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Multiple Epiphyseal Dysplasia

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Copyright 1987, 1990, 2001

Synonyms of Multiple Epiphyseal Dysplasia

Disorder Subdivisions

General Discussion

Multiple epiphyseal dysplasia (MED) is a rare inherited spectrum of disorders characterized by malformation (dysplasia) of the "growing portion" or head of the long bones (epiphyses). Affected individuals may have an abnormally short thighbone (femur), unusually short hands and fingers, mild short stature, a waddling gait, and/or pain in the hips and knees. In some cases, painful swelling and inflammation of certain joints (arthritis) may be present as early as five years of age. Most cases of multiple epiphyseal dysplasia are inherited as autosomal dominant traits; rare cases are inherited as autosomal recessive traits.

Symptoms

The symptoms of multiple epiphyseal dysplasia vary greatly from case to case. Historically, cases of multiple epiphyseal dysplasia have been classified as the more severe, Fairbank type, or the milder, Ribbing type. However, most affected individuals fall somewhere in-between this general classification.

Most cases of multiple epiphyseal dysplasia are characterized by malformations (dysplasia) of the "growing portion" or head of the long bones (epiphyses). Most cases become apparent between the ages of two and five because affected children exhibit slow growth and a characteristic waddling gait. In some cases, slow growth may result in mild to moderate short stature due to short legs (short-limbed dwarfism). Another earlier symptom associated with multiple epiphyseal dysplasia is back pain that may worsen with age.

Malformation of the epiphyses may result in an interruption of the blood supply (ischemia) the upper portion (capital) of the thighbone (femur) where it meets the hip (capital femoral epiphysis) potentially resulting in degeneration (avascular necrosis) and deformity of the thighbone in this area. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; delayed maturation of the femur (delayed bone age); and/or limited movements of the affected hip.

Affected children also experience stiff, painful joints usually of the hips, knees, and ankles. Less commonly, the shoulders, elbows, and wrists may also be affected. Joint pain and stiffness often worsens (progresses) with age.

Some individuals with multiple epiphyseal dysplasia may have abnormally short bones in the fingers (metacarpals and phalanges), resulting in short, stubby fingers (brachydactyly). In some cases, the joints of the fingers may be excessively loose or mobile (finger hyperextensibility). Some affected individuals may have abnormally small feet.

As affected individuals age, they may exhibit abnormally bowed legs (genu varum), a malformation in which the knees are abnormally close together and the ankles are unusually far apart (genu valgum), and/or a hip deformity in which the thighbone angles towards the center of the body (coxa vara).

In addition, affected individuals may experience progressive stiffness, tenderness, and pain of the joints accompanied by degeneration of the surrounding cartilage (osteoarthritis or degenerative arthritis). In some cases, affected individuals may experience inflammation of cartilage and bone tissue, resulting in the tearing of pieces of cartilage into an affected joint, most often the hips or knees (osteochondritis dissecans). Some individuals with multiple epiphyseal dysplasia may be prone to dislocation of the kneecaps (patellae).

Causes

Most cases of multiple epiphyseal dysplasia are inherited as autosomal dominant traits. Rare cases are inherited as autosomal recessive traits. 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) will 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.

In recessive disorders, the condition does not occur unless an individual inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Multiple epiphyseal dysplasia may be caused be genetic disruptions or changes (mutations) to one of several genes on different chromosomes. Investigators have determined that some cases of multiple epiphyseal dysplasia are caused by mutations of the cartilage oligomeric matrix protein (COMP) gene located on the short arm (p) of chromosome 19 (19p13.1). 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. For example, "chromosome 19p13.1" refers to band 13.1 on the short arm of chromosome 19.

Some cases of multiple epiphyseal dysplasia are thought to be caused by mutations of the COL9A2 gene located on the short arm (p) of chromosome 1 (1p33-p32.2).

Other cases of multiple epiphyseal dysplasia are thought to be caused by mutations of the COL9A3 gene located on the long arm (q) of chromosome 20 (20q13.3).

Cases of recessively-inherited multiple epiphyseal dysplasia may be caused by mutations of the DTDST gene located on the short arm (p) of chromosome 5(5p32-p33.1).

Affected Populations

Multiple epiphyseal dysplasia is a rare disorder that affects males and females in equal numbers. The exact numbers of cases is unknown. Onset is usually during childhood or early adolescence with most cases becoming apparent between the ages of two and ten.

Multiple epiphyseal dysplasia is one of a group of disorders that are referred to as osteochondroses or osteochondrodysplasias. These disorders typically are characterized by degeneration and subsequent regeneration of the growing end of a bone (epiphyses).

