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 complain of 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 the 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.

Many individuals with autosomal dominant MED have inherited the pathogenic variant from a parent. The prevalence of de novo pathogenic variants is not known. Each child of an individual with autosomal dominant MED has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for autosomal dominant multiple epiphyseal dysplasia are possible if the pathogenic variant has been identified in an affected family member.

Suggestive Findings

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

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 x-rays alone.

Establishing the Diagnosis

The diagnosis of autosomal dominant MED is established in a proband with the above clinical and radiographic 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 variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of autosomal dominant MED is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with atypical clinical findings in whom the diagnosis of autosomal dominant MED has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Autosomal dominant multiple epiphyseal dysplasia (MED) was originally divided into a mild form called "Ribbing type" and a more severe form known as "Fairbank type." However, much more clinical variability exists within the overall MED phenotype than is suggested by these two distinct entities. It is likely that the milder forms of MED either 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 complain of 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.

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.

Other. No other anomalies are associated with autosomal dominant MED. Intelligence is normal.

Genotype-Phenotype Correlations

Studies of genotype-phenotype correlations have been relatively successful and can be summarized briefly [Mortier et al 2001, Unger et al 2001]:

• MED resulting from COMP pathogenic variants is characterized by significant involvement at the capital femoral epiphyses and irregular acetabula [Unger et al 2001]. However, 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].
• Type IX collagen defects result in more severe involvement of the knees and relative sparing of the hips.
• MATN3 pathogenic variants result in knee abnormalities that are similar to those in individuals with a COL9A2 pathogenic variant; the hip abnormalities are more severe (although not as severe as those in individuals with a COMP pathogenic variant) [Mortier et al 2001]. However, more intra- and interfamilial variability is evident in MED caused by MATN3 pathogenic variants. A pathogenic variant such as 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].

It is important to note that striking intra- and interfamilial variability can be observed in MED caused by pathogenic variants in MATN3 [Chapman et al 2001, Mortier et al 2001, Jackson et al 2004, Mäkitie et al 2004], in COL9A3 [Bönnemann et al 2000, Nakashima et al 2005], and in some instances, in COMP. These findings make the establishment of strong genotype-phenotype correlations in autosomal dominant MED a challenge.

Briggs et al [2014] reviewed 300 COMP 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 MED caused by MATN3 pathogenic variants [Mortier et al 2001, Mäkitie et al 2004] while pathogenic variants in COMP and the type IX collagen genes 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

Studies undertaken to determine the birth prevalence of skeletal dysplasias suggest a prevalence of autosomal dominant MED of at least one per 10,000 births. However, as MED is usually not diagnosed at birth, the figure is most likely an underestimate.

COMP

Pseudoachondroplasia shares clinical and radiographic abnormalities with autosomal dominant 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.

COL9A1-3, MATN3

Other phenotypes associated with 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 multiple epiphyseal dysplasia (MED), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Elicitation of pain history
• Assessment of joint mobility
• Radiographs to determine the extent and severity of joint involvement
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

For pain control, a combination of analgesics and physiotherapy including hydrotherapy is helpful to many affected individuals; however, pain can be difficult to control. Referral to a rheumatologist or pain specialist may be indicated.

Limitation of joint destruction and the development of osteoarthritis is a goal. Consultation with an orthopedic surgeon can determine if realignment osteotomy and/or acetabular osteotomy may be helpful in slowing the progression of symptoms.

In some individuals, total joint arthroplasty may be required if the degenerative hip changes are causing too much pain or dysfunction.

Psychosocial support addressing issues of short stature, chronic pain, disability, and employment is appropriate.

