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Achondroplasia

Synonyms of Achondroplasia

  • ACH
  • Achondroplastic Dwarfism

Disorder Subdivisions

  • No subdivisions found.

General Discussion

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. An autosomal dominant genetic trait, achondroplasia occurs as a result of a fresh (new) spontaneous change (mutation) in genetic material in about 90 percent of cases. In achondroplasia, affected individuals have impaired ability to form bone from cartilage (endochondral bone formation).

Symptoms

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

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.)

Affected Populations

Achondroplasia appears to affect males and females in relatively 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.)

Standard Therapies

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.

Little People of America is an organization providing social services for persons with achondroplasia. The organization also acts as an advocate on their behalf (see Resources Section of this report).

The Vertical Expandable Prosthetic Titanium Rib (VEPTR) was approved by the FDA in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients. TIS, is a congenital condition where severe deformities of the chest, spine, and ribs prevent normal breathing and lung development. The VEPTR is an implanted, expandable device that helps straighten the spine and separate ribs so that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows. The titanium rib was developed at the University of Texas, Health Science Center in San Antonio. It is manufactured by Synthes Spine Co.: http://www.synthes.com/sites/NA/Products/Spine/Screw_Hook_Rod_and_Clamp_System/Pages/VEPTR_and_VEPTR_II.aspx

For more information, please contact:

Synthes, Inc.
1302 Wrights Lane East
West Chester, PA 19380
800-523-0322

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Two clinical trials associated with the Human Genome Project have been completed. One studied the genes responsible for skeletal disorders and short statue. The other study explored issues surrounding prenatal genetic testing for achondroplasia.

Achondroplasia Resources

Organizations:

References

TEXTBOOKS
Beers MH, Berkow, Robert, Mark H et al., eds. The Merck Manual. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:2409-10, 2474.

Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:346-53.

Wyngaarden JB, Lloyd H. Smith, J. Claude Bennett et al., eds. Cecil Textbook of Medicine. 19th ed. Philadelphia, PA: W.B. Saunders Company; 1992:1435-36.

Gorlin RJ, Cohen M, Hennekam RC et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:171-76.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:11-12, 918-19.

JOURNAL ARTICLES
Stoilov I, et al. A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia. Am J Med Genet. 1995;55:127-33.

Bellus GA, McIntosh I, Smith EA, et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995;10:357-59.

Shiang R, Thompson LM, Zhu YZ, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994;78:335-42.

Rousseau F, Bonaventure J, Legeai-Mallet L, et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature. 1994;371:252-54.

Velinov M, Slaugenhaupt SA, Stoilov I, Scott CI Jr, Gusella JF, Tsipouras P. The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genet. 1994;6:318-21.

Le Merrer M, Rousseau F, Legeai-Mallet L, et al. A gene for achondroplasia -hypochondroplasia maps to chromosome 4p. Nature Genet. 1994;6:314-17.

Horton WA. Growth hormone therapy in achondroplasia. Am J Med Genet. 1992; 42:667-70.

Philip N, Auger M, Mattei JF, Giraud F. Achondroplasia in sibs of normal parents. J Med Genet. 1988;25:857-59.

Stoll C, Roth MP, Bigel P. A reexamination of parental age effect on the occurrence of new mutations for achondroplasia. In: Papadatos CJ, et al., eds. Skeletal Dysplasias. New York, NY: Alan R. Liss; 1982:419-26.

INTERNET:
Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 100800; 2/6/01. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?100800.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 146000; 1/11/01. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?146000.

Achondroplasia
http://www.geneclinics.org/prfiles/achondroplasia/details/html

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2007/08/17 00:00:00 GMT+0

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