Alternative titles; symbols
SNOMEDCT: 111304003; ORPHA: 93314; DO: 0111554;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Spondylometaphyseal dysplasia, Kozlowski type | 184252 | Autosomal dominant | 3 | TRPV4 | 605427 |
A number sign (#) is used with this entry because of evidence that the Kozlowski type of spondylometaphyseal dysplasia (SMDK) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.
SMD Kozlowski (SMDK) is an autosomal dominant disorder characterized by significant scoliosis and mild metaphyseal abnormalities in the pelvis. The vertebrae exhibit platyspondyly and overfaced pedicles (Krakow et al., 2009).
Kozlowski et al. (1967) delineated this form of spondylometaphyseal dysplasia. The condition prompts medical attention because of short stature, usually between ages 1 and 4 years. Shortening of the trunk is the main factor in the short stature. Unusual, perhaps unique, radiologic changes occur in the distal metaphysis of the femur before age 6 years. Metaphyseal changes are prominent in the femoral neck and trochanteric area. Generalized platyspondyly is a striking feature. Similar cases of this condition, often termed Morquio syndrome, were found in the literature.
Dai et al. (2010) provided a detailed radiographic review of 20 patients diagnosed with SMDK and 22 patients diagnosed with metatropic dysplasia (MTD; 156530), noting that although some radiologic signs are shared by both disorders, the presence or absence of dumbbell-shaped femora ascertained distinction between MTD and SMDK, respectively. Two SMDK patients did not show overt metaphyseal changes and were considered to be of intermediate severity between SMDK and brachyolmia (113500). Unexpected radiologic findings included the fact that although narrow thorax, prominent joints, and coccygeal tail are considered to be clinical hallmarks of MTD, only prominent joints were consistently found in MTD, and these features were also occasionally found in SMDK. Delayed carpal age, a diagnostic criterion for SMDK, was not observed in half of the SMDK patients. MTD patients after infancy showed overfaced pedicles that were indistinguishable from those in SMDK patients. A small percentage of SMDK patients showed mild brachydactyly or mild epiphyseal dysplasia/premature degenerative joint disease, yet these cases were classified as SMDK based on the overall pattern of skeletal changes. Dai et al. (2010) concluded that accurate delineation of the total phenotypic spectrum in these disorders would require further accumulation of cases with radiographs taken at standard ages.
Krakow et al. (2009) and Dai et al. (2010) demonstrated autosomal dominant inheritance of SMDK.
Kozlowski et al. (1967) suspected autosomal recessive inheritance of this form of SMD. Kozlowski et al. (1982) attempted a classification of this nosologically difficult group and pointed to the report of van de Velde et al. (1972) as an example of recessive inheritance of typical SMD.
Meziane et al. (1987) described affected sibs (1 girl, 2 boys), the offspring of unaffected consanguineous parents, which suggested autosomal recessive inheritance.
Nores et al. (1993) tabulated 8 cases of parent-child transmission of SMDK distributed in 5 families; 3 of the families had 2 affected children (Refior, 1969; Le Quesne and Kozlowski, 1973; Thomas and Nevin, 1977). Nores et al. (1993) described spondylometaphyseal dysplasia in 2 half sisters. (They referred to the women as step-sisters; however, they had the same father and different mothers.) The older sister was the sixth of 7 children from the man's first marriage; the younger was the third of 6 children from his second marriage. Nores et al. (1993) suggested gonadal mosaicism as a likely explanation.
In 6 patients with SMDK, Krakow et al. (2009) identified heterozygosity for missense mutations in the TRPV4 gene; one of the mutations, R594H (605427.0003), was recurrent in 4 patients. Like the TRPV4 mutations in brachyolmia, these mutations altered basal calcium channel activity in vitro.
Dai et al. (2010) analyzed the TRPV4 gene in 22 MTD probands and 20 SMDK probands, and identified heterozygous TRPV4 mutations in all, except for 1 MTD proband. In the SMDK patients, the recurrent R594H mutation was found in 12 patients and 8 had novel missense mutations (see, e.g., 605427.0017 and 605427.0018).
