Alternative titles; symbols
SNOMEDCT: 254065005; ORPHA: 1159; DO: 0090004;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q21 | Progressive pseudorheumatoid dysplasia | 208230 | Autosomal recessive | 3 | CCN6 | 603400 |
A number sign (#) is used with this entry because of evidence that progressive pseudorheumatoid dysplasia (PPRD) is caused by homozygous or compound heterozygous mutation in the WISP3 gene (CCN6; 603400) on chromosome 6q21.
Progressive pseudorheumatoid dysplasia (PPRD) is an autosomal recessive skeletal dysplasia with radiographic changes similar to those of spondyloepiphyseal dysplasia tarda, and clinical, but not radiographic, resemblance to rheumatoid arthritis. It is a progressive chondropathy affecting primarily the articular cartilage with characteristic skeletal abnormalities notably in the spine (summary by El-Shanti et al., 1997). Signs and symptoms, typically consisting of stiffness and swelling of joints, motor weakness, and joint contractures, usually develop between 3 and 8 years of age (summary by Hurvitz et al., 1999).
Spranger et al. (1983) described an arthropathy of childhood beginning at about age 3 years with progressive joint stiffness that first affects the hips. Morning stiffness and decreased mobility of the cervical spine suggest rheumatoid arthritis. Swelling of the finger joints is caused not by soft tissue involvement but by osseous distention of the ends of the phalanges. Normal sedimentation rate, negative rheumatoid factor tests, and histologically normal synovium exclude rheumatoid disease. Furthermore, radiologic changes indicate bone dysplasia: the vertebral bodies are flattened with anterior ossification defects; the acetabular portion of the pelvis is abnormal, and the ends of the proximal and middle phalanges are expanded. The articular space may be narrow, but destructive bone changes characteristic of rheumatoid arthritis are not present. The diagnosis of 'rheumatoid arthritis with Scheuermann disease' is often rendered. Adults with PPRD are somewhat short (140 to 150 cm). Lack of response to antirheumatic drugs is characteristic. Histologic studies (Spranger et al., 1983) showed a peculiar nest-like clustering of chondrocytes in resting and growth cartilage, suggesting that this is a primary disorder of articular cartilage.
According to Wynne-Davies et al. (1982), who referred to the condition as spondyloepiphyseal dysplasia tarda with progressive arthropathy, the disorder has a striking clinical, though not radiologic, resemblance to rheumatoid arthritis but has the additional feature of platyspondyly. The 15 patients they studied were distributed in 9 families, of which 4 were Arab. All were considered normal for the first few years of life. In all but 1, joint symptoms began between ages 3 and 8 years. Usually several joints were affected with pain and soft tissue swelling. The proximal interphalangeal joints of the hand were most commonly affected and the hips and elbows next most often involved. Cystic swellings were present on the back of the hands in 2 and over the hallux in 1. Although juvenile rheumatoid arthritis was suggested by the symptoms, none had overt synovitis or elevation of erythrocyte sedimentation rate or acute-phase reactant proteins. Adult height ranged from 1.36 to 1.56 meters. Wynne-Davies et al. (1982) suggested that the same disorder may have been present in a case reported by Maroteaux (1974). This may be the condition called syndesmodysplasic dwarfism by Laplane et al. (1972); see 272450.
Perri (1981) described the main radiologic features of this disorder.
Kaibara et al. (1983) reported 3 Japanese families with this disorder.
Al-Awadi et al. (1984) reported a large family with 8 affected persons.
Legius et al. (1993) described 2 brothers and a sister with this disorder. Stiffness and restricted mobility of several large joints had been present since childhood. Their adult height was normal, and skeletal radiography showed mild platyspondyly, abnormal epiphyses, and severe osteoarthrosis with extensive synovial osteochondromatosis.
El-Shanti et al. (1997) reviewed the clinical and radiologic features of PPRD and reported 6 additional patients. One of these patients had undergone bone biopsy from the iliac crest that showed abnormal nesting of chondrocytes in both resting and proliferative cartilage embedded in material that stained deeply with PAS-alcian blue and toluidin blue. There was defective columnization of cells in growth zones, but normal osteoid formation. The chondrocytes had large Golgi bodies, intracytoplasmic vesicles, and dilated endoplasmic reticular cisterns. The collagen fibers were kinky and of variable thickness. El-Shanti et al. (1997) suggested the addition of the term 'spondyloepiphyseal' to the name of this condition to describe comprehensively the pathology of the disease.
Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations had not been reported in this disorder. Cartilage appears to be the primary affected tissue, and in 1 patient studied by Spranger et al. (1983), a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones (Hurvitz et al., 1999).
Wynne-Davies et al. (1982) estimated a frequency of 1 per million in the U.K., but the disorder is likely to be higher in the Middle East and Gulf states (Teebi and Al-Awadi, 1986).
Wynne-Davies et al. (1982) stated that parental consanguinity and multiple affected brothers and sisters with PPRD pointed to autosomal recessive inheritance.
By the DNA pooling approach to homozygosity mapping, El-Shanti et al. (1997, 1998) mapped the PPRD locus to 6q in an affected inbred family from Jordan. The mapping made COL10A1 (120110) a candidate gene, but no mutation was found within the coding sequence of the gene in the family.
By linkage analysis of 3 families of different geographic and ethnic origin that included 11 individuals with PPRD, Fischer et al. (1998) showed localization to a 3-cM interval of 6q22 between D6S1594 and D6S432. No significant shared haplotype was found for markers of the linked interval in the 3 families analyzed.
