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Achondroplasia

What is Achondroplasia?

Achondroplasia is the most common form of disproportionate short stature, affecting approximately 1 in 20,000 to 30,000 live births worldwide. It is a genetic disorder characterized by impaired endochondral ossification, leading to abnormalities in bone growth, particularly in the long bones, skull, and spine.

Causes

Achondroplasia is caused by a mutation in the FGFR3 (fibroblast growth factor receptor 3) gene, located on chromosome 4. This mutation leads to excessive activation of FGFR3, which inhibits chondrocyte proliferation and differentiation, impairing cartilage development and bone growth. In more than 80% of cases, achondroplasia arises due to a new (de novo) mutation, while the remaining cases follow an autosomal dominant inheritance pattern.

Clinical Features

Children with achondroplasia typically present with:

  • Disproportionate short stature (short limbs with a relatively normal trunk length)
  • Macrocephaly with frontal bossing
  • Midface hypoplasia with a depressed nasal bridge
  • Short fingers (brachydactyly) with a characteristic trident hand
  • Hyperlordosis of the lumbar spine, leading to exaggerated curvature
  • Genu varum (bowed legs)
  • Joint hyperlaxity, particularly in the hands

Associated Conditions

Achondroplasia is associated with several medical complications that may require monitoring and intervention:

  • Foramen magnum stenosis, which can lead to cervicomedullary compression and life-threatening respiratory complications in infancy
  • Hydrocephalus due to impaired cerebrospinal fluid circulation
  • Recurrent otitis media, leading to conductive hearing loss
  • Obstructive sleep apnea due to airway narrowing
  • Spinal stenosis, which can cause neurogenic claudication in adulthood

Evaluation and Diagnosis

Diagnosis of achondroplasia is primarily clinical, supported by characteristic radiographic findings:

  • Rhizomelic shortening of long bones
  • Narrowing of the interpedicular distance in the lumbar spine
  • Squared iliac wings with a horizontal acetabulum
  • Large skull with a small skull base

Molecular genetic testing can confirm the presence of the FGFR3 mutation. Additional evaluations, including MRI of the foramen magnum and polysomnography for sleep apnea, may be required based on symptoms.

References

  1. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582):162-172.
  2. Pauli RM. Achondroplasia: A comprehensive clinical review. Orphanet J Rare Dis. 2019;14(1):1.
  3. Unger S, Bonafé L, Gouze E. Current care and investigational therapies in achondroplasia. Bone. 2020;137:115457.