Clinical Diagnosis

The diagnosis of autosomal dominant multiple epiphyseal dysplasia (MED) is based upon the clinical and radiographic presentation in the proband and other family members.

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.

Molecular Genetic Testing

Genes. Mutations in five genes have been shown to cause autosomal dominant MED [Unger & Hecht 2001, Briggs & Chapman 2002]:

• COMP
• COL9A1
• COL9A2
• COL9A3
• MATN3

Other loci

• Mutations remain undetected in approximately 10%-20% of individuals with MED, suggesting that mutations in additional, as-yet unidentified genes are also involved in the pathogenesis of MED.
• In some families genetic linkage studies have excluded linkage to the five genes in which mutations are known to be causal; however, additional genetic loci for MED have not yet been determined.

Clinical testing

• Sequence analysis/sequence analysis of select exons. Sequence analysis of select exons and splice junctions should be capable of detecting the vast majority of mutations located within the coding region of these genes (see Testing Strategy).
  
  Note: (1) Sequence analysis does not detect exonic, multiexonic, or whole-gene deletions [Mabuchi et al 2003]. (2) Normal allelic variants located within introns may disrupt the annealing of primers during PCR, resulting in the amplification of only one allele.
• COMP. Mutations in COMP are located in the exons encoding the type III repeats (exons 8-14) and C-terminal domain (exons 15-19) [Unger & Hecht 2001, Briggs & Chapman 2002]. A study by Kennedy et al [2005b] demonstrated that approximately 70% of MED-causing mutations in COMP reside in exons 10, 11, and 13.
• Deletion/duplication analysis. There is no evidence to date that exonic or whole-gene deletions in COMP can cause multiple epiphyseal dysplasia (or the related PSACH – see Genetically Related Disorders).
• COL9A1, COL9A2, COL9A3. Sequence analysis of the relevant exons and flanking intronic sequence includes: COL9A1 (exons 8-10), COL9A2 (exons 2-4), COL9A3 (exons 2-4). Mutations in COL9A2 and COL9A3 are found in the splice donor and/or acceptor sequences of exon 3, while a single mutation has been found in the splice acceptor sequence of exon 9 of COL9A1.
• MATN3. With one exception, all MED-causing mutations in MATN3 are missense mutations found within exon 2, which encodes the single A-domain of matrilin-3. The vast majority of these mutations affect conserved residues within the six beta-strands that comprise the single beta-sheet of the A-domain. Recently, however, several mutations have also been found in the alpha-helix regions of the A-domain, suggesting that MED-causing mutations in MATN3 are more widespread than previously thought [Chapman et al 2001, Jackson et al 2004, Mabuchi et al 2004, Cotterill et al 2005, Itoh et al 2006, Fresquet et al 2008]. The single exception is a missense mutation identified in exon 1 (p.Arg70His) [Maeda et al 2005]; however, this mutation is within five residues of the A-domain and may well play a role in its structure and/or function.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. Ideally a comprehensive clinical and radiographic review of the proband should precede molecular genetic testing. By confirming the clinical diagnosis of MED, the mutation detection rate can be significantly increased [Zankl et al 2007].

For autosomal dominant MED, genes are best tested in the following order, which reflects the relative contribution of each gene to the overall proportion of molecularly confirmed MED:

• COMP (~70%)
• MATN3 (~20%)
• COL9A1, COL9A2, and COL9A3 (~10%)

Based on molecular findings [Kennedy et al 2005b, Zankl et al 2007] the following testing regime has been recommended by the European Skeletal Dysplasia Network and Maeda et al [2005]:

• Level 1: COMP (exons 10-15) and MATN3 (exon 2)
• Level 2: COMP (exons 8 & 9 and 16-19)
• Level 3: COL9A1 (exon 8), COL9A2 and COL9A3 (exon 3)
  
  Note: Amplimers should include splice donor and acceptor sites.

