NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Townes-Brocks Syndrome

, MD
Center for Human Genetics
Freiburg, Germany

Initial Posting: ; Last Update: January 14, 2016.

Summary

Clinical characteristics.

Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (84%), dysplastic ears (87%; overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment [65%]), and thumb malformations (89%; triphalangeal thumbs, duplication of the thumb [preaxial polydactyly], and rarely hypoplasia of the thumbs). Renal impairment (42%), including end-stage renal disease (ESRD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%; flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of individuals. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation.

Diagnosis/testing.

The diagnosis of TBS is based on clinical findings; identification of a heterozygous SALL1 pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Immediate surgical intervention for imperforate anus; early treatment of hearing loss; surgery for severe malformations of the hands; hemodialysis and possibly kidney transplantation for ESRD; surgery or medical treatment by a cardiologist for congenital heart defects.

Surveillance: Annual hearing evaluation; regular monitoring of renal function in individuals with and without renal anomalies, even if renal function is normal on initial examination.

Agents/circumstances to avoid: Medications that cause renal or otic toxicity.

Genetic counseling.

TBS is inherited in an autosomal dominant manner. The proportion of cases caused by de novo pathogenic variants is estimated at 50%. Each child of an individual with TBS caused by a SALL1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant has been identified in the family.

Diagnosis

Suggestive Findings

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

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 TBS)

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

Establishing the Diagnosis

The diagnosis of TBS is established in a proband with three major features. If only two major features are present, the presence of minor features and the absence of atypical features further support the diagnosis. Identification of a heterozygous SALL1 pathogenic variant on molecular genetic testing (see Table 1) establishes the diagnosis if clinical features are inconclusive.

Molecular testing approaches can include single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

Single-gene testing. Sequence analysis of SALL1 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

A multi-gene panel that includes SALL1 and other genes of interest may also be considered. The genes included in multi-gene panels vary by laboratory and over time. However, due to the existence of a highly homologous SALL1 pseudogene (SALL1P1), capture-based gene panels may not be the optimal choice.

Note: (1) A few individuals with clinical features of TBS have been found to have pathogenic variants in SALL4 [Kohlhase et al 2002; Borozdin et al 2004; Kohlhase, personal communication]. Therefore, in individuals with a diagnosis of TBS and negative SALL1 testing, SALL4 molecular genetic testing should be considered. (2) Molecular genetic testing of SALL4 rather than SALL1 is suggested as the first molecular test if the radius is involved and/or if Duane anomaly is present. See Differential Diagnosis, Okihiro syndrome and SALL4-Related Disorders.

More comprehensive genomic testing may be considered if serial single gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of TBS. Such testing may include whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq). For issues to consider in interpretation of genomic test results, click here.

Table 1.

Molecular Genetic Testing Used in Townes-Brocks Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
SALL1Sequence analysis 3~70% 4
Gene-targeted deletion/duplication analysis 5~5% 6
Unknown 7NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Sequence analysis has detected pathogenic variants in more than 100 individuals with Townes-Brocks syndrome [Kohlhase et al 1998, Kohlhase et al 1999, Marlin et al 1999, Blanck et al 2000, Engels et al 2000, Kohlhase 2000, Salerno et al 2000, Surka et al 2001, Devriendt et al 2002, Kohlhase et al 2003, Botzenhart et al 2005, Walter et al 2006, Botzenhart et al 2007]. Sequence analysis in about 70% and deletion/duplication testing in about 5% identify a SALL1 pathogenic variant or deletion in approximately 75% of persons with the classic triad of malformations as described by Kohlhase et al [1999].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Borozdin et al [2006] identified three and Bardakjian et al [2009] and Miller et al [2012] identified two further multiexon/whole-gene deletions.

7.

A SALL1 pathogenic variant has not been found in a number of individuals with the classic TBS phenotype; thus, locus heterogeneity appears likely.

Clinical Characteristics

In the two most recent studies [Botzenhart et al 2005, Botzenhart et al 2007] of 61 persons with novel SALL1 pathogenic variants (not including the most common pathogenic variant, p.Arg276Ter), 84% had anal anomalies, 89% hand anomalies, and 87% ear anomalies; 67% had the characteristic triad.

