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Other entities represented in this entry:
SNOMEDCT: 715673002; ORPHA: 93308; DO: 0070303;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 19p13.11 | Epiphyseal dysplasia, multiple, 1 | 132400 | Autosomal dominant | 3 | COMP | 600310 |
A number sign (#) is used with this entry because of evidence that multiple epiphyseal dysplasia-1 (EDM1) is caused by heterozygous mutation in the gene encoding cartilage oligomeric matrix protein (COMP; 600310) on chromosome 19p13.
Mutation in the COMP gene can also cause the more severe disorder pseudoachondroplasia (PSACH; 177170).
Multiple epiphyseal dysplasia is a skeletal disorder characterized by short stature and early-onset osteoarthrosis (Briggs et al., 1995).
Genetic Heterogeneity of Multiple Epiphyseal Dysplasia
Multiple epiphyseal dysplasia is a genetically heterogeneous disorder. See also EDM2 (600204), caused by mutation in the COL9A2 gene (120260); EDM3 (600969), caused by mutation in the COL9A3 gene (120270); EDM4 (226900), caused by mutation in the DTDST gene (606718); EDM5 (607078), caused by mutation in the MATN3 gene (602109); EDM6 (614135), caused by mutation in the COL9A1 gene (120210); and EDM7 (617719), caused by mutation in the CANT1 gene (613165).
Severe osteoarthritis of the hips develops in early adulthood. The diagnosis in the adult is aided by the changes in the distal tibia (Leeds, 1960). A deficiency in the lateral part of the distal tibial ossification center seen in children results in a sloping end of the tibia in adulthood. Short stature and brachydactyly are features. Considerable heterogeneity undoubtedly exists within this category. Chondrodystrophia calcificans congenita is a congenital form of multiple epiphyseal dysplasia (215100). Bachman (1967) described a 47-year-old woman, height 61.5 inches, with marked hyperextensibility of fingers and precocious osteoarthritis of the hips. A son and a daughter had very flexible fingers and, by hand x-ray, delay in carpal ossification, proximal pseudoepiphyses of metacarpals 2-5, cone-cup epiphyses-metaphyses, and widened joint spaces. Other joints showed extensive changes with widening of joint spaces and irregular epiphyses. The mother's mother, aunt, uncle, and cousin had hyperextensibility of the fingers and premature osteoarthritis. These authors referred to the condition as peripheral dysostosis but it seems different from the peripheral dysostosis (170700) described by Singleton et al. (1960); the term 'peripheral' seems inappropriate, and the description suggests what others would call Fairbank multiple epiphyseal dysplasia. (See 105835 for another interpretation of the family reported by Bachman (1967).)
Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank (Fairbank, 1945) and milder Ribbing (Ribbing, 1937) types. Fairbank multiple epiphyseal dysplasia is probably the same as that described as enchondral dysostosis by Odman (1959). Hulvey and Keats (1969) commented on the variability in the extent of spinal involvement and presented a family in which many members had severe peripheral involvement with no spinal involvement. The dividing line between multiple epiphyseal dysplasia and spondyloepiphyseal dysplasia tarda (see 313400) can be indistinct, as evidenced by the family reported by Diamond (1970)--see 184100.
Wynne-Davies et al. (1985) stated that the wrists and hands are often normal in the mild, or Ribbing, type, whereas they are short and stubby in the severe Fairbank type.
Villarreal et al. (1992) described a form of epiphyseal dysplasia in a mother and 5 of her 10 children. A distinctive feature was unusually short hands and feet and particularly a short fourth metatarsal bone. Round face was also described. Curiously, the height of the affected individuals was not given.
Stanescu et al. (1993) performed morphologic and biochemical studies on the upper tibial cartilage from a case of multiple epiphyseal dysplasia of the Fairbank type. They concluded that the changes are similar to those described in pseudoachondroplasia (e.g., 177170) by Stanescu et al. (1982, 1984). However, the inclusions were smaller and the growth cartilage much less disorganized in MED. The similarities between the 2 disorders suggested that they have a similar pathogenesis.
The transmission pattern of EDM1 in the family reported by Ballo et al. (1997) was consistent with autosomal dominant inheritance.
Genetic diagnosis of the COMP-related skeletal dysplasias pseudoachondroplasia and multiple epiphyseal dysplasia is difficult because COMP mutations are scattered throughout the gene and 5 additional disease genes for multiple epiphyseal dysplasia exist. Mabuchi et al. (2004) presented evidence that plasma COMP levels are significantly decreased in patients with COMP mutations compared with controls (p less than 0.0001). In addition, plasma COMP levels were significantly decreased in MED patients carrying mutations in COMP relative to those who lacked COMP mutations (p = 0.001). These results indicated that measuring the level of circulating COMP may be an easier, more rapid, and cost-efficient method for diagnosing PSACH and particularly for diagnosing MED.
By demonstrating discordant inheritance of restriction fragment length polymorphisms (RFLPs) and MED in an extensively affected kindred, Weaver et al. (1993) excluded the gene for type II (120140) collagen and the genes for the 3 chains of type VI (120220, 120240, 120250) collagen as the site of the mutation. By linkage studies, Oehlmann et al. (1993) also excluded the COL9A1 gene (120210), which maps to 6q13, and the CRTL1 gene (HAPLN1; 115435), which maps to 5q13. However, linkage to DNA markers suggested location of the gene close to the centromere of chromosome 19. The highest lod score was observed for D19S199; maximum lod = 4.67 at theta = 0.09. Oehlmann et al. (1994) later reported a maximum lod score of 6.37 at theta = 0.05 for linkage with D19S215. Multipoint linkage analysis indicated that MED was located between D19S212 and D19S215, a map interval of 1.7 cM. The gene for pseudoachondroplastic dysplasia (177170) has been mapped to the pericentric region of chromosome 19; this finding, combined with the morphologic similarity between pseudoachondroplasia and MED, mentioned earlier, again raised the possibility of allelism of the 2 disorders.
