Multiple Epiphyseal Dysplasia, Autosomal Dominant

Clinical characteristics.

Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early childhood, usually with pain in the hips and/or knees after exercise. Affected children report fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints.

Diagnosis/testing.

The diagnosis of autosomal dominant MED is established in a proband with typical clinical and radiographic findings and/or a heterozygous pathogenic variant in COL9A1, COL9A2, COL9A3, COMP, or MATN3 identified by molecular genetic testing.

Management.

Treatment of manifestations: For pain control, a combination of analgesics and physiotherapy including hydrotherapy; referral to a rheumatologist or pain specialist as needed; consideration of realignment osteotomy and/or acetabular osteotomy to limit joint destruction and development of osteoarthritis. Consider total joint arthroplasty if the degenerative hip changes cause uncontrollable pain/dysfunction. Offer psychosocial support addressing issues of short stature, chronic pain, disability, and employment.

Surveillance: Evaluation by an orthopedic surgeon for chronic pain and/or limb deformities (genu varum, genu valgum).

Agents/circumstances to avoid: Obesity; exercise causing repetitive strain on affected joints.

Genetic counseling.

By definition, autosomal dominant MED is inherited in an autosomal dominant manner. Many individuals with autosomal dominant MED have an affected parent. The proportion of individuals with autosomal dominant MED who have the disorder as the result of a de novo pathogenic variant is unknown. Each child of an individual with autosomal dominant MED has a 50% chance of inheriting the pathogenic variant. Once the autosomal dominant MED-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

• Initially, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is observed. When the epiphyses appear, the ossification centers are small with irregular contours. Epiphyseal abnormalities are usually most pronounced in the knees and/or hips, where they may resemble bilateral Perthes disease (see Differential Diagnosis).
• In childhood, the tubular bones may be mildly shortened. Ivory (very dense) epiphyses may be present in the hands. By definition, the spine is normal; however, Schmorl bodies (i.e., the displacement of intervertebral disk tissue into the vertebral bodies) and irregular vertebral end plates can be observed.
• In adulthood, signs of osteoarthritis are usually observed. It is often impossible to make a diagnosis of MED on adult radiographs alone.

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of autosomal dominant MED is established in a proband with characteristic clinical and radiographic findings (see Suggestive Findings) and/or a heterozygous pathogenic (or likely pathogenic) variant in a MED-related gene (see Table 1) identified by molecular genetic testing.

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Autosomal dominant multiple epiphyseal dysplasia (MED) includes a spectrum of severity from early-onset joint pain, joint deformity, and short stature to milder forms of MED that remain undiagnosed or are misdiagnosed as bilateral Perthes disease or even early-onset familial osteoarthritis.

Presentation. The presenting symptom early in childhood is usually pain in the hips and/or knees after exercise.

• Affected children report fatigue with long-distance walking.
• Waddling gait may be present.
• Angular deformities, including coxa vara and genu varum or genu valgum, are relatively rare.
• In contrast to the restricted mobility in the elbows, hypermobility in the knee and finger joints can be observed.

Growth. Adult height is either in the lower range of normal or mildly shortened. The shortness of the limbs relative to the trunk first becomes apparent in childhood. Head circumference is normal.

Intelligence is normal.

Progression. The natural history of autosomal dominant MED is of progressively worsening pain and joint deformity resulting in early-onset osteoarthritis. In adulthood, the condition is characterized by early-onset osteoarthritis, particularly of the large weight-bearing joints. In some individuals, the osteoarthritis is sufficiently severe to require joint replacement in early adult life.

Phenotype Correlations by Gene

COMP-related MED is characterized by significant involvement at the capital femoral epiphyses and irregular acetabula [Unger et al 2001].

COL9A1-, COL9A2-, and COL9A3-related MED. Type IX collagen defects result in more severe involvement of the knees and relative sparing of the hips.

MATN3-related MED results in knee abnormalities that are similar to those in individuals with COL9A2-related MED; the hip abnormalities are more severe (although not as severe as those in individuals with COMP-related MED) [Mortier et al 2001]. However, more intra- and interfamilial variability is evident in MATN3-related MED; for example, p.Arg121Trp can result in a spectrum of clinical and radiographic features, suggesting that other genetic and/or environmental factors modify the severity of this particular form of MED [Jackson et al 2004, Mäkitie et al 2004].

Genotype-Phenotype Correlations

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 p.Arg718Trp 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 [Jakkula et al 2003]. Briggs et al [2014] 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.

Penetrance

There is some evidence for reduced penetrance in MATN3-related MED [Mortier et al 2001, Mäkitie et al 2004], while pathogenic variants in COL9A1, COL9A2, COL9A3, and COMP are believed to be fully penetrant.