Clinical Description

  • Gastrointestinal. Imperforate anus, anal stenosis, chronic constipation, gastroesophageal reflux [Engels et al 2000]
  • Dysplastic ears (overfolded superior helices, microtia), congenital sensorineural and/or conductive hearing loss ranging from mild to severe. Hearing loss that is mild may worsen with age (65% of individuals).
  • Thumb malformations. Preaxial polydactyly, triphalangeal thumbs, and hypoplastic thumbs without hypoplasia of the radius
  • Lower extremities. Club foot, overlapping toes (II and IV over III), syndactyly of toes, missing toes (III) (52% of individuals) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]
  • Kidneys. Renal agenesis, renal hypoplasia, polycystic kidneys; functional impairment with or without structural abnormalities (42% of individuals) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]
  • Genitourinary. Hypospadias, vaginal aplasia with bifid uterus, bifid scrotum, cryptorchidism (36% of individuals) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]
  • Heart. Congenital heart disease in 50% of persons with the common p.Arg276Ter pathogenic variant [Kohlhase et al 2003] and 12%-25% of persons with other SALL1 pathogenic variants [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007]. Defects include atrial septal defect, ventricular septal defect, tetralogy of Fallot, lethal truncus arteriosus, pulmonary valve atresia, and persistent ductus arteriosus [Surka et al 2001].
  • Central nervous system
    • Intellectual disability (~10%)
    • Behavioral problems, observed in many children with TBS [Kohlhase, unpublished observations]
    • Arnold-Chiari malformation type I [Kohlhase, unpublished observations]
    • Cranial nerve palsy (nerves VI and VII)
    • Duane anomaly. Uni- or bilateral limitation of abduction of the eye associated with retraction of the globe and narrowing of the palpebral fissure on adduction. The abducens nucleus and nerve (cranial nerve VI) are absent and the lateral rectus muscle is innervated by a branch of the oculomotor nerve (cranial nerve III), accounting for the aberrant ocular movements.
    • Hypoplasia of the dorsal part of corpus callosum
  • Growth. Postnatal growth retardation. This poorly documented feature has been described in fewer than 6% to 29% of persons reported with TBS in the literature [Surka et al 2001]. The occurrence of postnatal growth retardation among individuals with a confirmed pathogenic variant is not known. Lawrence et al [2013] reported growth hormone deficiency in an individual with TBS, suggesting that this may also be the cause for growth retardation in other individuals with TBS.
  • Skeletal. Rib anomalies (fused ribs, missing ribs, additional cervical ribs), mild vertebral anomalies (9%). Painful joints have been observed in several adults with TBS [Kohlhase, unpublished observations].
  • Eyes. Microphthalmia (rare), iris coloboma, lamellar cataract, chorioretinal coloboma with loss of vision
  • Face. Hemifacial microsomia [Kohlhase et al 1999, Keegan et al 2001]
  • Endocrine. Congenital hypothyroidism (rare) [Lawrence et al 2013]

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been made for the majority of pathogenic variants, most of which are private.

The most common pathogenic variant and the only pathogenic variant found in more than two families is c.826C>T (p.Arg276Ter), detected in approximately half of simplex cases with TBS (i.e., a single occurrence in a family) and in one familial case to date [Kohlhase et al 2003]. This pathogenic variant is associated with greater frequency (50%) and severity of congenital heart defects than other pathogenic variants. Fifteen of 16 individuals with this pathogenic variant showed the characteristic triad of anal, thumb, and ear malformations (94%), indicating that this pathogenic variant is associated with a more severe phenotype.

In general, pathogenic variants within the hot spot region that is towards the 5' end in exon 2 appear to be associated with a more severe outcome than pathogenic variants towards the 3' in exon 2. In addition, the phenotype associated with deletions of SALL1 appears to be milder than that associated with pathogenic variants in the hot spot region, but only five families with larger deletions have been reported to date [Borozdin et al 2006, Bardakjian et al 2009, Miller et al 2012].

Penetrance

Penetrance appears to be complete, but expressivity is highly variable.

Anticipation

Apparent increased severity in successive generations is likely attributable to ascertainment bias.

Nomenclature

Feichtiger [1943] provided one of the earliest reports of Townes-Brocks syndrome.

Townes & Brocks [1972] were the first to report autosomal dominant transmission of the characteristic anomalies.

Kurnit et al [1978] used the term REAR syndrome (for renal, ear, anal, and radial malformations).

Monteiro de Pina-Neto [1984] was the first to use the term Townes-Brocks syndrome.

Prevalence

The prevalence is unknown, partly because the clinical diagnosis of Townes-Brocks syndrome is often complicated by overlap with VACTERL association, which may lead to an over-ascertainment of TBS prevalence. Martínez-Frías estimated the prevalence at 1:250,000 but did not use stringent diagnostic criteria for TBS [Martínez-Frías et al 1999].

