Alternative titles; symbols
SNOMEDCT: 717264003; ORPHA: 93304; DO: 0050690;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Brachyolmia type 3 | 113500 | Autosomal dominant | 3 | TRPV4 | 605427 |
A number sign (#) is used with this entry because of evidence that brachyolmia type 3 (BCYM3) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.
Type 3 brachyolmia (BCYM3) is an autosomal dominant skeletal dysplasia affecting the spine characterized by severe kyphoscoliosis and flattened, irregular cervical vertebrae (summary by Rock et al., 2008).
For a discussion of heterogeneity of brachyolmia, see 271530.
Lenz (1964) observed father and son with a very short spine and deformity of the anterior chest rather like that in Morquio disease. Except for marked changes in the femoral epiphyses, the extremities were normal. The vertebral bodies were small, irregular, and radiolucent. Perhaps the family of Lomas and Boyle (1959) in which 3 generations were affected had the same condition. See also the dominant type of spondyloepiphyseal dysplasia tarda (184100).
Kozlowski et al. (1982) stated that pure brachyolmia does not exist and that metaphyseal involvement may be minimal and scattered but always is present along with involvement of the spine in cases labeled brachyolmia. Shohat et al. (1989), however, described a mother and son with severe spinal changes with no metaphyseal or epiphyseal changes in the long bones. These patients showed the most severe scoliosis of the patients they studied, and demonstrated marked cervical vertebral flattening and irregularity.
Gardner and Beighton (1994) investigated the cases of a mother and son of South African Xhosa stock who presented with short-trunk dwarfism and kyphoscoliosis. Radiographs showed the marked platyspondyly and vertebral irregularity characteristic of brachyolmia. In the mother, the femoral necks were very short with a varus deformity; in the 6-year-old son, the femoral necks were likewise short and their metaphyseal regions were irregular, with areas of patchy lucency and sclerosis.
Rock et al. (2008) described type 3 brachyolmia as an autosomal dominant form with severe kyphoscoliosis and flattened, irregular cervical vertebrae. Paradoxically, although the limbs are mildly shortened in all 3 types of brachyolmia, they show only minimal epiphyseal and metaphyseal abnormalities on radiographs. Rock et al. (2008) characterized a large family (R99-102) with autosomal dominant brachyolmia. The clinical phenotype was characterized by moderately short-trunk short stature, mildly short limbs, mild brachydactyly, and no extraskeletal clinical findings. The most characteristic radiographic features were scoliosis with platyspondyly and overfaced pedicles, which were most prominent in the lumbar vertebrae. There were mild irregularities at the metaphyses of the proximal femora, and the hands showed delayed epiphyseal and carpal ossification.
Grigelioniene et al. (2014) reported a large Swedish family with brachyolmia in 11 individuals over 4 generations. The proband was a 2-year-old boy who had a normal growth curve but features suggestive of a skeletal dysplasia on radiography: x-rays showed alterations in the spine typical for brachyolmia, with flat and oval-shaped vertebrae, and he also had mild metaphyseal changes, most noticeably at the proximal femur. The authors stated that the phenotype of other affected family members was not easily recognizable, although review of x-rays showed more pronounced vertebral changes with advancing age, and vertebrae were flat, with irregular endplates and narrow disc spaces. Short pedicles and narrow canal spaces were observed, indicating likely spinal stenosis. Short stature was variable in this family, usually relatively mild but progressive with age. Affected adults reported generalized spine stiffness, with limitation of flexion in the thoracic and lumbar spine, as well as skeletal pain in the extremities and hips that began in mid- to late childhood. Paresthesias were present in upper and lower extremities, involving burning and prickling sensations that varied in intensity and location. The oldest affected family member was wheelchair-bound at age 83, due to pain, kyphoscoliosis, and hip arthrosis; 2 other adults had to change occupations due to musculoskeletal pain.
The transmission pattern of BCYM3 in 2 families reported by Rock et al. (2008) (R99-102 and R99-457) was consistent with autosomal dominant inheritance.
