Achondroplasia

What is Achondroplasia?

Achondroplasia is a rare genetic disorder that is the leading cause of dwarfism, making up over 90% of such cases. The term “achondroplasia”, first used in 1878, means “without cartilage formation”. This disorder sets in when there’s an issue with the growth plate, resulting in abnormalities in bone growth. It’s different from a different bone condition called rickets.

The cause behind this condition, a mutation of a specific gene known as the fibroblast growth factor receptor 3 (FGFR3), was discovered in 1995. This mutation gets passed down in an autosomal dominant manner, meaning a person can get it even if just one parent has the mutated gene. Interestingly, more than 80% of the instances of this condition come from a sudden, new mutation. It’s also noted that men who become fathers at an older age are at a higher risk of having children with the disorder. Doctors can usually identify this condition in unborn babies through an ultrasound and in newborn babies during an examination.

People with achondroplasia generally have normal intelligence levels and can expect to live around 61 years, which is about ten years less than people without the condition. Physically, they may have a larger head, a slightly compressed midface, shorter arms and legs, short fingers with a specific hand shape, and legs that bow out.

This condition can lead to a higher rate of death in early childhood, ear, nose, and throat problems during later childhood, and an increased chance of obesity in adulthood. Some people with achondroplasia might also have loose joints, a spinal condition called thoracolumbar kyphosis (TLK), and spinal stenosis, which can worsen and impact quality of life as they grow older.

What Causes Achondroplasia?

Achondroplasia, a type of dwarfism, is caused by a specific gene mutation. The affected gene, known as fibroblast growth factor receptor 3 (FGFR3), is found on chromosome 4. The mutation in this gene hampers the formation of chondroid, a material important for bone formation. This results in shorter bone growth but usually doesn’t impact the flat bones in the body such as the skull, face, and collarbones.

In most cases, about 80%, achondroplasia is caused by a new mutation and can occur in children of parents who don’t have the condition or any family history of it. The remaining 20% of individuals with achondroplasia have inherited the condition from at least one affected parent.

Achondroplasia is inherited in an interesting way – it’s what’s called ‘autosomal dominant’. This means that if you inherit the mutated FGFR3 gene from just one parent, you’ll get the characteristic features of achondroplasia. Also, the way the mutation happens results in most people with achondroplasia having similar features.

If a parent has achondroplasia, there’s a 50% chance they’ll pass the mutated gene to their child. If both parents have the condition, there’s a 25% chance their child will be of normal height, a 50% chance they’ll have achondroplasia, and a 25% chance they’ll inherit the condition from both parents (known as homozygous achondroplasia).

Homozygous achondroplasia is usually life-threatening. It often results in early death shortly after birth due to breathing difficulties and neurological issues, caused by a small chest cavity and narrowing of the part of the spine that connects to the brain.

We do know that older fathers are more likely to have children with the new mutation causing achondroplasia. This is thought to occur during the formation of sperm. However, an older maternal age doesn’t independently increase the risk of having a child with achondroplasia.

Risk Factors and Frequency for Achondroplasia

Achondroplasia is a condition that affects the way bones grow and it happens in about 1 in every 20,000 to 30,000 babies that are born each year. However, it’s tricky to know exactly how many people worldwide have the condition, but the estimate is between 1 to 9 in every 100,000 people. Through a large study done in Europe, researchers figured out that for every 100,000 babies born, about 3.72 have achondroplasia. This figure was the same over time, although there were some regional differences noticed.

This condition is inherited in a way that means both males and females have an equal chance of getting it. For children with fathers over the age of 50, the rate of achondroplasia is much higher. It’s about 1 in every 1,875 births, which is a lot more than the rate of 1 in 15,000 in the general population. Additionally, fathers who are 35 years or older had much higher rates of having children with the condition.

Signs and Symptoms of Achondroplasia

Achondroplasia is a condition that results in short height due to certain physical characteristics. These characteristics include a significantly broad forehead, a small nasal bridge, abbreviated limbs, and short fingers with a noticeable gap between the ring and middle fingers, a feature known as a “trident hand”. An individual with Achondroplasia may also exhibit bowed legs, an exaggerated curve of the lower spine, and radial head subluxation, a condition that restricts the full extension of the elbow.

In terms of height, while an individual with achondroplasia might have a torso of average size, their short limbs result in overall low stature, often below the 5th percentile. Over 90% of adults with this condition, if left untreated, may have bowed legs. This deformity is not just a simple outward curvature of the legs, but results from various factors such as inward twisting of the shin bone and instability of the knee.