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

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.
• A proband 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 cases caused by a de novo pathogenic variant is unknown.
• Recommendations for the parents of a proband with an apparent de novo pathogenic variant may include evaluation for signs of MED or early-onset osteoarthritis and, if a pathogenic variant has been identified in an affected family member, molecular genetic testing.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism has been reported in a number of families [Jackson et al 2004].
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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%.
• If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism; germline mosaicism has been reported in a number of families [Jackson et al 2004].
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for autosomal dominant MED because of the possibility of reduced penetrance in a heterozygous parent (see Penetrance) or the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant MED has a 50% chance of inheriting the COL9A1, COL9A2, COL9A3, COMP, or MATN3 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

MED of unknown mode of inheritance

• Until the mode of inheritance in an individual with MED can be determined, it may be appropriate to consider that the risk of transmitting the disorder to each of the offspring is as high as 50%.
• A number of families in which one of the parents has germline mosaicism for a dominantly inherited pathogenic variant have been reported, resulting in a family history suggestive of autosomal recessive inheritance.

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.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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).

Prenatal Testing and Preimplantation Genetic Testing

Once the COL9A1, COL9A2, COL9A3, COMP, or MATN3 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for autosomal dominant multiple epiphyseal dysplasia are possible.

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 both in vitro [Rosenberg et al 1998, Holden et al 2001, Thur et al 2001, Mann et al 2004, Budde et al 2005, Wagener et al 2005, Fresquet et al 2007, Fresquet et al 2008, Fresquet et al 2010] and in vivo [Budde et al 2005, Blumbach et al 2008, Zaucke & Grässel 2009].