Differential Diagnosis

The clinical presentation of Townes-Brocks syndrome (TBS) can overlap with Goldenhar syndrome (hemifacial microsomia) [Gabrielli et al 1993, Kohlhase et al 1999, Keegan et al 2001], Okihiro syndrome (but without malformations of the radius) [Borozdin et al 2004], and branchiootorenal syndrome [Engels et al 2000, Albrecht et al 2004]. TBS also overlaps with VACTERL association.

Goldenhar syndrome. The majority of individuals with oculo-auriculo-vertebral spectrum phenotypes do not have upper-limb or anal malformations. However, some persons with SALL1 pathogenic variants have hemifacial microsomia. [Gabrielli et al 1993, Johnson et al 1996, Kohlhase et al 1999, Keegan et al 2001]. Therefore, while hemifacial microsomia alone is not suggestive of the presence of a SALL1 pathogenic variant, it may occur in individuals with a SALL1 pathogenic variant in addition to more typical TBS malformations.

Okihiro syndrome (Duane-radial ray syndrome) is characterized by Duane anomaly and radial ray defects, and less commonly by hearing loss and renal position anomalies (see SALL4-Related Disorders).

  • In a few individuals with clinical TBS, causative SALL4 variants were found instead of SALL1 [Kohlhase et al 2002; Borozdin et al 2004; Kohlhase, personal communication]. In those individuals, both SALL1 and SALL4 molecular genetic testing should be considered.
  • Duane anomaly can also occur with a SALL1 pathogenic variant [Kohlhase et al 1999, Botzenhart et al 2005].
  • Because radial aplasia or hypoplasia and thumb aplasia have not been observed in individuals with a SALL1 pathogenic variant [Kohlhase, unpublished data], their presence points toward a SALL4 pathogenic variant, even if all other features suggest TBS.

Branchiootorenal (BOR) syndrome. In two families eventually determined to have SALL1 pathogenic variants, no affected individual had the typical triad of thumb, anal, and ear malformations. Instead, the presence of dysplastic ears and renal malformations or impaired renal function in family members initially led to the consideration of BOR syndrome [Engels et al 2000, Albrecht et al 2004].

VACTERL association (OMIM 192350) comprises vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal malformations, and limb defects. VACTERL is therefore an important differential diagnosis for simplex cases (i.e., a single affected individual in a family) with suspected TBS. To date, severe vertebral defects and tracheo-esophageal fistula have not been observed in persons with a SALL1 pathogenic variant [Kohlhase, unpublished data]. Sib and offspring recurrence risks for VACTERL association are estimated at approximately 1%. A review summarizes current information on VACTERL association [Shaw-Smith 2006].

STAR syndrome (OMIM 300707) is characterized by toe syndactyly, telecanthus, anogenital malformations, and renal malformations similar to TBS. Facial features and toe syndactyly distinguish STAR syndrome from TBS. STAR syndrome is caused by mutation of FAM58A and inherited in an X-linked manner with likely lethality in males.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Townes-Brocks syndrome (TBS), the following evaluations are recommended:

  • Hearing. Hearing evaluation as soon as the diagnosis of TBS is suspected (see Deafness and Hereditary Hearing Loss Overview)
  • Kidneys. Renal ultrasound examination and routine laboratory tests for renal function
  • Heart. Baseline evaluation by a cardiologist including an echocardiogram
  • Eyes. Ophthalmology examination to evaluate for ocular features of TBS and atypical finding of Duane anomaly.
  • Medical genetics consultation

Treatment of Manifestations

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.

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.

Agents/Circumstances to Avoid

Medications that cause renal or otic toxicity should be avoided.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, clinical evaluation for physical features, hearing problems, renal disease, and heart defects can be used to clarify the disease status of at-risk relatives.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Townes-Brocks syndrome (TBS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • About 50% of individuals diagnosed with TBS resulting from a SALL1 pathogenic variant have an affected parent; about 50% have the disorder as the result of a de novo pathogenic variant [Kohlhase, unpublished observation].
  • De novo SALL1 pathogenic variants most commonly occur (~87.5%) on the paternally derived chromosome 16 without an obvious age effect [Böhm et al 2006].
  • If the SALL1 pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Three individuals with mosaicism including the germline have been reported [Kohlhase et al 1999, Blanck et al 2000, Devriendt et al 2002].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo SALL1 pathogenic variant include molecular genetic testing or physical examination, examination of the limbs (x-rays of the forearms, inspection of the feet) and ears, a hearing test, ultrasound examination of the kidneys and laboratory tests for renal function, and heart examination.
  • The family history of some individuals diagnosed with TBS may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., molecular genetic testing, physical examination) have been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a pathogenic variant may be as mild as toes II and IV overlapping the third toe [Devriendt et al 2002].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

  • If a parent of the proband has a SALL1 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. With the exception of the p.Arg276Ter pathogenic variant, which has caused a severe phenotype in all known instances, results of molecular genetic testing cannot predict which manifestations will be present or their severity.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be about 1%-2% because of the possibility of germline mosaicism [Kohlhase, unpublished observation].

