Townes-Brocks Syndrome 1

A number sign (#) is used with this entry because of evidence that Townes-Brocks syndrome-1 (TBS1) is caused by heterozygous mutation in the gene encoding the SALL1 putative transcription factor (602218) on chromosome 16q12.

There is also evidence that a Townes-Brocks-branchiootorenal-like syndrome is caused by heterozygous mutation in the SALL1 gene.

Description

Townes-Brocks syndrome-1 (TBS1) is characterized by the triad of imperforate anus, dysplastic ears, and thumb malformations. Minor features of the condition include hearing loss, foot malformations, renal impairment with or without renal malformations, genitourinary malformations, and congenital heart disease (Webb et al., 2017).

Genetic Heterogeneity of Townes-Brocks Syndrome

Townes-Brocks syndrome-2 (TBS2; 617466) is caused by mutation in the DACT1 gene (607861) on chromosome 14q23.

Clinical Features

Townes and Brocks (1972) observed a father and 5 of his 7 children who had imperforate anus, triphalangeal thumbs, and other anomalies of the hands and feet, including fusion of metatarsals, absent bones, and supernumerary thumbs. Other features included mild sensorineural deafness, and lop ears. Reid and Turner (1976) described the same syndrome.

Kurnit et al. (1978) described autosomal dominant inheritance of a syndrome of anal stenosis, other anal abnormalities, deformed external ears and perceptive deafness, renal anomalies, including hypoplastic kidney, and radial dysplasia (REAR syndrome). The features are those of the VATER syndrome (192350), which has been subsequently expanded into the VACTERL syndrome (acronym for vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects).

Walpole and Hockey (1982) reported cases. Monteiro de Pina-Neto (1984) reported a case in which congenital heart defect was also present and proposed that the cases of Silver et al. (1972) were instances of this syndrome rather than the Holt-Oram syndrome (142900).

Aylsworth (1985) observed the Townes-Brocks syndrome in a mother and 2 children. De Vries-Van der Weerd et al. (1988) described TBS in a father and son. The son, the proband, showed the full spectrum of anomalies, including imperforate anus, prominent perineal raphe, rectoperineal fistula, triphalangeal thumb, preaxial hexadactyly, syndactyly, clinodactyly, preauricular protuberances, hypoplastic 'satyr' ears, sensorineural hearing loss, and urorenal anomalies. In contrast, the father showed only limb anomalies, sensorineural hearing loss, and renal anomalies. Anorectal malformations, which are present in most patients with TBS, were absent in the father.

Ferraz et al. (1989) reported a sporadic case. The patient's 'satyr ear' and CT scans of the deformities in the ossicles of the ear were pictured. The cardiac lesion was ventricular septal defect. At birth the girl had been noted to have type I imperforate anus with rectovaginal fistula, bilateral supernumerary digits on the radial side of the thumb base, and incomplete soft tissue syndactyly between fingers 2 and 3 on the right. Bilateral symmetric mixed deafness was discovered at age 6 years. The maternal grandfather may have been affected, since he had deafness, polycystic kidneys, and a short proximal phalanx of the left fifth finger.

In a review of the Townes-Brocks syndrome, O'Callaghan and Young (1990) pointed out that patients may have a prominent midline perineal raphe extending from the site of the anal orifice to the scrotum. They pictured the feet of a mother and son, both showing hypoplastic third toes overlapped by the second and fourth toes, as well as a 'satyr' form of lopped ear.

Cameron et al. (1991) suggested that there may be an increase of mental retardation in persons with TBS. Ishikiriyama et al. (1996) also saw a boy with both TBS and mental retardation.

Serville et al. (1993) listed the main features of TBS as follows: abnormal placement of the anus, anal atresia or stenosis; auricular pits, fistulas, or tags; conductive and sensorineural deafness; dysplastic ears; hypoplastic or bifid thumbs; deviation of distal phalanges of the thumbs; triphalangeal thumbs; and cardiac and renal abnormalities. They noted that neither of the patients reported by Friedman et al. (1987) had thumb anomalies, but pointed to the fact that clinical variability is known in TBS.