Literature Cited

• Annunen S, Paassilta P, Lohiniva J, Perala M, Pihlajamaa T, Karppinen J, Tervonen O, Kroger H, Lahde S, Vanharanta H, Ryhanen L, Goring HH, Ott J, Prockop DJ, Ala-Kokko L. An allele of COL9A2 associated with intervertebral disc disease. Science. 1999;285:409–12. [PubMed: 10411504]
• Blumbach K, Niehoff A, Paulsson M, Zaucke F. Ablation of collagen IX and COMP disrupts epiphyseal cartilage architecture. Matrix Biol. 2008;27:306–18. [PubMed: 18191556]
• Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, Nishimura G, Sangiorgi L, Savarirayan R, Sillence D, Spranger J, Superti-Furga A, Warman M, Unger S. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A. 2015;167A:2869–92. [PubMed: 26394607]
• Bönnemann CG, Cox GF, Shapiro F, Wu JJ, Feener CA, Thompson TG, Anthony DC, Eyre DR, Darras BT, Kunkel LM. A mutation in the alpha 3 chain of type IX collagen causes autosomal dominant multiple epiphyseal dysplasia with mild myopathy. Proc Natl Acad Sci U S A. 2000;97:1212–7. [PMC free article: PMC15572] [PubMed: 10655510]
• Borochowitz ZU, Scheffer D, Adir V, Dagoneau N, Munnich A, Cormier-Daire V. Spondylo-epi-metaphyseal dysplasia (SEMD) matrilin 3 type: homozygote matrilin 3 mutation in a novel form of SEMD. J Med Genet. 2004;41:366–72. [PMC free article: PMC1735768] [PubMed: 15121775]
• Briggs MD, Bell PA, Wright MJ, Pirog KA. New therapeutic targets in rare genetic skeletal diseases. Expert Opin Orphan Drugs. 2015;3:1137–54. [PMC free article: PMC4643203] [PubMed: 26635999]
• Briggs MD, Brock J, Ramsden SC, Bell PA. Genotype to phenotype correlations in cartilage oligomeric matrix protein associated chondrodysplasias. Eur J Hum Genet. 2014;22:1278–82. [PMC free article: PMC4051597] [PubMed: 24595329]
• Briggs MD, Chapman KL. Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat. 2002;19:465–78. [PubMed: 11968079]
• Budde B, Blumbach K, Ylöstalo J, Zaucke F, Ehlen HW, Wagener R, Ala-Kokko L, Paulsson M, Bruckner P, Grässel S. Altered integration of matrilin-3 into cartilage extracellular matrix in the absence of collagen IX. Mol Cell Biol. 2005;25:10465–78. [PMC free article: PMC1291247] [PubMed: 16287859]
• Chapman KL, Mortier GR, Chapman K, Loughlin J, Grant ME, Briggs MD. Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nat Genet. 2001;28:393–6. [PubMed: 11479597]
• Chen H, Deere M, Hecht JT, Lawler J. Cartilage oligomeric matrix protein is a calcium-binding protein, and a mutation in its type 3 repeats causes conformational changes. J Biol Chem. 2000;275:26538–44. [PubMed: 10852928]
• Cilliers HJ, Beighton P. Beukes familial hip dysplasia: an autosomal dominant entity. Am J Med Genet. 1990;36:386–90. [PubMed: 2389793]
• Cotterill SL, Jackson GC, Leighton MP, Wagener R, Makitie O, Cole WG, Briggs MD. Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3. Hum Mutat. 2005;26:557–65. [PMC free article: PMC2726956] [PubMed: 16287128]
• Di Cesare PE, Chen FS, Moergelin M, Carlson CS, Leslie MP, Perris R, Fang C. Matrix-matrix interaction of cartilage oligomeric matrix protein and fibronectin. Matrix Biol. 2002;21:461–70. [PubMed: 12225811]
• Elsbach L. Bilateral hereditary micro-epiphysial dysplasia of the hips. J Bone Joint Surg Br. 1959;41-B:514–23. [PubMed: 13849708]
• Fresquet M, Jackson GC, Loughlin J, Briggs MD. Novel mutations in exon 2 of MATN3 affect residues within the alpha-helices of the A-domain and can result in the intracellular retention of mutant matrilin-3. Hum Mutat. 2008;29:330. [PubMed: 18205203]
• Fresquet M, Jowitt TA, Stephen LA, Ylöstalo J, Briggs MD. Structural and functional investigations of Matrilin-1 A-domains reveal insights into their role in cartilage ECM assembly. J Biol Chem. 2010;285:34048–61. [PMC free article: PMC2962504] [PubMed: 20729554]
