ACHONDROPLASIA
DEFINITION:
A non-lethal type of congenital dwarfism characterized by typical
skeletal dysplasias (rhizometric micromelia), a large head, and
neurological manifestations.
EPIDEMIOLOGY:
- incidence: 1/25,000 births (most common skeletal dysplasia)
- age of onset:
- risk factors:
- familial - autosomal dominant, (but with a high spontaneous
mutation rate [50-80%])
- chrom.#: 4p
- gene: fibroblast growth factor receptor-3 gene
- increased paternal age
- M = F
PATHOGENESIS:
- the fibroblast growth factor receptor-3 gene (FGFR3 gene) is
a transmembrane receptor comprised of three domains:
- an extracellular ligand-binding domain consisting of three
immunoglobulin-like (sub)domains
- a transmembrane domain
- an intracellular cytoplasmic domain consisting of two
tyrosine kinase (sub)domains
- a mutation in the FGFR3 gene as the cause of Achondroplasia
was first reported by two groups - Shiang et al., Cell 78:335
(1994); Rousseau et al., Nature 371:252 (1994).
- there are several disorders which arise from mutations
within the FGFR3 gene:
- Achondroplasia
- Hypochondroplasia
- Thanatophoric Dwarfism - Types I and II
2. Nonchondrodysplastic Disorders
- Crouzon Syndrome (with acanthosis nigricans)
- Pfeiffer-like Craniosynostosis Syndrome
2. Genetic Defect
- adenosine or cytosine replacement of guanosine at nucleotide
1138 of the FGFR3 gene -> Gly380Arg substitution -> mutation of
the transmembrane domain of the FGFR3 receptor -> FGFR3 activation
-> inhibition of linear bone growth
CLINICAL FEATURES:
- rhizometric micromelia
- shortened limbs
- proximal > distal shortening
- elbows - lack of full extension and supination
- legs - genu varum (bowleg)
- hands - trident (splayed), deviated towards ulna, short
and broad
2. Head
- large, frontal bossing
- coarse facial features
- recessed nasal bridge
- hypoplasia of midface (maxilla)
- prognathism
- dental malocclusion
3. Spine
- short stature - dwarf
- thoracolumbar - kyphotic
- lumbar - lordotic
2. Neurological Manifestations
- infantile hypotonia and gross motor developmental delay
- normal neuromuscular tone by age 2-3 years
- hydrocephalus
- sleep apnea
- normal intelligence
3. Complications
- recurrent otitis media (OM) and chronic serous OM ->
conductive hearing loss
- strabismus
INVESTIGATIONS:
- limbs - as above, shortened but normal width
- spine - progressive narrowing of lumbar spinal canal
- head - as above, small foramen magnum
MANAGEMENT:
- multidisciplinary approach:
- Paediatrics, Orthopedics, Dentistry, Neurosurgery,
ENT,Genetics
- management of complications:
- spinal and nerve root compression, bowed legs, paraplegia,
arthritis, hydrocephalus, hearing impairment, strabismus,
lordosis, kyphosis
- genetic counselling
2. Prognosis
- normal life span
- adult height: M (131 cm) F (125 cm)
ADDITIONAL REFERENCES:
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