Alternative titles; symbols
SNOMEDCT: 254064009; ORPHA: 93279;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.11 | Osteoarthritis with mild chondrodysplasia | 604864 | Autosomal dominant | 3 | COL2A1 | 120140 |
A number sign (#) is used with this entry because of evidence that osteoarthritis with mild chondrodysplasia (OSCDP) is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13.
Knowlton et al. (1990) reported 10 members over 3 generations with primary osteoarthritis associated with mild chondrodysplasia. Onset of symptoms in the proband and 2 of his brothers began in the second or third decade of life and consisted of limited range of motion of the elbows. Over the next 20 years, the range of motion became limited in the metacarpophalangeal joints, proximal and distal interphalangeal joints, shoulders, hips, and knees. Physical examinations revealed bony enlargement of the metacarpophalangeal joints and the proximal and distal interphalangeal joints as well as limited range of motion of the joints. Their sister reported only intermittent discomfort in the lower back and limited range of motion of her hips. Their father, who had died at age 75 of pneumonia and heart failure, reportedly had a syndrome identical to his affected sons. No family member had signs of mental retardation, ocular disease, central nervous system disease, joint hypermobility, spontaneous fractures, or abnormalities of the internal organs. Radiographs of the father and 4 second-generation members revealed advanced degeneration of multiple peripheral weight-bearing and non-weight-bearing joints identical to the changes that occur in primary osteoarthritis. During a 3-year period, osteoarthritis of the hips was noted in the proband. Three of 4 affected members in the second generations had Heberden nodes. Two members of the third generation had early-onset osteoarthritis of the hips and metacarpal heads at the ages of 28 and 16 years. These 7 affected members and 3 other third-generation members (mean age, 16 years) had abnormalities of the vertebral bodies consistent with mild chondrodysplasia, including flattening of the vertebral bodies, irregular end plates, herniations within the vertebral bodies (Schmorl nodes), and anterior wedging.
Beighton et al. (1984) described a skeletal disorder in 45 persons in 5 generations of a kindred of mixed ancestry in Namaqualand, South Africa. Discomfort in the hips developed in childhood and the course was progressive, with handicap in middle age. General health was good, height was not significantly reduced, and no extraskeletal involvement was identified. The major changes occurred in the femoral capital epiphyses, which were flattened and fragmented; secondary degenerative arthropathy developed at a later stage. Platyspondyly of variable but mild degree was present in about 60% of affected persons. Other minor changes, including iliac exostoses, were present in some. The pedigree findings indicate autosomal dominant inheritance. Beighton et al. (1984) designated the disorder 'Namaqualand hip dysplasia.' Learmonth et al. (1987) pointed out that the maximal changes in the femoral capital epiphyses lead to severe progressive degenerative osteoarthropathy of the hip joint that frequently necessitates prosthetic joint replacement in adulthood.
The transmission pattern of osteoarthritis with mild chondrodysplasia in the family reported by Knowlton et al. (1990) was consistent with autosomal dominant inheritance.
In Finland, early-onset osteoarthrosis is relatively frequent and seems to run in certain families in an autosomal dominant pedigree pattern. In a large Finnish family in which members in at least 5 generations had early-onset osteoarthrosis, Vaisanen et al. (1987) found linkage with 2 RFLPs of the type II collagen locus on chromosome 12. The lod score was 1.7 with 1 marker and 1.4 with a second, both at theta = 0.0. Palotie et al. (1989) extended these observations, reporting a maximum lod score of 3.20 at theta = 0.0 in 2 families.
In a 3-generation family segregating autosomal dominant osteoarthritis with mild chondrodysplasia, Knowlton et al. (1990) found linkage of the disorder to the COL2A1 locus with a maximal lod score of 2.39 in multipoint analysis.
By linkage analysis in the family with Namaqualand hip dysplasia reported by Beighton et al. (1984), Sher et al. (1991) found close linkage with the COL2A1 gene with no recombination (lod = 7.98).
In a kindred described by Knowlton et al. (1990) with dominantly inherited generalized osteoarthritis associated with a mild chondrodysplasia, Ala-Kokko et al. (1990) identified an arg519-to-cys mutation of the type II collagen gene (R519C; 120140.0003).
Holderbaum et al. (1993) referred to 2 additional families with precocious-onset osteoarthritis and mild chondrodysplasia caused by the R519C mutation in the COL2A1 gene. They reported studies suggesting that the mutation arose independently in at least 2 of the 3 known affected families.
Williams et al. (1995) found the R519C mutation in a fourth family with early-onset osteoarthritis and late-onset spondyloepiphyseal dysplasia.
Ala-Kokko, L., Baldwin, C. T., Moskowitz, R. W., Prockop, D. J. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc. Nat. Acad. Sci. 87: 6565-6568, 1990. [PubMed: 1975693] [Full Text: https://doi.org/10.1073/pnas.87.17.6565]
Beighton, P., Christy, G., Learmonth, I. D. Namaqualand hip dysplasia: an autosomal dominant entity. Am. J. Med. Genet. 19: 161-169, 1984. [PubMed: 6496567] [Full Text: https://doi.org/10.1002/ajmg.1320190116]
Holderbaum, D., Malemud, C. J., Moskowitz, R. W., Haqqi, T. M. Human cartilage from late stage familial osteoarthritis transcribes type II collagen mRNA encoding a cysteine in position 519. Biochem. Biophys. Res. Commun. 192: 1169-1174, 1993. [PubMed: 8507190] [Full Text: https://doi.org/10.1006/bbrc.1993.1539]
Knowlton, R. G., Katzenstein, P. L., Moskowitz, R. W., Weaver, E. J., Malemud, C. J., Pathria, M. N., Jimenez, S. A., Prockop, D. J. Genetic linkage of a polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia. New Eng. J. Med. 322: 526-530, 1990. [PubMed: 2300123] [Full Text: https://doi.org/10.1056/NEJM199002223220807]
Learmonth, I. D., Christy, G., Beighton, P. Namaqualand hip dysplasia: orthopaedic implications. Clin. Orthop. 218: 142-147, 1987.
Palotie, A., Vaisanen, P., Ott, J., Ryhanen, L., Vikkula, M., Cheah, K. S. E., Vuorio, E., Peltonen, L. Predisposition to familial osteoarthrosis is linked to type II collagen gene. (Abstract) Cytogenet. Cell Genet. 51: 1058 only, 1989.
Sher, C., Ramesar, R., Martell, R., Learmonth, I., Tsipouras, P., Beighton, P. Mild spondyloepiphyseal dysplasia (Namaqualand type): genetic linkage to the type II collagen gene (COL2A1). Am. J. Hum. Genet. 48: 518-524, 1991. [PubMed: 1671807]
Vaisanen, P., Palotie, A., Ott, J., Peltonen, L. RFLP studies of type II collagen gene for finding the possible linkage between the gene and osteoarthrosis (OA). (Abstract) Cytogenet. Cell Genet. 46: 707 only, 1987.
Williams, C. J., Rock, M., Considine, E., McCarron, S., Gow, P., Ladda, R., McLain, D., Michels, V. M., Murphy, W., Prockop, D. J., Ganguly, A. Three new point mutations in type II procollagen (COL2A1) and identification of a fourth family with the COL2A1 arg519-to-cys base substitution using conformation sensitive gel electrophoresis. Hum. Molec. Genet. 4: 309-312, 1995. [PubMed: 7757086] [Full Text: https://doi.org/10.1093/hmg/4.2.309]