Townes Brocks syndrome

Townes Brocks syndrome is a genetic condition that affects several parts of the body. The most common features of Townes-Brocks syndrome are a malformation of the anal opening (imperforate anus), abnormally shaped ears (dysplastic ears) and hand malformations that most often affecting the thumbs. People with Townes Brocks syndrome 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, congenital heart defects, foot abnormalities (flat feet, overlapping toes) and genital or urinary malformations. Kidney problems such as end-stage renal disease (ESRD) may occur with or without kidney malformations (malrotation, abnormal position (ectopia), abnormal shape (horseshoe kidney), small size (renal hypoplasia), multiple cysts in the kidney (polycystic kidneys), or vesicoutereral reflux). These features vary among affected individuals, even within the same family. Rare features include eye anomalies (a defect on the iris of the eye (iris coloboma), or an eye movement disorder known as Duane anomaly), Arnold-Chiari malformation type 1, and growth delay. Mild intellectual disability or learning problems have been reported in about 10 percent of people with Townes-Brocks syndrome.

Townes Brocks syndrome is caused by mutations in the SALL1 gene which provides instructions for making proteins that are involved in the formation of tissues and organs before birth. In rare cases, Townes Brocks syndrome may be caused by a mutation in the SALL4 gene. Inheritance is autosomal dominant ¹. The prevalence of Townes Brocks syndrome 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, but has been estimated to be at least 1 in 250,000 births ². More than 100 cases have been reported to date. Townes Brocks syndrome affects males and females in equal numbers.

Treatment is directed towards the specific symptoms, including immediate surgical intervention for imperforate anus, surgery for severe malformations of the thumbs, and early treatment of hearing loss. When heart defects are present, treatment is with the routine management of congenital heart defects, such as surgery and medication; Kidney impairment is treated with hemodialysis and, in some cases, with kidney transplantation for end-stage renal disease (ESRD). Regular monitoring of kidney function in individuals, with and without kidney anomalies, is recommended. An annual hearing testing is recommended ³.

Townes Brocks syndrome causes

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.

Townes Brocks syndrome inheritance pattern

Townes Brocks syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Often autosomal dominant conditions can be seen in multiple generations within the family. If one looks back through their family history they notice their mother, grandfather, aunt/uncle, etc., all had the same condition. In cases where the autosomal dominant condition does run in the family, the chance for an affected person to have a child with the same condition is 50% regardless of whether it is a boy or a girl. These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

• When one parent has the abnormal gene, they will pass on either their normal gene or their abnormal gene to their child. Each of their children therefore has a 50% (1 in 2) chance of inheriting the changed gene and being affected by the condition.
• There is also a 50% (1 in 2) chance that a child will inherit the normal copy of the gene. If this happens the child will not be affected by the disorder and cannot pass it on to any of his or her children.

Figure 1 illustrates autosomal dominant inheritance. The example below shows what happens when dad has the condition, but the chances of having a child with the condition would be the same if mom had the condition.

Figure 1. Townes Brocks syndrome autosomal dominant inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Townes Brocks syndrome symptoms

The absence of the anal opening (imperforate anus) is the most common feature (84%) of Townes Brocks syndrome. Small ears and a folded rim of skin and cartilage around the outer ear (dysplastic ears) are usually present. Congenital sensorineural and/or conductive hearing loss can range from mild to severe and can be progressive. The most common thumb malformations are three bones instead of two (triphalangeal thumbs) and duplicated thumbs (preaxial polydactyly). Feet anomalies occur less frequently and include a short third toe, overlapping toes and flat feet. Kidney dysfunction can occur with or without kidney malformations. Typical kidney anomalies include displaced or rotated kidneys, horseshoe kidney, polycystic kidneys, and underdeveloped kidneys. Abnormalities of the heart, eye and spine are infrequently associated with Townes-Brocks syndrome. Mental retardation occurs in approximately 10% of affected individuals.

Townes-Brocks syndrome should be suspected in individuals with the following major and minor clinical features ³.