In a cohort of 26 patients diagnosed with various skeletal dysplasias, including 15 with MTD, 9 with SMDK, and 2 with brachyolmia, Andreucci et al. (2011) sequenced the TRPV4 gene and identified heterozygous mutations in 8 of the 9 patients with SMDK (see, e.g., 605427.0003). Andreucci et al. (2011) noted that within a family with an affected mother and 2 sons (patients 5, 6, and 7), one of the sons had radiologic features more consistent with MTD whereas the other showed features more consistent with SMDK, thus illustrating the degree of intrafamilial variability within this spectrum of skeletal dysplasias. The 4 patients in whom no mutation was detected in TRPV4 all exhibited atypical features for their respective clinical diagnoses.
Andreucci, E., Aftimos, S., Alcausin, M., Haan, E., Hunter, W., Kannu, P., Kerr, B., McGillivray, G., McKinlay Gardner, R. J., Patricelli, M. G., Sillence, D., Thompson, E., Zacharin, M., Zankl, A., Lamande, S. R., Savarirayan, R. TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted by clinical, radiographic, and molecular studies in 21 new families. Orphanet J. Rare Dis. 6: 37, 2011. [PubMed: 21658220] [Full Text: https://doi.org/10.1186/1750-1172-6-37]
Dai, J., Kim, O.-H., Cho, T.-J., Schmidt-Rimpler, M., Tonoki, H., Takikawa, K., Haga, N., Miyoshi, K., Kitoh, H., Yoo, W.-J., Choi, I.-H., Song, H.-R., and 23 others. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. J. Med. Genet. 47: 704-709, 2010. [PubMed: 20577006] [Full Text: https://doi.org/10.1136/jmg.2009.075358]
Kozlowski, K., Beemer, F. A., Bens, G., Kijkstra, P. F., Iannaccone, G., Emons, D., Lopez-Ruiz, P., Masel, J., van Nieuwenhuizen, O., Rodriguez-Barrionuevo, C. Spondylo-metaphyseal dysplasia: report of 7 cases and essay of classification. In: Papadatos, C. J.; Bartsocas, C. S.: Skeletal Dysplasias. New York: Alan R. Liss (pub.) 1982.
Kozlowski, K., Maroteaux, P., Spranger, J. W. La dysostose spondylo-metaphysaire. Presse Med. 75: 2769-2774, 1967.
Krakow, D., Vriens, J., Camacho, N., Luong, P., Deixler, H., Funari, T. L., Bacino, C. A., Irons, M. B., Holm, I. A., Sadler, L., Okenfuss, E. B., Janssens, A., Voets, T., Rimoin, D. L., Lachman, R. S., Nilius, B., Cohn, D. H. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am. J. Hum. Genet. 84: 307-315, 2009. [PubMed: 19232556] [Full Text: https://doi.org/10.1016/j.ajhg.2009.01.021]
Le Quesne, G. W., Kozlowski, K. Spondylometaphyseal dysplasia. Brit. J. Radiol. 46: 685-691, 1973. [PubMed: 4199241] [Full Text: https://doi.org/10.1259/0007-1285-46-549-685]
Meziane, A. O., Meziane, A., Ksiyer, M., Bennani-Smires, C., Hadj Khalifa, H. Spondylometaphyseal dysplasia: report of three familial cases. Ann. Genet. 30: 216-220, 1987. [PubMed: 3501265]
Nores, J.-M., Dizien, O., Remy, J.-M., Maroteaux, P. Two cases of spondylometaphyseal dysplasia: literature review and discussion of the genetic inheritance of the disease. J. Rheum. 20: 170-172, 1993. [PubMed: 8441154]
Refior, H. J. Zur spondylo-metaphysaren Dysostose (Typ Kozlowski-Maroteaux-Spranger). Arch. Orthop. Unfallchir. 66: 334-346, 1969. [PubMed: 4981286]
Thomas, P. S., Nevin, N. C. Spondylometaphyseal dysplasia. Am. J. Roentgen. 128: 89-93, 1977. [PubMed: 401596] [Full Text: https://doi.org/10.2214/ajr.128.1.89]
van de Velde, E., Hooft, C., Vandenabeele, B., Redant, W. Trois cas familiaux de dysplasie spondylo-metaphysaire. J. Belge Radiol. 55: 623-630, 1972. [PubMed: 4661491]