Using a positional candidate approach, Hurvitz et al. (1999) examined the WISP3 gene, which maps to the same region of 6q, and in unrelated individuals with PPRD and identified 9 different mutations (603400.0001-603400.0009), indicating that the WISP3 gene is essential for normal postnatal skeletal growth and cartilage homeostasis.
Al-Awadi, S. A., Farag, T. I., Naguib, K., El-Khalifa, M. Y., Cuschieri, A., Hosny, G., Zahran, M., Al-Ansari, A. G. Spondyloepiphyseal dysplasia tarda with progressive arthropathy. J. Med. Genet. 21: 193-196, 1984. [PubMed: 6431106] [Full Text: https://doi.org/10.1136/jmg.21.3.193]
El-Shanti, H. E., Omari, H. Z., Qubain, H. I. Progressive pseudorheumatoid dysplasia: report of a family and review. J. Med. Genet. 34: 559-563, 1997. [PubMed: 9222963] [Full Text: https://doi.org/10.1136/jmg.34.7.559]
El-Shanti, H., Murray, J. C., Semina, E. V., Beutow, K. H., Scherpbier, T., Al-Alami, J. Assignment of gene responsible for progressive pseudorheumatoid dysplasia to chromosome 6 and examination of COL10A1 as candidate gene. Europ. J. Hum. Genet. 6: 251-256, 1998. [PubMed: 9781029] [Full Text: https://doi.org/10.1038/sj.ejhg.5200187]
El-Shanti, H., Murray, J., Semina, E., Beutow, K., Scherpbier, T., Al-Alami, J., Al-Khatib, A. The assignment of the gene responsible for progressive pseudorheumatoid dysplasia to the long arm of chromosome six and examination of COL10A1 as a candidate gene. (Abstract) Am. J. Hum. Genet. 61 (suppl.): A274 only, 1997.
Fischer, J., Urtizberea, J. A., Pavek, S., Vandiedonck, C., Bruls, T., Saker, S., Alkatip, Y., Prud'homme, J.-F., Weissenbach, J. Genetic linkage of progressive pseudorheumatoid dysplasia to a 3-cM interval of chromosome 6q22. Hum. Genet. 103: 60-64, 1998. [PubMed: 9737778] [Full Text: https://doi.org/10.1007/s004390050784]
Hurvitz, J. R., Suwairi, W. M., Van Hul, W., El-Shanti, H., Superti-Furga, A., Roudier, J., Holderbaum, D., Pauli, R. M., Herd, J. K., Van Hul, E., Rezai-Delui, H., Legius, E., Le Merrer, M., Al-Alami, J., Bahabri, S. A., Warman, M. L. Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia. Nature Genet. 23: 94-98, 1999. [PubMed: 10471507] [Full Text: https://doi.org/10.1038/12699]
Kaibara, N., Takagishi, K., Katsuki, I., Eguchi, M., Masumi, S., Nishio, A. Spondyloepiphyseal dysplasia tarda with progressive arthropathy. Skeletal Radiol. 10: 13-16, 1983. [PubMed: 6410512] [Full Text: https://doi.org/10.1007/BF00355384]
Laplane, R., Fontaine, J.-L., Lagardere, B., Sambury, F. Nanisme syndesmodysplasique familial: une entite morbide nouvelle. Arch. Franc. Pediat. 29: 831-838, 1972. [PubMed: 4657332]
Legius, E., Mulier, M., Van Damme, B., Fryns, J. P. Progressive pseudorheumatoid arthritis of childhood (PPAC) and normal adult height. Clin. Genet. 44: 152-155, 1993. [PubMed: 8275575] [Full Text: https://doi.org/10.1111/j.1399-0004.1993.tb03868.x]
Maroteaux, P. Les Maladies Osseuses de l'Enfant. Paris: Flammarion Medecin-Sciences (pub.) 1974. Pp. 96-98.
Perri, G. The radiological features of a new bone dysplasia. Pediat. Radiol. 11: 109-113, 1981. [PubMed: 7301445] [Full Text: https://doi.org/10.1007/BF00971792]
Spranger, J., Albert, C., Schilling, F., Bartsocas, C., Stoss, H. Progressive pseudorheumatoid arthritis of childhood (PPAC): a hereditary disorder simulating rheumatoid arthritis. Europ. J. Pediat. 140: 34-40, 1983. [PubMed: 6873109] [Full Text: https://doi.org/10.1007/BF00661902]
Spranger, J., Albert, C., Schilling, F., Bartsocas, C. Progressive pseudorheumatoid arthropathy of childhood (PPAC): a hereditary disorder simulating juvenile rheumatoid arthritis. (Letter) Am. J. Med. Genet. 14: 399-401, 1983. [PubMed: 6837637] [Full Text: https://doi.org/10.1002/ajmg.1320140224]
Teebi, A. S., Al-Awadi, S. A. Spondyloepiphyseal dysplasia tarda with progressive arthropathy: a rare disorder frequently diagnosed among Arabs. (Letter) J. Med. Genet. 23: 189-191, 1986. [PubMed: 3712405] [Full Text: https://doi.org/10.1136/jmg.23.2.189-a]
Wynne-Davies, R., Hall, C., Ansell, B. M. Spondylo-epiphyseal dysplasia tarda with progressive arthropathy: a 'new' disorder of autosomal recessive inheritance. J. Bone Joint Surg. Br. 64: 442-445, 1982. [PubMed: 6807993] [Full Text: https://doi.org/10.1302/0301-620X.64B4.6807993]