It is important to note that in some situations, autosomal dominant MED may not be distinguishable from autosomal recessive forms of MED; therefore, it may be appropriate to test SCLA26A2 after testing COMP.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

Natural History

Autosomal dominant multiple epiphyseal dysplasia (MED) was originally divided into a mild form called Ribbing disease and a more severe form known as Fairbank disease. 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 osteoarthritis.

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.

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.

The natural history of 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 cases, the osteoarthritis is sufficiently severe to require joint replacement in early adult life.

Associated anomalies are absent. Intelligence is normal.

Genotype-Phenotype Correlations

Preliminary 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 mutations is characterized by significant involvement at the capital femoral epiphyses and irregular acetabuli [Unger et al 2001]. However, the recurrent p.Arg718Trp mutation in COMP appears to cause a mild form of the disorder, more consistent with MED caused by a type IX collagen gene mutation [Jakkula et al 2003].
• Type IX collagen defects result in more severe involvement of the knees and relative sparing of the hips.
• MATN3 mutations result in knee abnormalities that are similar to those in individuals with a COL9A2 mutation; the hip abnormalities are more severe (although not as severe as those in individuals with a COMP mutation) [Mortier et al 2001]. However, more intra- and interfamilial variability is evident in MED caused by MATN3 mutations. A mutation 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 mutations in MATN3 [Chapman et al 2001, Mortier et al 2001, Jackson et al 2004, Mäkitie et al 2004], in COL9A3 [Bonnemann et al 2000, Nakashima et al 2005], and in some instances, in COMP. These findings make the establishment of strong genotype-phenotype correlations in dominant MED less likely in the long term.

Penetrance

There is some evidence for reduced penetrance in MED caused by MATN3 mutations [Mortier et al 2001, Mäkitie et al 2004].

Anticipation

Anticipation is not observed.

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 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with multiple epiphyseal dysplasia (MED), the following evaluations are recommended:

• Elicitation of pain history
• Assessment of joint mobility
• Radiographs to determine the extent and severity of joint involvement

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 [Hunter 1998a, Hunter 1998b].

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 for access to 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 dominant MED have inherited the mutant allele from one parent.
• A proband with dominant MED may have the disorder as the result of a de novo gene mutation. The prevalence of de novo gene mutations is not known.
• When a diagnosis of MED is considered, it is sometimes worthwhile to evaluate both parents for signs of MED or early-onset osteoarthritis. If a disease-causing mutation has been identified in an affected family member, molecular genetic testing of the parents is possible.

Sibs of a proband

• The risk to sibs depends on the genetic status of the proband's parents.
• If a parent has dominant MED, the risk to each sib of the proband is 50%.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. However, a number of families in which one of the parents has germline mosaicism for a dominantly inherited mutation have been reported, resulting in a family history suggestive of autosomal recessive inheritance [Jackson et al 2004].

Offspring of a proband. Each child of an individual with dominant MED has a 50% chance of inheriting the mutation.

Other family members

• The risk to other family members depends on the status of the proband's parents.
• If a parent is affected, his or her family members are 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 mutation have been reported, resulting in a family history suggestive of autosomal recessive inheritance.

Testing of at-risk individuals during childhood. The testing of asymptomatic at-risk individuals younger than age 18 years is controversial. This testing can be justified only if it is believed that knowledge of the disease status of the child will influence care of that 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal 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 is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Molecular Genetic Pathogenesis

The five genes (COMP, COL9A1, COL9A2, COL9A3, and MATN3) in which mutations are known to cause dominant MED code for three structural macromolecules of the cartilage extracellular matrix (cartilage oligomeric matrix protein, type IX collagen, and matrilin-3) [Unger & Hecht 2001, Briggs & Chapman 2002]. These proteins have been shown to interact with each other and also 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].