Related Disorders

Symptoms of the following disorders can be similar to those of multiple epiphyseal dysplasia. Comparisons may be useful for a differential diagnosis:

Legg-Calve-Perthes disease (LCPD) is one of a group of disorders known as the osteochondroses. In Legg-Calve-Perthes disease, the growing end (epiphysis) of the upper portion (capital) of the thighbone (femur) is affected. Researchers believe that an unexplained interruption of the blood supply (ischemia) to the capital femoral epiphysis results in degeneration (avascular necrosis) and deformity of the thighbone in this area. Symptoms may include a limp with or without pain in the hip, knee, thigh, and/or groin; muscle spasms; delayed maturation of the femur (delayed bone age); mild short stature; and/or limited movements of the affected hip. The disease process seems to be self-limiting as new blood supplies are established (revascularization) and new healthy bone forms (reossifies) in the affected area. Most cases of Legg-Calve-Perthes Disease occur randomly for no apparent reason (sporadically). Other cases are thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose Legg-Calve-Perthes as your search term in the Rare Disease Database.)

Pseudoachondroplastic dysplasia is a rare inherited disorder characterized by skeletal malformations resulting in short legs and mild to moderate short stature (short-limbed dwarfism). Affected individuals may have short, stubby fingers (brachydactyly), abnormally bowed legs (genu varum), and/or a malformation in which the knees are abnormally close together and the ankles are unusually far apart (genu valgum). In addition, affected individuals may have spinal abnormalities including abnormally increased curvature of the bones of the lower spine (lumbar lordosis) and front-to-back curvature of the spine (kyphosis). In some cases, the wrist may abnormally flexed toward the pinky side of the hand (ulnar deviation of the wrist) and the elbows and hips may have limited flexibility. Cases of pseudoachondroplastic dysplasia are due to mutations of the COMP gene, meaning that this disorder is allelic to some cases of multiple epiphyseal dysplasia (i.e., caused by different mutations of the same disease gene). Pseudochondroplastic dysplasia is inherited as an autosomal dominant trait.

Standard Therapies

The treatment of multiple epiphyseal dysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists or orthopedic surgeons), physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Surgery may be necessary to treat malformation of the hip (osteotomy of the pelvis or the collum femoris) and, in some cases, malformation (e.g., genu varum or genu valgum) of the legs (osteotomy of the leg). Surgical procedures may be necessary to correct abnormalities of the knee. In some cases, total hip replacement may be necessary.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

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 web site.

For information about clinical trials being conducted at the NIH Clinical Center 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

Organizations related to Multiple Epiphyseal Dysplasia

Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder (e.g., visual handicaps, heart disease, etc.)

References

TEXTBOOKS
Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:

Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W. B. Saunders Co: 1997:380.

JOURNAL ARTICLES
Menezes AH. Specific entities affecting the craniocervical region : Osteogenesis imperfecta and related osteochondrodysplasias: medical and surgical management of basilar impression.
Childs Nerv Syst. 2008 Apr 10

Unger S, Bonafe L, Superti-Furga A. Multiple epiphyseal dysplasia: clinical and radiographic features, differential diagnosis and molecular basis. Best Pract Res Clin Rheumatol. 2008 Mar;22(1):19-32.

Al-Tamimi YZ, Tyagi AK, Chumas PD, Crimmins DW. Patients with autosomal-recessive osteopetrosis presenting with hydrocephalus and hindbrain posterior fossa crowding. J Neurosurg Pediatrics. 2008 Jan;1(1):103-6.

Unger SL, et al. Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype. Pediatr Radiol. 2001;31:10-18.

Van Mourik JB, et al. Magnetic resonance imaging of multiple epiphyseal dysplasia (type 2) of the knee. Radiography. 2001;7:61-64

Hatori M, et al. Multiple epiphyseal dysplasia--report of two families. Arch Orthop Trauma Surg. 2000;120:372-75.

Bonnemann CG, et al. A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy. Proc Natl Acad Sci USA. 2000;1:1212-17.

Miura H, et al. Clinical features of multiple epiphyseal dysplasia expressed in the knee. Clin Orthop. 2000;380:184-90.

Paassilta P, et al. COL9A3: A third locus for multiple epiphyseal dysplasia. Am J Hum Genet. 1999;64:1036-44.

Superti-Furga A, et al. Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by DTDST mutation. J Med Genet. 1999;36:621-24.

Sebik A, et al. The orthopaedic aspects of multiple epiphyseal dysplasia. Int Orthop. 1998;22:417-21.

Briggs MD, et al. Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum. Am J Hum Genet. 1998;62:311-19.

Van Mourik JB, et al. A large family with multiple epiphyseal dysplasia linked to COL9A2 gene. Am J Med Genet. 1998;18:234-40.

Report last updated: 2008/04/25 00:00:00 GMT+0