Achondroplasia is the most common form of short-limbed dwarfism. The word achondroplasia means "without cartilage formation." Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. However, in people with achondroplasia the problem is not forming cartilage but converting it to bone (a process called ossification), particularly in the long bones of the arms and legs. Achondroplasia is similar to another skeletal disorder called hypochondroplasia, but the features of achondroplasia tend to be more severe.

All people with achondroplasia have short stature. Without treatment, the average height of an adult male with achondroplasia is 131 centimeters (4 feet, 4 inches), and the average height for adult females is 124 centimeters (4 feet, 1 inch). Characteristic features of achondroplasia include an average-size trunk, short arms and legs with particularly short upper arms and thighs, limited range of motion at the elbows, and an enlarged head (macrocephaly) with a prominent forehead. Fingers are typically short and the ring finger and middle finger may diverge, giving the hand a three-pronged (trident) appearance.

Health problems commonly associated with achondroplasia include obesity and recurrent ear infections. People with achondroplasia are generally of normal intelligence. In childhood, individuals with the condition usually develop a pronounced and permanent sway of the lower back (lordosis) and bowed legs. Some affected people also develop abnormal front-to-back curvature of the spine (kyphosis) and back pain.

As affected individuals age, they may experience a potentially serious complication of achondroplasia called spinal stenosis. Spinal stenosis is a narrowing of the spinal canal that can pinch (compress) the upper part of the spinal cord. Spinal stenosis causes with pain, tingling, and weakness in the legs that can make walking difficult. An uncommon but serious complication of achondroplasia in early childhood is stenosis of the hole at the base of the skull where the spinal cord comes out of brain (foramen magnum). This complication can cause compression of the brain stem, which can lead to pauses in breathing during sleep (sleep apnea) or a condition known as hydrocephalus. Hydrocephalus is a buildup of fluid in the brain that can lead to increased head size and related brain abnormalities.

Achondroplasia is caused by a gene alteration (mutation) in the FGFR3 gene. The FGFR3 gene makes a protein called fibroblast growth factor receptor 3 that is involved in converting cartilage to bone. FGFR3 is the only gene known to be associated with achondroplasia. All people who have only a single copy of the normal FGFR3 gene and a single copy of the FGFR3 gene mutation have achondroplasia.

Most people who have achondroplasia have average-size parents. In this situation, the FGFR3 gene mutation occurs in one parent's egg or sperm cell before conception. Other people with achondroplasia inherit the condition from a parent who has achondroplasia.

Variants (also called mutations) in the FGFR3 gene cause achondroplasia. The FGFR3 gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. Two specific variants in the FGFR3 gene are responsible for almost all cases of achondroplasia. These variants cause the FGFR3 protein to be overly active, which interferes with skeletal development and leads to the disturbances in bone growth seen with this disorder.

Normal Function

The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is part of a family of four fibroblast growth factor receptors that share similar structures and functions. These proteins play a role in several important cellular processes, including regulation of cell growth and division (proliferation), determination of cell type, formation of blood vessels (angiogenesis), wound healing, and embryo development.

The FGFR3 protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This allows the protein to interact with specific growth factors outside the cell and receive signals that control growth and development. When these growth factors attach to the FGFR3 protein, the protein is turned on (activated). This triggers a cascade of chemical reactions inside the cell that instruct the cell to undergo certain changes, such as maturing to take on specialized functions (differentiation).

Several versions (isoforms) of the FGFR3 protein are produced from the FGFR3 gene. The different isoforms are found in various tissues of the body, and they interact with a variety of growth factors. Many isoforms are found in the cells that form bones. Researchers believe that the FGFR3 protein regulates bone growth by limiting the formation of bone from cartilage. Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. The process of converting cartilage to bone is called ossification. One particular isoform of the FGFR3 protein is found specifically in cells that line the surfaces of the body (epithelial cells), including the cells that form the outermost layer of skin, called the epidermis.