• Fresquet M, Jowitt TA, Ylöstalo J, Coffey P, Meadows RS, Ala-Kokko L, Thornton DJ, Briggs MD. Structural and functional characterization of recombinant matrilin-3 A-domain and implications for human genetic bone diseases. J Biol Chem. 2007;282:34634–43. [PMC free article: PMC2673055] [PubMed: 17881354]
• Gu J, Rong J, Guan F, Jiang L, Tao S, Guan G, Tao T. MATN3 gene polymorphism is associated with osteoarthritis in Chinese Han population: a community-based case-control study. ScientificWorldJournal. 2012;2012:656084. [PMC free article: PMC3432353] [PubMed: 22973175]
• Holden P, Meadows RS, Chapman KL, Grant ME, Kadler KE, Briggs MD. Cartilage oligomeric matrix protein interacts with type IX collagen, and disruptions to these interactions identify a pathogenetic mechanism in a bone dysplasia family. J Biol Chem. 2001;276:6046–55. [PubMed: 11087755]
• Itoh T, Shirahama S, Nakashima E, Maeda K, Haga N, Kitoh H, Kosaki R, Ohashi H, Nishimura G, Ikegawa S. Comprehensive screening of multiple epiphyseal dysplasia mutations in Japanese population. Am J Med Genet A. 2006;140:1280–4. [PubMed: 16691584]
• Jackson GC, Barker FS, Jakkula E, Czarny-Ratajczak M, Makitie O, Cole WG, Wright MJ, Smithson SF, Suri M, Rogala P, Mortier GR, Baldock C, Wallace A, Elles R, Ala-Kokko L, Briggs MD. Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. J Med Genet. 2004;41:52–9. [PMC free article: PMC1757268] [PubMed: 14729835]
• Jackson GC, Mittaz-Crettol L, Taylor JA, Mortier GR, Spranger J, Zabel B, LeMerrer M, Cormier-Daire V, Hall CM, Offiah A, Wright MJ, Savarirayan R, Nishimura G, Ramsden SC, Elles R, Bonafe L, Superti-Furga A, Unger S, Zankl A, Briggs MD. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum Mutat. 2012;33:144–57. [PMC free article: PMC3272220] [PubMed: 21922596]
• Jakkula E, Lohiniva J, Capone A, Bonafe L, Marti M, Schuster V, Giedion A, Eich G, Boltshauser E, Ala-Kokko L, Superti-Furga A. A recurrent R718W mutation in COMP results in multiple epiphyseal dysplasia with mild myopathy: clinical and pathogenetic overlap with collagen IX mutations. J Med Genet. 2003;40:942–8. [PMC free article: PMC1735347] [PubMed: 14684695]
• Jakkula E, Makitie O, Czarny-Ratajczak M, Jackson GC, Damignani R, Susic M, Briggs MD, Cole WG, Ala-Kokko L. Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations. Eur J Hum Genet. 2005;13:292–301. [PubMed: 15523498]
• Kannu P, Irving M, Aftimos S, Savarirayan R. Two novel COL2A1 mutations associated with a Legg-Calvé-Perthes disease-like presentation. Clin Orthop Relat Res. 2011;469:1785–90. [PMC free article: PMC3094608] [PubMed: 21442341]
• Kennedy J, Jackson G, Barker FS, Nundlall S, Bella J, Wright MJ, Mortier GR, Neas K, Thompson E, Elles R, Briggs MD. Novel and recurrent mutations in the C-terminal domain of COMP cluster in two distinct regions and result in a spectrum of phenotypes within the pseudoachondroplasia -- multiple epiphyseal dysplasia disease group. Hum Mutat. 2005a;25:593–4. [PubMed: 15880723]
• Kennedy J, Jackson G, Ramsden S, Taylor J, Newman W, Wright MJ, Donnai D, Elles R, Briggs MD. COMP mutation screening as an aid for the clinical diagnosis and counselling of patients with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal dysplasia. Eur J Hum Genet. 2005b;13:547–55. [PMC free article: PMC2673054] [PubMed: 15756302]
