Multiple Epiphyseal Dysplasia

Bone Dysplasia Clinic

Multiple Epiphyseal Dysplasia

Unlike many bone dysplasias, Multiple Epiphyseal Dysplasia may be delayed in presentation and frequently diagnosis is not made until an individual is between 2 and 10 years of age. Diagnosis is sometimes even delayed beyond these ages. First indicators of the presence of this disorder are waddling gait, difficulties running, limping, joint stiffness, joint pain (particularly of the hips and/or knees), activity-precipitated fatigability, and/or subtle slowing of growth velocity.

Multiple Epiphyseal Dysplasia is a descriptive diagnosis, simply implying that an individual has an intrinsic bone dysplasia limited to the ends (epiphyses) of the long bones and with little or no spine involvement. In general, there is profound delay in epiphyseal maturation and deformity of epiphyses. The best described of the various clinical forms of multiple epiphyseal dysplasia is sometimes termed the Fairbank type. Most of the information outlined here is most specifically applicable to those with this type of multiple epiphyseal dysplasia. It is now recognized that the clinical variability seen in Multiple Epiphyseal Dysplasia is paralleled by even greater molecular heterogeneity. The latter is summarized under Genetics and Molecular Biology, below.

Medical Issues and Parental Concerns to be anticipated

Growth

  • Expectations: Initial growth in infancy and early childhood is often normal. Minimal to moderate short stature is usual, with adult heights ranging from about 135 cm to 155 cm (53” – 61”). A substantial minority of affected individuals are of normal stature. Head growth is normal. Growth delay (late blooming) may also be present in these individuals.
  • Monitoring: There are no growth charts available. Plotting linear growth on regular growth standards may provide some guide to whether growth velocity is being maintained.
  • Intervention: There is no known specific treatment. Growth hormone etc. is not likely to be effective since this disorder is secondary to intrinsic abnormality of bone growth. Limb lengthening has been used occasionally but remains controversial.

Hips

  • Expectations: Hip pain is often the first presenting symptom. Stiffness, abnormal gait (waddling) and limping may also be the first recognized characteristics in early childhood. In addition to the intrinsic and constant abnormalities of the hip, Perthes disease develops in a substantial minority. In fact, Multiple Epiphyseal Dysplasia is the most common cause of bilateral Perthes disease. Hip degeneration and premature osteoarthritis is nearly uniform, often arising in early adolescence.
  • Monitoring: Periodic clinical history regarding severity of pain and functional difficulties should be sought. Radiologic assessment can be reserved for those with symptoms.
  • Intervention: Limitations of repetitive weight bearing activities and other activities that result in repetitive stress on the hips, such as rope jumping, trampoline use etc., can slow degenerative arthritic change. Low impact or no impact aerobic activities should be encouraged (e.g. swimming). Collision sports and other activities that result in a high risk for joint injury should be prohibited since such trauma can further predispose to degenerative arthritic changes. Because all collagens require vitamin C as a co-factor for post-translational modification, it may be beneficial to supplement (a vitamin C rich diet in childhood; an additional 1000 mg of vitamin C per day in adolescence and adulthood), particularly in those with demonstrated mutations in type 9 collagen. Glucosoamine may also be of some benefit in decreasing severity of osteoarthritis, but this remains controversial. Pain management is the same as in idiopathic osteoarthritis. If Perthes disease develops this is treated with traditional methods (a period of non-weight-bearing and physical therapy followed by abduction bracing). Use of a motorized scooter for long distance mobility is warranted when osteoarthritic problems become severe –sometimes as early as adolescence. Many will have total hip replacement, often in the 30s or 40s.

Other Large Joint Symptoms

  • Expectations: More generalized osteoarthritis is common, particularly in the knees and the shoulders. As with Perthes developing in the hips, osteochondritis dessicans may develop in the knees.
  • Monitoring: Clinical monitoring. Radiologic assessment may help predict the severity of problems that can be expected – for example, the shape of the proximal humerus and humeral head is an excellent sign to assess likelihood of and severity of shoulder arthritis later in life; likewise the degree of fragmentation of the femoral head allows prediction in late childhood of how severe osteoarthritic changes will become in the ensuing decades.
  • Intervention: The usual treatments for osteoarthritis are applicable, but may need to commence in adolescence and young adult life (see above, under Hips).

