Achondroplasia

Achondroplasia is the most commonly occurring abnormality of bone growth (skeletal dysplasia), occurring in approximately 1 in 20,000-30,000 live births. This genetic disorder is caused by a change (mutation) in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia occurs as a result of a spontaneous genetic mutation in approximately 80 percent of patients; in the remaining 20 percent it is inherited from a parent. This genetic disorder is characterized by an unusually large head (macrocephaly), short upper arms (rhizomelic dwarfism), and short stature (adult height of approximately 4 feet). Achondroplasia does not typically cause impairment or deficiencies in mental abilities. If the bones that join the head and neck do not compress the brainstem or upper spinal cord (craniocervical junction compression), life expectancy is near normal.

Causes

Achondroplasia results from specific changes (mutations) of a gene known as fibroblast growth factor receptor 3 (FGFR3).

For most patients, there is no apparent family history of the condition. Increased age of the father (advanced paternal age) may be a contributing factor in cases of sporadic achondroplasia.

Less commonly, familial cases of achondroplasia follow an autosomal dominant pattern of inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disorder. The abnormal gene can be inherited from either parent or can be the result of a mutated (changed) gene in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

Causes by disease condition

Symptoms of the following disorders may be similar to those of Achondroplasia. Comparisons may be useful for a differential diagnosis:

Hypochondroplasia is a genetic disorder characterized by small stature and disproportionately short arms, legs, hands, and feet (i.e., short-limbed dwarfism). In those with the disorder, short stature often is not recognized until early to mid-childhood or, in some cases, as late as adulthood. Affected individuals may also develop bowing of the legs during early childhood that often improves spontaneously with age. In some cases, additional abnormalities may be present, such as an unusually large head (macrocephaly), a relatively prominent forehead, limited extension and rotation of the elbows, and/or other physical findings. In addition, in about 10 percent of cases, mild mental retardation may be present. In some instances, hypochondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history. In other cases, the disorder is familial with autosomal dominant inheritance. As noted above (see “Causes”), hypochondroplasia and achondroplasia may result from different mutations of the same gene (i.e., FGFR3). (For more information on this disorder, choose “Hypochondroplasia” as your search term in the Rare Disease Database.)

Additional disorders may be characterized by small stature and disproportionately short arms and legs (short-limbed dwarfism), abnormal enlargement of the head (macrocephaly), additional malformations of the skull and facial (craniofacial) region, and/or other symptoms and findings similar to those potentially associated with achondroplasia. Achondroplasia may be distinguished from other forms of short-limbed dwarfism through thorough clinical examination, x-ray studies, and/or additional diagnostic techniques. (For more information on these disorders, choose “dwarfism” or the exact disease name in question as your search term in the Rare Disease Database.)

Symptoms

General – This rare genetic disorder is characterized by distinctive features: short stature (usually under 4 feet 6 inches); an unusually large head (macrocephaly) with a prominent forehead (frontal bossing) and flat (depressed) nasal bridge; short arms and legs; prominent abdomen and buttocks (due to inward curve of the spine); and short hands with fingers that assume a “trident” or three-pronged position during extension.
Infancy – Infants born with achondroplasia typically have a “dome-like” (vaulted) skull, and a very broad forehead. In a small proportion, there is excessive accumulation of fluid around the brain (hydrocephalus). Low muscle tone (hypotonia) in infancy is typical of achondroplasia. Acquisition of developmental motor milestones may be delayed.
Shortened arms and legs, with the upper arms and thighs more affected than the forearms and lower legs.
Large head size with a prominent forehead and a flattened nasal bridge.
Crowded or misaligned teeth.

The following are the most common symptoms of achondroplasia; however, each child may experience the condition differently:

Shortened arms and legs, with the upper arms and thighs more affected than the forearms and lower legs
Large head size with a prominent forehead and a flattened nasal bridge
Crowded or misaligned teeth
Curved lower spine, a condition also called lordosis (or sway-back) which may lead to kyphosis or the development of a small hump near the shoulders that usually goes away after the child begins walking
Small vertebral canals that may lead to spinal cord compression in adolescence
Bowed lower legs
Flat feet that are short and broad
Extra space between the middle and ring fingers (also called a trident hand)
Poor muscle tone and loose joints
Frequent middle ear infections that may lead to hearing loss
Delayed developmental milestones — for instance, walking may occur between 18 to 24 months of age instead of around 12 months

The symptoms of achondroplasia may resemble other problems or medical conditions. Always consult a physician for a diagnosis.

Diagnosis

Clinical and radiologic features of achondroplasia are well-characterized. Those with typical findings generally do not need molecular genetic testing to confirm the diagnosis. When clinical features raise suspicion in a newborn, X-ray (radiography) findings can be used to help confirm the diagnosis. However, if there is uncertainty, identification of the genetic variant of the FGFR3 gene by molecular genetic testing can be used to establish the diagnosis. Below is a list adapted from Pauli and Legare (2018) that provides clinical signs that may be used in the diagnosis of achondroplasia.

Disproportionate short stature
Macrocephaly with frontal bossing
Backward displacement of the midface and depressed nasal bridge
Shortening of the arms with redundant skin folds on limbs
Limitation of elbow extension
Shortened fingers and toes (brachydactyly)
Trident configuration of the hands
Bow legs
Exaggerated inward curve of the spine (lumbar lordosis)
Joint laxity

Treatment

Recommendations for managing children with achondroplasia are outlined by the American Academy of Pediatrics Committee on Genetics, which are designed to supplement guidelines for children with average stature.

