Brachyolmia Type 3

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.

For a discussion of heterogeneity of brachyolmia, see 271530.

Clinical Features

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 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.

Mapping

Using a 2-stage genome scan in a large family 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.

Molecular Genetics

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 in which the critical interval for autosomal dominant brachyolmia was mapped, and in another family with a similar phenotype, Rock et al. (2008) identified heterozygosity for single-base changes within exon 12 of the TRPV4 gene (605427.0001-605427.0002). 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.

History

Brown (1933) described the condition in a mother and 2 daughters as Morquio disease (see 253000).