SNOMEDCT: 53974002; ORPHA: 485; DO: 0080045;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.11 | Kniest dysplasia | 156550 | Autosomal dominant | 3 | COL2A1 | 120140 |
A number sign (#) is used with this entry because of evidence that Kniest dysplasia is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13.
Kniest dysplasia is characterized by skeletal and craniofacial anomalies. Skeletal anomalies include disproportionate dwarfism, a short trunk and small pelvis, kyphoscoliosis, short limbs, and prominent joints and premature osteoarthritis that restrict movement. Craniofacial manifestations include midface hypoplasia, cleft palate, early-onset myopia, retinal detachment, and hearing loss. The phenotype is severe in some patients and mild in others. There are distinct radiographic changes including coronal clefts of vertebrae and dumbbell-shaped femora. The chondrooseous morphology is pathognomonic with perilacunar 'foaminess' and sparse, aggregated collagen fibrils resulting in an interterritorial matrix with a 'Swiss-cheese' appearance (summary by Wilkin et al., 1999).
Siggers et al. (1974) reported 8 patients with Kniest dysplasia. Two were identical twins; the other cases were sporadic. All of the patients had short stature, round face with central depression, prominent eyes, enlargement and stiffness of joints, contractures of fingers, normal head circumference, bell-shaped chest, and myopia. Cleft palate was present in 5, deafness in 6, retinal detachment in 3. Cartilage obtained by biopsy felt soft. Histology showed lacunae in the cartilage, giving it a Swiss-cheese appearance. Electron microscopy showed abnormality of the collagen of cartilage. The patients cannot make a tight fist, seemingly because of thin joint spaces, and have a violaceous hue of the palms. Siggers et al. (1974) cited cases in mother and daughter known to Dr. J. Spranger of Kiel. The mean paternal age of the 8 cases was 28.5 years.
Kim et al. (1975) described affected mother and daughter. Excessive urinary excretion of keratan sulfate was noted. The daughter had myopia and chorioretinal thinning. The mother had cataracts and myopia.
Stanescu et al. (1976) suggested that an abnormal proteoglycan is synthesized in this disease. Horton and Rimoin (1979) described chondrocyte inclusions.
Friede et al. (1985) confirmed the high excretion of keratan sulfate in the urine. Characteristic craniofacial changes were described. There was macrocephaly with increased size of the neurocranium in all 3 dimensions. The odontoid process was short and wide. At 11 years of age in the patient most extensively studied, there was bony fusion between the anterior arch of the atlas and the odontoid and between the posterior arch of the atlas and the cranial base.
In all of 7 patients with Kniest dysplasia, Maumenee and Traboulsi (1985) found congenital severe myopia and vitreoretinal degeneration. Rhegmatogenous retinal detachment developed in 4 of them. Other ocular findings included cataract in 2, dislocated lenses in 1, and blepharoptosis in 1.
Sayli and Brooker (1989) reported hip replacement in a 26-year-old woman with successful relief of pain and functional improvement.
Gilbert-Barnes et al. (1996) reviewed the radiologic, histopathologic, and spanning electron microscopic findings in Kniest dysplasia.
Poole et al. (1988) studied epiphyseal cartilages from 4 cases of Kniest dysplasia and demonstrated abnormality of collagen fibril organization by electron microscopy in each. Fibrils were much thinner than normal and were irregular in shape, without the characteristic banding pattern. Furthermore, chondrocalcin was found to be absent from the extracellular matrix of epiphyseal cartilages and to be abnormally concentrated in intracellular vacuolar sites where it was not part of the procollagen molecule. Type II collagen alpha chain size was normal, indicating the formation of a triple helix; the content of type II collagen was also normal. Poole et al. (1988) believed these observations indicated that the defect in Kniest dysplasia results from the secretion of type II procollagen lacking the C-propeptide and abnormal fibril formation, and that the C-propeptide is normally required for fibril formation.
The transmission pattern of Kniest dysplasia in the families reported by Winterpacht et al. (1993) and Spranger et al. (1994) was consistent with autosomal dominant inheritance.
Winterpacht et al. (1993) and Spranger et al. (1994) described heterozygous COL2A1 mutations in patients with Kniest dysplasia. The patient described by Winterpacht et al. (1993) had a 28-bp deletion involving exon 12 and intron 12 in the COL2A1 gene (120140.0012). The patient described by Spranger et al. (1994) had a splice site mutation in exon 20. In each case, 1 parent was a somatic mosaic for the same mutation as seen in their children and was significantly more mildly affected. Wilkin et al. (1994) reported a single amino acid substitution in the triple helical domain of COL2A1 (120140.0020) resulting in Kniest dysplasia.
Wilkin et al. (1999) pointed out that all but 2 of the previously described Kniest dysplasia mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but 1 of these mutations were located between exons 12 and 24 in the COL2A1 gene. Wilkin et al. (1999) used heteroduplex analysis to identify sequence anomalies in 5 individuals with Kniest dysplasia. Sequencing of the genomic DNA in each index patient identified 4 new dominant mutations in COL2A1 that resulted in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth patient. The latter 3 mutations were predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggested that Kniest dysplasia results from shorter type II collagen monomers, and supported the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.
Spranger et al. (1997) described, with a photograph, Dr. Wilhelm Kniest and the patient he described in 1952. At the time of the report, Kniest was chief resident of the Children's Hospital of the University of Jena in Thuringia. At the time of the report by Spranger et al. (1997), his patient was aged 50 years and severely handicapped with short stature, restricted joint mobility, and blindness, but was mentally alert and leading an active life. Molecular analysis of the patient's DNA showed a single base (G) deletion involving the GT dinucleotide at the start of intron 18 destroying a splice site of the COL2A1 gene (120140.0025).
