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Internal Medicine

Achondroplasia

Peter Dinklage attends the "X-Men: Days of Future Past" Southeast Asia premiere on May 14, 2014, in Singapore. (Photo by Nicky Loh/Getty Images)

Autosomal dominant genetic disorder causing disproportionate dwarfism.

  • M/C skeletal dysplasia
  • M/C cause of disproportionate dwarfism (accounts for > 90% of all cases)
  • Autosomal dominant inheritance
  • Average adult height:
    • 131 cm (4 ft 4 in) for males
    • 123 cm (4 ft) for females

Aetiology

Fibroblast growth factor receptor 3 (FGFR3) mutation:

Achondroplasia results from a point mutation in the gene coding for the transmembrane portion of FGFR3 on the short arm of chromosome 4. The resultant abnormal chondroid production affects endochondral ossification, resulting in decreased linear bone growth, among other functions. This pathologic process generally spares intramembranous ossification, which takes place in flat bones such as those in the skull (with the exception of the base of the skull), face, and clavicles.
  • Those with two affected genes do not typically survive
  • Increased risk of achondroplasia is not associated with older maternal age, independently of the older paternal ages

Clinical features

Affected individuals usually present average intelligence and have an estimated mean lifespan of 61 years, about ten years less than the general population.

Cephalic defects:

  • Macrocephaly with frontal bossing
  • Midface hypoplasia (small nasal bridge)

Limb defects:

  • Rhizomelic shortening of the extremities (proximal portion shorter than distal portion of limb)
  • Brachydactyly (short fingers) with trident hand (prominent gap between ring and middle fingers)
  • Radial head subluxation, posterior bowing of the humerus,
  • Genu varum (bowed legs)

Spinal defects:

  • Thoracolumbar kyphosis (TLK) (convex curvature)
  • Lumbar hyperlordosis (concave curvature)
  • Foramen magnum stenosis (FMS) (first spinal manifestation observed): Common signs and symptoms include periods of apnea while sleeping and excessive snoring. Other subjective or objective findings include difficulty swallowing, lower cranial nerve palsies, hyperreflexia, generalized hypotonia, weakness, and clonus. Intelligence is usually average unless the child develops hydrocephalus or has other central nervous system complications.

Associated conditions:

  • Repeated ear infections (due to Eustachian tube blockages)
  • Sleep apnea (central or obstructive)
  • Hydrocephalus
  • Dental malocclusion

Diagnosis

There are no diagnostic algorithms for achondroplasia; the diagnosis can usually be made with certain characteristics and specific radiologic features.

Prenatal diagnosis:

Can occur incidentally during a routine second or third-trimester ultrasound if shortened long bones are appreciated in the developing fetus.
  • Noninvasive prenatal diagnosis using cell-free fetal DNA in mother’s serum
  • Prenatal ultrasound
    • ↑ Skull-width:Femur-length
    • Megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-face hypoplasia
  • Preimplantation genetic diagnosis: For parents pursuing in-vitro fertilization and embryo implantation procedures.

Molecular diagnosis:

  • FGFR3 testing: Indicated in children with atypical presentation or to differentiate from similar disorders

Skeletal surveys:

  • Contracted skull base
  • Rhizomelic shortening of long bones
  • Proximal femoral radiolucency
  • Generalized metaphyseal “flaring” irregularities
  • Inverted “V-shaped or chevron-shaped” distal femoral epiphyses
  • “Champagne-glass” shaped pelvis (wider than deep pelvic outlet with small sacrosciatic notch)
  • Characteristic radiographic appearance of spine:
    • Narrowed interpedicular distances (short pedicles usually found from L1-S1)
    • Vertebral body wedging (usually at T12 or L1)
    • Generalized posterior vertebral scalloping

Management

Management of achondroplasia involves an interprofessional team approach, and anticipatory care is essential. Multiple versions of health supervision and treatment guidelines exist for those with achondroplasia, with most including detailed examinations and specific anticipatory guidance for each separate age group.

  • Human growth hormone does not help people with achondroplasia (which involve a different hormonal pathway)

Treatment of manifestations:

  • Increased intracranial pressure: Ventriculoperitoneal shunt
  • Craniocervical junction compression: Suboccipital decompression
  • Obstructive sleep apnea: Adenotonsillectomy, positive airway pressure, and tracheostomy
  • Middle ear dysfunction: Pressure-equalizing tubes
  • Monitor and treat obesity
  • Orthopedic treatment: Bowing of legs
  • Severe, persistent kyphosis: Spinal surgery
  • Spinal stenosis: Surgical correction
  • Modification in the school and work setting to optimize function; educational support in socialization and school adjustment.

Summary

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