RARE DISEASE
Townes-Brocks syndrome
Townes-Brocks syndrome
Townes-Brocks syndrome
Synonyms: Imperforate anus-hand, foot and ear anomalies syndrome, REAR syndrome, Renal-ear-anal-radial syndrome, Sensorineural deafness with imperforate anus and hypoplastic thumbs, Sensorineural hearing loss with imperforate anus and hypoplastic thumbs, TBS, Townes syndrome
Synonyms: Imperforate anus-hand, foot and ear anomalies syndrome, REAR syndrome, Renal-ear-anal-radial syndrome, Sensorineural deafness with imperforate anus and hypoplastic thumbs, Sensorineural hearing loss with imperforate anus and hypoplastic thumbs, TBS, Townes syndrome
Synonyms: Imperforate anus-hand, foot and ear anomalies syndrome, REAR syndrome, Renal-ear-anal-radial syndrome, Sensorineural deafness with imperforate anus and hypoplastic thumbs, Sensorineural hearing loss with imperforate anus and hypoplastic thumbs, TBS, Townes syndrome
Drug discovery
17
papers
On emerging therapies
Overview
Townes-Brocks Syndrome (TBS) is a rare autosomal dominant disorder caused by SALL1 gene mutations, characterized by the triad of imperforate anus/anal stenosis, dysplastic ears with hearing loss, and thumb anomalies. Multisystem involvement (renal, cardiac, genitourinary, and ophthalmic) is common, with variable expressivity. Renal dysfunction (27%) and congenital heart defects (25%) significantly impact prognosis. Diagnosis combines clinical evaluation and molecular testing [1][3][6][7].
Therapies
Surgical correction of imperforate anus/anal stenosis [3][13], hand/foot malformations [2][3], and cardiac defects (e.g., tetralogy of Fallot) [7][9].
Early audiological intervention (hearing aids/cochlear implants) [1][6] and renal replacement therapies (42% develop ESRD) [1][3].
Multidisciplinary monitoring for renal, cardiac, and developmental complications [3].
Categories: rare abdominal surgical diseases, rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare otorhinolaryngological diseases, rare transplant-related disorders
Research Papers
17 drug discovery papers about Townes-Brocks syndrome. Recent publications:
17 drug discovery papers about Townes-Brocks syndrome. Recent publications:
categories:
Small molecules
gene therapies
2026-05-18 | Townes-Brocks Syndrome With Consistent Renal Hypodysplasia and Variable Extrarenal Features Across Three Generations of Serbian Family.
Townes-Brocks syndrome (TBS) is a rare autosomal dominant disorder caused by pathogenic variants in SALL1, classically defined by dysplastic ears, anorectal malformations, and thumb anomalies. Renal involvement is a major determinant of prognosis. We report a Serbian family with multiple members with TBS and molecular confirmation of a SALL1 familial nonsense variant (c.1509C>A, p. Tyr503Ter). Detailed phenotypic data were obtained from paediatric and adult medical records. Seven affected patients across three generations exhibited a remarkably consistent renal phenotype characterized by bilateral renal Hypodysplasia and chronic kidney disease (CKD), contrasted by variable extrarenal features. The proband developed CKD progressing to end-stage renal disease (ESRD) in adolescence, requiring kidney transplantation. Her first male cousin (patient 2) presented with anal atresia, dysplastic ears, hypospadias, and congenital hypothyroidism, and currently has stable CKD stage II. Mother of patient 2 has CKD stage III with small hyperechogenic kidneys and proteinuria. The affected grandfather has ESRD and sensorineural hearing loss. Notably, none of the affected individuals fulfilled the complete classical triad of TBS. This family demonstrates intrafamilial phenotypic variability of TBS but with strikingly consistent renal involvement linked to a familial SALL1 variant. TBS should be considered in patients with congenital anomalies of the kidney and Urinary tract (CAKUT) even in the absence of typical limb or anorectal anomalies. Early molecular diagnosis enables appropriate surveillance and timely management of progressive kidney disease.
2026-01-07 | Delayed diagnosis of Townes-Brocks syndrome accompanied with kidney failure.
Townes-Brocks syndrome (TBS) is a rare autosomal dominant disorder typically characterized by the triad of anorectal malformations, external ear anomalies and hand malformations such as preaxial polydactyly, caused by mutations in the SALL1 gene. Kidney involvement, although less common, can progress to end-stage kidney failure. Early recognition of the characteristic features, particularly those related to SALL1, is crucial for accurate diagnosis, management, and genetic counseling. Here, we present a Turkish family with TBS in which the diagnosis was delayed due to the absence of the classic triad. The proband exhibited significant developmental delay, kidney failure and a congenital foot abnormality, while other family members showed milder manifestations. A multigene panel revealed a heterozygous variant in SALL1 (NM_002968.3:c.2287dup p.R763Kfs*42), which was also identified in the affected family members presenting with milder phenotypes. This case highlights the broad clinical spectrum of TBS, even within the same family. Because major features may not always be present, it can sometimes be overlooked or misdiagnosed; as in our case, which presents with nearly isolated kidney abnormalities. Our report emphasizes the importance of a comprehensive approach, detailed family history and genetic testing in patients with chronic kidney disease of unknown origin.