Offspring of a proband. Each child of an individual with Townes-Brocks syndrome has a 50% chance of inheriting the SALL1 pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant, it is likely that the proband has a de novo variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Fetus with high a priori risk. If the SALL1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Although this testing can determine whether or not the fetus has inherited the SALL1 pathogenic variant, it cannot predict which manifestations will be present or their severity, with the exception of the p.Arg276Ter pathogenic variant, which has caused a severe phenotype in all known instances. High-resolution ultrasound examination is therefore recommended to evaluate the fetus for phenotypic manifestations. In a study of families with the pathogenic variant p.Arg276Ter, a fetus at risk was found to have a complex heart defect, preaxial polydactyly, foot malformations, and preauricular tags, suggesting TBS as the diagnosis [Kohlhase et al 2003].

Fetus with low a priori risk. If a fetus at no known increased risk for TBS has what appear to be features of classic TBS detected as early as the 16th week of pregnancy by a combination of high-resolution ultrasound and 3D ultrasound examinations, molecular genetic testing of SALL1 can confirm the diagnosis.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the SALL1 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Alexander Graham Bell Association for the Deaf and Hard of Hearing
    3417 Volta Place Northwest
    Washington DC 20007
    Phone: 866-337-5220 (toll-free); 202-337-5220; 202-337-5221 (TTY)
    Fax: 202-337-8314
    Email: info@agbell.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Congenital Heart Information Network (CHIN)
    101 North Washington Avenue
    Suite 1A
    Margate City NJ 08402-1195
    Phone: 609-822-1572
    Fax: 609-822-1574
    Email: mb@tchin.org
  • Medline Plus
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Townes-Brocks Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
SALL116q12​.1Sal-like protein 1SALL1 databaseSALL1

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Townes-Brocks Syndrome (View All in OMIM)

107480TOWNES-BROCKS SYNDROME; TBS
602218SAL-LIKE 1; SALL1

Gene structure. SALL1 occupies about 14.1 kb (start codon to stop codon). It contains four exons (all coding, two alternate first exons) and two introns. The genomic sequence is NC_000016.10.

Benign allelic variants. More than 29 different non-pathogenic polymorphisms are currently known [Böhm et al 2006].

Pathogenic allelic variants. All reported and confirmed pathogenic variants are truncating and located in exon 2 and intron 2 of the gene [Kohlhase et al 1998, Kohlhase et al 1999, Marlin et al 1999, Blanck et al 2000, Engels et al 2000, Kohlhase 2000, Salerno et al 2000, Surka et al 2001, Devriendt et al 2002, Kohlhase et al 2003, Walter et al 2006, Reardon et al 2007, van den Akker et al 2009, Choi et al 2010, Hwang et al 2014].

Forty-six out of the 56 known SALL1 pathogenic variants (2013 data) were located between the coding regions for the glutamine-rich domain mediating SALL protein interactions and 65 bp 3' of the coding region for the first double zinc finger domain, narrowing the SALL1 mutational hot spot region to a stretch of 802 bp within exon 2.

Based on studies in mouse and chicken [Kiefer et al 2003, Sweetman et al 2003], it appears likely that the pathogenic variants escape nonsense-mediated messenger decay and therefore do not result in haploinsufficiency of the protein encoded by SALL1. However, three families in whom larger deletions partially or completely removing SALL1 clearly result in TBS have been described [Borozdin et al 2006]. One family had a heterozygous deletion of all exons, one had deletion of the entire SALL1 gene and several neighboring genes, and one had deletion of intron 2 and partial deletion of exons 2 and 3. These findings confirm that SALL1 haploinsufficiency can cause the phenotype, but it appears that the phenotype associated with larger deletions is at least milder than that of c.826C>T (though not milder than the phenotype associated with several other single-nucleotide variants).

Table 2.