• Kim OH, Park H, Seong MW, Cho TJ, Nishimura G, Superti-Furga A, Unger S, Ikegawa S, Choi IH, Song HR, Kim HW, Yoo WJ, Shim JS, Chung CY, Oh CW, Jeong C, Song KS, Seo SG, Cho SI, Yeo IK, Kim SY, Park S, Park SS. Revisit of multiple epiphyseal dysplasia: ethnic difference in genotypes and comparison of radiographic features linked to the COMP and MATN3 genes. Am J Med Genet A. 2011;155A:2669–80. [PubMed: 21965141]
• Kleerekoper Q, Hecht JT, Putkey JA. Disease-causing mutations in cartilage oligomeric matrix protein cause an unstructured Ca2+ binding domain. J Biol Chem. 2002;277:10581–9. [PubMed: 11782471]
• Leighton MP, Nundlall S, Starborg T, Meadows RS, Suleman F, Knowles L, Wagener R, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD. Decreased chondrocyte proliferation and dysregulated apoptosis in the cartilage growth plate are key features of a murine model of epiphyseal dysplasia caused by a matn3 mutation. Hum Mol Genet. 2007;16:1728–41. [PMC free article: PMC2674230] [PubMed: 17517694]
• Liu YF, Chen WM, Lin YF, Yang RC, Lin MW, Li LH, Chang YH, Jou YS, Lin PY, Su JS, Huang SF, Hsiao KJ, Fann CS, Hwang HW, Chen YT, Tsai SF. Type II collagen gene variants and inherited osteonecrosis of the femoral head. N Engl J Med. 2005;352:2294–301. [PubMed: 15930420]
• Mabuchi A, Haga N, Maeda K, Nakashima E, Manabe N, Hiraoka H, Kitoh H, Kosaki R, Nishimura G, Ohashi H, Ikegawa S. Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. Hum Mutat. 2004;24:439–40. [PubMed: 15459972]
• Maddox BK, Mokashi A, Keene DR, Bachinger HP. A cartilage oligomeric matrix protein mutation associated with pseudoachondroplasia changes the structural and functional properties of the type 3 domain. J Biol Chem. 2000;275:11412–7. [PubMed: 10753957]
• Maeda K, Nakashima E, Horikoshi T, Mabuchi A, Ikegawa S. Mutation in the von Willebrand factor-A domain is not a prerequisite for the MATN3 mutation in multiple epiphyseal dysplasia. Am J Med Genet A. 2005;136:285–6. [PubMed: 15948199]
• Mäkitie O, Mortier GR, Czarny-Ratajczak M, Wright MJ, Suri M, Rogala P, Freund M, Jackson GC, Jakkula E, Ala-Kokko L, Briggs MD, Cole WG. Clinical and radiographic findings in multiple epiphyseal dysplasia caused by MATN3 mutations: description of 12 patients. Am J Med Genet A. 2004;125A:278–84. [PubMed: 14994237]
• Mann HH, Ozbek S, Engel J, Paulsson M, Wagener R. Interactions between the cartilage oligomeric matrix protein and matrilins. Implications for matrix assembly and the pathogenesis of chondrodysplasias. J Biol Chem. 2004;279:25294–8. [PubMed: 15075323]
• Min JL, Meulenbelt I, Riyazi N, Kloppenburg M, Houwing-Duistermaat JJ, Seymour AB, van Duijn CM, Slagboom PE. Association of matrilin-3 polymorphisms with spinal disc degeneration and osteoarthritis of the first carpometacarpal joint of the hand. Ann Rheum Dis. 2006;65:1060–6. [PMC free article: PMC1798238] [PubMed: 16396979]
• Miyamoto Y, Matsuda T, Kitoh H, Haga N, Ohashi H, Nishimura G, Ikegawa S. A recurrent mutation in type II collagen gene causes Legg-Calvé-Perthes disease in a Japanese family. Hum Genet. 2007;121:625–9. [PubMed: 17394019]
• Mortier GR, Chapman K, Leroy JL, Briggs MD. Clinical and radiographic features of multiple epiphyseal dysplasia not linked to the COMP or type IX collagen genes. Eur J Hum Genet. 2001;9:606–12. [PubMed: 11528506]
• Mostert AK, Dijkstra PF, Jansen BR, van Horn JR, de Graaf B, Heutink P, Lindhout D. Familial multiple epiphyseal dysplasia due to a matrilin-3 mutation: further delineation of the phenotype including 40 years follow-up. Am J Med Genet. 2003;120A:490–7. [PubMed: 12884427]
• Nakashima E, Kitoh H, Maeda K, Haga N, Kosaki R, Mabuchi A, Nishimura G, Ohashi H, Ikegawa S. Novel COL9A3 mutation in a family with multiple epiphyseal dysplasia. Am J Med Genet A. 2005;132A:181–4. [PubMed: 15551337]