Nomenclature

Multiple epiphyseal dysplasia was originally classified into the severe Fairbank type (MED-Fairbank) and milder Ribbing type (MED-Ribbing).

MED-Fairbank type is probably the same disease as "enchondral dysostosis" described by Odman [1959] and "microepiphyseal dysplasia" described by Elsbach [1959].

MED-Ribbing should not be confused with Ribbing disease (OMIM 601477), a form of multiple diaphyseal sclerosis.

Prevalence

The prevalence of autosomal dominant MED is estimated to be least one in 10,000 births. However, as MED is usually not diagnosed at birth, the figure is most likely an underestimate.

COMP

COMP-related pseudoachondroplasia shares clinical and radiographic abnormalities with autosomal dominant multiple epiphyseal dysplasia (MED) and should be considered in the differential diagnosis. However, individuals with pseudoachondroplasia have short-limb dwarfism with spondyloepimetaphyseal involvement on radiographs. Unlike MED, pseudoachondroplasia is not known to be genetically heterogeneous and appears to result exclusively from pathogenic variants in COMP. Inheritance is autosomal dominant.

Pseudoachondroplasia was originally defined as a condition resembling achondroplasia but with normal craniofacial features. Intelligence is normal. At birth, body length is usually normal. The diagnosis is often made between age one and three years when radiographic abnormalities are found, skeletal growth slows, and/or a waddling gait becomes apparent. Joint pain is common beginning in childhood, particularly in the large joints of the lower extremities. Adult height ranges from 105 to 128 cm. Orthopedic complications are common. Affected individuals exhibit generalized ligamentous laxity, most pronounced in the fingers and knees. Laxity at the knees contributes significantly to leg deformities, including genu varum or genu valgum. Ligamentous laxity with odontoid hypoplasia can result in cervical spine instability. Degenerative joint disease is progressive. The radiographic manifestations involve the spine and epimetaphyseal regions of the tubular bones. Characteristic findings are the tongue-like projections on the anterior borders of the vertebral bodies (on lateral views of the spine), small proximal femoral epiphyses ("mini-epiphyses"), irregularly shaped carpal and tarsal bones, and short tubular bones with small and fragmented epiphyses and metaphyseal irregularities.

COL9A1, COL9A2, COL9A3, and MATN3

Other phenotypes caused by germline pathogenic variants in COL9A1, COL9A2, COL9A3, and MATN3 are summarized in Table 2.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with autosomal dominant MED, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

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

Agents/Circumstances to Avoid

The following should be avoided:

• Obesity, which increases stress on joints
• Exercise that causes repetitive strain on affected joints

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

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.

Mode of Inheritance

By definition, autosomal dominant multiple epiphyseal dysplasia (MED) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals with autosomal dominant MED have an affected parent.
• An individual with autosomal dominant MED may have the disorder as the result of a de novo COL9A1, COL9A2, COL9A3, COMP, or MATN3 pathogenic variant. The proportion of individuals with autosomal dominant MED who have the disorder as the result of a de novo pathogenic variant is unknown.
• If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment include:
  • Evaluation for signs of MED or early-onset osteoarthritis;
  • Molecular genetic testing (if a molecular diagnosis has been established in an affected family member).
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband is not identified in either parent, and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• The family history of some individuals diagnosed with autosomal dominant MED may appear to be negative because of failure to recognize the disorder in affected family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband).

Sibs of a proband. The risk to sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband has autosomal dominant MED and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%.
  • Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related pathogenic variants in MATN3, COL9A3, or, in some instances, COMP (see Genotype-Phenotype Correlations).
• If the proband has a known autosomal dominant MED-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent (see Penetrance) or parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant MED has a 50% chance of inheriting the autosomal dominant MED-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Related Genetic Counseling Issues

Testing of asymptomatic at-risk individuals younger than age 18 years is controversial. Testing may be appropriate if it is believed that knowledge of the disease status will influence care of the child. Since early orthopedic intervention and limitation of inappropriate exercise may ameliorate the severity of joint disease in the long term, it has been argued that predictive testing is justified in children at risk for MED.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the autosomal dominant MED-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The five genes (COL9A1, COL9A2, COL9A3, COMP, and MATN3) in which pathogenic variants cause autosomal dominant multiple epiphyseal dysplasia (MED) encode three structural macromolecules of the cartilage extracellular matrix (type IX collagen, cartilage oligomeric matrix protein, and matrilin-3) [Unger & Hecht 2001, Briggs & Chapman 2002]. These proteins interact with each other and with type II collagen.

