Craniofacial-deafness-hand syndrome is an extremely rare condition. Only a few cases have been reported in the scientific literature.

Craniofacial-deafness-hand syndrome is caused by mutations in the PAX3 gene. The PAX3 gene plays a critical role in the formation of tissues and organs during embryonic development. To perform this function, the gene provides instructions for making a protein that attaches (binds) to specific areas of DNA to help control the activity of particular genes. During embryonic development, the PAX3 gene is active in cells called neural crest cells. These cells migrate from the developing spinal cord to specific regions in the embryo. The protein produced from the PAX3 gene directs the activity of other genes that signal neural crest cells to form specialized tissues or cell types. These include some nerve tissues, bones in the face and skull (craniofacial bones), and muscle tissue.

At least one PAX3 gene mutation has been identified in individuals with craniofacial-deafness-hand syndrome. This mutation appears to affect the ability of the PAX3 protein to bind to DNA. As a result, the PAX3 protein cannot control the activity of other genes and cannot regulate the differentiation of neural crest cells. A lack of specialization of neural crest cells leads to the impaired growth of craniofacial bones, nerve tissue, and muscles seen in craniofacial-deafness-hand syndrome.