Multiple Epiphyseal Dysplasia

Epiphysis refers to the ends of long bones that are adjacent to the joints. Therefore, this disorder is one that involves more than one epiphysis. MED occurs in approximately 9 in 100,000 live births (4). Initially, two types of MED were identified: Fairbank Type (severe) and Ribbing Type (mild). However, the MED is now considered one clinically heterogenous disorder, and the two classifications have been abandoned (5).

 
How Multiple Epiphyseal Dysplasia Is Inherited

MED is typically inherited in an autosomal dominant manner (2). However, an autosomal recessive form of MED has also been identified (2). Due to non-allelic mutations, genetic heterogeneity does occur, resulting in a wide variability of expression.

 
Causes of Multiple Epiphyseal Dysplasia

The Fairbank type of MED is caused by a mutation in the gene encoding the cartilage oligomeric matrix protein, or COMP. A less severe form can be caused by point mutations in any three of the type IX collagen genes (COL9A1, COL9A2, COL9A3). Type IX collagen is found on the surface of type II collagen and is necessary for the integrity of articular cartilage. Another mutation in the gene that encodes matrilin-3 causes a distinctively mild form of MED. Finally, the autosomal recessive form of MED is caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene or by mutations in the solute carrier family 26, member 2 gene (SLC26A2). Overall, the mutations result in a retarded formation of epiphyseal ossification centers. The bones most commonly affected are the humeral and femoral heads. Bones of the pelvis, spinal column and skull are typically normal.

 
Physical Characteristics

MED is a disorder of bone and cartilage development that results in small irregular epiphyses, proportionate short stature, frequently painful joints, and early onset degenerative arthritis. MED is not typically recognized until after two-years of age and in some cases, not until early adulthood. Typically adults will grow to be between 145 and 170 cm.

Face and Skull
  • normal facial features
Trunk, Chest and Spine:
  • accentuated thoracic kyphosis
  • possibility for blunted, flattened or slightly ovoid vertebral bodies
Arms and Legs:
What Are the X-Ray Characteristics?

The major radiographic features of MED include irregular epiphyses and, in childhood, irregularity of the tubular bones, usually at the hips, knees, ankles, wrists and hands. In middle to late childhood, the epiphyses are either flat or small. An important sign is the epiphyses of distal tibias are laterally malformed to produce a sloping wedge-shaped articular surface in adults. Bipartite (split) patella is common. Metaphyses are normal with mild shortening of the tubular bones. The phalanges are short and stubby, and the metacarpals have epiphyseal irregularities. Vertebral bodies are flat, with irregular end plates markedly in the thoracic spine.

 
Making the Diagnosis

Clinical features and X-rays are the mainstay of diagnosis.

Mutations in 5 known gene locations account for 50% of cases. Molecular genetic testing is available on a clinical basis for the COMP gene on chromosome 19. Prenatal diagnosis is possible for the COMP mutation, if the diagnosis is suspected on ultrasound.

Often, MED is misdiagnosed as Legg-Calvé-Perthes disease. In order to distinguish between the two conditions, bone scans and full skeletal radiographic surveys are often necessary.

 
Musculoskeletal Problems
Joints

Degenerative joint disease occurs principally in the weight-bearing joints (hips, knees, and ankles) of the lower limbs but is also seen in the shoulders. The joint deformities oftentimes cause progressive “degenerative” osteoarthroses. If gone untreated, patients may be unable to stand or walk by age 50. Around the ages of 30 to 35, joint replacement is sometimes required.

Lower Limbs

Genu varus or valgus oftentimes occur.

 
Problems Elsewhere in the Body

Apart from problems in joints, no other system is affected.

 
What to Look for

Increasing pain, decreased endurance or limping in an individual with MED may be indicative of progressive arthritis. Arthritis develops in MED due to an intrinsic abnormality in the joint cartilage as previously explained. The only solution in the longer term is a hip or shoulder joint replacement. The ankle joint may be involved in MED. Because of the early onset of degenerative arthritis, vigorous, non-weight bearing exercise must be avoided to prevent disability that would require joint replacements. Both swimming and bike riding are recommended. Generally all skeletal dysplasias warrant multidisciplinary attention.

Regular assessment by an orthopedist, geneticist, pediatrician, dentist, neurologist, and physical therapist will provide the most comprehensive treatment.

 
References
  1. Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006.
  2. Scott, Charles I. Dwarfism. Clinical Symposium, 1988; 40(1):17-18.
  3. Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.
  4. Taybi, H. Lachman, RS. Skeletal Dysplasias. In "Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias." St. Louis: Mosby-Year Book, Inc., pp 858-870. 1996.
  5. Unger, Sheila. Hecht, Jacqueline T. Pseudoachondroplasia and Multiple Epiphyseal Dysplasia: New Etiologic Developments. American Journal of Medical Genetics, 2001; 106: 244-250.

