General Discussion

Summary

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.

Signs & 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.

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.

Affected Populations

Achondroplasia appears to affect males and females in equal numbers. This disorder begins in the developing fetus and is one of the most common forms of skeletal dysplasia that causes dwarfism. The estimated frequency of achondroplasia has ranged from about one in 15,000 to one in 35,000 births.

Related Disorders

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

Hypochrondroplasia 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.)

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