Brachydactyly, Type C

A number sign (#) is used with this entry because type C brachydactyly (BDC) is caused by heterozygous mutation in the growth/differentiation factor-5 gene (GDF5; 601146) on chromosome 20q11.

Mutation in the GDF5 gene has also been reported to cause brachydactyly of the A1 (BDA1C; 615072) and A2 (BDA2; 112600) types.

Clinical Features

Haws (1963) described an extensively affected Mormon kindred. The anomalies of the digits are of many types: brachydactyly of the middle phalanx of the index and middle fingers, triangulation of the fifth middle phalanx, brachymetapody, hyperphalangy (more than 3 phalanges per finger), symphalangism, etc. About 600 family members were examined, of whom 86 were affected. The characteristic change should be considered a deformity of the middle and proximal phalanges of the second and third fingers, sometimes with hypersegmentation of the proximal phalanx. The ring finger may be essentially normal and project beyond the others.

In a kindred with brachydactyly considered by the authors as type C, Robinson et al. (1968) found Legg-Perthes disease of the hip in 3 affected persons: 2 sisters and their maternal uncle. The family reported by Ventruto et al. (1976) may have had BDC, but Fitch (1980) favored type B as part of a syndrome.

Baraitser and Burn (1983) described an affected brother and sister whose Iraqi first-cousin parents were unaffected, which raised the possibility of autosomal recessive inheritance of this phenotype.

Sanz and Gilgenkrantz (1988) described affected individuals in 4 generations of a family. Rowe-Jones et al. (1992) described BDC in 4 generations of a family. Characteristic hypersegmentation producing an extra, wedge-shaped bone at the base of the proximal phalanx in the index and middle fingers was found with ulnar deviation of the index finger. Members of this family also had shortening of the hallux with hypersegmentation. All affected members had similar small cupped-shaped ears.

Robin et al. (1997) studied a family in which 12 members in 5 generations had BDC. Affected individuals had upper extremity involvement only, with shortness of the second and fifth phalanges and first metacarpal; 1 member had a bilateral Madelung deformity. Nonskeletal manifestations were absent in this pedigree.

In a study of the large kindred reported by Haws (1963), Polymeropoulos et al. (1996) erroneously found linkage of BDC to DNA markers in the 12q24 region. Robin et al. (1997) excluded the 12q24 region as a candidate region for the mutated gene in their family. These discrepant findings led to a discussion of whether there was genetic and phenotypic heterogeneity in this form of brachydactyly and whether the family reported by Robin et al. (1997) had a form of brachydactyly other than type C.

Robin (1997) argued that the family he and his colleagues studied indeed had BDC. He stated that BDC is differentiated from BDA in that BDC has involvement of the first metacarpal, whereas BDA does not; the relative size of the digits is preserved in BDA (3 greater than 4 greater than 2 greater than 5), which is not the case for BDC where digit 4 is the largest and least involved; and the apparent 'hypersegmentation' is classic for BDC, not BDA. All of these criteria were met by the family he and his colleagues studied.

Inheritance

Debeer et al. (2001) reported a 4-generation family in which 3 members presented variable clinical and radiographic manifestations of BDC. The observation of 'skipped generations' in this family and in a few other families reported previously may indicate that the inheritance of BDC is more complicated than simple autosomal dominant transmission.

Molecular Genetics

In a study of the family reported by Robin et al. (1997), Polinkovsky et al. (1997) found linkage of the disorder to chromosome 20 within the region harboring the cartilage-derived morphogenetic protein-1 (CDMP1, or GDF5; 601146). They identified an arg301-to-ter mutation in the CDMP1 gene (601146.0002) in affected members of this family. The murine autosomal recessive phenotype brachypodism (bp) had previously been shown to be caused by homozygosity for functional null alleles in Cdmp1 (Storm et al., 1994).

Galjaard et al. (2001) presented 2 families whose phenotypic variability suggested that clinical subclassification of BDC based on the degree of complexity of the phenotype is not possible. Their patients with a complex BDC phenotype showed considerable intra- and interfamilial variation. Haplotype analysis in both families showed segregation of the disease phenotype with markers on chromosome 20q11.2, but not on chromosome 12q24. The authors concluded that factors other than locus heterogeneity, such as genetic modifiers and/or environmental factors, must play a role in phenotypic variability.

The conclusion of Galjaard et al. (2001) that BDC is caused by factors other than locus heterogeneity was validated by Everman et al. (2002). They showed that the classic kindred studied by Haws (1963), whose BDC was initially thought to map to chromosome 12 by Polymeropoulos et al. (1996), in fact had a 23-bp insertion mutation in the GDF5 gene (601146.0006). Everman et al. (2002) identified heterozygous GDF5 mutations in 9 additional probands/families with brachydactyly type C and presented in vitro expression data that suggested functional haploinsufficiency as the mechanism of mutational effect that caused BDC. They found no evidence of locus heterogeneity for BDC.

In a large consanguineous Turkish kindred with BDC, Schwabe et al. (2004) identified a mutation in the GDF5 gene (601146.0008). Homozygous offspring of consanguineous unions exhibited brachymesophalangy and hyperphalangy of the second, third, and fifth fingers with some phenotypic variability. Schwabe et al. (2004) noted that all heterozygous mutation carriers showed mild shortening of metacarpals 4 and 5, suggesting a semidominant pattern of inheritance.

In 8 members of 3 unrelated families with BDC, Savarirayan et al. (2003) identified a heterozygous 1-bp insertion in the GDF5 gene (601146.0009). Four members from the 3 families were also heterozygous for the 1-bp insertion, but had normal hands and feet. Two of these 4 nonpenetrant cases had what had been regarded as constitutional short stature.

In a 34-year-old German woman with a hand phenotype resembling BDC but with additional features of symphalangism-1 (SYM1; 185800) who was negative for mutations in the coding regions of the GDF5 and NOG (602991) genes, Lehmann et al. (2006) identified a de novo missense mutation in the BMPR1B gene (603248.0004). The mutation was also identified in an unrelated 26-month-old boy with typical type A2 brachydactyly (BDA2; 112600). A possible modifying mutation in the IHH gene (600726), which causes type A1 brachydactyly (112500), was excluded in both patients. Lehmann et al. (2006) suggested that the phenotypic variability between the 2 patients is due to unknown modifiers and/or stochastic effects, and that the phenotypic overlap in the female patient reflects interactions within the BMP/GDF pathway among the ligand (GDF5), its receptor (BMPR1B), and the inhibitor (NOG).

Yang et al. (2008) identified a Y487X mutation (601146.0016) in the GDF5 gene in a Han Chinese family with brachydactyly type C. Mature GDF5 protein was not detected in supernatant derived from Y487X-transfected cells, supporting the role of GDF5 haploinsufficiency in BDC. An affected mother and son from the family with BDC also had palmoplantar keratoderma (144200); the authors stated that it was most likely that the 2 diseases originated from independent mutations of different genes.