COL9A1, COL9A2, and COL9A3. Type IX collagen, a heterotrimer [α1(IX)α2(IX)α3(IX)] of polypeptides encoded by COL9A1, COL9A2, and COL9A3, is an integral component of cartilage and a member of the FACIT (fibril-associated collagen with interrupted triple helix) group of collagens. Type IX collagen has three collagenous (COL) domains separated by non-collagenous (NC) domains. The amino-terminal NC domain (NC4) is encoded entirely by COL9A1. The collagenous domains (COL1-COL3) are separated by four non-collagenous (NC1-NC4) domains. The COL domains closely associate with type II collagen fibrils and are thought to act as a molecular bridge between collagen fibrils and other cartilage matrix components.

All reported COL9A1-, COL9A2-, and COL9A3-related MED pathogenic variants are clustered in the splice acceptor site of exon 8 of COL9A1, the splice donor site of exon 3 of COL9A2, or the splice acceptor site of exon 3 of COL9A3. These pathogenic variants result in deletions located in a similar region of the COL3 domain of type IX collagen, demonstrating the importance of this domain. Studies have confirmed that a COL9A3 pathogenic variant abolishes binding of type IX collagen to matrilin-3 and type II collagen [Fresquet et al 2007].

COMP encodes cartilage oligomeric matrix protein (COMP), a pentameric adhesive glycoprotein found predominantly in the extracellular matrix (ECM) of cartilage but also in tendons and ligaments. It is a member of the thrombospondin protein family comprising:

• A coiled-coil oligomerization domain;
• Four type II (EGF-like) repeats;
• Eight type III (CaM-like) repeats;
• A large COOH-terminal globular domain.

The type III repeats bind Ca²⁺ cooperatively and with high affinity, while the C-terminal globular domain has the ability to interact with both fibrillar (type I, II, and III) and non-fibrillar collagens, such as type IX [Rosenberg et al 1998, Holden et al 2001, Thur et al 2001, Mann et al 2004], as well as fibronectin [Di Cesare et al 2002].

All MED-related COMP pathogenic variants are missense variants or small in-frame deletions and duplications found in the type III repeats (85%) or C-terminal domain (15%) [Kennedy et al 2005a, Kennedy et al 2005b, Jackson et al 2012]. Approximately 70% of MED-related COMP pathogenic variants reside in exons 10, 11, and 13 [Kennedy et al 2005b, Jackson et al 2012]; MED-related COMP variants are not found in exons 15, 17, or 19.

MATN3 encodes matrilin-3, the third member of a family of oligomeric multidomain ECM proteins comprising matrilin-1, matrilin-2, matrilin-3, and matrilin-4 [Wagener et al 2005]. The domain structure of the matrilin family of proteins is similar; each consists of:

• One or two vWFA domains;
• A varying number of EGF-like repeats;
• A coiled-coil domain, which facilitates oligomerization.

Matrilins have been found in collagen-dependent and collagen-independent filament networks within the tissues in which they are expressed and may perform analogous functions in these different tissues. Matrilin-3 has been shown to interact with COMP and other cartilage collagens through the A domain [Mann et al 2004, Fresquet et al 2007, Fresquet et al 2008, Fresquet et al 2010].

With one exception, all MATN3-relate MED pathogenic variants are missense variants found within exon 2, which encodes the single A domain of matrilin-3. The exception is a missense variant within five residues of the A domain and may well play a role in its structure and/or function. The vast majority of A-domain variants (~70%) affect conserved residues within the six beta-strands that comprise the single beta-sheet of the A domain. Other variants have been described in the alpha-helix regions of the A domain (~30%).

MATN3 pathogenic variants appear to delay the folding of the A domain, which elicits an unfolded protein response and results in the retention of abnormal matrilin-3 in the rough endoplasmic reticulum. This results in a reduction in chondrocyte proliferation and dysregulated apoptosis [Leighton et al 2007, Nundlall et al 2010]. Retained abnormal matrilin-3 forms non-native disulphide-bonded aggregates.

Author Notes

European Skeletal Dysplasia Network (ESDN)

Revision History

• 4 July 2024 (sw) Comprehensive update posted live
• 25 April 2019 (ha) Comprehensive update posted live
• 19 November 2015 (me) Comprehensive update posted live
• 25 July 2013 (me) Comprehensive update posted live
• 1 February 2011 (me) Comprehensive update posted live
• 18 April 2007 (me) Comprehensive update posted live
• 24 January 2005 (me) Comprehensive update posted live
• 8 January 2003 (me) Review posted live
• 10 October 2002 (gm) Original submission

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