Townes-Brocks Syndrome

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.

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.

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.

Genetic Testing Information

• Genetic Testing Registry: Townes-Brocks syndrome 1

Genetic and Rare Diseases Information Center

• Townes-Brocks syndrome

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

• TOWNES-BROCKS SYNDROME 1; TBS1
• TOWNES-BROCKS SYNDROME 2; TBS2

Scientific Articles on PubMed

• PubMed

• Botzenhart EM, Bartalini G, Blair E, Brady AF, Elmslie F, Chong KL, Christy K, Torres-Martinez W, Danesino C, Deardorff MA, Fryns JP, Marlin S, Garcia-Minaur S, Hellenbroich Y, Hay BN, Penttinen M, Shashi V, Terhal P, Van Maldergem L, Whiteford ML, Zackai E, Kohlhase J. Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region. Hum Mutat. 2007 Feb;28(2):204-5. doi: 10.1002/humu.9476. Citation on PubMed
• Botzenhart EM, Green A, Ilyina H, Konig R, Lowry RB, Lo IF, Shohat M, Burke L, McGaughran J, Chafai R, Pierquin G, Michaelis RC, Whiteford ML, Simola KO, Rosler B, Kohlhase J. SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype. Hum Mutat. 2005 Sep;26(3):282. doi: 10.1002/humu.9362. Citation on PubMed
• Bozal-Basterra L, Martin-Ruiz I, Pirone L, Liang Y, Sigurethsson JO, Gonzalez-Santamarta M, Giordano I, Gabicagogeascoa E, de Luca A, Rodriguez JA, Wilkie AOM, Kohlhase J, Eastwood D, Yale C, Olsen JV, Rauchman M, Anderson KV, Sutherland JD, Barrio R. Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome. Am J Hum Genet. 2018 Feb 1;102(2):249-265. doi: 10.1016/j.ajhg.2017.12.017. Citation on PubMed or Free article on PubMed Central
• de Celis JF, Barrio R. Regulation and function of Spalt proteins during animal development. Int J Dev Biol. 2009;53(8-10):1385-98. doi: 10.1387/ijdb.072408jd. Citation on PubMed
• Keegan CE, Mulliken JB, Wu BL, Korf BR. Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia: review of eight patients and further evidence of a "hot spot" for mutation in the SALL1 gene. Genet Med. 2001 Jul-Aug;3(4):310-3. doi: 10.1097/00125817-200107000-00007. Citation on PubMed
• Kiefer SM, Ohlemiller KK, Yang J, McDill BW, Kohlhase J, Rauchman M. Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects. Hum Mol Genet. 2003 Sep 1;12(17):2221-7. doi: 10.1093/hmg/ddg233. Epub 2003 Jul 15. Citation on PubMed
• Kohlhase J. Townes-Brocks Syndrome. 2007 Jan 24 [updated 2016 Jan 14]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from http://www.ncbi.nlm.nih.gov/books/NBK1445/ Citation on PubMed
• Powell CM, Michaelis RC. Townes-Brocks syndrome. J Med Genet. 1999 Feb;36(2):89-93. Citation on PubMed or Free article on PubMed Central