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Achondroplasia

ACH, Achondroplastic dwarfism

Overview

Achondroplasia is a form of short-limbed dwarfism. The word achondroplasia literally means "without cartilage formation." Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. However, in achondroplasia the problem is not in forming cartilage but in 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. 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. People with achondroplasia are generally of normal intelligence.

Health problems commonly associated with achondroplasia include episodes in which breathing slows or stops for short periods (apnea), obesity, and recurrent ear infections. 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. A potentially serious complication of achondroplasia is spinal stenosis, which is a narrowing of the spinal canal that can pinch (compress) the upper part of the spinal cord. Spinal stenosis is associated with pain, tingling, and weakness in the legs that can cause difficulty with walking. Another uncommon but serious complication of achondroplasia is hydrocephalus, which is a buildup of fluid in the brain in affected children that can lead to increased head size and related brain abnormalities.

Symptoms - Achondroplasia

Achondroplasia is a rare genetic disorder characterized by an unusually large head (macrocephaly) with a prominent forehead (frontal bossing) and flat (depressed) nasal bridge, short upper arms and legs (rhizomelic dwarfism), unusually prominent abdomen and buttocks, and short hands with fingers that assume a "trident" or three-pronged position during extension.

Infants born with achondroplasia typically have an arched or "dome-like" (vaulted) skull to adapt to the abnormally enlarged brain (megalencephaly) that is characteristic in this syndrome. This results in a very broad forehead. Excessive accumulation of fluid around the brain (hydrocephalus) may also be present. Compression of the brain stem may occur in some children with achondroplasia resulting in a life-threatening condition. (For more information on this disorder, choose "Hydrocephalus" as your search term in the Rare Disease Database.)

Infants with achondroplasia typically have a flat (depressed) nasal bridge. Arms and legs are usually very short and the trunk of the body appears long in comparison. The hands of children with this disorder are generally short and broad. The index and middle finger are typically close together as are the ring finger and the pinkie, giving the hand a three pronged (trident) appearance. An abnormal condition of the spine characterized by the outward (convex) curvature of the upper back (dorsal kyphosis) is usually present in children with this disorder and their legs may be bowed. Most adult males with Achondroplasia are under, 4 feet 6 inches tall, while females are typically 3 inches shorter than males.

Children with achondroplasia may also have deformities of the rib cage including the excessive curvature or "cupping" of the ribs. Achondroplasia does not cause any impairment or deficiencies in mental abilities. The life expectancy of infants over the age of 12 months is normal.

Causes - Achondroplasia

In most cases, achondroplasia appears to occur randomly for unknown reasons (sporadically) with no apparent family history. According to researchers, many such cases may represent new (sporadic) genetic changes (mutations) that may be transmitted as an autosomal dominant trait (i.e., new dominant gene mutations). Investigators indicate that increased age of the father (advanced paternal age) may be a contributing factor in cases of sporadic achondroplasia.

Less commonly, familial cases of achondroplasia have been reported. In such instances, autosomal dominant inheritance has been demonstrated. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother. In dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed "dominating" the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.

Achondroplasia has been shown to result from specific mutations of a gene known as "fibroblast growth factor receptor-3" (FGFR3). The FGFR3 gene is located on the short arm (p) of chromosome 4 (4p16.3). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." Chromosomes are further subdivided into bands that are numbered. Therefore, chromosome 4p16.3 refers to band 16.3 on the short arm of chromosome 4.

Genetic analysis has also revealed that different mutations of the same gene (i.e., FGFR3) may cause a disorder known as hypochondroplasia, indicating that achondroplasia and hypochondroplasia are allelic disorders. (An allele is one of two or more alternative forms of a gene that may occupy a particular chromosomal location.) Hypochondroplasia is a form of short-limbed dwarfism that may be characterized by certain features similar to those seen in achondroplasia. (For more information, please see the "Related Disorders" section of this report below.)

Prevention - Achondroplasia

Genetic counseling may be helpful for prospective parents when one or both have achondroplasia. However, because achondroplasia most often develops spontaneously, prevention is not always possible.

Diagnosis - Achondroplasia

Achondroplasia can be detected before birth by the use of prenatal ultrasound. A DNA test can be performed before birth to detect homozygosity, wherein two copies of the mutant gene are inherited, a lethal condition leading to stillbirths. Clinical features include megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-facial hypoplasia. Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed. The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction.

Radiologic findings

A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow foramen magnum, and relatively small skull base. The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. The iliac wings are small and squared, with a narrow sciatic notch and horizontal acetabular roof. The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates. Fibular overgrowth is present. The hand is broad with short metacarpals and phalanges, and a trident configuration. The ribs are short with cupped anterior ends. If the radiographic features are not classic, a search for a different diagnosis should be entertained. Because of the extremely deformed bone structure, people with achondroplasia are often "double jointed".

The diagnosis can be made by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended.

Another distinct characteristic of the syndrome is thoracolumbar gibbus in infancy.

Prognosis - Achondroplasia

People with achondroplasia seldom reach 5 feet in height. Intelligence is in the normal range. Infants who receives the abnormal gene from both parents do not often live beyond a few months

Treatment - Achondroplasia

At present, there is no known treatment for achondroplasia, even though the cause of the mutation in the growth factor receptor has been found.

Ultrasonography or magnetic resonance imaging (MRI) of the brain in infancy may be done to determine the presence of hydrocephalus which is sometimes associated with achondroplasia. Orthopedic surgery and physical therapy may be beneficial in the management of this disorder. Genetic counseling may also be useful.

Although used by those without achondroplasia to aid in growth, human growth hormone does not help people with achondroplasia. However, if desired, the controversial surgery of limb-lengthening will lengthen the legs and arms of someone with achondroplasia.

Usually, the best results appear within the first and second year of therapy. After the second year of GH therapy, beneficial bone growth decreases. Therefore, GH therapy is not a satisfactory long term treatment.

Gene based therapy may possibly serve as a future treatment option. BioMarin Pharmaceutical Inc. announced in 2012 the initiation of a Phase 1 study in healthy volunteers for BMN-111, an analog of C-type Natriuretic Peptide (CNP), for the treatment of achondroplasia.

Latest research and related efforts are tracked by the non-profit Growing Stronger.

Resources - Achondroplasia

  • Genetics Home Reference
  • NIH
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