SALL1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.826C>Tp.Arg276TerNM_002968​.2
c.3160C>Tp.Arg1054Ter

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. SALL1 encodes a C2H2 zinc finger protein of the SAL type, similar to the SAL protein encoded by the Drosophila gene spalt. It contains four double zinc finger domains characteristically distributed over the protein. There are also two single zinc fingers, a C2HC domain at the N terminus and a C2H2 finger attached to the second double zinc finger. SALL1 is found strictly in the cell nucleus; it binds to heterochromatic foci and contains repressor domains at the N-terminus and in the central region [Netzer et al 2001, Netzer et al 2006]. Expression of csal1 (the chick ortholog of SALL1) in the limb is activated by ectopic SHH. However, this activation requires signals from the apical ectodermal ridge and involves FGF4/8 as well as Wnt3a and Wnt7a [Farrell & Munsterberg 2000], showing that csal1 expression is under control of at least three different pathways. In zebrafish, the SALL1 homolog sall1a is regulated by tbx5 and required for fgf10 and fgfr2 expression in the posterior pectoral fin bud [Harvey & Logan 2006]. In the mouse, Sall1 was found to enhance the canonical Wnt signaling pathway by localizing to pericentromeric heterochromatin [Sato et al 2004].

Abnormal gene product. All SALL1 pathogenic variants (except for the larger deletions) detected in persons with TBS to date result in premature stop codons. Since transcripts with a premature stop codon are in most instances rapidly degraded, these pathogenic variants are a priori likely to cause TBS via SALL1 haploinsufficiency [Hentze & Kulozik 1999, Maquat 2004]. Proof for SALL1 haploinsufficiency being involved in the pathogenesis of human TBS came from the recent detection of a heterozygous 75-kb deletion of the entire SALL1 coding region in a family with TBS [Borozdin et al 2006].

However, the Sall1 knock-out mouse showed that loss of Sall1 function does not result in defects that affect tissues other than kidney [Nishinakamura et al 2001]. Introducing a TBS pathogenic variant in mouse Sall1 instead leads to a TBS-like phenotype, and the detection of truncated Sall1 proteins points to a role of those proteins in the pathogenesis of TBS [Kiefer et al 2003]. In the zebrafish, sall1a loss of function leads to defective limb development, which can be aggravated by concomitant knock-down of sall4 [Harvey & Logan 2006].

Comparison of the phenotypes associated with a SALL1 deletion or with the severe p.Arg276Ter pathogenic variant indicate that the malformations in the family with the 75-kb deletion were relatively mild [Borozdin et al 2006]. It could therefore be that SALL1 deletions (i.e., SALL1 haploinsufficiency) cause milder phenotypes than truncating mutations. This would require that mutated SALL1 transcripts with premature stop codons escape the NMD pathway and lead to truncated proteins similar to those detected in mice. However, truncated SALL1 proteins have not been found in lymphoblastoid and amniotic fluid cells of persons with TBS [Kohlhase & Rauchman, unpublished data], possibly because tissues most strongly expressing SALL1 in the adult (brain and kidney) have not been accessible for investigation.

Csal (chicken) and Sall (mouse) proteins can interact with each other via mediation of an N-terminal glutamine-rich domain conserved in all known Sal proteins. Expression of truncated Sall1/ csal1 proteins is detected throughout the cell and not confined to the nucleus as full-length Sall1. Truncated Sall1 can interact with full-length Sall proteins and cause their displacement from the nucleus [Kiefer et al 2003, Sweetman et al 2003].

Alleles resulting from SALL1 pathogenic variants in the 5' region of exon 2 encode for truncated proteins with strong repressor activity but without the central repression and heterochromatin localization domain [Netzer et al 2006]. Despite their potential to act as strong transcriptional repressors, these proteins will probably not localize to the physiologic site of action, but bind other SAL proteins and move them from the nucleus to the cytoplasm. Pathogenic variants further 3' in SALL1 likely result in milder phenotypes than the 5' pathogenic variants [Blanck et al 2000, Botzenhart et al 2005]. If some of those pathogenic variants lead to truncated proteins including both repression domains and the heterochromatin localization domain, these proteins could still localize to their place of action and have some residual function, which could explain the milder phenotype.

The critical point in pathogenesis appears to be the correct dosage of functional SALL1 protein at the heterochromatic foci. A deletion of one allele results in a 50% reduction of this dosage. A 5' truncating mutation possibly leads to a truncated protein, which does not reach its site of action and in addition probably even removes some full-length protein of the normal allele from the nucleus. Therefore, in most instances the more severe phenotype of the 5' truncating mutations may result from a greater than 50% reduction of the functional protein at the site of action.

