155: Achondroplasia

Key Points

• Disease summary:

  • Achondroplasia is the most common form of inherited short stature.

  • Incidence is approximately 1 in 15,000 to 1 in 40,000 live births.

  • Clinical features include rhizomelic disproportionate short stature, macrocephaly, midface hypoplasia, trident hand conformation with brachydactyly, lordosis, genu varum, and normal cognitive development.

  • Neurologic complications occur with cervicomedullary cord compression, spinal stenosis, and kyphosis. Potential respiratory complications include central sleep apnea due to cervicomedullary cord compression, and mechanical sleep apnea due to midface hypoplasia and relatively large adenotonsillar tissue compounded by hypotonia.

• Hereditary basis:

  • Achondroplasia is inherited in an autosomal dominant fashion and has 100% penetrance.

  • Approximately 99% of patients with achondroplasia have a point mutation (G changed to an A or G changed to a C) at nucleotide 1138 in the gene fibroblast growth factor receptor 3 (FGFR3) located at chromosome 4p16.3. This nucleotide change (G>A or G>C) results in a Gly380Arg amino acid substitution.

  • Approximately 80% of patients with achondroplasia are born to parents of average height without FGFR3 mutations. De novo mutations have been associated with advanced paternal age.

• Differential diagnosis:

  • Achondroplasia can be distinguished from other forms of disproportionate short stature including hypochondroplasia (OMIM 146000) and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), both caused by different FGFR3 mutations. Thanatophoric dysplasia I (OMIM 187600) and thanatophoric dysplasia II (OMIM 187601) are also caused by mutations in FGFR3, but are easily differentiated from achondroplasia by their more severe pulmonary phenotype and lethality.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

Clinical features of achondroplasia include

• Rhizomelic (proximal limb) short stature

• Macrocephaly with frontal bossing

• Midface hypoplasia

• Trident hands

• Genu varum (bow legs)

• Limitation of elbow extension

Distinctive radiographic features include

• Hypolucency at proximal femora

• Interpedicular narrowing of the lumbar vertebrae

• Broad metaphyses and shortened tubular bones

Clinical features are often apparent at birth and radiographic features are diagnostic at any time. For patients with a suspected clinical diagnosis, molecular testing can be performed to confirm the diagnosis.

Clinical Characteristics

Achondroplasia is characterized by disproportionate short stature with rhizomelic shortening (shortening of the proximal segments of the limbs), macrocephaly, prominent forehead, and depressed nasal bridge. Hands are noted to have a trident configuration due to fingers of roughly the same length. The average adult height is 131 cm for males and 124 cm for females. Most individuals with achondroplasia have normal intelligence and lifespan.

Skeletal abnormalities in patients with achondroplasia include lumbar lordosis, kyphosis, limited elbow extension, limited hip extension, and tibial bowing. Tibial bowing results from the relative overgrowth of the fibula when compared to the tibia.

The most serious complication of achondroplasia is cervicomedullary cord compression, which may cause sudden death in infants. In adults, neurologic complications include claudication and ...