Johnson et al. (1996) described a 3-generation family in which the grandmother and mother were thought to have Goldenhar syndrome (164210), but the birth of a grandson with typical features of TBS redirected the diagnosis to that possibility. The mother was of short stature with small ears, preauricular and tragal tags on the right and postauricular tag on the left, facial asymmetry, epibulbar dermoids bilaterally, micrognathia, and macrostomia with lateral extension more prominent on the right. The thumbs were triphalangeal with a previously removed, rudimentary, supernumerary digit that had been attached to the right thumb. Midline clefting of the uterus was reported. The anus was normal. The IQ at age 10 was 84; microcephaly was noted at the age of 24 years. The grandmother had small ears with preauricular tags, epibulbar dermoid on the right, and micrognathia without facial asymmetry. The thumbs were triphalangeal and the great toe on the left was bifid representing syndactyly of toes 1 and 2 or absence of 2. Genitourinary abnormalities included urethrostenosis and septate uterus. The anus showed redundant skin. Height was 147 cm. The grandson was born with an imperforate anus covered by a thin membrane requiring a minor surgical procedure. The left side of the face was smaller than the right. The ears were small with overfolding of the helix more prominent on the right which showed a small preauricular tag. Other findings were epibulbar dermoid on the left, triphalangeal thumbs with ulnar deviation.

Newman et al. (1997) reported a case of Townes-Brock syndrome in a male who presented at the age of 23 years with end-stage renal failure. He had severe hypertension and bilaterally small kidneys by ultrasound scan. Surgery had been performed after birth to correct anal stenosis. At that time the ears were noted to be low set with overfolded helices and bilateral preauricular tags, bilateral preaxial hexadactyly of the hands, and syndactyly of the third and fourth toes. Bilateral sensorineural deafness was noted at 3 years of age.

Kohlhase et al. (1998) reported 2 half-sibs with TBS, born of the same mother. Photographs illustrated the presence of duplicated triphalangeal left thumb and duplicated triphalangeal right thumb combined with a third dysplastic thumb. Dysplastic ears were also illustrated. The affected mother displayed low birth weight and presented with imperforate anus, preauricular tags, microtia and dysplastic ears, sensorineural hearing loss, bifid right thumb, and rudimentary bifid left thumb. Her son had imperforate anus type 3 with rectoperineal fistula, microtia and dysplastic ears, sensorineural hearing loss, bifid left and distally broadened right thumb. His sister likewise showed imperforate anus type 3 with rectovaginal fistula, preauricular tags, microtia and dysplastic ears, sensorineural hearing loss, bifid triphalangeal left thumb, and triple triphalangeal right thumb.

Doray et al. (1999) described 2 unrelated, apparently sporadic cases of Townes-Brocks syndrome.

Surka et al. (2001) described a 3-generation family in which 7 individuals had TBS confirmed by genetic analysis (602218.0008). Cardiac anomalies seen in this family included lethal truncus arteriosus in 1 patient and a lethal complicated defect that included pulmonary valve atresia in a second. These severe cardiac anomalies had not previously been reported in a familial case of TBS. On the basis of this family and a review of the literature, Surka et al. (2001) suggested that cardiac evaluation is warranted in all patients with this disorder. The authors stated that hypoplastic thumbs were observed in 2 individuals in their family and therefore should be considered a feature of TBS. In fact, the thumb anomalies as indicated by the photographs were bilateral triphalangeal thumbs in at least 2 individuals, a right hypoplastic thumb with absent distal phalanx and left preaxial polydactyly and triphalangeal thumb in one, and left preaxial polydactyly and triphalangeal thumb in another. A severely affected child who died at the age of 3 days from cardiac malformations had bilateral preaxial polydactyly.

Botzenhart et al. (2005) reported 13 unrelated families with TBS confirmed by genetic analysis. Rare phenotypic features included hypothyroidism, gastroesophageal reflux, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, Duane anomaly, dorsal hypoplasia of the corpus callosum, and umbilical hernia.

Sudo et al. (2010) reported a Japanese family in which the 4-year-old female proband had bilateral preauricular tags, bilateral preaxial polydactyly, syndactyly of the right toe, overriding toes of the left foot, anteriorly placed and stenosed anus, mild bilateral sensorineural hearing loss, ventricular septal defect, and small right kidney. Her mother and her maternal uncle, grandfather, and great aunt were also affected. Her mother had right preaxial polydactyly, anterior placement of the anus, small right kidney, and mild sensorineural hearing loss, whereas her uncle had right preaxial polydactyly, imperforate anus, and mild hearing loss. Her grandfather and great aunt had only unilateral preaxial polydactyly and deafness. The proband and her mother were found to be heterozygous for a frameshift mutation in the SALL1 gene. Sudo et al. (2010) noted that there was an anticipation-like increase in severity of the phenotype with each succeeding generation in this family, and stated that similar increases in clinical severity had been observed in other TBS families, frequently in patients who inherited the disease from their mothers.