• A broad forehead
• A small nasal bridge
• Shorter limbs in particular the upper arm and thigh
• Short fingers
• A noticeable gap between the ring and middle fingers
• A limitation in full elbow extension
• Bowed legs
• Exaggerated curve of the lower spine

Certain spinal features may be observed in infants, like thoracolumbar kyphosis, a curvature of the spine that appears when the infant starts sitting up. This curvature can actually correct itself when the child lies down on their stomach. Other features that may appear as the child starts standing and walking include an excessive inward curve of the lower spine.

Foramen magnum stenosis (FMS), a narrowing at the base of the skull, is a serious condition typically found in infants with achondroplasia. It’s associated with a high mortality rate of 2 to 5%. This condition may manifest itself through symptoms like difficulty breathing during sleep, snoring, and difficulty swallowing among others. Mental development is usually normal except in cases where the child develops a build-up of fluid in the brain or faces other brain complications. These brain complications might include hydrocephalus, a condition that is estimated to require treatment in 5% of those affected.

Furthermore, hearing impairment is a common issue in children with achondroplasia due to a dysfunction in the middle ear. If not properly treated, this can lead to a hearing loss severe enough to interfere with language development. Roughly, half of the children with achondroplasia might require surgical intervention to treat this condition, and around 40% of them may experience significant hearing loss.

As they grow older, individuals with achondroplasia might start experiencing discomfort while walking or standing for longer periods, numbness in the lower body, or weakness. These signs usually suggest a narrowing of the spinal canal, a condition to which they are more prone due to their small spinal vertebrae, thickened spine joints, and ligaments. Lumbar spinal stenosis, a condition that restricts the space in the lower spine, occurs in approximately 25% of those with achondroplasia.

Testing for Achondroplasia

: Achondroplasia is a condition that is usually diagnosed by observing specific characteristics and unique features in X-ray images.

To confirm the diagnosis, doctors typically perform a genetic test for a mark known as FGFR3 mutation. This test is particularly necessary for children who do not show the typical signs or to distinguish achondroplasia from similar disorders. A panel of genes, including FGFR3, can be checked to help determine the specific type of bone growth disorder.

It’s also possible to identify achondroplasia before the baby is born. During a routine ultrasound in the second or third trimester, short long bones in the fetus might be noticed. A test using cell-free fetal DNA found in the mother’s blood can also be used and has a high rate of reliability. Parents planning for in-vitro fertilization and embryo implantation can opt for genetic diagnosis before implantation. In recent years, there’s been a considerable increase in prenatal detection rates.

Children with achondroplasia may show certain specific features on X-ray images, such as a contracted base of the skull, shortening of long bones, a “champagne-glass” shaped pelvis, and a specific appearance of the spine.

In cases where the person exhibits signs of sleep apnea or cervicomedullary myelopathy – a condition affecting the junction between the spine and the brain – a sleep study may be conducted. Advanced imaging of the cervicomedullary junction might be necessary, so your doctor may order a CT scan or an MRI.

Treatment Options for Achondroplasia

Achondroplasia is typically managed by a team of healthcare professionals, and needs to be closely monitored. There are guidelines, specific to different age groups, to spot and prevent health issues early. Pediatricians or other health professionals should follow these guidelines. It’s important to also watch out for the development of obesity in children with achondroplasia to prevent health issues in the future. Each health issue associated with achondroplasia has a specific set of treatments.

If a child has an abnormally large head (macrocephaly), it’s important to understand whether it’s normal for them or whether it’s due to a serious condition called hydrocephalus. Regular measurements of their head size should be taken at each health visit, and these should be compared with typical measurements for children with achondroplasia. If hydrocephalus is suspected (which affects about 5% of children with achondroplasia), it can be treated with various surgical techniques.

Foramen Magnum Stenosis (FMS) is another condition that some children with achondroplasia might experience, related to the narrowing of the large hole at the base of the skull. Techniques like sleep studies, CT or MRI scans can be used to confirm the diagnosis and decide whether surgery is required. Exercises or activities that could potentially injure the head or neck should be avoided for children discovered to have FMS in imaging studies.

Hearing issues may be a concern for some children due to frequent ear infections. Interventions such as audiometric evaluations, speech therapy, and surgery for severe sleep apnea may be necessary. Long-lasting ear tubes may be required up to the age of 8 years in some cases.