Mutations in COMP exons encoding the type III repeats of COMP result in the misfolding of the protein and its retention in the rough endoplasmic reticulum (rER) of chondrocytes. This is thought to result in ER stress and an unfolded protein response (UPR), which ultimately causes increased cell death in vitro [Chen et al 2000, Maddox et al 2000, Unger & Hecht 2001, Kleerekoper et al 2002]. Over the last three years several transgenic mouse models of COMP mutations have been developed to study disease mechanisms in vivo [Schmitz et al 2008, Posey et al 2009]. Although these models all have the same PSACH-causing COMP mutation (i.e., p.Asp469del) they nonetheless provide some insight into the disease mechanisms of MED caused by similar COMP mutations. For example, mutant COMP is retained in the ER of chondrocytes causing premature cell death.

The effect of mutations in the exons encoding the C-terminal domain of COMP is not fully resolved, but these mutations are not thought to prevent the secretion of mutant COMP in vitro [Spitznagel et al 2004, Schmitz et al 2006]. The generation of a mouse model of MED-PSACH with a p.Thr585Met mutation in the C-terminal domain has provided novel insight into disease mechanisms in vivo. Mutant COMP protein is efficiently secreted from the rER of chondrocytes, but still elicits a classic unfolded protein response (UPR). This intimately results in decreased chondrocyte proliferation and increased and dysregulated apoptosis that is mediated by CHOP [Piróg -Garcia et al 2007]. More recently, a mild myopathy that originates from an underlying tendon and ligament pathology which is a direct result of structural abnormalities to the collagen fibril architecture has been demonstrated in this mouse model [Piróg & Briggs 2010, Piróg et al 2010].

The effect of MATN3 mutations appears similar to the effect caused by type III COMP mutations and results in the retention of mutant matrilin-3 in the rER of cells in vitro [Cotterill et al 2005, Otten et al 2005]. More recently the study of a mouse model of MED harboring the p.Val194Asp mutation has demonstrated that the expression of this mutation causes ER stress and an unfolded protein response (UPR). Ultimately this results in a reduction in chondrocyte proliferation and dysregulated apoptosis [Leighton et al 2007, Nundlall et al 2010].

The pathologic effect of mutations in COL9A1, COL9A2, and COL9A3 is not well understood and a number of mechanisms have been proposed for these mutations including the degradation of mRNA from the mutant allele [Holden et al 1999, Spayde et al 2000], an accumulation of abnormal type IX collagen α-chains in the rER of chondrocytes [Bonnemann et al 2000], and/or the degradation of abnormal α-chains [van Mourik et al 1998]. However, the remarkable clustering of all COL9A1, COL9A2 and COL9A3 MED mutations, which result in the in-frame deletion of equivalent regions of the COL3 domain of type IX collagen, led to the hypothesis that the deletion of these specific amino acids was a significant contributing factor to the development of the disease [Briggs & Chapman 2002]. Recent studies have confirmed that a COL9A3 mutation indeed abolishes binding of type IX collagen to matrilin-3 and type II collagen, thus identifying for the first time a molecular consequence of these mutations [Fresquet et al 2007].

