Multiple epiphyseal dysplasia

Definition

Multiple epiphyseal dysplasia (MED) is a hereditary disorder characterized by abnormal epiphyses (bone extremities) that lead to early-onset joint pain and recurrent inflammation of cartilage and bone. There are five subtypes of MED, each with varying clinical manifestations and inheritance patterns.

Description

Multiple epiphyseal dysplasia (MED) is a hereditary condition characterized by abnormal development of cartilage and bone. The epiphysis is the portion at the end of a long bone where growth occurs. Dysplasia is an abnormality in development leading to alteration in size, shape, and organization of cells. Thus, in MED, the epiphyses of the long bones are dysplastic and, as a result, joint pain and inflammation result. On x ray, the epiphyses will appear flattened and irregular. Cartilage in the joints becomes irregular and this leads to early-onset osteoarthritis . Patients often have short hands and stubby fingers.

MED can be divided into five subtypes, four of which are inherited in an autosomal dominant fashion (EDM1, EDM2, EDM3, and EDM5) and one of which is inherited in an autosomal recessive fashion (EDM4). All of the subtypes are characterized by early-onset joint pain, most often in the hips and knees. Most individuals with MED have adult heights that are in the low range of normal, although some may have slightly short stature.

Dominant MED

Dominant MED was initially divided into two forms: a mild form, called Ribbing disease, and a more severe form, called Fairbank disease. However, dominant MED has been further classified into four subtypes to accommodate the extreme clinical variability that exists. In addition to hip and knee pain and occasional short stature, individuals with dominant MED may have a waddling gait and their limbs may be relatively short when compared to the trunk. Joint pain and deformity become worse with age in these patients and early-onset osteoarthritis is often a problem, especially in the large, weight-bearing joints.

Recessive MED

Recessive MED is also known as EDM4 and rMED. In addition to early-onset joint pain and possible short stature, this disorder is associated with scoliosis (curvature of the spine), as well as malformations of the hands, feet, and knees. Some affected individuals may also present with a clubfoot or an abnormality of the kneecap, called a double-layered patella. This finding is very suggestive of recessive MED.

Genetic profile

Dominant MED

Mutations in five different genes have been associated with dominant MED:

• EDM1 is caused by mutations in the COMP gene , which codes for the cartilage oligomeric matrix protein. This gene is also responsible for the more severe disorder, called pseudoachondroplasia.
• EDM2 and EDM3 result from mutations in two of the three genes that code for the protein chains of type IX collagen. COL9A2 mutations lead to EDM2 and COL9A3 mutations lead to EDM3. Mutations in these genes can also lead to lumbar/intervertebral disk disease (IDD), which is a very common musculoskeletal disorder.
• Defects in the matrilin 3 protein, caused by mutations in the MATN3 gene, lead to a diagnosis of EDM5. Matrilin 3 plays a key role in the cartilage extracellular matrix.

Extreme variability in clinical manifestations can be seen both between and within families with mutations in the various genes responsible for dominant MED.

EDM1, EDM2, EDM3, and EDM5 are all dominant forms of MED and are inherited in an autosomal dominant pattern. Thus, the majority of affected individuals have a parent that is affected as well. However, this is not always the case as there may be a new (de novo) mutationinthe affected individual that was not present in either parent. Additionally, there may appear to be a lack of family history due to the affected parent dying at a young age or the failure to recognize symptoms of the disorder in a parent. Asymptomatic parents of affected individuals should be given a careful clinical and radiographic examination to completely rule out any signs of the disorder.

Most often, one parent of the affected individual will have signs of dominant MED and/or a disease-causing mutation. In this case, siblings of the affected individual have a 50% chance of inheriting the same mutation and being affected as well. However, if a mutation is identified in the affected individual and both parents test negative for this mutation, it is likely that the gene mutation is de novo and, therefore, recurrence risk to siblings is very low. The prevalence of de novo mutations in dominant MED is unknown.

Another possibility is germline mosaicism. In this case, the gene mutation may be present only in the egg cells of the mother or the sperm cells of the father. Thus, the parent will not show signs of the disorder, since the gene mutation is confined to the sex cells. However, the mutations present in the egg or sperm would leave a significant recurrence risk for future pregnancies.

No matter how the affected individual inherits the gene mutation, each of his or her children has a 50% chance to inherit the disease-causing mutation and, therefore, be affected with dominant MED.

Recessive MED

Recessive MED is caused by mutations in the SLC26A2 gene, also known as DTDST. Mutations in this gene cause a spectrum of skeletal disorders of which recessive MED is the mildest. SLC26A2 codes for a protein that plays a key role in the normal development of cartilage and its conversion to bone. When the SLC26A2 gene is mutated, cartilage cannot develop properly and, as a result, bones do not form correctly and skeletal problems result.

As implied by its name, recessive MED is inherited in an autosomal recessive manner. This means that an affected individual will have two abnormal copies of the SLC26A2 gene in each cell. Most often, the parents of an affected individual each carry a mutation on one of their two copies of the SLC26A2 gene. Mutation carriers do not show signs or symptoms of recessive MED. Siblings of affected individuals have a 25% chance of being affected with the disorder and a 50% chance of being carriers of the disorder. Offspring of an affected individual will be obligate carriers of an SLC26A2 gene mutation, but will not show signs or symptoms of the disorder.