2025-05-11 | Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature.
Townes-Brocks syndrome (TBS, MIM#107480) is an autosomal dominant disorder linked to SALL1 alterations and characterized by a clinical triad (anorectal, thumb, and external-ear malformations), along with variable features. Renal failure and deafness can occur at any age, making follow-up essential. Some genotype-phenotype correlations have been suggested but data are limited. We collected clinical and molecular data from 49 patients with a SALL1 (likely) pathogenic variant identified in our laboratory or through collaborations, and reviewed the 207 SALL1 related-TBS patients previously reported in the literature. We performed statistical analysis to study genotype-phenotype correlations based notably on the variant position in relation to the glutamine-rich region. In our series, 25% of individuals presented with the clinical triad compared to 49.7% in the literature. The deafness frequency was similar (65%). Renal failure was diagnosed in 39.6% of our patients compared to 29.3% in the literature. Developmental delay or intellectual disability affected 9% of patients. Of the 22 SALL1 variants in our series, 35% were located upstream of the glutamine-rich region, compared to 6.5% in the literature. Statistical analysis was performed on all patients, of which 26 and 200 carried a variant upstream and downstream of the glutamine-rich region, respectively. A significant increase in deafness, dysplastic ear, and thumb malformations and a significant decrease in renal failure were observed in the individuals carrying a variant located downstream of the region, but the patients were significantly younger. Future studies should aim to elucidate the complex pathophysiological mechanisms and prognosis of TBS, functionally and prospectively.
2008-05-10 | SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes
Mutations in SALL1 lead to the dominant multiorgan congenital anomalies that define Townes-Brocks syndrome (TBS). The majority of these mutations result in premature termination codons that would be predicted to trigger nonsense-mediated decay (NMD) of mutant mRNA and cause haploinsufficiency. Our previous studies using a gene targeted mouse model (Sall1-ΔZn) suggested that TBS phenotypes are due to expression of a truncated mutant protein, not haploinsufficiency. In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients. We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient. TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb. We propose a model for the pathogenesis of TBS in which truncated Sall1 protein causes derepression of Sall-responsive target genes. Hum Mutat 0,1–8, 2008. Published 2008 Wiley-Liss, Inc.
small molecules
2018-12-11 | Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.
Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.
cell therapies
2024-11-15 | Cochlear implantation of a child with Townes-Brocks Syndrome in Tanzania: a case report
Abstract Background Townes-Brocks Syndrome (TBS), an autosomal dominant disorder, is known to cause hearing loss amongst other expressions including anomalies that affect the external ear, hands, feet, anus, and kidneys. Case presentation This report describes a case of a four-year-old male of Iranian origin with TBS diagnosed with bilateral profound sensorineural hearing loss who underwent unilateral cochlear implantation in Tanzania. Along with sensorineural hearing loss, the child has dysplastic external ears, ulnar deviation of the thumbs, and overlapping toes. Radiological evaluation revealed cochlear hypoplasia with an enlarged vestibular aqueduct. This is the first known published case of TBS with a cochlear implant in East Africa and details the child’s history, audiological findings, surgical procedure, and post-surgical outcomes. The patient has shown a remarkable increase in Infant–Toddler Meaningful Auditory Integration Scale (IT-MAIS) scores and aided sound-field thresholds at 3 months and 6 months post-switch on. Conclusion This case advocates for encouraging intervention via cochlear implantation and increased awareness of such syndromes. It also adds to the literature on TBS, and its relation to sensorineural hearing loss and inner ear malformations.