Thoracolumbar Kyphosis (a curvature of the spine) often occurs in newborns with achondroplasia but usually resolves by 18 months as the child’s trunk muscles get stronger. It’s suggested to limit unsupported sitting for children younger than a year old to prevent this curvature progressing. Intervention may be required if the curvature becomes fixed and is over 30 degrees. Bracing can be continued until the child is walking independently, and surgery may be considered if necessary.

Lumbar Spinal Stenosis (a narrowing of the spinal canal in the lower back) can often cause disability late in life. It’s important for children with this condition, who wish to participate in contact sports, to get it checked out. Treatments include weight loss, physical therapy, corticosteroid injections and in some cases, surgery.

Children with achondroplasia might also experience bowed legs, which should be regularly checked by an orthopedic specialist. Surgery may be necessary if the child experiences knee or leg pain, changes in walking patterns, or severe misalignment of the leg.

Pharmacological therapy is also being explored. A drug called vosoritide, known to potentially boost bone growth, has shown promising initial trial results. It has been observed to increase growth speed in children with achondroplasia, leading to sustained increase over a period of 42 months with mild side-effects.

What else can Achondroplasia be?

There are over 350 different conditions that can cause a person to be shorter than average, but only very few resemble achondroplasia. Conditions such as hypochondroplasia and thanatophoric dysplasia exhibit features similar to achondroplasia, primarily affecting the growth of arms and legs. These conditions occur due to quirks in the same gene, the FGFR3 gene, causing differing activation levels of the gene.

In hypochondroplasia, children may appear normal when they are born, but as they grow, their limbs do not develop properly. This results in the body becoming thicker and shorter than normal. While the difference in height is less than in achondroplasia, around 10% of the children affected may have mild mental impairment.

In contrast, thanatophoric dysplasia is a more severe condition, which is typically fatal shortly after birth. This form of dwarfism has two distinct types, with both resulting in short limbs, large head, flat face, short fingers and toes, and underdeveloped muscles. This condition is usually picked up during a routine prenatal ultrasound, where fetus’s short limbs, large head, and other features can be spotted as early as 14 weeks into pregnancy.

Another condition that can be confused with achondroplasia is pseudoachondroplasia. This condition can cause cervical instability, scoliosis, significant lower leg bowing, and early-onset osteoarthritis. It differs from achondroplasia in its genetic root – it stems from a defect in a different gene found on chromosome 19.

A more severe condition, known as severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), is caused by a different mutation in the FGFR3 gene. Individuals with this condition experience severe neurological impairments, and in their early childhood, can develop vast areas of dark, thickened skin known as acanthosis nigricans. It’s essential to note that these skin changes can also occur in other conditions linked to the FGFR3 gene. Thus, in such cases, these changes should be considered a longer-term complication, and not a specific symptom of SADDAN.

What to expect with Achondroplasia

People diagnosed with this condition often have a higher death rate during childhood. Research has shown that the bone abnormalities found in patients with achondroplasia, like FMS and spinal stenosis, significantly impact health and survival rates across all age groups. However, these effects are primarily seen in children who have FMS.

The average life expectancy for patients with achondroplasia is around 61 years, which is about ten years less than the overall population’s average.

Possible Complications When Diagnosed with Achondroplasia

People diagnosed with achondroplasia can experience a variety of medical complications. These are not limited to, but often include problems like:

• Hydrocephalus (a condition where fluid builds up in the brain)
• Otolaryngology problems, such as repeated ear infections, hearing loss, and obstructive sleep apnea
• Rapid weight gain in infancy
• Obesity during childhood

In addition to these, surgical complications associated with achondroplasia can also lead to health issues.

Preventing Achondroplasia

Achondroplasia is the cause of over 90% of dwarfism cases. Despite its ability to be passed down through families (with a 100% chance of occurrence if a parent carries the gene), over 80% of the time it comes about through a spontaneous change in genes. It’s recommended that people with this condition seek genetic counseling. It can result in a higher risk of passing away in early childhood, issues with ears, nose, and throat during later childhood, and a heightened risk of becoming obese in adulthood.

Achondroplasia comes with a variety of health complications, and careful monitoring is necessary to properly manage the condition. Those affected may experience loose joints, a forward curve in the spine, and narrowing of the spinal column that can get worse over time and cause health issues in adulthood. The first symptom usually noticed in babies with this condition is a problem with the spine. Around 25% of people with achondroplasia experience this type of spinal problem. Controlling the symptoms of achondroplasia involves a team of healthcare professionals, and proactive care is key. People with achondroplasia tend to have a slightly shorter life expectancy compared to the general population.