Brachydactyly, Type B1

A number sign (#) is used with this entry because of evidence that brachydactyly type B1 (BDB1) is caused by heterozygous mutation in the ROR2 gene (602337) on chromosome 9q22.

Autosomal recessive Robinow syndrome (RRS; 268310) is an allelic disorder; see also 268310 for RRS with severe malformations of the hands and feet.

Clinical Features

Involvement of the distal phalanges and the association of nail aplasia distinguishes type B brachydactyly, which is said (Gong et al., 1999) to have been the first of the heritable brachydactylies to be described in the medical literature (Kellie, 1808). In this form, as in the 4 A types, the middle phalanges are short but in addition the terminal phalanges are rudimentary or absent. Both fingers and toes are affected. The thumbs and big toes are usually deformed. This type of hand malformation presents the severest deformity in the brachydactyly group. Symphalangism is also a feature. There is also mild syndactyly between the digits, leading some authors to describe this deformity as symbrachydactyly. Syndactyly in the feet usually involves the second and third toes. MacKinder (1857) described this hand deformity in 6 generations. MacArthur and McCullough (1932) described the same deformity in 3 generations and preferred the term 'apical dystrophy.' Goeminne et al. (1970) observed affected persons in 5 generations. Lenz (1977) made brief reference (with photographs) to peripheral defects simulating amniogenic ('constriction band') defects but distinct from those and from type B brachydactyly. Five persons in 4 generations were affected. Failing penetrance was observed in 2 persons.

Lv et al. (2009) reported a large Chinese family in which multiple individuals had a severe form of type B brachydactyly showing autosomal dominant inheritance. Five affected individuals were studied in detail. The proband had hypoplastic distal phalanges of digits 2 through 5 of the hands and feet, and marked hypoplasia of the third toes. The 4 other affected individuals had bilateral syndactyly, marked hypoplastic distal phalanges and absent nails of fingers 2 and 5, and flat and broad thumbs. Three individuals had cutaneous syndactyly of fingers 3 and 4, 2 of whom also had toe syndactyly. Radiographic examination of the proband showed bifid distal phalanges of the thumbs, hypoplastic distal phalanges of fingers 2 and 4, with distal symphalangism of finger 2 and 3, absent distal phalanges of finger 5 and biphalangeal toes. Lv et al. (2009) commented on the unusual cutaneous syndactyly phenotype in this family. Genetic analysis identified a heterozygous mutation in the ROR2 gene (2243delC; 602337.0014).

Mapping

Gong et al. (1999) described 2 unrelated families with BDB: one English and the other Canadian but of English ancestry. In the Canadian family, they assigned the BDB locus to an 18-cM interval on 9q (lod score 3.5 at theta = 0.0 for marker D9S938). Markers across this interval also cosegregated with the BDB phenotype in the English family (lod score 2.1 at theta = 0.0 for marker D9S277). The authors found within this interval a 7.5-cM region that contained 10 contiguous markers whose disease-associated haplotype was shared by the 2 families, suggesting a common founder among families of English descent with BDB. Gong et al. (1999) evaluated one candidate gene, that for type I transforming growth factor-beta receptor (190181), which maps to 9q33-q34, but identified no mutation in either family.

Oldridge et al. (1999) performed a genomewide linkage analysis of 3 families with BDB, 2 English and 1 Portuguese. The 2 English families showed linkage to the same region on chromosome 9 (combined multipoint maximum lod score = 8.69 with marker D9S257). The 16-cM disease interval was defined by recombinations with markers D9S1680 and D9S1786. These 2 families shared an identical disease haplotype over 18 markers, inclusive of D9S278-D9S280. This provided strong evidence that the English families had the same ancestral mutation, which reduced the disease interval to less than 12.7 cM between markers D9S257 and D9S1851 in chromosome band 9q22. In the Portuguese family, Oldridge et al. (1999) excluded linkage to this region, a result indicating that BDB is genetically heterogeneous. Reflecting this, there were atypical clinical features in the Portuguese family, with shortening of the thumbs and absence or hypoplasia of the nails of the thumb and hallux. These results enabled a refined phenotypic classification of type B brachydactyly and identified a novel locus for digit morphogenesis in 9q22.

Molecular Genetics

The ROR2 gene (602337) is localized in the region of 9q22 to which the BDB1 gene had been mapped. Furthermore, mice homozygous for an intragenic lacZ insertion into Ror2 were found by DeChiara et al. (2000) to have abnormal patterning of the digits and other skeletal defects. Ror2 maps to mouse chromosome 13 in a region of conserved synteny with human 9q (Oishi et al., 1999). These observations prompted Oldridge et al. (2000) to perform mutation analysis of the ROR2 gene in 3 unrelated families with BDB1. They identified distinct heterozygous mutations within a 7-amino acid segment of the 943-amino acid protein, all of which predicted truncation of the intracellular portion of protein immediately after the tyrosine kinase (TK) domain.

In 5 families with BDB1, Schwabe et al. (2000) found 4 novel mutations in the ROR2 gene: 2 frameshifts, 1 splice mutation, and 1 nonsense mutation. The mutations predicted truncation of the protein within 2 distinct regions immediately before and after the TK domain, resulting in a complete or partial loss of the intracellular portion of the protein. Patients with the distal mutations had a more severe phenotype than did those with the proximal mutations. In 1 of the BDB1 families with frameshift mutations (602337.0008), Schwabe et al. (2000) reported an individual, born of consanguineous parents with BDB1, who had a phenotype reminiscent of Robinow syndrome with aplasia/hypoplasia of the phalanges and metacarpals/metatarsals (see 268310).

Hamamy et al. (2006) reported a Jordanian man with brachydactyly type B who had a heterozygous mutation in the ROR2 gene (602337.0001). He had a severe form of the disease with classic brachydactyly and specific facial features, including prominent nose, high nasal bridge, hypoplastic alae nasi, and high-arched palate. His 3-year-old affected son also had the mutation.

In a large Turkish family with brachydactyly type B1 and distal symphalangism of the fourth finger, Kjaer et al. (2009) sequenced the ROR2, NOG (602991), and GDF5 (601146) genes and identified a truncating mutation in the ROR2 gene in 10 affected and 3 unaffected individuals. However, no mutations were detected in 3 individuals with isolated distal symphalangism of the fourth finger, which the authors designated 'DS2' (with 'DS1' representing distal symphalangism of the index finger, 185700); they suggested that DS2 should be regarded as a separate genetic entity segregating in the family. Kjaer et al. (2009) also noted that this family presented the mildest mutation-positive BDB1 phenotype reported to date, with 3 unaffected ROR2 mutation carriers and only 3 carriers with the typical BDB1 distal reductions.

History

Sorsby (1935) described the association of congenital coloboma of the macula with type B brachydactyly (120400). This large English family was followed up by Thompson and Baraitser (1988). Some affected individuals also had unilateral renal agenesis, double uterus and vagina, mixed hearing loss, high-arched palate, crowded irregular teeth, and supernumerary ribs. Bacchelli et al. (2003) had recontacted 1 affected family member and also ascertained a sporadic case with a combination of BDB, left choridal coloboma, and oligodontia. Direct sequencing of the entire ROR2 gene (602337), which is mutant in most cases of brachydactyly type B1, showed no changes in the coding region in these patients.