Achondroplasia (ORPHA:15)
A primary bone dysplasia with micromelia characterized by rhizomelia, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia.
Epidemiology
Achondroplasia estimated incidence is at about 1/25,000 live births worldwide.
Clinical description
Characteristic clinical features (short limbs with rhizomelia, long and narrow trunk and macrocephaly with frontal bossing and midfacial hypoplasia with depressed nasal bridge) are often times visible at birth. Hands are broad, short and trident shaped. Hypotonia is common, leading to hypermobile joints particularly in the lower extremities. A smaller foreamen magnum or abnormal shape can lead to serious sequelae in infancy like spinal cord compression or vertebral artery compression leading to central apnea. Thoracolumbar kyphosis is very common in infancy, with 90% resolving over time. Midface hypoplasia in combination with adenoid and tonsil hypertrophy can lead to obstructive sleep apnea. Chronic otitis media can lead to conductive hearing loss. Achievement of gross motor skills is slower than typical due to short limbs, short neck, and large head, in addition to hypotonia. Dental crowding is common. Genu varum often occurs in childhood. Lower lumbar spinal stenosis with accompanying neurological deficits, has an increased frequency in adulthood, as does cardiovascular disease. Obesity is a common issue. Adults reach a height of 131±5.6 cm (men) and 124±5.9 cm (women). Affected women must deliver by caesarian section due to small pelvis size.
Etiology
Achondroplasia is due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, encoding a transmembrane receptor that is important in regulating linear bone growth, among other functions. Almost all mutations affect a specific glycine that is substituted to an arginine (G380R), leading to a gain of function mutation.
Diagnostic methods
There are no clinical diagnostic criteria for achondroplasia. Diagnosis is based on radiological and clinical findings. A skeletal survey will demonstrate generalized metaphyseal irregularities. Molecular genetic testing can confirm a diagnosis by the presence of a FGFR3 mutation in almost all individuals.
Differential diagnosis
Differential diagnoses include hypochondroplasia, thanatophoric dwarfism (types I and II), and SADDAN.
Antenatal diagnosis
Prenatal diagnosis can occur incidentally during routine prenatal ultrasound examination in the 3rd trimester when shortened long bones are noted. In these cases or when a parent is known to have achondroplasia, fetal DNA can be tested for the FGFR3 mutation to confirm diagnosis. Pre-implantation genetic diagnosis is possible in specialized laboratories.
Genetic counseling
Inheritance is autosomal dominant so genetic counseling is warranted. In 80% of cases, it is due to a de novo mutation in children with parents of average stature. If one parent has achondroplasia there is a 50% risk at each pregnancy of passing it on to offspring. If both parents have achondroplasia, there is another 25% risk that the offspring will have homozygous achondroplasia which is incompatible with life.
Management and treatment
Management is multidisciplinary and anticipatory care is essential. Neonates should have imaging of the brain and cervical spine to access the foreamen magnum and check for hydrocephalus as well as polysomnography to check for central sleep apnea. Abnormalities in either study should warrant a prompt referral to neurosurgical colleagues for evaluation and possible surgical treatment. Regardless of imaging, activities which lead to a risk of injury to the craniocervical junction should be avoided. Treatment of ear infections and serous otitis media, along with assessment of any hearing problems is needed. Speech therapy can be offered if concerns arise. Treatment of obstructed sleep apnea may include adenotonsillectomy, weight loss, and/or continuous positive airway pressure. Weight gain should be monitored in childhood to avoid later complications. Social and psychological support should be offered. Progressive and symptomatic leg bowing can be treated surgically. Adult patients may require a lumbar laminectomy to treat spinal stenosis. Some may choose controversial limb lengthening procedures.
Prognosis
There is only a slight decrease in life expectancy compared to the general population, potentially due to cardiovascular disease.

                            Last update: 
                            September 2019


                            - Expert reviewer(s): 
                            Dr Elaine PEREIRA