Health Conditions Related to Genetic Changes

Achondroplasia

Two variants (also called mutations) in the FGFR3 gene cause more than 99 percent of cases of achondroplasia, which is the most common form of short-limbed dwarfism. Both variants lead to the same change in the FGFR3 protein. This change replaces the protein building block (amino acid) glycine with the amino acid arginine at a specific location within the FGFR3 protein. This genetic change causes the receptor to be overly active, which leads to the disturbances in bone growth that occur in people with this disorder.

Crouzon syndrome with acanthosis nigricans

A single FGFR3 gene variant has been identified in people with Crouzon syndrome with acanthosis nigricans. This rare condition causes premature joining of the bones of the skull (craniosynostosis), leading to a misshapen head and distinctive facial features. It also causes a skin abnormality called acanthosis nigricans that is characterized by thick, dark, velvety skin in body folds and creases.

The genetic change that causes Crouzon syndrome with acanthosis nigricans replaces the amino acid alanine with the amino acid glutamic acid at a specific position in the FGFR3 protein (known as A391E). The altered protein is activated more easily than normal, and this overactivity disrupts the normal growth of the skull bones and skin, leading to features of Crouzon syndrome with acanthosis nigricans.

Epidermal nevus

Variants in the FGFR3 gene have been found in approximately 30 percent of people with a certain type of epidermal nevus (plural: nevi). Specifically, FGFR3 gene variants are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of skin cells called keratinocytes. FGFR3 gene variants have not been found in people with other types of epidermal nevi.

The most common FGFR3 gene variant in people with epidermal nevi changes a single amino acid in the FGFR3 protein. This variant creates a protein that turns on without the help of a growth factor, which means that the FGFR3 protein is constantly active. Studies suggest that cells with this FGFR3 gene variant grow larger and divide more often than normal cells. The resulting overgrowth of skin cells leads to epidermal nevi.

The FGFR3 gene variant found in people with epidermal nevi also occur in people with another skin abnormality called seborrheic keratosis and in people with skeletal disorders known as thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). However, in contrast to the skeletal conditions, the variants associated with epidermal nevi (and seborrheic keratosis) are somatic variants. Somatic gene variants are not inherited; they are acquired during a person's lifetime and are present only in certain cells. In epidermal nevi, the variants occur during the early stages of development and are present only in the cells of the nevus, not in the normal skin cells surrounding it.

Hypochondroplasia

Multiple variants in the FGFR3 gene have been identified in people with hypochondroplasia, another form of short-limbed dwarfism that is milder than achondroplasia. Many cases are caused by one of two specific FGFR3 gene variants, both of which lead to the same change in the FGFR3 protein. This change replaces the amino acid asparagine with the amino acid lysine at a specific position in the FGFR3 protein (known as N540K). Other FGFR3 gene variants probably cause a small number of cases of hypochondroplasia. These hypochondroplasia-associated variants probably cause the receptor to be mildly overactive, which leads to the disturbances in bone growth that occur in people with this disorder.

Lacrimo-auriculo-dento-digital syndrome

At least one variant in the FGFR3 gene has been found to cause lacrimo-auriculo-dento-digital (LADD) syndrome. The main features of LADD syndrome are abnormal tear production, malformed ears with hearing loss, decreased saliva production, small teeth, and hand deformities. The FGFR3 gene variant that causes LADD syndrome replaces the amino acid aspartic acid with the amino acid asparagine at a specific position in the receptor protein (known as D513N). When a growth factor attaches to this modified version of FGFR3 receptor protein, the protein has difficulty triggering the normal chemical signals within the cell. These defects in cell signaling disrupt cell maturation and development, which results in abnormal formation of the ears, the skeleton, and the glands in the eyes and mouth in people with LADD syndrome.

Muenke syndrome

A single variant in the FGFR3 gene has been shown to cause Muenke syndrome, which is a condition that causes craniosynostosis and leads to a misshapen head and distinctive facial features. Additional signs and symptoms can include hearing loss, subtle hand and foot abnormalities, and developmental delays. The variant that causes Muenke syndrome substitutes the amino acid arginine for the amino acid proline at a specific position in the FGFR3 protein (known as P250R). This variant results in the production of a receptor that is overly active, which allows the bones of the skull to fuse sooner than normal.

