Townes-Brocks syndrome is a genetic condition that affects several parts of the body. The most common features of this condition are a malformation of the anal opening (imperforate anus), abnormally shaped ears, and hand malformations that most often affect the thumbs. People with this condition often have at least two of these three major features.
Other signs and symptoms of Townes-Brocks syndrome can include kidney abnormalities, mild to profound hearing loss, eye abnormalities, heart defects, foot abnormalities, and genital malformations. These features vary among affected individuals, even within the same family. Mild intellectual disability or learning problems have been reported in about 10 percent of people with Townes-Brocks syndrome.
Mutations in the SALL1 gene cause Townes-Brocks Syndrome. This gene provides instructions for making a protein that is involved in development before birth. The SALL1 protein acts as a transcription factor, which means it attaches (binds) to specific regions of DNA and helps control the activity of particular genes that direct the formation of many different tissues and organs before birth.
It is uncertain how SALL1 gene mutations result in the features of Townes-Brocks syndrome. Most mutations lead to the production of an abnormally short version of the SALL1 protein that malfunctions within the cell. The malfunctioning protein is thought to interfere with normal copies of the SALL1 protein, which are produced from the other copy of the SALL1 gene that does not have a mutation. This interference prevents the normal proteins from regulating gene activity. In addition, the malfunctioning protein may interact with other proteins, disrupting their function. For example, some research indicates that the abnormally short SALL1 protein interferes with proteins that control the formation of cellular structures called cilia. Cilia are important for the structure and function of many types of cells and the normal development of several tissues. Abnormalities in cilia can disrupt development and may contribute to the features of Townes-Brocks syndrome.
Some rare mutations prevent the gene from making any protein; this reduces by half the amount of SALL1 protein produced in cells. A shortage of functioning SALL1 protein, due to either type of mutation, likely impairs the regulation of genes that direct the development of many different organs and tissues before birth. Interference by the malfunctioning SALL1 protein, if present, may disrupt other developmental processes and contribute to the birth defects associated with Townes-Brocks syndrome.
The prevalence of this condition is unknown. It is difficult to determine how frequently Townes-Brocks syndrome occurs because the varied signs and symptoms of this disorder overlap with those of other genetic syndromes.
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
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