Inheritance

Autosomal dominant inheritance of TBS is well established, with multiple cases of male-to-male transmission reported by Townes and Brocks (1972), Reid and Turner (1976), Kurnit et al. (1978) and de Vries-Van der Weerd et al. (1988).

Pathogenesis

Bozal-Basterra et al. (2018) showed that TBS-derived primary fibroblasts exhibit changes in SALL1 localization, a higher rate of ciliogenesis, abnormally elongated cilia, aberrant cilia disassembly, and SHH signaling defects. Through proximity proteomics, Bozal-Basterra et al. (2018) identified 2 main ciliogenesis suppressors, CCP110 (609544) and CEP97 (615864), as interactors of TBS-causing truncated SALL1. The higher rate of ciliogenesis detected in TBS-derived primary fibroblasts is consistent with an observed lower amount of CCP110 and CEP97 at the mother centriole in these fibroblasts compared with controls. The authors noted that truncated SALL1, alone or with full-length SALL1, sequesters CCP110 and CEP97, disrupting cilia formation and function. Bozal-Basterra et al. (2018) concluded that TBS might be considered a ciliopathy.

Cytogenetics

Serville et al. (1993) described TBS in an infant with a 2-break reciprocal translocation between chromosomes 5 and 16. They noted that Friedman et al. (1987) described father and daughter with this syndrome associated with a pericentric inversion of chromosome 16 with breakpoints at p11.2 and q12.1. Since 16p12.1 was the location of 1 of the breakpoints in the patient reported by Serville et al. (1993), they suggested that this may be the location of the gene for TBS.

Molecular Genetics

In 2 half-sibs with TBS, born of the same mother, and a sporadic TBS patient, Kohlhase et al. (1998) identified 2 different heterozygous mutations in the SALL1 gene (602218.0001; 602218.0002).

In a father and 2 daughters with features overlapping those of Townes-Brocks syndrome and branchiootorenal syndrome (113650), Engels et al. (2000) identified a mutation in the SALL1 gene (602218.0007). The daughters had dysplastic ears, hypoplastic kidneys with impaired renal function, gastroesophageal reflux, hypermetropia, and mild developmental delay. The father showed impaired renal function, dysplastic ears, and gastroesophageal reflux. None of the affected family members had anal or hand malformations. Engels et al. (2000) considered this family to demonstrate phenotypic overlap between the 2 conditions.

In 3 members of a nonconsanguineous German family who had only some features of Townes-Brocks syndrome, Albrecht et al. (2004) identified a mutation in the SALL1 gene (602218.0009). Characteristic features of TBS included preauricular tags, overfolded helices, hypospadias, and impaired renal function; 1 brother had only hypospadias and underriding third toes. None of the affected family members had the characteristic anal or hand malformations of TBS. Albrecht et al. (2004) considered the disorder in their patients to be different from that described by Engels et al. (2000).

Powell and Michaelis (1999) reviewed the clinical features and molecular basis of Townes-Brocks syndrome.

Botzenhart et al. (2005) stated that 35 mutations had been identified in the SALL1 gene. Most mutations occur 5-prime to or within the region encoding the first double zinc finger.

Kosaki et al. (2007) analyzed the SALL1 gene in 2 sisters, 1 with a Townes-Brocks syndrome phenotype and the other exhibiting features of Goldenhar syndrome (see hemifacial microsomia, 164210), and identified heterozygosity for a mutation (L419X; 602218.0010). Their mother, who had dysplastic external ears but was otherwise normal, also carried the mutation. The authors noted that Johnson et al. (1996) had previously reported an affected family member with a Goldenhar syndrome-like phenotype in a 3-generation TBS family.

Genotype/Phenotype Correlations

Furniss et al. (2007) reported a heterozygous mutation in the SALL1 gene (995delC; 602218.0011) in a patient with a relatively severe form of Townes-Brocks syndrome. The patient had bilateral preaxial polydactyly, imperforate anus, rectal atresia, hypospadias, and overfolded helices. The mutation was found to be resistant to nonsense-mediated decay. Furniss et al. (2007) concluded that the phenotype was caused by a truncated SALL1 protein acting in a dominant-negative manner. These findings were in contrast to another SALL1 mutation (602218.0012) that did undergo nonsense-mediated decay and was associated with a milder phenotype of Townes-Brocks syndrome.