Chen, H., Yang, S. S., Gonzalez, E. Kniest dysplasia: neonatal death with necropsy. Am. J. Med. Genet. 6: 171-178, 1980. [PubMed: 7446563] [Full Text: https://doi.org/10.1002/ajmg.1320060211]
Frayha, R., Melhem, R., Idriss, H. The Kniest (Swiss cheese cartilage) syndrome: description of a distinct arthropathy. Arthritis Rheum. 22: 286-289, 1979. [PubMed: 420720] [Full Text: https://doi.org/10.1002/art.1780220312]
Friede, H., Matalon, R., Harris, V., Rosenthal, I. M. Craniofacial and mucopolysaccharide abnormalities in Kniest dysplasia. J. Craniofac. Genet. Dev. Biol. 5: 267-276, 1985. [PubMed: 2931448]
Gilbert-Barnes, E., Langer, L. O., Jr., Opitz, J. M., Laxova, R., Sotelo-Arila, C. Kniest dysplasia: radiologic, histopathological, and scanning electronmicroscopic findings. Am. J. Med. Genet. 63: 34-45, 1996. [PubMed: 8723084] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960503)63:1<34::AID-AJMG9>3.0.CO;2-S]
Horton, W. A., Rimoin, D. L. Kniest dysplasia: a histochemical study of the growth plate. Pediat. Res. 13: 1266-1270, 1979. [PubMed: 514691] [Full Text: https://doi.org/10.1203/00006450-197911000-00012]
Kim, H. J., Beratis, N. G., Brill, P., Raab, E., Hirschhorn, K., Matalon, R. Kniest syndrome with dominant inheritance and mucopolysacchariduria. Am. J. Hum. Genet. 27: 755-764, 1975. [PubMed: 128291]
Kniest, W. Zur Abgrenzung der Dysostosis enchondralis von der Chondrodystrophie. Z. Kinderheilkd. 70: 633-640, 1952. [PubMed: 12995812]
Maumenee, I. H., Traboulsi, E. I. The ocular findings in Kniest dysplasia. Am. J. Ophthal. 100: 155-160, 1985. [PubMed: 4014370] [Full Text: https://doi.org/10.1016/s0002-9394(14)74998-0]
Poole, A. R., Pidoux, I., Reiner, A., Rosenberg, L., Hollister, D., Murray, L., Rimoin, D. Kniest dysplasia: a defect in the processing of the type II collagen C-propeptide. (Abstract) Clin. Res. 35: 650A only, 1987.
Poole, A. R., Pidoux, I., Reiner, A., Rosenberg, L., Hollister, D., Murray, L., Rimoin, D. Kniest dysplasia is characterized by an apparent abnormal processing of the C-propeptide of type II cartilage collagen resulting in imperfect fibril assembly. J. Clin. Invest. 81: 579-589, 1988. [PubMed: 3276736] [Full Text: https://doi.org/10.1172/JCI113356]
Sayli, U., Brooker, A. F., Jr. Kniest disease and total joint replacement for functional salvage. Adv. Orthop. Surg. 13: 85-87, 1989.
Siggers, D. C., Rimoin, D. L., Dorst, J. P., Doty, S. B., Williams, B. R., Hollister, D. W., Silberberg, R., Granley, R. E., Kaufman, R. L., McKusick, V. A. The Kniest syndrome. Birth Defects Orig. Art. Ser. 10(9): 193-208, 1974. [PubMed: 4214536]
Spranger, J., Menger, H., Mundlos, S., Winterpacht, A., Zabel, R. Kniest dysplasia is caused by dominant collagen TT (COL2A1) mutations: parental somatic mosaicism manifesting as Stickler phenotype and mild spondyloepiphyseal dysplasia. Pediat. Radiol. 24: 431-435, 1994. [PubMed: 7700721] [Full Text: https://doi.org/10.1007/BF02011911]
Spranger, J., Winterpacht, A., Zabel, B. Kniest dysplasia: Dr. W. Kniest, his patient, the molecular defect. Am. J. Med. Genet. 69: 79-84, 1997. [PubMed: 9066888] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970303)69:1<79::aid-ajmg15>3.0.co;2-l]
Stanescu, V., Stanescu, R., Maroteaux, P. Kniest syndrome. (Letter) Am. J. Hum. Genet. 28: 527-528, 1976. [PubMed: 984048]
Wilkin, D. J., Artz, A. S., South, S., Lachman, R. S., Rimoin, D. L., Wilcox, W. R., McKusick, V. A., Stratakis, C. A., Francomano, C. A., Cohn, D. H. Small deletions in the type II collagen triple helix produce Kniest dysplasia. Am. J. Med. Genet. 85: 105-112, 1999. [PubMed: 10406661]
Wilkin, D. J., Bogaert, R., Lachman, R. S., Rimoin, D. L., Ryre, D. R., Cohn, D. H. A single amino acid substitution (G103D) in the type II collagen triple helix produces Kniest dysplasia. Hum. Molec. Genet. 3: 1999-2003, 1994. [PubMed: 7874117] [Full Text: https://doi.org/10.1093/hmg/3.11.1999]
Winterpacht, A., Hilbert, M., Schwarze U., Mundlos, S., Spranger, J., Zabel, R. U. Kniest and Stickler dysplasia phenotypes caused by collagen type II gene (COL2A1) defect. Nature Genet. 3: 323-326, 1993. [PubMed: 7981752] [Full Text: https://doi.org/10.1038/ng0493-323]