Special thanks to: 

Writer: Dorsa Kord, Research Associate, RareShare

Reviewer: Dr. Morrys Kaisermann, Clinical Research manager, GlaxoSmithKline, Brazil

Achondroplasia is the most common form of skeletal dysplasia, occurring in about 1 in every 20,000 to 30,000 newborn children. In about 80% of cases, it is caused by a random mutation to the FGFR3 gene, but in 20% of cases it is inherited from one of the child’s parents.

Achondroplasia is caused by a mutation in the gene fibroblast growth factor receptor 3 (FGFR3), on chromosome 4. This gene regulates development and maintenance of bone tissue. The mutated gene generates malfunctioning proteins that consequently results in severely shortened bones. Inheritance is autosomal dominant, meaning one copy of the altered gene is sufficient to cause the disorder. If two mutated genes are inherited, achondroplasia is fatal.

Achondroplasia is characterized by long narrow trunks and short limbs. Affected individuals have enlarged head, with a prominent forehead, and a flat depressed nasal bridge. Hands are usually in a trident formation, or three-pronged position during extension. Compression of the brain stem may occur in some children with achondroplasia resulting in accumulation of fluids in brain and consequently, abnormally large heads. The spine may be excessively curved, either inwards or outwards.  One of the serious complications of the disorder is that the spinal canal may narrow and compress the upper parts of the spinal cord and the brain stem in some individuals, which can result in pain, tangling and weakness in the legs. Legs might also be bowed. Adults reach a height of 131±5.6 cm (men) and 124±5.9 cm (women). Other health problem associated with achondroplasia include obesity, recurrent ear infection, and apnea.

Due to the abnormal bone growth experienced by individuals with achondroplasia, some of the physical characteristics associated with this rare disorder include the following:

• Large head (macrocephaly)

• Short upper arms (rhizomelic dwarfism)

• Shortened stature (4 feet at full adult height)

• Prominent forehead (frontal bossing)

• Flattened nasal bridge

• Prominent midsection due to curvature of the spine

• Short hands and fingers that resemble a “trident” or 3-pronged appearance during full extension

Individuals with achondroplasia will not typically experience impaired mental abilities. Neurological functions such as movement can be impaired by a narrowing of the spinal canal between the head and neck due to abnormal spine curvature. This could result in spinal stenosis, a pinching of the upper spinal cord that can cause pain, tingling, weakness in the limbs, and/or difficulty walking. 

Infants born with achondroplasia have a dome-like skull and broad forehead. In rare cases there may be a build-up of fluid around the brain (hydrocephalus) which can cause other complications and must be relieved through surgery. Low muscle tone in infants is common and may cause delayed progression of motor milestones.

Because this disorder has distinctive physical characteristics, it is easy to identify clinically and radiologically at birth. There are a limited number of mutations related to achondroplasia and they are easily detectable, providing a simple method for prenatal diagnosis. A definitive in utero diagnosis may be difficult to come by as there are other forms of dwarfism and babies may just be small.

One polymerase chain reaction (PCR) and one restriction digest, also known as DNA fragmentation, is adequate to diagnose this condition prenatally. Skeletal survey (a series of X-rays that cover all bones in the body) shows shortened limbs, metaphyseal enlargement, narrowing of the distance between vertebral pedicles in a particular section of the vertebrae (lumbar vertebrae), and an abnormal hip bone with small square iliac wings. Presence of FGFR3 mutation can be tested by molecular genetic testing.  It is also possible to determine if the genetic test is present in the embryo using a screening method called PGD in specialized laboratories.

It is possible to manage achondroplasia through multidisciplinary care. Orthopedic surgery such as surgical lengthening of the limbs, and surgical correction of bowed legs physical therapy can be helpful to affected individuals. Infants may require surgical enlargement of foramen magnum to relieve pressure from brain stem, while adults may require lumbar laminectomy to relieve pressure from lower sections of the spinal cord. It is important to control weight, to prevent obesity from early childhood. Ear infections also need to be treated and an assessment of potential hearing loss is required. Weight loss can also help treat obstructive sleep apnea. Surgical removal of tonsils and adenoids, and/or continuous positive airway pressure can also be beneficial to treat sleep apnea. Growth development curves and health surveillance guidelines for medical issues in achondroplasia are available and may help to follow up the kid’s growth and health status, as well prevent common complications. This includes recommendations for further testing, such as brain and spine CT, MRI, somatosensory evoked potentials and polysomnography for sleep apnea.

The American Academy of Pediatrics Committee on Genetics has outlined recommendations for treatment of children with achondroplasia. Most treatment options are tailored to the potential risks associated with the disorder. However, some recommendations are designed to improve stature so that the children can grow to a more average height and proportions. This may or may not be of interest to people with achondroplasia or other types of dwarfism or their families, and more information about perspectives of these drugs can be found at: https://www.theguardian.com/science/2020/sep/28/there-is-a-fear-that-this-will-eradicate-dwarfism-the-controversy-over-a-new-growth-drug

1. Increased cranial pressure (hydrocephalus) poses a risk to the developing brain. Children should be referred to a neurosurgeon for testing via computerized tomography (CT) scan and magnetic resonance imaging (MRI) of the brain. This will detect any abnormalities for early and effective treatment.

2. If the bones joining the head to the neck are compressing the brainstem or upper spinal cord, the child with achondroplasia may need decompression of the craniocervical junction. This can be diagnosed and treated by a neurosurgeon.

3. Obstructive sleep apnea experienced by some individuals with achondroplasia can be treated by losing weight, surgery to remove tonsils and adenoids, applying positive airway pressure using a medical device, and, in rare cases, a surgery to create an opening in the neck (tracheostomy).

4. Young children with achondroplasia may succumb to middle ear infections which can pose a risk to hearing loss. Treatments include ear tubes inserted to prevent infection.

5. A shortened stature may be increased by treatment with growth hormones, however most studies have shown that the effects are reduced as the child ages and there are few lasting benefits.

6. To prevent obesity in children with achondroplasia, early measures should be taken and monitored via weight-by-height grids specific to achondroplasia development.

7. If an individual with achondroplasia experiences bowed legs, they may seek treatment from an orthopedist if they experience discomfort but may not need surgical correction if there is not discomfort.

8. In order to prevent infants from developing a fixed backwards curve in the mid-spine (kyphosis), they must be supported at all times when sitting until 1-1.5years old. If unsuccessful in preventing curvature, braces or surgery can be used to treat this growth abnormality.

9. Individuals experiencing spinal stenosis as a result of curved spine should seek advice and treatment by a medical professional.

10. Children and young adults with achondroplasia may experience physical or social difficulties as they age that require certain adaptation to their size and characteristics. Accommodations for short stature can be made, and social support groups can help children and their families understand their unique physicality and bond with peers.

11. Adaptations and/or modifications in home, school, and work environments to increase childrens’ confidence and comfort who are affected with this condition.

One risk to children born with achondroplasia is the bones joining the head and neck compressing the brainstem or upper spinal cord in what is known as craniocervical junction compression. If this does not occur, then life expectancy is normal. Individuals with achondroplasia rarely experience impaired mental abilities. Life expectancy of individuals with achondroplasia is only slightly decreased relative to the general population, due to increased risk of cardiovascular disease.

Affected individuals should avoid activities that increase the risk of craniocervical junction injuries. In addition, weight control is essential for people with Achondroplasia. Obesity can worsen the joint and back problems caused by the disorder.

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