Townes-Brocks Syndrome

Disease Overview

Summary

Townes-Brocks syndrome (TBS) is a genetic condition caused by a harmful change (mutation) in a gene called SALL1. Features include no anal opening (imperforate anus) and differently shaped ears and thumbs. There can also be problems with the feet, heart and kidneys.

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Synonyms

• deafness, sensorineural, with imperforate anus and hypoplastic thumbs
• imperforate anus with hand, foot and ear anomalies
• Townes syndrome
• TBS

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Signs & Symptoms

There are three major symptoms of TBS: A closed anal opening (imperforate anus), small ears that usually have a folded rim of skin and cartilage around the outer ear, and differences in the structures of the thumbs. The thumbs have three bones (triphalangeal) instead of two. People with this syndrome may also have an extra thumb (preaxial polydactyly). Another symptom may be hearing loss present at birth (congenital). The hearing loss can be sensorineural and/or conductive, range from mild to severe and may be progressive. Differences in the feet occur less frequently and include a short third toe, overlapping toes and flat feet. Typical kidney (renal) differences include displaced or rotated kidneys, horseshoe kidney, polycystic kidneys and underdeveloped kidneys. There can also be heart and genital problems present at birth. Intellectual disability occurs in about 10% of affected individuals.

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Causes

TBS is caused by a harmful genetic change (mutation) in a gene called SALL1. The SALL1 gene has instructions for the body to form certain tissues and organs such as the hands (particularly the thumbs), ears, anus and kidneys. Humans should have two working copies of the SALL1 gene, but people with TBS have one copy of the gene that does not work properly.

There is also evidence that this condition could be caused by a mutation in the DACT1 gene, but a mutation in the SALL1 gene is the more common cause.

TBS is inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

It has been estimated that TBS occurs in at least 1 in 250,000 births.

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Disorders with Similar Symptoms

The physical features of TBS are similar to oculo-auriculo-vertebral spectrum disorder, Okihiro syndrome, branchiootorenal syndrome, VACTERL association and STAR syndrome.

People with oculo-auriculo-vertebral spectrum disorder can have a wide range of problems affecting the eyes, ears and spine. In some forms, one side of the face may be underdeveloped (hemifacial microstomia). Patients with TBS can also have hemifacial microstomia. (For more information about this disorder, choose “oculo-auriculo-vertebral spectrum” as your search term in the Rare Disease Database.)

Okihiro syndrome (Duane-radial ray syndrome) affects the eyes and causes differences of bones in the arms and hands. Bone changes in the hands include structurally different or absent thumbs, an extra thumb or a thumb that looks like a finger. There is limited ability to move the eye inward toward the nose (adduction), outward toward the ear (abduction) or in both directions.

Branchiootorenal spectrum disorders are associated with pits or ear tags in front of the outer ear, and kidney defects or impaired renal function. There are no other TBS associated symptoms. It is also associated with abnormal passages from the throat to the outside surface of the neck (branchial fistulas), branchial cysts and hearing loss. (For more information about this disorder, choose “branchiootorenal spectrum” as your search term in the Rare Disease Database.)

VACTERL association is a nonrandom association of birth defects that affects multiple anatomical structures. The term VACTERL is an acronym with each letter representing the first letter of one of the more common findings seen in affected children: (V) = vertebral (spinal) abnormalities, (A) = anal atresia, (C) = cardiac (heart) defects, (T) = tracheoesophageal fistula, (E) =esophageal atresia, (R) = renal (kidney) abnormalities and (L) = limb abnormalities. TBS does not have the vertebral defects. (For more information about this disorder, choose “VACTERL” as your search term in the Rare Disease Database.)

STAR syndrome is associated with fusion of the toes (syndactyly), wide-spaced eyes (telecanthus), and anal, genital and kidney defects similar to TBS. The facial features and toe fusion are the differences between STAR syndrome and TBS. This syndrome also more commonly affects males due to the X-linked inheritance pattern.

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Diagnosis

The clinical diagnosis of TBS is based on the presence of the three common symptoms (differences of the anus, ear and thumb) and sometimes the minor features. Genetic testing that reveals a harmful variant in the SALL1 gene can confirm the diagnosis.

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Standard Therapies

Treatment includes surgery to correct the differences of the anus and thumbs. Hearing evaluation should be conducted if TBS is suspected. Ultrasound and laboratory tests should be performed to monitor kidney function. A baseline echocardiogram should be performed by a cardiologist.

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS

Lachiewicz AM, Hodge C. Townes-Brocks Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:262.

JOURNAL ARTICLES

Yang G, Yin Y, Tan Z, Liu J, Deng X, Yang Y. Whole-exome sequencing identified a novel heterozygous mutation of SALL1 and a new homozygous mutation of PTPRQ in a Chinese family with Townes-Brocks syndrome and hearing loss. BMC Med Genomics. 2021 Jan 21;14(1):24. doi: 10.1186/s12920-021-00871-9. PMID: 33478437; PMCID: PMC7819242.

Valikodath NG, Jain S, Miller M, Kaufman LM. Ocular features of Townes-Brocks syndrome. J AAPOS. 2020 Apr;24(2):115-118. doi: 10.1016/j.jaapos.2019.12.004. Epub 2020 Jan 23. PMID: 31981611.

Bozal-Basterra L, Gonzalez-Santamarta M, Muratore V, Bermejo-Arteagabeitia A, Da Fonseca C, Barroso-Gomila O, Azkargorta M, Iloro I, Pampliega O, Andrade R, Martín-Martín N, Branon TC, Ting AY, Rodríguez JA, Carracedo A, Elortza F, Sutherland JD, Barrio R. LUZP1, a novel regulator of primary cilia and the actin cytoskeleton, is a contributing factor in Townes-Brocks Syndrome. Elife. 2020 Jun 18;9:e55957. doi: 10.7554/eLife.55957. PMID: 32553112; PMCID: PMC7363444.

Bozal-Basterra L, Martín-Ruíz I, Pirone L, et al. Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome. Am J Hum Genet. 2018;102(2):249-265.

Botzenhart EM, Bartalini G, Blair E, et al. Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region. Hum Mutat 2007:28:204-5.

Botzenhart EM, Green A, Ilyina H, et al. SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype. Hum Mutat 2005:26-282.

Devriendt K, Fryns JP, Lemmens F, et al. Somatic mosaicism and variable expression of Townes-Brocks syndrome. Am J Med Genet 2002: 111-230-1.

Kohlhase J. SALL1 mutations in Townes-Brocks syndrome and related disorders. Hum Mutat 2000: 16:460-6.

Townes PL and Brocks ER. Hereditary syndrome of imperforate anus with hand, foot and ear anomalies. J Pediatr 1972:81;321-326.

INTERNET

Townes Brocks Syndrome. Medline Plus.Updated Aug 18, 2020, https://medlineplus.gov/genetics/condition/townes-brocks-syndrome/#resources Accessed Nov 17, 2021.

OMIM (Online Mendelian Inheritance in Man). Johns Hopkins University, Baltimore, MD. MIM Number: #107480. Updated 03/28/2019. https://www.omim.org/entry/107480?search=townes-brock%20syndrome&highlight=%22towne%7Cbrock%22%20%28syndrome%7Csyndromic%29%20%28townesbrock%7C%20%29 Accessed Nov 17, 2021.

Kohlhase J. Townes-Brocks Syndrome. 2007 Jan 24 [Updated 2016 Jan 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1445/ Accessed Nov 17, 2021.

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