2024-10-01 | Towne Brocks Syndrome Presenting as ESKD
Introduction: Townes Brocks Syndrome (TBS) is rare autosomal dominant disorder with multiple organ involvement with mutation of SALL1 on chromosome 16q12.1. Cardiac and renal abnormalities have been reported infrequently.We present one case with TBS who presented with end stage renal disease. Mutation analysis showed de novo mutation in the SALL1 gene. Case Description: Proband,15 years old female presented with anasarca and decreased appetite. She has history of imperforate anus for which operated on 3rd year of life. No significant history in grandparents, parents, siblings. On examination, growth retardation, ear anomaly (overfolding of superior helix of left ear and pre-auricular tag), thumb anomaly (rudimentary Right thumb), flat foot, toe anomaly, atrial septal defect, bilateral sensorineural hearing loss were present.Investigation showed anemia with raised urea and serum creatinine. USG showed both small sized kidneys.Genetic testing confirmed diagnosis with heterozygous nonsense variation of SALL 1gene. Geneting screening of both parents were normal. She was initiated on hemodialysis for renal dysfunction. Discussion: Malformations related to TBS are usually diagnosed in the neonatal period and less known by adult specialists.Renal anomalies,including functional and structural abnormalities has been resported in 43% of patients. In this case report, typical extra renal manifestations led us to genetic testing and confirming diagnosis of TBS , but uremia was the first symptom to prompt the proband to visit the hospital.Sanger sequencing
gene therapies
2026-05-18 | Townes-Brocks Syndrome With Consistent Renal Hypodysplasia and Variable Extrarenal Features Across Three Generations of Serbian Family.
Townes-Brocks syndrome (TBS) is a rare autosomal dominant disorder caused by pathogenic variants in SALL1, classically defined by dysplastic ears, anorectal malformations, and thumb anomalies. Renal involvement is a major determinant of prognosis. We report a Serbian family with multiple members with TBS and molecular confirmation of a SALL1 familial nonsense variant (c.1509C>A, p. Tyr503Ter). Detailed phenotypic data were obtained from paediatric and adult medical records. Seven affected patients across three generations exhibited a remarkably consistent renal phenotype characterized by bilateral renal Hypodysplasia and chronic kidney disease (CKD), contrasted by variable extrarenal features. The proband developed CKD progressing to end-stage renal disease (ESRD) in adolescence, requiring kidney transplantation. Her first male cousin (patient 2) presented with anal atresia, dysplastic ears, hypospadias, and congenital hypothyroidism, and currently has stable CKD stage II. Mother of patient 2 has CKD stage III with small hyperechogenic kidneys and proteinuria. The affected grandfather has ESRD and sensorineural hearing loss. Notably, none of the affected individuals fulfilled the complete classical triad of TBS. This family demonstrates intrafamilial phenotypic variability of TBS but with strikingly consistent renal involvement linked to a familial SALL1 variant. TBS should be considered in patients with congenital anomalies of the kidney and Urinary tract (CAKUT) even in the absence of typical limb or anorectal anomalies. Early molecular diagnosis enables appropriate surveillance and timely management of progressive kidney disease.
2026-01-07 | Delayed diagnosis of Townes-Brocks syndrome accompanied with kidney failure.
Townes-Brocks syndrome (TBS) is a rare autosomal dominant disorder typically characterized by the triad of anorectal malformations, external ear anomalies and hand malformations such as preaxial polydactyly, caused by mutations in the SALL1 gene. Kidney involvement, although less common, can progress to end-stage kidney failure. Early recognition of the characteristic features, particularly those related to SALL1, is crucial for accurate diagnosis, management, and genetic counseling. Here, we present a Turkish family with TBS in which the diagnosis was delayed due to the absence of the classic triad. The proband exhibited significant developmental delay, kidney failure and a congenital foot abnormality, while other family members showed milder manifestations. A multigene panel revealed a heterozygous variant in SALL1 (NM_002968.3:c.2287dup p.R763Kfs*42), which was also identified in the affected family members presenting with milder phenotypes. This case highlights the broad clinical spectrum of TBS, even within the same family. Because major features may not always be present, it can sometimes be overlooked or misdiagnosed; as in our case, which presents with nearly isolated kidney abnormalities. Our report emphasizes the importance of a comprehensive approach, detailed family history and genetic testing in patients with chronic kidney disease of unknown origin.
2025-05-11 | Townes-Brocks syndrome: genotype-phenotype correlations of SALL1 variants in our series and the literature.
Townes-Brocks syndrome (TBS, MIM#107480) is an autosomal dominant disorder linked to SALL1 alterations and characterized by a clinical triad (anorectal, thumb, and external-ear malformations), along with variable features. Renal failure and deafness can occur at any age, making follow-up essential. Some genotype-phenotype correlations have been suggested but data are limited. We collected clinical and molecular data from 49 patients with a SALL1 (likely) pathogenic variant identified in our laboratory or through collaborations, and reviewed the 207 SALL1 related-TBS patients previously reported in the literature. We performed statistical analysis to study genotype-phenotype correlations based notably on the variant position in relation to the glutamine-rich region. In our series, 25% of individuals presented with the clinical triad compared to 49.7% in the literature. The deafness frequency was similar (65%). Renal failure was diagnosed in 39.6% of our patients compared to 29.3% in the literature. Developmental delay or intellectual disability affected 9% of patients. Of the 22 SALL1 variants in our series, 35% were located upstream of the glutamine-rich region, compared to 6.5% in the literature. Statistical analysis was performed on all patients, of which 26 and 200 carried a variant upstream and downstream of the glutamine-rich region, respectively. A significant increase in deafness, dysplastic ear, and thumb malformations and a significant decrease in renal failure were observed in the individuals carrying a variant located downstream of the region, but the patients were significantly younger. Future studies should aim to elucidate the complex pathophysiological mechanisms and prognosis of TBS, functionally and prospectively.
