The brachydactylies are a group of inherited disorders characterized by shortening of the digits and is due to abnormal development of the phalanges and/or metacarpals. It may occur as an isolated trait or as part of complex malformation syndromes. According to their patterns of skeletal involvement heritable brachydactylies have been classified into the subtypes A to E (Bell 1951). Numerous genes have been identified that can be mutated in brachydactyly syndromes.

The brachydactyly disease family. Affected skeletal elements are depicted black.

Brachydactyly type B (BDB) characterized by the shortening/hypoplasia of the distal phalanges, is caused by mutations in ROR2, encoding a receptor tyrosine kinase. BDB mutations in ROR2 truncate the protein either immediately in front of or after the tyrosine kinase domain leading to the expression of truncated proteins. In contrast, missense or nonsense mutations leading to amino acid exchange or truncation of extracellular domains of ROR2, truncation within the TK domain, or selective inactivation of TK activity lead to autosomal recessive Robinow syndrome (RS).

Mutations in ROR2 cause BDB (left) and RS (right). Mutations in BDB lead to the expression of truncated proteins while RS mutations most likely lead to a loss of function of the protein.

The key questions we address are:

• what is the pathogenesis of BDB?
• what is the downstream signalling mechanism of Ror2 and how does it interact with other pathways during limb development?
• is there a common pathomechanism for the brachydactylies as a molecular disease family?