• Nundlall S, Rajpar MH, Bell PA, Clowes C, Zeeff LA, Gardner B, Thornton DJ, Boot-Handford RP, Briggs MD. An unfolded protein response is the initial cellular response to the expression of mutant matrilin-3 in a mouse model of multiple epiphyseal dysplasia. Cell Stress Chaperones. 2010;15:835–49. [PMC free article: PMC3024081] [PubMed: 20428984]
• Odman P. Hereditary enchondral dysostosis; twelve cases in three generations mainly with peripheral location. Acta Radiol. 1959;52:97–113. [PubMed: 14428296]
• Otten C, Hansen U, Talke A, Wagener R, Paulsson M, Zaucke F. A matrilin-3 mutation associated with osteoarthritis does not affect collagen affinity but promotes the formation of wider cartilage collagen fibrils. Hum Mutat. 2010;31:254–63. [PubMed: 20077500]
• Otten C, Wagener R, Paulsson M, Zaucke F. Matrilin-3 mutations that cause chondrodysplasias interfere with protein trafficking while a mutation associated with hand osteoarthritis does not. J Med Genet. 2005;42:774–9. [PMC free article: PMC1735938] [PubMed: 16199550]
• Paassilta P, Lohiniva J, Goring HH, Perala M, Raina SS, Karppinen J, Hakala M, Palm T, Kroger H, Kaitila I, Vanharanta H, Ott J, Ala-Kokko L. Identification of a novel common genetic risk factor for lumbar disk disease. JAMA. 2001;285:1843–9. [PubMed: 11308397]
• Paassilta P, Pihlajamaa T, Annunen S, Brewton RG, Wood BM, Johnson CC, Liu J, Gong Y, Warman ML, Prockop DJ, Mayne R, Ala-Kokko L. Complete sequence of the 23-kilobase human COL9A3 gene. Detection of Gly-X-Y triplet deletions that represent neutral variants. J Biol Chem. 1999;274:22469–75. [PubMed: 10428822]
• Pihlajamaa T, Vuoristo MM, Annunen S, Perala M, Prockop DJ, Ala-Kokko L. Human COL9A1 and COL9A2 genes. Two genes of 90 and 15 kb code for similar polypeptides of the same collagen molecule. Matrix Biol. 1998;17:237–41. [PubMed: 9707347]
• Piróg KA, Briggs MD. Skeletal dysplasias associated with mild myopathy-a clinical and molecular review. J Biomed Biotechnol. 2010;2010:686457. [PMC free article: PMC2875749] [PubMed: 20508815]
• Piróg KA, Jaka O, Katakura Y, Meadows RS, Kadler KE, Boot-Handford RP, Briggs MD. A mouse model offers novel insights into the myopathy and tendinopathy often associated with pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Mol Genet. 2010;19:52–64. [PMC free article: PMC2792148] [PubMed: 19808781]
• Piróg-Garcia KA, Meadows RS, Knowles L, Heinegård D, Thornton DJ, Kadler KE, Boot-Handford RP, Briggs MD. Reduced cell proliferation and increased apoptosis are significant pathological mechanisms in a murine model of mild pseudoachondroplasia resulting from a mutation in the C-terminal domain of COMP. Hum Mol Genet. 2007;16:2072–88. [PMC free article: PMC2674228] [PubMed: 17588960]
• Posey KL, Veerisetty AC, Liu P, Wang HR, Poindexter BJ, Bick R, Alcorn JL, Hecht JT. An inducible cartilage oligomeric matrix protein mouse model recapitulates human pseudoachondroplasia phenotype. Am J Pathol. 2009;175:1555–63. [PMC free article: PMC2751552] [PubMed: 19762713]
• Pullig O, Tagariello A, Schweizer A, Swoboda B, Schaller P, Winterpacht A. MATN3 (matrilin-3) sequence variation (pT303M) is a risk factor for osteoarthritis of the CMC1 joint of the hand, but not for knee osteoarthritis. Ann Rheum Dis. 2007;66:279–80. [PMC free article: PMC1798488] [PubMed: 17242023]
• Rosenberg K, Olsson H, Morgelin M, Heinegard D. Cartilage oligomeric matrix protein shows high affinity zinc-dependent interaction with triple helical collagen. J Biol Chem. 1998;273:20397–403. [PubMed: 9685393]