Genetic Testing

Genetic tests are done by analyzing small samples of blood or body tissues. They determine whether you, your partner, or your baby carry genes for certain inherited disorders.

Genetic testing has developed enough so that doctors can often pinpoint missing or defective genes. The type of genetic test needed to make a specific diagnosis depends on the particular illness that a doctor suspects.

Many different types of body fluids and tissues can be used in genetic testing. For deoxyribonucleic acid (DNA) screening, only a very tiny bit of blood, skin, bone, or other tissue is needed.

Genetic Testing During Pregnancy

For genetic testing before birth, pregnant women may decide to undergo amniocentesis or chorionic villus sampling. There is also a blood test available to women to screen for some disorders. If this screening test finds a possible problem, amniocentesis or chorionic villus sampling may be recommended.

Amniocentesis is a test usually performed between weeks 15 and 20 of a woman's pregnancy. The doctor inserts a hollow needle into the woman's abdomen to remove a small amount of amniotic fluid from around the developing fetus. This fluid can be tested to check for genetic problems and to determine the sex of the child. When there's risk of premature birth, amniocentesis may be done to see how far the baby's lungs have matured. Amniocentesis carries a slight risk of inducing a miscarriage.

Chorionic villus sampling (CVS) is usually performed between the 10th and 12th weeks of pregnancy. The doctor removes a small piece of the placenta to check for genetic problems in the fetus. Because chorionic villus sampling is an invasive test, there's a small risk that it can induce a miscarriage.

Why Doctors Recommend Genetic Testing

A doctor may recommend genetic counseling or testing for any of the following reasons:

  • A couple plans to start a family and one of them or a close relative has an inherited illness. Some people are carriers of genes for genetic illnesses, even though they don't show, or manifest, the illness themselves. This happens because some genetic illnesses are recessive — meaning that they're only expressed if a person inherits two copies of the problem gene, one from each parent. Offspring who inherit one problem gene from one parent but a normal gene from the other parent won't have symptoms of a recessive illness but will have a 50% chance of passing the problem gene on to their children.
  • A parent already has one child with a severe birth defect. Not all children who have birth defects have genetic problems. Sometimes, birth defects are caused by exposure to a toxin (poison), infection, or physical trauma before birth. Often, the cause of a birth defect isn't known. Even if a child does have a genetic problem, there's always a chance that it wasn't inherited and that it happened because of some spontaneous error in the child's cells, not the parents' cells.
  • A woman has had two or more miscarriages. Severe chromosome problems in the fetus can sometimes lead to a spontaneous miscarriage. Several miscarriages may point to a genetic problem.
  • A woman has delivered a stillborn child with physical signs of a genetic illness. Many serious genetic illnesses cause specific physical abnormalities that give an affected child a very distinctive appearance.
  • The pregnant woman is over age 34. Chances of having a child with a chromosomal problem (such as trisomy) increase when a pregnant woman is older. Older fathers are at risk to have children with new dominant genetic mutations (those caused by a single genetic defect that hasn't run in the family before).
  • A standard prenatal screening test had an abnormal result. If a screening test indicates a possible genetic problem, genetic testing may be recommended.
  • A child has medical problems that might be genetic. When a child has medical problems involving more than one body system, genetic testing may be recommended to identify the cause and make a diagnosis.
  • A child has medical problems that are recognized as a specific genetic syndrome. Genetic testing is performed to confirm the diagnosis. In some cases, it also might aid in identifying the specific type or severity of a genetic illness, which can help identify the most appropriate treatment.

A Word of Caution

Although advances in genetic testing have improved doctors' ability to diagnose and treat certain illnesses, there are still some limits. Genetic tests can identify a particular problem gene, but can't always predict how severely that gene will affect the person who carries it. In cystic fibrosis, for example, finding a problem gene on chromosome number 7 can't necessarily predict whether a child will have serious lung problems or milder respiratory symptoms.

Also, simply having problem genes is only half the story because many illnesses develop from a mix of high-risk genes and environmental factors. Knowing that you carry high-risk genes may actually be an advantage if it gives you the chance to modify your lifestyle to avoid becoming sick.

As research continues, genes are being identified that put people at risk for illnesses like cancer, heart disease, psychiatric disorders, and many other medical problems. The hope is that someday it will be possible to develop specific types of gene therapy to totally prevent some diseases and illnesses.

Gene therapy is already being studied as a possible way to treat conditions like cystic fibrosis, cancer, and ADA deficiency (an immune deficiency), sickle cell disease, hemophilia, and thalassemia. However, severe complications have occurred in some patients receiving gene therapy, so current research with gene therapy is very carefully controlled.

Although genetic treatments for some conditions may be a long way off, there is still great hope that many more genetic cures will be found. The Human Genome Project, which was completed in 2003, identified and mapped out all of the genes (about 25,000) carried in our human chromosomes. The map is just the start, but it's a very hopeful beginning.

Reviewed by: Larissa Hirsch, MD
Date reviewed: September 26, 2016