hypoplasia
   o 5% may have symptomatic hydrocephalus
4. Fatal apnea (~10%) especially before age 2yrs
   o Misshaped and small foramen magnum
   o Vascular and cervicomedullary constriction
5. OSA is very common
   o Obesity, small airway, lymphatic hypertrophy
6. Chronic hypoxemia can be associated with small thoraces/constricted chest
7. Middle ear dysfunction – CHL
8. Kyphosis –> resolves in most
9. Spinal stenosis is uniformly present
10. Knee instability in toddlers, varus deformity (bowlegs)
11. Orthodontic problems associated with crowding and overbite
12. Anesthesia risks (cervical spinal stenosis, small airway, OSA, restrictive lung
    disease)

Question 5

What are the developmental outcomes for achondroplasia?

Answer 5

1. Cognitive development and function is typically normal
   o ~10% may have severe learning disabilities, intellectual disability or ASD
2. Motor development is delayed and atypical due to hypotonia, disproportion, joint hypermobility
   a) Sit 9-20months
   b) Walk 14-27months
3. Increased language delays
   o Associated with chronic OME and conductive hearing loss
4. If marked developmental delays or hypotonia –> evaluate for craniocervical
   junction compression!

Question 6

What is the DDx for achondroplasia?

Answer 6

1. Other skeletal dysplasias + disproportionate short stature incld:
   a) Hypochrondroplasia (milder bone dysplasia, often FGFR3)
   b) Thanatophoric dysplasia (severe, usu. lethal, also FGFR3)
   c) Pseudoachondroplasia (epiphyseal + metaphyseal dysplasia, COMP gene)

Question 7

What are the recommendations for achondroplasia?

Answer 7

1. Standardized linear growth charts
2. Environmental and adaptive modifications
   o Driving, reaching, etc
3. MRI or CT brain and C-spine after diagnosis during neonatal period or early infancy
   o Close monitoring of OFC
4. Sleep study
5. Audiology
6. Avoid poor infant positioning (<12months)
   o NO unsupported sitting, umbrella strollers, swings
7. Close neurologic monitoring with regular exams