Townes–Brocks syndrome

Other Names: TBS; Renal-ear-anal-radial syndrome; REAR syndrome; Anus, imperforate, with hand, foot and ear anomalies; Deafness, sensorineural, with imperforate anus and hypoplastic thumbs; Imperforate anus with hand, foot and ear anomalies; Sensorineural deafness with imperforate anus and hypoplastic thumbs; Townes syndrome; Imperforate anus-hand, foot and ear anomalies syndrome

Townes–Brocks syndrome (TBS) is a rare genetic disease that has been described in approximately 200 cases in the published literature. It affects both males and females equally. The condition was first identified in 1972. by Philip L. Townes, MD, PhD, who was at the time a human geneticists and Professor of Pediatrics, and Eric Brocks, MD, who was at the time a medical student, both at the University of Rochester.

Symptoms

TBS patients may have the following symptoms:

• Abnormalities of the external ears (unusually large or small, unusually shaped, sometimes with sensorineural hearing loss or deafness due to lesions or dysfunctions of part of the internal ear or its nerve tracts and centers or conductive hearing loss from the external or middle ear), dysplastic ears, lop ear (over-folded ear helix), preauricular tags or pits (a rudimentary tag of ear tissue typically located just in front of the ear).
• Anorectal malformations, including imperforate anus/absence of an anal opening, rectovaginal fistula, anal stenosis, unusually placed anus.
• Renal abnormalities, sometimes leading to impaired renal function or renal failure, including hypoplastic kidneys (underdeveloped), multicystic kidneys, dyspastic kidneys.
• Heart abnormalities, including tetralogy of fallot and defects of the ventricular septum.
• Hand and foot abnormalities, such as hypoplastic thumbs, fingerlike thumbs, syndactyly (webbed fingers/toes), fusion of the wrist bones, overlapping foot and/or toe bones.

Learning difficulties have been reported in some children with TBS. For others, intelligence is within the normal range.

These abnormalities, which are present prenatally, can range from minor to severe, and as with similar disorders, most individuals with this condition have some, but not all, of these traits.

Causes

Townes-Brocks syndrome is caused by mutations in the SALL1 gene. This gene is part of a group of genes called the SALL family. These genes provide instructions for making proteins that are involved in the formation of tissues and organs before birth. SALL proteins act as transcription factors, which means they attach (bind) to specific regions of DNA and help control the activity of particular genes. Some mutations in the SALL1 gene lead to the production of an abnormally short version of the SALL1 protein that malfunctions within the cell. Other mutations prevent one copy of the gene in each cell from making any protein. Some patients with the clinical features of the syndrome have a mutation in the SALL4 gene rather than SALL1 gene. It is unclear how these genetic changes disrupt normal development and cause the symptoms associated with Townes-Brocks syndrome.

Diagnosis

Townes-Brocks syndrome (TBS) is diagnosed when a patient has the following three major features: 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: 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.

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.

Treatment

Treatment 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.

Prognosis

The prognosis is variable; it depends on the symptoms present and their severity. Generally, when imperforate anus is treated early, the prognosis is good. The disorder becomes life-threatening only in cases of severe heart and kidney malformations.

External links

Classification	ICD-10: Q87.8 OMIM: 107480 DiseasesDB: 32163

• GeneReview/NCBI/NIH/UW entry on Townes-Brocks Syndrome