Demographics

Dominant MED

Dominant MED is thought to present in at least one in 10,000 births. Due to the clinical variability and range of severity associated with the disorder, it is likely that many individuals have yet to be diagnosed. There are no reports of the condition being more common in specific ethnic groups or geographical regions.

Recessive MED

The prevalence of recessive MED is currently unknown. There are no reports of the condition being more common in specific ethnic groups or geographical regions. Due to the mild signs and symptoms of the disorder, it is likely that the disease is underdiagnosed and is more common than once thought.

Signs and symptoms

Dominant MED

Dominant MED often presents in early childhood with pain in the hips and/or knees. Affected patients often complain of this pain, accompanied by fatigue, after physical activity. Over time, this pain progressively worsens, joints become deformed, and early osteoarthritis results, most often in the large, weight-bearing joints. In some cases, joint replacement may be necessary.

Individuals with dominant MED may walk with a waddling gait. Restriction in the range of motion in the elbows is apparent in many cases, as is hypermobility in the knee and finger joints. Characteristic radiographic findings of dominant MED include abnormalities of the epiphyses of the long tubular bones, especially in the hips and/or knees. These abnormalities are due to delayed ossification and manifest as small and irregular ossification centers. This finding may be present very early, even before other clinical signs and symptoms are evident. Later, in adulthood, signs of osteoarthritis can be seen on x rays and the tubular bones may be slightly shortened. The spine is generally not involved in dominant MED. Adult height may be slightly shorter than normal and the limbs are often short relative to the trunk. Intelligence is normal.

There are various clinical manifestations that distinguish the subtypes of dominant MED:

• EDM1 is characterized by mild to moderate short stature and the limbs are usually short when compared to the trunk. Individuals with EDM1 may have minor spine irregularities that can be seen on x ray, but nothing as severe as the scoliosis associated with EDM4. The fingers and metacarpals (bones from the wrists to the fingers) are usually shortened. The main complication of this subtype is early arthritis of the hip.
• EDM2 and EDM3 are associated with mild short stature. There is more severe knee involvement in these subtypes and hip problems are often less severe. The courses of EDM2 and EDM3 are milder than EDM1 and EDM4. In EDM2, the hands are somewhat short but in EDM3, they tend to be normal with shortened metacarpals.
• EDM5 is the mildest form of MED. Affected patients usually have normal stature and less severe involvement of joints. Mild abnormalities in the pelvis seem to be more common in this subtype compared to the others.

Recessive MED

Approximately 50% of individuals affected with recessive MED show signs or symptoms of the disorder at birth. Examples include clubfoot, cleft palate, ear swelling, or clinodactyly (a condition where the little finger is curved towards the ring finger). Joint pain in the hips and knees is very common in affected individuals and most often onsets in late childhood. However, this pain may onset at various times in different individuals and is not always present. Individuals affected with recessive MED are of normal stature, although some may be slightly shorter than expected in adulthood. As in dominant MED, intelligence is normal.

Affected individuals tend to have characteristic facial features, such as anteverted nares (nasal passages) and a round, flat face. They may also be myopic (nearsighted). Malformations of the hands, feet, and knees are very common. These may include brachydactyly (abnormal shortness) of toes and fingers, small hands/feet, and absent/small fingernails. A double-layered patella (kneecap) is found in 60% of patients and is very suggestive of recessive MED. This finding seems to be age-dependent and may disappear when the affected individual reaches adulthood. Scoliosis is fairly common in affected individuals as well and this finding distinguishes recessive MED from dominant forms of MED. Occasionally, recessive MED may be associated with sensorineural deafness, hip anomalies, wrist anomalies, or delayed bone age.

Diagnosis

Dominant MED

Clinical and radiographic findings of the patient and family members can assist in the diagnosis of dominant MED. Even before the onset of clinical signs and symptoms, x rays often show delayed ossification of the epiphyses of the long tubular bones. This delayed ossification is usually most noticeable in the hips and/or knees. Additionally, the x rays may show slightly shortened long tubular bones. Radiographic diagnosis of MED is often difficult, if not impossible, in adults. Thus, x rays should be completed in childhood, if possible. Due to the autosomal dominant pattern of inheritance, there will usually be multiple family members affected with the disorder.

Molecular genetic testing can be used to confirm a diagnosis of dominant MED in a patient with characteristic clinical and radiographic features. Sequence analysis is available to analyze all five genes implicated in dominant MED. Mutations are found in the COMP gene in approximately 35% of cases, in the MATN3 gene in approximately 10% of cases, and in the COL9A2 and COL9A3 genes in less than 5% of cases. However, in about 50% of individuals with clinical and radiographic features consistent with dominant MED, no mutation can be found by molecular genetic testing. Thus, it is believed that other unidentified genes are likely responsible for this disorder. However, there are other conditions that can result from mutations in some of these genes (namely, COMP, COL9A2, and COL9A3). The type of disorder that results depends on the type of mutation in the gene. Thus, genetic test results must be interpreted based on clinical and radiographic findings.