2008-05-10 | SALL1 truncated protein expression in Townes-Brocks syndrome leads to ectopic expression of downstream genes
Mutations in SALL1 lead to the dominant multiorgan congenital anomalies that define Townes-Brocks syndrome (TBS). The majority of these mutations result in premature termination codons that would be predicted to trigger nonsense-mediated decay (NMD) of mutant mRNA and cause haploinsufficiency. Our previous studies using a gene targeted mouse model (Sall1-ΔZn) suggested that TBS phenotypes are due to expression of a truncated mutant protein, not haploinsufficiency. In this report, we strengthen this hypothesis by showing that expression of the mutant protein alone in transgenic mice is sufficient to cause limb phenotypes that are characteristic of TBS patients. We prove that the same pathogenetic mechanism elucidated in mice is occurring in humans by demonstrating that truncated SALL1 protein is expressed in cells derived from a TBS patient. TBS mutant protein is capable of dominant negative activity that results in ectopic activation of two downstream genes, Nppa and Shox2, in the developing heart and limb. We propose a model for the pathogenesis of TBS in which truncated Sall1 protein causes derepression of Sall-responsive target genes. Hum Mutat 0,1–8, 2008. Published 2008 Wiley-Liss, Inc.
small molecules
2018-12-11 | Truncated SALL1 Impedes Primary Cilia Function in Townes-Brocks Syndrome.
Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.
cell therapies
2024-11-15 | Cochlear implantation of a child with Townes-Brocks Syndrome in Tanzania: a case report
Abstract Background Townes-Brocks Syndrome (TBS), an autosomal dominant disorder, is known to cause hearing loss amongst other expressions including anomalies that affect the external ear, hands, feet, anus, and kidneys. Case presentation This report describes a case of a four-year-old male of Iranian origin with TBS diagnosed with bilateral profound sensorineural hearing loss who underwent unilateral cochlear implantation in Tanzania. Along with sensorineural hearing loss, the child has dysplastic external ears, ulnar deviation of the thumbs, and overlapping toes. Radiological evaluation revealed cochlear hypoplasia with an enlarged vestibular aqueduct. This is the first known published case of TBS with a cochlear implant in East Africa and details the child’s history, audiological findings, surgical procedure, and post-surgical outcomes. The patient has shown a remarkable increase in Infant–Toddler Meaningful Auditory Integration Scale (IT-MAIS) scores and aided sound-field thresholds at 3 months and 6 months post-switch on. Conclusion This case advocates for encouraging intervention via cochlear implantation and increased awareness of such syndromes. It also adds to the literature on TBS, and its relation to sensorineural hearing loss and inner ear malformations.
2024-10-01 | Towne Brocks Syndrome Presenting as ESKD
Introduction: Townes Brocks Syndrome (TBS) is rare autosomal dominant disorder with multiple organ involvement with mutation of SALL1 on chromosome 16q12.1. Cardiac and renal abnormalities have been reported infrequently.We present one case with TBS who presented with end stage renal disease. Mutation analysis showed de novo mutation in the SALL1 gene. Case Description: Proband,15 years old female presented with anasarca and decreased appetite. She has history of imperforate anus for which operated on 3rd year of life. No significant history in grandparents, parents, siblings. On examination, growth retardation, ear anomaly (overfolding of superior helix of left ear and pre-auricular tag), thumb anomaly (rudimentary Right thumb), flat foot, toe anomaly, atrial septal defect, bilateral sensorineural hearing loss were present.Investigation showed anemia with raised urea and serum creatinine. USG showed both small sized kidneys.Genetic testing confirmed diagnosis with heterozygous nonsense variation of SALL 1gene. Geneting screening of both parents were normal. She was initiated on hemodialysis for renal dysfunction. Discussion: Malformations related to TBS are usually diagnosed in the neonatal period and less known by adult specialists.Renal anomalies,including functional and structural abnormalities has been resported in 43% of patients. In this case report, typical extra renal manifestations led us to genetic testing and confirming diagnosis of TBS , but uremia was the first symptom to prompt the proband to visit the hospital.Sanger sequencing
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