The FGFR3 gene variant that causes Muenke syndrome has also been identified in some people with isolated coronal craniosynostosis. This condition is characterized by a premature fusion of the growth line that runs across the top of the head from ear to ear (the coronal suture). People with isolated coronal craniosynostosis do not have the other features that are sometimes associated with Muenke syndrome (such as hand and foot abnormalities).

SADDAN

One variant in the FGFR3 gene has been identified in people with SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). SADDAN is characterized by short-limb dwarfism (achondroplasia); profound developmental delay; and thick, dark, velvety skin. The genetic change that causes this condition substitutes the amino acid methionine for the amino acid lysine at a specific position in the FGFR3 protein (known as K650M). Researchers believe that this variant strongly overactivates the FGFR3 protein, which leads to severe problems with bone growth. It remains uncertain how the variant causes developmental delays or acanthosis nigricans.

Thanatophoric dysplasia

Variants in the FGFR3 gene have been identified in people with thanatophoric dysplasia, which is a severe skeletal disorder characterized by extremely short limbs and a narrow chest. Most individuals with thanatophoric dysplasia are stillborn or die shortly after birth.

Most of these FGFR3 gene variants change a single amino acid in the FGFR3 protein or create a protein that is longer than normal. These variants cause type I thanatophoric dysplasia.

Only one FGFR3 gene variant has been shown to cause type II thanatophoric dysplasia. This variant affects a different part of the FGFR3 protein than the variants that cause type I thanatophoric dysplasia.

The genetic changes responsible for both types of thanatophoric dysplasia cause the FGFR3 receptor to be overactive, which leads to the severe problems with bone growth that occur in people with this condition.

Bladder cancer

Somatic variants in the FGFR3 gene have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. Approximately 80 percent of NMIBC tumors have FGFR3 gene variants. FGFR3 gene variants change single amino acids in the FGFR3 protein, which appears to overactivate protein signaling. As a result, bladder cells are likely directed to grow and divide abnormally. This uncontrolled cell division leads to bladder cancer.

Multiple myeloma

MedlinePlus Genetics provides information about Multiple myeloma

Other disorders

At least two FGFR3 gene variants have been found to cause a rare disorder called camptodactyly, tall stature, hearing loss (CATSHL) syndrome. Individuals with this condition are taller than average and typically have hearing loss. They can also have permanently bent fingers or toes (camptodactyly) and other skeletal abnormalities. Researchers suggest that the FGFR3 gene variants involved in CATSHL syndrome reduce the function of the FGFR3 protein, although it is unclear how the variants cause the signs and symptoms of the condition.

Variants in the FGFR3 gene have been found in 30 to 70 percent of people with seborrheic keratoses, which are small, dark, noncancerous (benign) tumors of the skin caused by overgrowth of skin cells. Seborrheic keratoses develop in adulthood and are seen in a majority of people older than age 50. The FGFR3 gene variants associated with seborrheic keratoses are somatic variants, which means that they are only found in the tumors and are not inherited. These variants change single amino acids in the FGFR3 protein. The altered FGFR3 proteins are abnormally active, which results in the overgrowth of skin cells. It has been suggested that the variants involved in seborrheic keratosis may be caused by exposure to ultraviolet light.

A somatic FGFR3 gene mutation that causes epidermal nevus can also cause Garcia-Hafner-Happle syndrome (also known as fibroblast growth factor receptor 3 epidermal nevus syndrome). This condition is characterized by a soft, velvety keratinocytic epidermal nevus and neurological problems, such as seizures, intellectual disability, underdevelopment of the tissue that connects the two halves of the brain (corpus callosum), and a loss of brain cells (cortical atrophy). It is thought that the neurological problems occur because the somatic variant affects brain cells in addition to cells in the skin.

Other cancers

In addition to bladder cancer, somatic variants in the FGFR3 gene have been associated with a cancer of white blood cells (multiple myeloma) and cervical cancer. Some cases of multiple myeloma are related to rearrangements (translocations) of genetic material between chromosome 14 and the region of chromosome 4 that contains the FGFR3 gene. Variants that have been associated with cervical cancer are changes in single DNA building blocks (nucleotides) in the FGFR3 gene.