The additive phenotype of the combined sall4 and sall1a knock-down in zebrafish suggests that both genes may be able to compensate to some extent for each other. In view of the additive effects of sall1a and sall4 knock-down on limb development it remains unclear if the TBS phenotype in humans is only caused by loss of SALL1 function or also by an effect of the hypothetic truncated SALL1 proteins on the function of other SALL proteins.

As the interaction between truncated SALL1 and functional SALL1 or other SALL proteins and the relocalization of the functional proteins requires the presence of the evolutionarily conserved glutamine-rich region in the amino-terminal part of the truncated protein, the effect of the SALL1 pathogenic variants c.419delC and c.313delA, which would result in truncated proteins lacking the interaction domain, still needs to be explained, since the phenotypes associated with these pathogenic variants did not appear milder than the phenotypes resulting from other pathogenic variants [Kohlhase et al 1999, Botzenhart et al 2007].

Interestingly, 47 (82.5%) of 57 smaller pathogenic variants (2013 data) cluster within the 802-bp refined "hot spot region" between the coding sequence for the glutamine-rich domain and the coding sequence for the first double zinc finger, whereas only two pathogenic variants were found within the remaining 763 bp upstream in the coding region, and only six within the 2.4-kb coding region to the 3' end. Therefore, the existence of truncated proteins in cells of persons with TBS would not be surprising. If it holds true that SALL1 single-nucleotide pathogenic variants lead to truncated SALL1 proteins with dominant-negative action, one could expect that all truncated proteins have at least slightly different characteristics. This could explain the considerable phenotypic variability observed in TBS.