Prenatal diagnosis for at-risk pregnancies is possible via molecular genetic testing, but is not commonly requested. Once a disease-causing mutation has been found in a family, fetal cells obtained by chorionic villus sampling (CVS) or amniocentesis can be analyzed for this mutation to determine the mutation status of the fetus.

Recessive MED

A diagnosis of recessive MED is based on clinical and x-ray findings during childhood or early in adult life. The disorder is suspected when an autosomal recessive pattern of inheritance is seen and when characteristic signs and symptoms are noted, such as hip and knee pain, malformations of hands, feet, and knees, and scoliosis. X rays may show flat epiphyses with early arthritis, mild brachydactyly, and the characteristic double-layered patella.

The diagnosis of recessive MED can be confirmed via molecular genetic testing of the SLC26A2 gene. A mutation will be found in approximately 70% of patients who are suspected to have the disorder based on clinical and radiographic features. Interestingly, mutations were found in 100% of patients with double-layered patella, which is a very specific sign for recessive MED. There are three common mutations in the SLC26A2 gene that account for approximately 90% of genetically characterized cases of recessive MED. Thus, molecular genetic testing often begins with analysis for these three mutations. It can be followed by full gene sequence analysis if necessary. There are three other autosomal recessive skeletal dysplasias that can result from mutations in the SLC26A2 gene. The type of disorder that results depends on the severity of the genetic mutations in the gene. Thus, genetic test results must be interpreted based on clinical and radiographic findings.

Carrier testing for at-risk family members who do not show any clinical signs of the disorder is available once the SLC26A2 gene mutations have been identified in an affected individual. Carrier detection in reproductive partners of SLC26A2 gene carriers is available as well. If a mutation is found in a reproductive partner, details about the severity of that mutation should be provided due to the fact that various SLC26A2 mutations can lead to various genetic conditions.

Prenatal diagnosis for at-risk pregnancies is possible via molecular genetic testing, but is not commonly requested. Once both disease-causing mutations have been found in the family, fetal cells obtained by chorionic villus sampling (CVS) or amniocentesis can be analyzed for these mutations to determine the mutation status of the fetus.

Treatment and management

Dominant MED

The goal for patients with dominant MED is to decrease pain, restrict joint destruction, and prevent the development of osteoarthritis. Pain is often difficult to control in affected individuals, however, analgesics (i.e., nonsteroidal anti-inflammatory drugs) and physiotherapy have been shown to be effective in some cases. An orthopedic surgeon can advise patients on whether surgical procedures (i.e., realignment osteotomy or acetabular osteotomy) might slow the progression of symptoms. In some patients, joint replacement may be necessary. Affected patients should avoid obesity and activities that strain affected joints.

Recessive MED

Individuals with recessive MED should seen by an orthopedist who can assess the possibility of treatment. This may include physiotherapy for the purpose of strengthening muscles, use of analgesics (i.e., nonsteroidal anti-inflammatory drugs), and the timing of surgery, if necessary. As in dominant MED, affected patients should avoid obesity and activities that strain affected joints.

Prognosis

Patients with dominant and recessive MED have a normal life expectancy and generally lead productive and healthy adult lives.

Resources

ORGANIZATIONS

International Skeletal Dysplasia Registry, Medical Genetics Institute. 8700 Beverly Blvd., West Tower, Suite 665, Los Angeles, CA 90048. (800) 233-2771. (April 6, 2005.) <http://www.csmc.edu/3805.html>.

Little People of America, Inc., 5289 NE Elam Young Parkway, Suite F-100, Hillsboro, OR 97124. (888) LPA-2001. (April 6, 2005.) <http://www.lpaonline.org/index.html>.

National Organization for Rare Disorders (NORD). 55 Kenosia Avenue, PO Box 1968, Danbury, CT 06813-1968. (800) 999-6673. (April 6, 2005.) <http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Multiple%20Epiphyseal%20Dysplasia>.

WEBSITES

Bonafe, L., D. Ballhausen, and A. Superti-Furga. "Multiple Epiphyseal Dysplasia, Recessive." Gene Reviews. (April 6, 2005.) http://www.genetests.org/servlet/access?db=geneclinics&site=gt&id=8888891&key=FnPPkPSrKElS&gry=&fcn=y&fw=du5t&filename=/profiles/edm/index.html.

Briggs, M. D., M. J. Wright, and G. R. Mortier. "Multiple Epiphyseal Dysplasia, Dominant." Gene Reviews. (April 6, 2005.) http://www.genetests.org/servlet/access?db=geneclinics&site=gt&id=8888891&key=FnPPkPSrKElS&gry=&fcn=y&fw=sr1T&filename=/profiles/edm-ad/index.html.

"Recessive Multiple Epiphyseal Dysplasia." Genetics Home Reference. (April 6, 2005.) <http://ghr.nlm.nih.gov/condition=recessivemultipleepiphysealdysplasia>.

Mary E. Freivogel, MS, CGC