Achondroplasia

Achondroplasia is the commonest skeletal dysplasia causing disproportionate short stature, with an incidence of about 1 in 15,000 to 25,000.

It is an autosomal dominant condition caused by activating variants in FGFR3 (4p16.3): 98% are the c.1138G>A (p.Gly380Arg) variant, which impairs endochondral ossification by constitutive inhibition of chondrocyte proliferation and differentiation.

About 80% of cases are de novo, associated with advanced paternal age, and homozygous achondroplasia is severe and usually lethal in the perinatal period.

• Rhizomelic limb shortening, trident hand, short stature (adult height about 131 cm for men and 124 cm for women), macrocephaly with frontal bossing, midface hypoplasia, depressed nasal bridge, lumbar hyperlordosis, thoracolumbar kyphosis in infancy, and genu varum
• Foramen magnum stenosis (risk of central apnoea, cervicomedullary compression, hydrocephalus, and sudden death in infancy)
• Spinal canal stenosis (lumbar, in adults; neurogenic claudication, radiculopathy and cauda equina)
• Obstructive sleep apnoea (adenotonsillar hypertrophy and midface hypoplasia), recurrent otitis media with conductive hearing loss, dental crowding
• Motor delay (hypotonia, head control), with normal intelligence
• Obesity in later life, with cardiovascular risk

• Clinical and radiographic: squared iliac wings with a narrow sacrosciatic notch, a champagne glass pelvic inlet, short and flat topped vertebrae with decreasing interpedicular distance from L1 to L5, short long bones with metaphyseal flaring, and a chevron shaped distal femoral epiphysis.

• Prenatal ultrasound shows femur length below the 5th percentile from the third trimester. FGFR3 mutation testing confirms the diagnosis in uncertain cases and is available prenatally.

• Baseline evaluation: MRI or CT of the craniocervical junction in infancy to assess foramen magnum, polysomnography, and neurological examination.

• Vosoritide (C-type natriuretic peptide analogue): 15 micrograms/kg subcutaneously once daily for children aged 4 months and above (dose according to weight bands for children over 10 kg, with age related weight band tables); increases annualised growth velocity by about 1.5 to 2 cm per year; adverse effects include injection site reactions and transient hypotension (take with 240 to 300 mL of fluid within 1 hour before administration). Treatment continues until growth plates close. Infigratinib (oral FGFR inhibitor) and navepegritide (once weekly) are in late stages of development.
• Surveillance: head circumference on achondroplasia growth charts, regular neurological review in infancy, and polysomnography; early decompression surgery (foramen magnum decompression) for symptomatic stenosis or abnormal polysomnography with cord compression signal.
• Hydrocephalus: shunt for symptomatic progression.
• Sleep apnoea: adenotonsillectomy, CPAP, and supervised sleeping position.
• Ear: tympanostomy tubes for recurrent otitis media, hearing aids; speech assessment.
• Orthopaedics: avoid unsupported sitting before motor maturity (to reduce thoracolumbar kyphosis), and avoid walkers and baby carriers that load the spine; bracing and surgery for progressive kyphosis; guided growth (hemiepiphysiodesis) or osteotomy for severe genu varum; limb lengthening is an option in adolescence (by specialist teams).
• Spinal stenosis in adulthood: decompressive laminectomy.
• Weight control from childhood.
• Psychosocial support, support groups (Little People of America), and educational and occupational adaptations.
• Pregnancy: caesarean delivery is required in affected women because of a small pelvis.
• Genetic counselling: 50% recurrence risk in affected parents; negligible recurrence for sporadic cases.