FGFR3 gene variants that lead to multiple myeloma and cervical cancer are thought to overactivate the FGFR3 protein in certain cells. The mutated receptor directs the cells to grow and divide in the absence of signals from outside the cell. This uncontrolled division can lead to the overgrowth of cancer cells.

Other Names for This Gene

• ACH
• CD333
• CEK2
• FGFR-3
• FGR3_HUMAN
• fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)
• HBGFR
• hydroxyaryl-protein kinase
• JTK4
• tyrosine kinase JTK4

Genomic Location

Most cases of achondroplasia are not inherited. When achondroplasia is inherited, it is inherited in an autosomal dominant manner.

Over 80 percent of individuals who have achondroplasia have parents with normal stature and are born with achondroplasia as a result of a new (de novo) gene alteration (mutation). These parents have a small chance of having another child with achondroplasia.

A person who has achondroplasia who is planning to have children with a partner who does not have achondroplasia has a 50 percent chance, with each pregnancy, of having a child with achondroplasia. When both parents have achondroplasia, the chance for them, together, to have a child with normal stature is 25 percent. Their chance of having a child with achondroplasia is 50 percent. Their chance for having a child who inherits the gene mutation from both parents (called homozygous achondroplasia - a condition that leads to death) is 25 percent.

People who have achondroplasia have abnormal bone growth that causes the following clinical symptoms: short stature with disproportionately short arms and legs, short fingers, a large head (macrocephaly) and specific facial features with a prominent forehead (frontal bossing) and mid-face hypoplasia.

The intelligence and life span in individuals with achondroplasia is usually normal.

Infants born with achondroplasia typically have weak muscle tone (hypotonia). Because of the hypotonia, there may be delays in walking and other motor skills. Compression of the spinal cord and/or upper airway obstruction increases the risk of death in infancy.

People with achondroplasia commonly have breathing problems in which breathing stops or slows down for short periods (apnea). Other health issues include obesity and recurrent ear infections. Adults with achondroplasia may develop a pronounced and permanent sway of the lower back (lordosis) and bowed legs. The problems with the lower back can cause back pain leading to difficulty with walking.

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.

Genetic testing can identify mutations in 99 percent of individuals who have achondroplasia. Testing for the FGFR3 gene mutation is available in clinical laboratories.

No specific treatment is available for achondroplasia. Children born with achondroplasia need to have their height, weight and head circumference monitored using special growth curves standardized for achondroplasia. Measures to avoid obesity at an early age are recommended.

A magnetic resonance imaging (MRI) or CT scan may be needed for further evaluation of severe muscle weakness (hypotonia) or signs of spinal cord compression. To help with breathing, surgical removal of the adenoids and tonsils, continuous positive airway pressure (CPAP) by nasal mask, or a surgical opening in the airway (tracheostomy) may be needed to correct obstructive sleep apnea.

When there are problems with the lower limbs, such as hyperreflexia, clonus or central hypopnea, then surgery called suboccipital decompression is performed to decrease pressure on the brain.

Children who have achondroplasia need careful monitoring and support for social adjustment.

Recommendations for management of children with achondroplasia were outlined by the American Academy of Pediatrics Committee on Genetics in the article, Health Supervision for Children with Achondroplasia. We recommend that you review this article with your child’s health care provider(s).

These recommendations include:

• Monitoring of height, weight, and head circumference using growth curves standardized for achondroplasia
• Measures to avoid obesity starting in early childhood.
• Careful neurologic examinations, with referral to a pediatric neurologist as necessary
• MRI or CT of the foramen magnum region for evaluation of severe hypotonia or signs of spinal cord compression
• Obtaining history for possible sleep apnea, with sleep studies as necessary
• Evaluation for low thoracic or high lumbar gibbus if truncal weakness is present
• Referral to a pediatric orthopedist if bowing of the legs interferes with walking
• Management of frequent middle-ear infections
• Speech evaluation by age two years
• Careful monitoring of social adjustment