Leg Positional Abnormalities

  • Expectations: Beginning after orthograde weight bearing, nearly all develop some knee and leg position abnormality, but these are usually relatively mild. Either varus deformity (bowleg) or valgus deformity (knock-knee) may develop. Progressive deformity may arise and may be sufficiently severe in some older children to warrant surgical intervention.
  • Monitoring: Monitor clinically for alignment, development of chronic knee pain, limitation of ambulation (usually secondary to pain).
  • Intervention: Surgery should be reserved for those with severe and symptomatic mal-alignment. Various techniques may be appropriate including use of 8-plates, hemiepiphyseal stapling, angular osteotomies, etc.

Small Joint Changes

  • Expectations: Hands may be short with particularly short fingers. There is often mild generalized hypermobility (particularly in those with COMP mutations).
  • Monitoring: Function is usually fine, but some individuals may experience moderate fine motor difficulties or fatigue secondary to efforts to stabilize intrinsically unstable small joints.
  • Intervention: Usually none is needed. Minor adaptations for fine motor activities in school may be needed.

Adaptive

  • Expectations: In general short stature is not so severe that major environmental adaptations are needed.
  • Monitoring: Assess for age appropriate needs.
  • Intervention: School adaptations, stools, etc. if needed. De-activate air bag when driving if closer than 12” to the steering wheel.

Genetics and Molecular Biology

Multiple Epiphyseal Dysplasia (MED) is relatively common, arising in around 1 in every 10,000 individuals. Multiple epiphyseal dysplasia is usually caused by an autosomal dominant gene abnormality. Most instances of MED is inherited in an autosomal dominant fashion. Autosomal dominant means that an adult with this disorder will have a 50% chance to pass this poorly functional gene on to each child.

Occasionally an individual with this disorder will be born to average statured parents. Sometimes this arises because of a new chance change (mutation) in a single egg or single sperm giving rise to the affected individual. More often it is because there are autosomal recessive forms of Multiple Epiphyseal Dysplasia. In fact, as many as ¼ of all MED is of the autosomal recessive type. Autosomal recessive means and if two parents carry a problem in one of the genes, then they will have a 25% chance of having an affected child. In this scenario, parents are usually not affected.

Given the complexities of accurate diagnosis of subtypes of this disorder, diagnostic evaluation in a bone dysplasia center prior to any counseling regarding recurrence risk is essential.

Thus far changes in six different genes are known to cause Multiple Epiphyseal Dysplasia.  These include:

  1. Cartilage Oligomeric Matrix Protein (COMP). Mutations in COMP also cause a somewhat more severe disorder, Pseudoachondroplasia. Current thought is that clinical picture is determined by where the mutation resides in the gene. Probably around 25-30% of all MED patients and a majority of all molecularly confirmed dominant forms of Multiple Epiphyseal Dysplasia results from COMP
  2. Col9A1, Col9A2, Col9A3. These three genes, together, code for the type 9 collagen trimer. Together, these are likely the second most common cause of Multiple Epiphyseal Dysplasia, accounting for 10-20% of instances.
  3. Matrilin-3 (MATN3). This gene has been found in about 20% of autosomal dominant MED. This mutation tends be associated with a more mild clinical picture.
  4. DTDST (also called SLC26A2). This is the one clearly identified cause of autosomal recessive Multiple Epiphyseal Dysplasia (rMED) and is present in 90% of cases. Mutations in this gene also cause diastrophic dysplasia and a number of other far more severe bone growth disorders. Intermediate clinical finding (between rMED and diastrophic dysplasia) have been reported. Uniparental disomy has been described in rMED.
  5. Around ½ of all individuals with Multiple Epiphyseal Dysplasia will have no identifiable change in any of these known genes. It is for this reason, in particular, that Multiple Epiphyseal Dysplasia remains a clinical and radiologic diagnosis.

There are subtle radiographic differences among the known molecular causes of Multiple Epiphyseal Dysplasia. For example, those with COMP mutations have more hip involvement, those with col9 mutations have more abnormality at the knees and those with DTDST mutations have a characteristic double patella. These and other differences can be used to guide molecular diagnostic assessment. More importantly, while features of the different forms of Multiple Epiphyseal Dysplasia overlap, certain distinctions based on the gene causing the disorder are evident:

  1. Those secondary to COMP tend to be of smaller stature, while those secondary to MATN3 are associated with normal stature.
  2. Col9 mutations tend to result in milder and later onset joint manifestations than other forms Myopathy seems to be associated with Multiple Epiphyseal Dysplasia caused by changes in MATN3 or col9A3, and has been reported in a patient with a COMP mutation as well.
  3. Joint stiffness, rather than loose jointedness, is usually seen when Multiple Epiphyseal Dysplasia is caused by mutations in DTDST.
  4. Clubfoot is common in association with DTDST Multiple Epiphyseal Dysplasia but is virtually never seen in any other forms. Also, double patella, if seen, is associated with DTDST.