Major features

• Imperforate anus or anal stenosis in 84%
• Dysplastic ears in 87% (overfolded superior helices, microtia)
• Typical thumb malformations in 89% (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius

Minor features

• Sensorineural and/or conductive hearing impairment
• Foot malformations
• Renal impairment with or without renal malformations
• Genitourinary malformations
• Congenital heart disease

Atypical (not suggestive of Townes Brocks syndrome)

• Radius hypoplasia on clinical examination or radiographs
• Cleft lip/palate

Townes Brocks syndrome diagnosis

The diagnosis of Townes-Brocks syndrome is based on clinical symptoms. Molecular genetic testing for mutations in the SALL1 gene is available to confirm the diagnosis. A genetic test identifying a mutation in the SALL1 gene establishes the diagnosis if clinical features are inconclusive. A few patients with clinical features of the syndrome have a mutation in the SALL4 gene. Therefore, people with a diagnosis of Townes-Brocks syndrome, who have a negative SALL1 testing, should also have a genetic testing for the SALL4 gene ³.

Townes-Brocks syndrome is diagnosed when a patient has the following three major features ³:

• Imperforate anus
• Abnormally shaped ears
• Typical thumb malformations (two thumbs (preaxial polydactyly), triphalangeal thumbs which have three bones in them, much like the fingers, instead of the normal two, hypoplastic or underdeveloped thumbs) without shortening of the radius (the larger of the two bones in the forearm).

If only two major features are present, the presence of minor features and the absence of atypical features further support the diagnosis ³:

Minor features:

• Hearing impairment
• Foot malformations
• Kidney impairment with or without kidney malformations
• Genital or urinary malformations
• Congenital heart disease.

Atypical features (not suggestive of the syndrome):

• Radius hypoplasia on clinical examination or radiographs of the forearm
• Cleft lip/palate.

Antenatal diagnosis

Prenatal diagnosis for pregnancies at increased risk is available and usually requires identification of the disease-causing mutation in the family. However, if typical malformations are seen on prenatal ultrasound, complete analysis of the SALL1 gene is also possible from prenatal samples.

Townes Brocks syndrome treatment

Treatment of Townes-Brocks syndrome often requires surgery for malformations associated with this condition. Hearing evaluation should be conducted if Townes Brocks syndrome is suspected. Ultrasound and laboratory tests should be performed to monitor kidney function with hemodialysis and possibly kidney transplantation for end-stage renal disease (ESRD). A baseline echocardiogram should be performed by a cardiologist with surgery or medical treatment by a cardiologist for congenital heart defects. Ophthalmology examination to evaluate for ocular features of Townes Brocks syndrome and atypical finding of Duane anomaly.

Treatment of Townes Brocks syndrome

The following are indicated:

• Imperforate anus. Immediate surgical intervention is required.
• Hearing loss. Significant impairment requires early treatment, typically with hearing aids (see Deafness and Hereditary Hearing Loss Overview).
• Thumb malformations. Severe malformations of the hands may require surgery (e.g., removal of additional thumbs).
• Renal. Impaired renal function requires continuous monitoring, hemodialysis, and possibly kidney transplantation.
• Heart defects. Congenital heart defects may require surgery or medical treatment by a cardiologist.
• Genetic counseling is recommended for affected individuals and their families.

Surveillance

Annual hearing evaluation is indicated.

Renal function should be regularly monitored in all individuals with and without renal anomalies, even if no impairment of renal function is detected on initial examination.

Townes Brocks syndrome prognosis

Townes Brocks syndrome prognosis is variable; it depends on the symptoms present and their severity. Generally, when imperforate anus is treated early, the prognosis is good. Townes Brocks syndrome becomes life-threatening only in cases of severe heart and kidney malformations ⁴. A prognosis with respect to intellectual development is not possible.

References

1. Townes-Brocks Syndrome. https://medlineplus.gov/genetics/condition/townes-brocks-syndrome
2. Martínez-Frías ML, Bermejo Sánchez E, Arroyo Carrera I, Pérez Fernández JL, Pardo Romero M, Burón Martínez E, Hernández Ramón F. The Townes-Brocks syndrome in Spain: the epidemiological aspects in a consecutive series of cases An Esp Pediatr. 1999;50:57-60.
3. 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; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1445
4. Townes-Brocks syndrome. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=857