References

Literature Cited

  1. Albrecht B, Liebers M, Kohlhase J. Atypical phenotype and intrafamilial variability associated with a novel SALL1 mutation. Am J Med Genet A. 2004;125A:102–4. [PubMed: 14755477]
  2. Bardakjian TM, Schneider AS, Ng D, Johnston JJ, Biesecker LG. Association of a de novo 16q copy number variant with a phenotype that overlaps with Lenz microphthalmia and Townes-Brocks syndromes. BMC Med Genet. 2009;10:137. [PMC free article: PMC2806267] [PubMed: 20003547]
  3. Blanck C, Kohlhase J, Engels S, Burfeind P, Engel W, Bottani A, Patel MS, Kroes HY, Cobben JM. Three novel SALL1 mutations extend the mutational spectrum in Townes-Brocks syndrome. J Med Genet. 2000;37:303–7. [PMC free article: PMC1734570] [PubMed: 10819639]
  4. Böhm J, Munk-Schulenburg S, Felscher S, Kohlhase J. SALL1 mutations in sporadic Townes-Brocks syndrome are of predominantly paternal origin without obvious paternal age effect. Am J Med Genet A. 2006;140:1904–8. [PubMed: 16892410]
  5. Borozdin W, Steinmann K, Albrecht B, Bottani A, Devriendt K, Leipoldt M, Kohlhase J. Detection of heterozygous SALL1 deletions by quantitative real time PCR proves the contribution of a SALL1 dosage effect in the pathogenesis of Townes-Brocks syndrome. Hum Mutat. 2006;27:211–2. [PubMed: 16429401]
  6. Borozdin W, Wright M, Hennekam R, Hannibal M, Crow Y, Neumann T, Kohlhase J. Novel mutations in the gene SALL4 provide further evidence for Acro-Renal-Ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum. J Med Genet. 2004;41:e102. [PMC free article: PMC1735876] [PubMed: 15286162]
  7. Botzenhart EM, Bartalini G, Blair E, Brady AF, Elmslie F, Chong KL, Christy K, Torres-Martinez W, Danesino C, Deardorff MA, Fryns JP, Marlin S, Garcia-Minaur S, Hellenbroich Y, Hay BN, Penttinen M, Shashi V, Terhal P, Van Maldergem L, Whiteford ML, Zackai E, Kohlhase J. Townes-Brocks syndrome: twenty novel SALL1 mutations in sporadic and familial cases and refinement of the SALL1 hot spot region. Hum Mutat. 2007;28:204–5. [PubMed: 17221874]
  8. Botzenhart EM, Green A, Ilyina H, Konig R, Lowry RB, Lo IF, Shohat M, Burke L, McGaughran J, Chafai R, Pierquin G, Michaelis RC, Whiteford ML, Simola KO, Rösler B, Kohlhase J. SALL1 mutation analysis in Townes-Brocks syndrome: twelve novel mutations and expansion of the phenotype. Hum Mutat. 2005;26:282. [PubMed: 16088922]
  9. Choi WI, Kim JH, Yoo HW, Oh SH. A family with Townes-Brocks syndrome with congenital hypothyroidism and a novel mutation of the SALL1 gene. Korean J Pediatr. 2010;53:1018–21. [PMC free article: PMC3021728] [PubMed: 21253317]
  10. Devriendt K, Fryns JP, Lemmens F, Kohlhase J, Liebers M. Somatic mosaicism and variable expression of Townes-Brocks syndrome. Am J Med Genet. 2002;111:230–1. [PubMed: 12210359]
  11. Engels S, Kohlhase J, McGaughran J. A SALL1 mutation causes a branchio-oto-renal syndrome-like phenotype. J Med Genet. 2000;37:458–60. [PMC free article: PMC1734618] [PubMed: 10928856]
  12. Farrell ER, Munsterberg AE. csal1 is controlled by a combination of FGF and Wnt signals in developing limb buds. Dev Biol. 2000;225:447–58. [PubMed: 10985862]
  13. Feichtiger H. A new malformation disorder primarily affecting the extremities. Germany: Medical Dissertation; 1943.
  14. Gabrielli O, Bonifazi V, Offidani AM, Cellini A, Coppa GV, Giorgi PL. Description of a patient with difficult nosological classification: Goldenhar syndrome or Townes-Brocks syndrome? Minerva Pediatr. 1993;45:459–62. [PubMed: 8133838]
  15. Harvey SA, Logan MP. sall4 acts downstream of tbx5 and is required for pectoral fin outgrowth. Development. 2006;133:1165–73. [PubMed: 16501170]
  16. Hentze MW, Kulozik AE. A perfect message: RNA surveillance and nonsense-mediated decay. Cell. 1999;96:307–10. [PubMed: 10025395]
  17. Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, Reutter HM, Soliman NA, Bogdanovic R, Kehinde EO, Tasic V, Hildebrandt F. Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 2014;2014;85:1429–33. [PMC free article: PMC4040148] [PubMed: 24429398]
  18. Johnson JP, Poskanzer LS, Sherman S. Three-generation family with resemblance to Townes-Brocks syndrome and Goldenhar/oculoauriculovertebral spectrum. Am J Med Genet. 1996;61:134–9. [PubMed: 8669439]
  19. Keegan CE, Mulliken JB, Wu BL, Korf BR. Townes-Brocks syndrome versus expanded spectrum hemifacial microsomia: review of eight patients and further evidence of a "hot spot" for mutation in the SALL1 gene. Genet Med. 2001;3:310–3. [PubMed: 11478532]
  20. Kiefer SM, Ohlemiller KK, Yang J, McDill BW, Kohlhase J, Rauchman M. Expression of a truncated Sall1 transcriptional repressor is responsible for Townes-Brocks syndrome birth defects. Hum Mol Genet. 2003;12:2221–7. [PubMed: 12915476]
  21. Kohlhase J. SALL1 mutations in Townes-Brocks syndrome and related disorders. Hum Mutat. 2000;16:460–6. [PubMed: 11102974]
