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Achondroplasia is a disorder that prevents cartilage from turning into bone younger ages where the body is still growing. The effect of this disorder on the body is that since long bones (typically in the legs and arms) cannot be grown properly, dwarfism is the outcome. Other effects are having a large head and small fingers as well as limited range of motion at the elbows.

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Achondroplasia occurs when theres mutations in the FGFR3 gene. This gene's job is related to the development of bone and brain tissue.

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Mutations 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 mutations are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of skin cells called keratinocytes. FGFR3 gene mutations have not been found in other types of epidermal nevi.

The most common FGFR3 gene mutation in epidermal nevi changes a single amino acid in the FGFR3 protein. The amino acid arginine is replaced with the amino acid cysteine at position 248 (written as Arg248Cys or R248C). This mutation creates a protein that is turned on without attachment of a growth factor, which means that the FGFR3 protein is constantly active. Studies suggest that cells with this FGFR3 gene mutation grow and divide more than normal cells. The resulting overgrowth of skin cells leads to epidermal nevi.

The FGFR3 gene mutations found in epidermal nevi also occur in people with another skin abnormality called seborrheic keratosis and in people with thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans, and SADDAN (each described in another section on this page). However, in contrast with the skeletal conditions, the mutations associated with epidermal nevi are somatic mutations that arise randomly during the early stages of development before birth. The mutations are present only in the cells of the nevus, not in the normal skin cells surrounding it.

A single mutation in the FGFR3 gene has been shown to cause Muenke syndrome, which is a condition that causes craniosynostosis, leading to a misshapen head and distinctive facial features. Additional signs and symptoms can include hearing loss, subtle hand and foot abnormalities, and developmental delay. The mutation that causes Muenke syndrome substitutes the amino acid arginine for the amino acid proline at position 250 in the FGFR3 protein (written as Pro250Arg or P250R). This mutation results in the production of a receptor that is overly active, which allows the bones of the skull to fuse sooner than normal.

The Pro250Arg mutation has also been identified in some people with apparently 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).

Mutations 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. More than 10 FGFR3 gene mutations have been found to cause type I thanatophoric dysplasia. Most of these mutations change a single amino acid in the FGFR3 protein. The most common mutation substitutes the amino acid cysteine for the amino acid arginine at protein position 248 (written as Arg248Cys or R248C). Other mutations cause the protein to be longer than normal.

Only one mutation has been shown to cause type II thanatophoric dysplasia. This mutation replaces the amino acid lysine with the amino acid glutamic acid at position 650 of the FGFR3 protein (written as Lys650Glu or K650E). This change affects a different part of the FGFR3 protein than the mutations 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 this condition.

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic mutations in the FGFR3 gene are associated with some cases of bladder cancer. These mutations overactivate the FGFR3 protein, which likely directs bladder cells to grow and divide abnormally. This uncontrolled cell division leads to the formation of a bladder tumor.

Somatic mutations in the FGFR3 gene are associated with bladder cancer when they occur only in bladder cells. These same mutations cause the skeletal disorder thanatophoric dysplasia (described above) when they are present in all of the body's cells.

At least two FGFR3 gene mutations have been found to cause a rare disorder called camptodactyly, tall stature, hearing loss syndrome (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 mutations involved in CATSHL syndrome reduce the function of the FGFR3 protein, although it is unclear how the mutations lead to the signs and symptoms of the condition.

Mutations 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 mutations associated with seborrheic keratosis are somatic mutations and are not inherited. At least nine FGFR3 gene mutations have been identified in people with seborrheic keratoses. These mutations change single amino acids in the FGFR3 protein. The mutated FGFR3 proteins are abnormally active, which results in the overgrowth of skin cells, leading to seborrheic keratosis. It has been suggested that the mutations involved in seborrheic keratosis may be caused by exposure to ultraviolet (UV) light.

The somatic Arg248Cys FGFR3 gene mutation found in epidermal nevus (described above) 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 mutation affects brain cells in addition to those in the skin.

In addition to bladder cancer, somatic mutations 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 a rearrangement of genetic material (a translocation) involving chromosome 14 and the region of chromosome 4 containing the FGFR3 gene. Mutations that have been associated with cervical cancer are changes in single nucleotides in the FGFR3 gene.

FGFR3 gene mutations 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.

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Mutations 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 mutations are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of skin cells called keratinocytes.

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Diagnosis for genetic diseases and disorders is really challenging. For achondroplasia the diagnosis comes from lots of different tests including:

-Mutation scanning of select exons
-Mutation scanning of the entire coding region
-Deletion/duplication analysis
-Targeted variant analysis
-Linkage analysis
-Sequence analysis of select exons
-Sequence analysis of the entire coding region

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Somatotropin, a recombinant growth hormone, is the most known treatment for the disorder at this time. Growth hormone (GH) revolutionized the treatment of short stature in patients with achondroplasia. The greatest acceleration of growth velocity in patients is seen in the first year of treatment.

Dwarfism is easy to spot after a few years and the symptoms of achondroplasia become prominent. This often leads to test being done to diagnose the disorder.

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The long bone in the arm, the humerus, is shortened in cases of Achondroplasia. The stature of a person with this disorder would be below 4 feet 6 inches in most cases.

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(80-99% of people with the disorder have these symptoms)

-Abnormality of the metaphysis (wide portion of the long bone)
-Rib abnormalities
-Nasal tip is upturned
-Chronic infections of the middle ear
-Depressed nasal bridge
-Outward bowing at the knees
-Hyperlordosis (prominent swayback)
-Macrochepaly (increased size of scull)
-Short limb dwarfism recognizable at birth
-Disproportionately short upper portion of limb
-Extra bones within cranial sutures

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Achondroplasia occurs in 1 in 15,000-40,000 newborns worldwide.