Using a 2-stage genome scan in a large family (R99-102) with autosomal dominant brachyolmia, Rock et al. (2008) mapped the phenotype to chromosome 12q24.1-q24.2, with a maximum lod score of 3.04 at a recombination fraction of zero for the marker D12S79. Recombination mapping limited the interval to 11.1 Mb.
To narrow the search for the genes in the critical 11.1-Mb interval for a form of brachyolmia, Rock et al. (2008) searched for genes with higher expression in cartilage and identified TRPV4 (605427) as having about 10-fold higher cartilage selectivity than the average of all other genes in the interval. In the family (R99-102) in which the critical interval for autosomal dominant brachyolmia was mapped, and in another family (R99-457) with a similar phenotype, Rock et al. (2008) identified heterozygosity for missense mutations within exon 12 of the TRPV4 gene: R616Q (605427.0001) and V620I (605427.0002), respectively. No mutations in the TRPV4 gene were found in 2 additional families with autosomal dominant brachyolmia, suggesting that autosomal dominant brachyolmia may be genetically heterogeneous.
In a large Swedish family in which 11 individuals over 4 generations had brachyolmia, Grigelioniene et al. (2014) identified heterozygosity for the previously reported R616Q substitution in the TRPV4 gene, which segregated fully with disease. Affected adults in the Swedish family reported paresthesias and significant musculoskeletal pain, symptoms that were not present in members of the previously described family (R99-102; Rock et al., 2008) with the same mutation.
Brown (1933) described the condition in a mother and 2 daughters as Morquio disease (see 253000).
Brown, D. O., MacDonald, C. Three cases of familial osseous dystrophy. Aust. New Zeal. J. Surg. 3: 78-88, 1933.
Brown, D. O. Morquio's disease. Med. J. Aust. 1: 598-600, 1933.
Gardner, J., Beighton, P. Brachyolmia: an autosomal dominant form. Am. J. Med. Genet. 49: 308-312, 1994. [PubMed: 8209891] [Full Text: https://doi.org/10.1002/ajmg.1320490313]
Grigelioniene, G., Geiberger, S., Horemuzova, E., Mostrom, E., Jantti, N., Neumeyer, L., Astrom, E., Nordenskjold, M., Nordgren, A., Makitie, O. Autosomal dominant brachyolmia in a large Swedish family: phenotypic spectrum and natural course. Am. J. Med. Genet. 164A: 1635-1641, 2014. [PubMed: 24677493] [Full Text: https://doi.org/10.1002/ajmg.a.36502]
Kozlowski, K., Beemer, F. A., Bens, G., Dijkstra, 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. (eds.): Skeletal Dysplasias. New York: Alan R. Liss (pub.) 1982. Pp. 89-101.
Lenz, W. Anomalien des Wachstums und der Koerperform. In: Becker, P. E.: Ein kurzes Handbuch in fuenf Baenden. Vol. 2. Stuttgart: Georg Thieme Verlag (pub.) 1964. Pp. 88-89. Note: Fig. 30.
Lomas, J. J. P., Boyle, A. C. Osteo-chondrodystrophy (Morquio's disease) in three generations. Lancet 274: 430-432, 1959. Note: Originally Volume II. [PubMed: 14418038] [Full Text: https://doi.org/10.1016/s0140-6736(59)90418-0]
Rock, M. J., Prenen, J., Funari, V. A., Funari, T. L., Merriman, B., Nelson, S. F., Lachman, R. S., Wilcox, W. R., Reyno, S., Quadrelli, R., Vaglio, A., Owsianik, G., Janssens, A., Voets, T., Ikegawa, S., Nagai, T., Rimoin, D. L., Nilius, B., Cohn, D. H. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nature Genet. 40: 999-1003, 2008. [PubMed: 18587396] [Full Text: https://doi.org/10.1038/ng.166]
Shohat, M., Lachman, R., Gruber, H. E., Rimoin, D. L. Brachyolmia: radiographic and genetic evidence of heterogeneity. Am. J. Med. Genet. 33: 209-219, 1989. [PubMed: 2669482] [Full Text: https://doi.org/10.1002/ajmg.1320330214]