Literature Cited

1. 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]
2. Belluoccio D, Schenker T, Baici A, Trueb B. Characterization of human matrilin-3 (MATN3). Genomics. 1998;53:391–4. [PubMed: 9799608]
3. 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]
4. Bonnemann 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. Cilliers HJ, Beighton P. Beukes familial hip dysplasia: an autosomal dominant entity. Am J Med Genet. 1990;36:386–90. [PubMed: 2389793]
11. 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]
12. 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]
13. Elsbach L. Bilateral hereditary micro-epiphysial dysplasia of the hips. J Bone Joint Surg Br. 1959;41-B:514–23. [PubMed: 13849708]
14. 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]
15. 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]
16. 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]
17. Holden P, Canty EG, Mortier GR, Zabel B, Spranger J, Carr A, Grant ME, Loughlin JA, Briggs MD. Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia. Am J Hum Genet. 1999;65:31–8. [PMC free article: PMC1378072] [PubMed: 10364514]
18. 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]
19. Hunter AG. Some psychological aspects of nonlethal chondrodysplasias: III. Self-esteem in children and adults. Am J Med Genet. 1998a;78:13–16. [PubMed: 9637416]
20. Hunter AG. Some psycholgical aspects of nonlethal chondrodysplasias: II. Depression and anxiety. Am J Med Genet. 1998b;78:9–12. [PubMed: 9637415]
21. 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]
22. 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]
23. 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]
24. Jakkula E, Makitie O, Czarny-Ratacjzak 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]
25. 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]
26. 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]
27. 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]
28. 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]
29. Loughlin J, Mustafa Z, Dowling B, Southam L, Marcelline L, Raina SS, Ala-Kokko L, Chapman K. Finer linkage mapping of a primary hip osteoarthritis susceptibility locus on chromosome 6. Eur J Hum Genet. 2002;10:562–8. [PubMed: 12173034]
30. 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]
31. Mabuchi A, Manabe N, Haga N, Kitoh H, Ikeda T, Kawaji H, Tamai K, Hamada J, Nakamura S, Brunetti-Pierri N, Kimizuka M, Takatori Y, Nakamura K, Nishimura G, Ohashi H, Ikegawa S. Novel types of COMP mutations and genotype-phenotype association in pseudoachondroplasia and multiple epiphyseal dysplasia. Hum Genet. 2003;112:84–90. [PubMed: 12483304]
32. 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]
33. 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]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. 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]
41. Odman P. Hereditary enchondral dysostosis; twelve cases in three generations mainly with peripheral location. Acta Radiol. 1959;52:97–113. [PubMed: 14428296]
42. 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]
43. 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]
44. 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]
45. 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]
46. 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]
47. 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]
48. 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]
49. 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]
50. Roby P, Eyre S, Worthington J, Ramesar R, Cilliers H, Beighton P, Grant M, Wallis G. Autosomal dominant (Beukes) premature degenerative osteoarthropathy of the hip joint maps to an 11-cM region on chromosome 4q35. Am J Hum Genet. 1999;64:904–8. [PMC free article: PMC1377811] [PubMed: 10053028]
51. 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]
52. 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]
53. 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]
54. Spayde EC, Joshi AP, Wilcox WR, Briggs M, Cohn DH, Olsen BR. Exon skipping mutation in the COL9A2 gene in a family with multiple epiphyseal dysplasia. Matrix Biol. 2000;19:121–8. [PubMed: 10842095]
55. 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]
56. Stefansson SE, Jonsson H, Ingvarsson T, Manolescu I, Jonsson HH, Olafsdottir G, Palsdottir E, Stefansdottir G, Sveinbjornsdottir G, Frigge ML, Kong A, Gulcher JR, Stefansson 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]
57. Superti-Furga A, Neumann L, Riebel T, Eich G, Steinmann B, Spranger J, Kunze J. Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation. J Med Genet. 1999;36:621–4. [PMC free article: PMC1762965] [PubMed: 10465113]
58. Superti-Furga A, Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A. 2007;143:1–18. [PubMed: 17120245]
59. 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]
60. Unger S, Hecht JT. Pseudoachondroplasia and multiple epiphyseal dysplasia: New etiologic developments. Am J Med Genet. 2001;106:244–50. [PubMed: 11891674]
61. 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]
62. van Mourik JB, Buma P, Wilcox WR. Electron microscopical study in multiple epiphyseal dysplasia type II. Ultrastruct Pathol. 1998;22:249–51. [PubMed: 9793205]
63. 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]
64. 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]
65. 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]

Author Notes

Web: European Skeletal Dysplasia Network (ESDN)

Revision History

• 1 February 2011 (me) Comprehensive update posted live
• 18 April 2007 (me) Comprehensive update posted to live Web site
• 24 January 2005 (me) Comprehensive update posted to live Web site
• 8 January 2003 (me) Review posted to live Web site
• 10 October 2002 (gm) Original submission