ORPHA: 85169;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Digital arthropathy-brachydactyly, familial | 606835 | Autosomal dominant | 3 | TRPV4 | 605427 |
A number sign (#) is used with this entry because of evidence that familial digital arthropathy-brachydactyly (FDAB) is caused by heterozygous mutation in the TRPV4 gene (605427) on chromosome 12q24.
Individuals with familial digital arthropathy-brachydactyly (FDAB) appear normal at birth, with no clinical or radiographic evidence of a developmental skeletal dysplasia. The earliest changes appear during the first decade of life and involve irregularities in the proximal articular surfaces of the distal interphalangeal joints of the hand. By adulthood, all interphalangeal, metacarpophalangeal, and metatarsophalangeal joints are affected by a deforming, painful osteoarthritis. The remainder of the skeleton is clinically and radiographically unaffected, thus distinguishing this disorder from other TRPV4 skeletal dysplasias, the cardinal features of which include abnormalities of the spine and disproportionate short stature (Lamande et al., 2011).
Amor et al. (2002) described a large, 5-generation pedigree in which many members had a dominantly inherited condition, which the authors designated familial digital arthropathy-brachydactyly, comprising progressive brachydactyly of the middle and distal phalanges of the hands and feet, with onset in the first decade of life. An associated deforming, progressive arthropathy of the interphalangeal, metacarpophalangeal, and metatarsophalangeal joints was seen. Early changes involved the proximal articular surfaces which became flattened and deformed while the distal articular surfaces and the joint spaces remained intact. Changes were usually more marked in the hands than the feet, with no other part of the skeleton showing involvement. Affected individuals were otherwise healthy. Amor et al. (2002) hypothesized from the radiologic appearance of patients at different ages that FDAB may result from subchondral pathology primarily affecting the heads of the phalanges, metacarpals, and metatarsals, with the arthropathy and brachydactyly being secondary effects.
In the family with digital arthropathy-brachydactyly originally described by Amor et al. (2002) and another affected family, Lamande et al. (2011) performed a genomewide microsatellite linkage scan and found linkage to an overlapping region on chromosome 12q23-q24. Analysis of additional markers narrowed the critical region to a 10-Mb interval flanked by markers D12S1597 and D12S79, with a combined maximum lod score of 6.9 (theta = 0).
The transmission pattern of FDAB in the pedigree described by Amor et al. (2002) was consistent with autosomal dominant inheritance.
In 2 families with digital arthropathy-brachydactyly mapping to chromosome 12q24, 1 of which was the family originally described by Amor et al. (2002), Lamande et al. (2011) analyzed the candidate gene TRPV4 and identified 2 different heterozygous missense mutations that segregated with disease in each family (605427.0030 and 605427.0031). In a sporadic patient with FDAB, heterozygosity for a third missense mutation in TRPV4 was identified (605427.0032). All 3 mutations were shown to reduce channel activity, in contrast to gain-of-function TRPV4 mutations that cause skeletal dysplasias and peripheral neuropathies.
Amor, D. J., Tudball, C., Gardner, R. J. M., Lamande, S. R., Bateman, J. F., Savarirayan, R. Familial digital arthropathy-brachydactyly. Am. J. Med. Genet. 108: 235-240, 2002. [PubMed: 11891693] [Full Text: https://doi.org/10.1002/ajmg.10269]
Lamande, S. R., Yuan, Y., Gresshoff, I. L., Rowley, L., Belluoccio, D., Kaluarachchi, K., Little, C. B., Botzenhart, E., Zerres, K., Amor, D. J., Cole, W. G., Savarirayan, R., McIntyre, P., Bateman, J. F. Mutations in TRPV4 cause an inherited arthropathy of hands and feet. Nature Genet. 43: 1142-1146, 2011. [PubMed: 21964574] [Full Text: https://doi.org/10.1038/ng.945]