• Schmitz M, Becker A, Schmitz A, Weirich C, Paulsson M, Zaucke F, Dinser R. Disruption of extracellular matrix structure may cause pseudoachondroplasia phenotypes in the absence of impaired cartilage oligomeric matrix protein secretion. J Biol Chem. 2006;281:32587–95. [PubMed: 16928687]
• Schmitz M, Niehoff A, Miosge N, Smyth N, Paulsson M, Zaucke F. Transgenic mice expressing D469Delta mutated cartilage oligomeric matrix protein (COMP) show growth plate abnormalities and sternal malformations. Matrix Biol. 2008;27:67–85. [PubMed: 17889519]
• Spitznagel L, Nitsche DP, Paulsson M, Maurer P, Zaucke F. Characterization of a pseudoachondroplasia-associated mutation (His587-->Arg) in the C-terminal, collagen-binding domain of cartilage oligomeric matrix protein (COMP). Biochem J. 2004;377:479–87. [PMC free article: PMC1223886] [PubMed: 14580238]
• Stefánsson SE, Jónsson H, Ingvarsson T, Manolescu I, Jónsson HH, Olafsdóttir G, Pálsdóttir E, Stefánsdóttir G, Sveinbjörnsdóttir G, Frigge ML, Kong A, Gulcher JR, Stefánsson K. Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am J Hum Genet. 2003;72:1448–59. [PMC free article: PMC1180305] [PubMed: 12736871]
• Suleman F, Gualeni B, Gregson HJ, Leighton MP, Piróg KA, Edwards S, Holden P, Boot-Handford RP, Briggs MD. A novel form of chondrocyte stress is triggered by a COMP mutation causing pseudoachondroplasia. Hum Mutat. 2012;33:218–31. [PMC free article: PMC3320758] [PubMed: 22006726]
• Thur J, Rosenberg K, Nitsche DP, Pihlajamaa T, Ala-Kokko L, Heinegard D, Paulsson M, Maurer P. Mutations in cartilage oligomeric matrix protein causing pseudoachondroplasia and multiple epiphyseal dysplasia affect binding of calcium and collagen I, II, and IX. J Biol Chem. 2001;276:6083–92. [PubMed: 11084047]
• Unger S, Hecht JT. Pseudoachondroplasia and multiple epiphyseal dysplasia: new etiologic developments. Am J Med Genet. 2001;106:244–50. [PubMed: 11891674]
• Unger SL, Briggs MD, Holden P, Zabel B, Ala-Kokko L, Paassilta P, Lohiniva J, Rimoin DL, Lachman RS, Cohn DH. Multiple epiphyseal dysplasia: radiographic abnormalities correlated with genotype. Pediatr Radiol. 2001;31:10–8. [PubMed: 11200990]
• Wagener R, Ehlen HW, Ko YP, Kobbe B, Mann HH, Sengle G, Paulsson M. The matrilins--adaptor proteins in the extracellular matrix. FEBS Lett. 2005;579:3323–9. [PubMed: 15943978]
• Watson CM, Crinnion LA, Gleghorn L, Newman WG, Ramesar R, Beighton P, Wallis GA. Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia. S Afr Med J. 2015;105:558–63. [PubMed: 26428751]
• Zankl A, Jackson GC, Crettol LM, Taylor J, Elles R, Mortier GR, Spranger J, Zabel B, Unger S, Merrer ML, Cormier-Daire V, Hall CM, Wright MJ, Bonafe L, Superti-Furga A, Briggs MD. Preselection of cases through expert clinical and radiological review significantly increases mutation detection rate in multiple epiphyseal dysplasia. Eur J Hum Genet. 2007;15:150–4. [PMC free article: PMC2670452] [PubMed: 17133256]
• Zaucke F, Grässel S. Genetic mouse models for the functional analysis of the perifibrillar components collagen IX, COMP and matrilin-3: implications for growth cartilage differentiation and endochondral ossification. Histol Histopathol. 2009;24:1067–79. [PubMed: 19554514]
• Zhao J, Xia W, Nie M, Zheng X, Wang Q, Wang X, Wang W, Ning Z, Huang W, Jiang Y, Li M, Wang O, Xing X, Sun Y, Luo L, He S, Yu W, Lin Q, Pei Y, Zhang F, Han Y, Tong Y, Che Y, Shen R, Hu Y, Zhou X, Chen Q, Xu L. A haplotype of MATN3 is associated with vertebral fracture in Chinese postmenopausal women: Peking Vertebral Fracture (PK-VF) study. Bone. 2012;50:917–24. [PMC free article: PMC6122846] [PubMed: 22270056]

Author Notes

European Skeletal Dysplasia Network (ESDN)

Revision History

• 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