Townes-Brocks syndrome (TBS)

What is Townes-Brocks syndrome (TBS)?

The main features are triphalangeal thumbs, an imperforate anus, overfolded helices to the ears, sensorineural deafness and pes planus. Preauricular pits or tags may be present, as may a conductive component to the deafness. Minor radiological features such as pseudoepiphyses of the metacarpals, an absent triquetrum and fused metatarsals have been reported. Renal anomalies have been documented including renal hypoplasia, unilateral renal agenesis, posterior urethral valves, vesicoureteric reflux and meatal stenosis (reviewed by Newman et al., 1997). Renal failure might be an under recognized phenomenon (Reardon et al., 2007). Marlin et al., (1998) reported two cases, one with growth retardation and delayed puberty, and the other with vertebral anomalies consisting of cervical vertebral fusion as well as fusion between D12 and L1, and L3 and L4. Severe swallowing and breathing problems can occur (van Bever et al., 2009).
Serville et al., (1993) reported a male with features of the condition who had a balanced 5;16 translocation (p15.3;q12.1). Unfortunately the parents were unavailable for chromosome studies.
Johnson et al., (1996) reported a family where the proband had classical features of Townes-Brocks syndrome, but his mother and maternal grandmother had additional features including facial asymmetry, macrostomia, and epibulbar dermoids that suggested Goldenhar syndrome. The grandmother also had a bifid right toe. The grandmother also had urethral stenosis and a septate uterus. In the Albrecht et al., (2004) family there was also considerable intrafamilial variability (all had a novel SALL1 mutation). There were no anal or thumb manifestations, although the ears were typical. Two of the 3 had impaired renal function. A patient (with a mutation) reported by van den Akker et al., (2009) had in addition a Duane anomaly.
The condition can be mimicked by a partial trisomy 22 (see for example Levonton et al., 1980). The case with limb asymmetry reported by Ishikiriyama et al., (1996) could well have mosaicism as skin chromosomes were not examined.Occasional families with autosomal dominant form of isolated anal stenosis have also been reported (Landau et al., 1997).

Kohlhase et al., (1998) reported mutations causing premature stop codons of the SALL1 gene in a dominant family and an isolated case. The SALL1 gene codes for a protein homologous to a drosophila developmental regulator. The SALL1 gene codes for a transcriptional repressor, which interacts with TRF1-PIN2 and localizes to pericentromeric heterochromatin (Netzer et al., (2003). Further mutations were reported by Kohlhase et al., (1999) and Blanck et al., (2000). Kiefer et al., (2003) showed that the mutations result in a truncated protein and act in a dominant negative or gain of function manner.
Kohlhase et al., (2003) point out that the Arg276X mutation had been demonstrated in approximately 50% of sporadic cases with detectable SALL1 mutations but, up to that point, had not been observed familial cases. The absence of the mutation in familial cases with SALL1 mutations had raised the question of whether the Arg276X mutation results in infertility. However they reported a mother and daughter with a Arg276X mutation.
Devriendt et al., (2002) reported a case where the father just had 3-4 toe syndactyly. He was found to have a mosaic SALL1 mutation in fibroblasts and buccal smear. Engels et al., (2000) reported a patient with a SALL1 mutation where there was phenotypic overlap with branchio-oto-renal (BOR) syndrome.
Surka et al., (2001) reported a mutation proven family where there were unusual cardiac abnormalities including truncus arteriosus, and a lethal complicated cardiac defect including pulmonary valve stenosis.
Keegan et al., (2001) studied eight patients with features of hemifacial microsomia, but with anal anomalies. They found a SALL1 mutation in one patient. This patient had bilateral microtia, facial asymmetry, bilateral duplicated thumbs, 1-2 syndactyly of the left foot; 4-5 syndactyly of the right foot with a cleft between the 1st and 2nd digits, hypospadias and an anal tag.
Powell and Michaelis (1999) provide a good review of the clinical and molecular features.Kosaki et al., (2007) reported a family in which one member had the Towns-Brooks phenotype, whereas her sister had features of Goldenhar including an epibulbar dermoid. Both had SALL1 mutations. A remarkable, probably multigenerational family, reported by Al-Qattan et al., (2012) had an initial diagnosis of Townes-Brocks syndrome because of triphalageal thums, thumb aplasia, polydactyly, radial ray aplasia and unilateral renal agenesis. ZRS mutations - this is the long-range regulator, was found. - see under "chromosome 7q36.3 - microdeletion"

Syndrome Synonyms

Anus, Imperforate, With Hand, Foot, And Ear Anomalies Deafness, Sensorineural, With Imperforate Anus And Thumb Anomalies Rear Syndrome Renal-ear-anal-radial Syndrome TBS Townes-Brocks syndrome

What gene changes cause Townes-Brocks syndrome (TBS)?

Genes, locations, and inheritance modes
DACT1, 14q23.1 - Autosomal Dominant, Mitochondrial
SALL1, 16q12.1 - Autosomal Dominant, Mitochondrial

OMIM Number - 107480 (please check the OMIM page for updated information)

What are the main symptoms of Townes-Brocks syndrome (TBS)?

Possible clinical traits/features:
Rectoperineal fistula, Pseudoepiphyses of second metacarpal, Urethral valve, Ulnar deviation of finger, Short metatarsal, Stahl ear, Urogenital fistula, Microcephaly, Strabismus, Ventricular septal defect, Tetralogy of Fallot, Umbilical hernia, Metatarsal synostosis, Preaxial foot polydactyly, Autosomal dominant inheritance, Sensorineural hearing impairment, Renal hypoplasia, Toe syndactyly, Preauricular skin tag, Pes planus, Overfolding of the superior helices, Partial duplication of thumb phalanx, Patent ductus arteriosus, Renal dysplasia, Rectovaginal fistula, Wide mouth, Vesicoureteral reflux, Renal insufficiency, Preaxial hand polydactyly, Hypothyroidism, Visual impairment, Hypospadias, Duane anomaly, Cognitive impairment, Gastroesophageal reflux, Hearing impairment, Short stature, Hypoplasia of penis, Intellectual disability, Iris coloboma, Microtia, Multicystic kidney dysplasia, Preauricular pit, Macrotia, 3-4 toe syndactyly, 3-4 finger syndactyly, 2-4 finger syndactyly, 2-3 toe syndactyly, Abnormal lo

How does someone get tested for Townes-Brocks syndrome (TBS)?

The initial testing for Townes-Brocks syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

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