Clinical Guidance

Intra- and interfamilial variability in MATN3-related MED, COL9A3-related MED, and in some instances COMP-related MED make the establishment of strong genotype-phenotype correlations in autosomal dominant MED a challenge. COMP. The recurrent pathogenic variant in COMP appears to cause a mild form of the disorder, more consistent with MED caused by a type IX collagen gene variant . reviewed 300 COMP pathogenic variants and the resulting phenotypes published between 1995 and 2014 and concluded that pathogenic variants in specific residues and/or regions of the type III repeats of COMP are significantly associated with either MED or pseudoachondroplasia.

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"

Penetrance

There is some evidence for reduced penetrance in MATN3-related MED , while pathogenic variants in COL9A1, COL9A2, COL9A3, and COMP are believed to be fully penetrant.

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"

Diagnostic Criteria

Suggestive Findings

Autosomal dominant multiple epiphyseal dysplasia (MED) should be suspected in individuals with the following clinical and radiographic findings and family history.

Clinical findings

• Pain in the hips and/or knees and fatigue, often after exercise (frequently starting in early childhood)

• Adult height in the lower range of normal or mildly shortened

• Restricted range of movement at the major joints (e.g., elbows)

• Early-onset osteoarthritis, often requiring joint replacement in the second or third decade of life

Radiographic findings

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"

Differential Diagnosis

Other disorders with features that overlap with those of autosomal dominant multiple epiphyseal dysplasia (MED) are summarized in .

Table 3.

Disorders to Consider in the Differential Diagnosis of Autosomal Dominant Multiple Epiphyseal Dysplasia

Gene | Disorder | MOI | Comments

COL2A1

| Dysplasia of proximal femoral epiphyses, COL2A1-related (Legg-Calve-Perthes; LCPD) (OMIM 150600) | AD | • Radiographic changes in LCPD show more involvement of metaphyses femoral neck.

• Usually affects males ages 3-15 yrs

• Up to 20% have bilateral involvement

Mild spondyloepiphyseal dysplasia (SED)1 | AD | • COL2A1 pathogenic variants have been identified in persons w/mild SED.

• Clinical radiographic features may be similar to MED.2

COMP | Pseudoachondroplasia, COMP-related | AD | See .

SLC26A2

| Multiple epiphyseal dyspl...

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"

Management Guidelines

No clinical practice guidelines for autosomal dominant multiple epiphyseal dysplasia (MED) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with autosomal dominant MED, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Autosomal Dominant Multiple Epiphyseal Dysplasia: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"

Clinical Guidance

The following should be avoided:

• Obesity, which increases stress on joints

• Exercise that causes repetitive strain on affected joints

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"

Surveillance Guidelines

Evaluation by an orthopedic surgeon is recommended if the affected individual has chronic pain or limb deformities (genu varum, genu valgum).

Source: GeneReviews — "Multiple Epiphyseal Dysplasia, Autosomal Dominant"