Deere et al. (1995) confirmed the linkage of autosomal dominant multiple epiphyseal dysplasia to D19S212; maximum lod = 3.22 at theta = 0.00. In a family in which 3 of 7 sibs were affected and the parents were unaffected, they excluded linkage to chromosome 19 (using both autosomal recessive and autosomal dominant models, with either reduced penetrance or germline mosaicism considered). Linkage to candidate genes COL9A1, COL9A2 (120260), and COL11A2 (120290) was tested and excluded for both genetic models in the latter family. COL11A1 (120280) was also excluded under a recessive model.
The EDM1/PSACH locus had been found to be flanked by D19S212 and D19S215. These 2 markers had been localized in the chromosome 19 physical map consisting of cosmid contigs ordered by high-resolution fluorescence in situ hybridization. These 2 markers defined an interval of approximately 3.1 Mb at the 19p13.1-p12 boundary. With as many as 5 informative crossovers in 1 family with EDM1 and 1 family with a mild form of PSACH, Knowlton et al. (1995) did recombination mapping at greater resolution. From cosmid contigs physically mapped within the D19S12/D19S215 interval, they found 4 new dinucleotide repeat polymorphisms. Analysis of recombinant haplotypes in the 2 families narrowed the possible location of the EDM1/PSACH gene to an interval of approximately 600 kb.
As outlined by Hecht et al. (1995) and by Briggs et al. (1995), it is generally agreed that the EDM1 and PSACH loci are in the centromeric region of 19p, 19p13.1-p12. Furthermore, the gene for cartilage oligomeric matrix protein (COMP; 600310) maps to the same region. Both Hecht et al. (1995) and Briggs et al. (1995) demonstrated mutations in the COMP gene in pseudoachondroplasia (e.g., 600310.0001) and Briggs et al. (1995) demonstrated a mutation in the COMP gene in a patient with multiple epiphyseal dysplasia (see 600310.0005).
Ballo et al. (1997) studied mild MED in a South African kindred and demonstrated heterozygosity for an asn523-to-lys amino acid substitution in the COMP protein (600310.0008).
In a 15-year-old girl with a severe form of EDM (family R94-344), Briggs et al. (1998) identified a missense mutation in the COMP gene (N453S; 600310.0009).
In the proband from a multigenerational family with EDM, Delot et al. (1999) identified heterozygosity for expansion of the short (GAC)5 repeat in the COMP gene (600310.0012).
In a patient with a mild form of EDM, Mabuchi et al. (2003) identified heterozygosity for a 1-bp insertion in the COMP gene (600310.0016). Affected members of the family showed involvement of hip and knee joints, but had normal stature.
In affected members of a large 4-generation family (family 2) segregating MED with carpal tunnel syndrome (see CTS2, 619161), Li et al. (2020) identified heterozygosity for the recurrent R718W mutation in the COMP gene (600310.0017).
Jakkula et al. (2003) found a heterozygous mutation in the COMP gene (600310.0017) in patients with muscle weakness, moderate creatine kinase elevation, and MED beginning with the knee joints, uncovering a clinical and radiologic overlap with MED caused by mutation in the collagen IX genes (see 600204 and 600969).
Reviews
Jackson et al. (2012) conducted a 7-year study (2003-2007) of 130 patients with pseudoachondroplasia or suspected multiple epiphyseal dysplasia and provided a detailed review of the clinical diagnoses and molecular findings in these patients compared to previously reported patients. The authors noted that whereas PSACH was relatively straightforward to diagnose based on clinical and radiographic information, the more subtle and variable radiographic signs of MED make that diagnosis more difficult. In contrast to previous studies suggesting that mutations in the known genes are not the major cause of MED, Jackson et al. (2012) concluded that mutations in COMP, MATN3, and type IX collagen genes account for the vast majority of classic autosomal dominant MED.
In 29 consecutive MED patients, Jakkula et al. (2005) found a DTDST mutation in 4 (14%), a COMP mutation in 3 (10%), and an MATN3 mutation in 3 (10%). Disease-causing mutations were identified in only 10 patients (34%). Jakkula et al. (2005) concluded that mutations in the known genes are not the major cause of MED and are responsible for less than half of the cases. Jakkula et al. (2005) described 2 distinct phenotypic entities in patients with MED but no observed mutations. Severe early-onset dysplasia of the proximal femurs with almost complete absence of the secondary ossification centers and abnormal development of the femoral necks was found in 3 patients (609324). Two patients had strikingly small secondary ossification centers ('mini-epiphyses') in all joints, resulting in severe dysplasia of the proximal femoral heads (609325).
PSACH and EDM1 patients often have a mild myopathy characterized by mildly increased plasma creatine kinase levels, a variation in myofiber size and/or small atrophic fibers. Pirog et al. (2010) studied skeletal muscle, tendon, and ligament in a mouse model of mild PSACH harboring a T585M mutation. T585M-mutant mice exhibited a progressive muscle weakness associated with an increased number of muscle fibers with central nuclei at the perimysium and at the myotendinous junction. Collagen fibril diameters in the mutant tendons and ligaments were thicker, and tendons became more lax in cyclic strain tests. Pirog et al. (2010) hypothesized that the myopathy in PSACH-MED may originate from underlying tendon and ligament pathology that may be a direct result of abnormalities in collagen fibril architecture.
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