As outlined in Pauli and Legare (2018), the recommendations for the manifestations of achondroplasia include:

Hydrocephalus: If signs/symptoms of increased intracranial pressure arise (accelerated head growth, bulging fontanelle, vision changes, headache), referral to a neurosurgeon is required. Computerized tomography (CT) or magnetic resonance imaging (MRI) of the brain in infancy may be done to determine the presence of hydrocephalus.
Craniocervical junction constriction: Predictors of the need for suboccipital decompression require evaluation by a medical professional. Indication of symptomatic compression requires urgent referral to a neurosurgeon.
Obstructive sleep apnea: Can be treated with weight reduction, surgery to remove tonsils and adenoids (adenotonsillectomy), positive airway pressure, and, rarely, surgery to create an opening in the neck (tracheostomy).
Middle ear dysfunction: Ear tubes may be needed until the age of seven or eight to manage frequent middle ear infections and prevent potential hearing loss.
Short stature: Studies on the use of growth hormone have shown initial acceleration of growth, but with lessening effect over time and little lasting benefit.
Obesity: Measures to avoid obesity should begin in early childhood. Standard weight-by-height grids specific for achondroplasia should be used to monitor progress.
Varus deformity: Symptomatic bowing of the legs (varus deformity) requires referral to an orthopedist. However, asymptomatic bowing does not usually warrant surgical correction.
Spinal deformities: Preventive measures including prohibition of unsupported sitting in the first 12-18 months of life decrease risk of developing a fixed backwards curve in the mid-spine (kyphosis). Bracing or surgery may be necessary, depending on the degree of severity of such a deformity if preventive measures are unsuccessful.
Spinal stenosis: If signs/symptoms of spinal stenosis arise, urgent surgical referral is appropriate.
Immunization: All routine immunizations are necessary.
Adaptive needs: Environmental modifications of the home and school may be necessary to accommodate for short stature.
Socialization: Patients with achondroplasia may encounter difficulties in socialization and school adjustment. Support groups (such as Little People of America) can help assist families with these issues through peer support, personal example, and social awareness programs.

In 2021, Voxzogo (vosoritide) was approved for children five years of age and older with achondroplasia and open epiphyses (growth plates), allowing the potential for growth.

FAQs

This genetic disorder is caused by a change (mutation) in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia occurs as a result of a spontaneous genetic mutation in approximately 80 percent of patients; in the remaining 20 percent it is inherited from a parent.

Achondroplasia is a bone growth disorder that causes disproportionate dwarfism. Dwarfism is defined as a condition of short stature as an adult. People with achondroplasia are short in stature with a normal sized torso and short limbs. It’s the most common type of disproportionate dwarfism.

The majority of people living with achondroplasia have a normal life span and normal intelligence, regardless of delayed development in infancy. Though complications from achondroplasia are a possibility, taking care of symptoms can help prevent serious health problems from occurring later in life.

Inheritance. Achondroplasia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. About 80 percent of people with achondroplasia have average-size parents; these cases result from new mutations in the FGFR3 gene.

Currently, there are no treatments able to reverse achondroplasia, which is caused by mutations in a gene — called FGFR3 — that result in the excess production of proteins that slow bone growth, nor are there ways to treat the genetic culprit itself.

Achondroplasia can be diagnosed before birth by fetal ultrasound. This test uses sound waves and a computer to create images of the baby growing in the womb. DNA testing can also be done before birth to confirm fetal ultrasound results. The condition can also be diagnosed after birth with a physical exam.

Primordial dwarfism is a rare and often dangerous group of genetic conditions that result in a small body size and other growth abnormalities. Signs of the condition first appear in the fetal stage and continue through childhood, adolescence, and adulthood.

In a baby, the signs of achondroplasia may include shorter limbs, a larger head than is typical, and space between the middle and ring fingers. A doctor can provide a diagnosis through a physical examination and medical imaging. Sometimes, they may perform tests to detect the genetic change.

So in the recessive case, passing on dwarfism to your child requires teamwork – both parents must give them a copy. Your child can inherit dwarfism from your father only if their other parent also gives them a dwarfism gene copy.

How do you diagnose achondroplasia?

Achondroplasia is diagnosed by characteristic clinical and X-ray findings in most affected individuals. In individuals who may be too young to make a diagnosis with certainty or in individuals who do not have the typical symptoms, genetic testing can be used to identify a mutation in the FGFR3 gene.

What is the life expectancy of someone with dwarfism?

As well as being short, some people with restricted growth also have other physical problems, such as bowed legs or an unusually curved spine. But most people don’t have any other serious problems and are able to live a relatively normal life, with a normal life expectancy.

Can dwarfism be detected in the womb?

Amniotic fluid check – A physician will measure amniotic fluid to determine whether or not dwarfism is present. If a mother has too much amniotic fluid, that can be an indication of dwarfism. Chorionic villus sampling – Chorionic villus sampling at 11 weeks can help a doctor confirm dwarfism.

How do I know if my child has dwarfism?

Imaging. Doctors may spot signs of achondroplasia, such as shorter limbs, or other causes of dwarfism on ultrasounds of a fetus during pregnancy. X-rays of babies or children may show that their arms or legs are not growing at a normal rate, or that their skeleton shows signs of dysplasia.

How can you prevent dwarfism during pregnancy?

There is nothing a parent could do before or during pregnancy to prevent this change from happening. A genetic counselor can help determine the chances of having a child with dwarfism. Depending on the type of dwarfism, two average-height parents can have a child with short stature.

Do babies with dwarfism crawl?

You can obtain growth and development charts for some forms of dwarfism. Not only do infants/children who have dwarfism accomplish certain milestones (i.e., sitting, crawling, walking, etc.) at their own pace, they often do it in their own unique way.

Can you fix dwarfism?

Dwarfism, regardless of the cause, can’t be cured or “corrected.” However, there are certain therapies that may help reduce the risk of complications.

Causes

Symptoms