  22. Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet. 2002;11:2979–87. [PubMed: 12393809]
  23. Kohlhase J, Liebers M, Backe J, Baumann-Muller A, Bembea M, Destree A, Gattas M, Grussner S, Muller T, Mortier G, et al. High incidence of the R276X SALL1 mutation in sporadic but not familial Townes-Brocks syndrome and report of the first familial case. J Med Genet. 2003;40:e127. [PMC free article: PMC1735324] [PubMed: 14627694]
  24. Kohlhase J, Taschner PE, Burfeind P, Pasche B, Newman B, Blanck C, Breuning MH, ten Kate LP, Maaswinkel-Mooy P, Mitulla B, Seidel J, Kirkpatrick SJ, Pauli RM, Wargowski DS, Devriendt K, Proesmans W, Gabrielli O, Coppa GV, Wesby-van Swaay E, Trembath RC, Schinzel AA, Reardon W, Seemanova E, Engel W. Molecular analysis of SALL1 mutations in Townes-Brocks syndrome. Am J Hum Genet. 1999;64:435–45. [PMC free article: PMC1377753] [PubMed: 9973281]
  25. Kohlhase J, Wischermann A, Reichenbach H, Froster U, Engel W. Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet. 1998;18:81–3. [PubMed: 9425907]
  26. Kurnit DM, Steele MW, Pinsky L, Dibbins A. Autosomal dominant transmission of a syndrome of anal, ear, renal, and radial congenital malformations. J Pediatr. 1978;93:270–3. [PubMed: 671168]
  27. Lawrence C, Hong-McAtee I, Hall B, Hartsfield J, Rutherford A, Bonilla T, Bay C. Endocrine abnormalities in Townes-Brocks syndrome. Am J Med Genet A. 2013;161A:2266–73. [PubMed: 23894113]
  28. Maquat LE. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol. 2004;5:89–99. [PubMed: 15040442]
  29. Marlin S, Blanchard S, Slim R, Lacombe D, Denoyelle F, Alessandri JL, Calzolari E, Drouin-Garraud V, Ferraz FG, Fourmaintraux A, Philip N, Toublanc JE, Petit C. Townes-Brocks syndrome: detection of a SALL1 mutation hot spot and evidence for a position effect in one patient. Hum Mutat. 1999;14:377–86. [PubMed: 10533063]
  30. 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. [PubMed: 10083645]
  31. Miller EM, Hopkin R, Bao L, Ware SM. Implications for genotype-phenotype predictions in Townes-Brocks syndrome: case report of a novel SALL1 deletion and review of the literature. Am J Med Genet A. 2012;2012;158A:533–40. [PubMed: 22308078]
  32. Monteiro de Pina-Neto J. Phenotypic variability in Townes-Brocks syndrome. Am J Med Genet. 1984;18:147–52. [PubMed: 6741990]
  33. Netzer C, Bohlander SK, Hinzke M, Chen Y, Kohlhase J. Defining the heterochromatin localization and repression domains of SALL1. Biochim Biophys Acta. 2006;1762:386–91. [PubMed: 16443351]
  34. Netzer C, Rieger L, Brero A, Zhang CD, Hinzke M, Kohlhase J, Bohlander SK. SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin. Hum Mol Genet. 2001;10:3017–24. [PubMed: 11751684]
  35. Nishinakamura R, Matsumoto Y, Nakao K, Nakamura K, Sato A, Copeland NG, Gilbert DJ, Jenkins NA, Scully S, Lacey DL, Katsuki M, Asashima M, Yokota T. Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development. 2001;128:3105–15. [PubMed: 11688560]
  36. Reardon W, Casserly LF, Birkenhäger R, Kohlhase J. Kidney failure in Townes-Brocks syndrome: an under recognized phenomenon? Am J Med Genet A. 2007;143A:2588–91. [PubMed: 17910067]
  37. Salerno A, Kohlhase J, Kaplan BS. Townes-Brocks syndrome and renal dysplasia: a novel mutation in the SALL1 gene. Pediatr Nephrol. 2000;14:25–8. [PubMed: 10654325]
  38. Sato A, Kishida S, Tanaka T, Kikuchi A, Kodama T, Asashima M, Nishinakamura R. Sall1, a causative gene for Townes-Brocks syndrome, enhances the canonical Wnt signaling by localizing to heterochromatin. Biochem Biophys Res Commun. 2004;319:103–13. [PubMed: 15158448]
  39. Shaw-Smith C. Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. J Med Genet. 2006;43:545–54. [PMC free article: PMC2564549] [PubMed: 16299066]
  40. Surka WS, Kohlhase J, Neunert CE, Schneider DS, Proud VK. Unique family with Townes-Brocks syndrome, SALL1 mutation, and cardiac defects. Am J Med Genet. 2001;102:250–7. [PubMed: 11484202]
  41. Sweetman D, Smith T, Farrell ER, Chantry A, Munsterberg A. The conserved glutamine-rich region of chick csal1 and csal3 mediates protein interactions with other spalt family members. Implications for Townes-Brocks syndrome. J Biol Chem. 2003;278:6560–6. [PubMed: 12482848]
  42. Townes PL, Brocks ER. Hereditary syndrome of imperforate anus with hand, foot, and ear anomalies. J Pediatr. 1972;81:321–6. [PubMed: 5042490]
  43. van den Akker PC, van de Graaf R, Dooijes D, van Essen AJ. Somatic mosaicism for the SALL1 mutation p.Ser371X in full-blown Townes-Brocks syndrome with Duane anomaly. Am J Med Genet A. 2009;149A:812–5. [PubMed: 19291771]
  44. Vodopiutz J, Zoller H, Fenwick AL, Arnhold R, Schmid M, Prayer D, Müller T, Repa A, Pollak A, Aufricht C, Wilkie AO, Janecke AR. Homozygous SALL1 mutation causes a novel multiple congenital anomaly-mental retardation syndrome. J Pediatr. 2013;162:612–7. [PMC free article: PMC3757162] [PubMed: 23069192]
  45. Walter KN, Greenhalgh KL, Newbury-Ecob RA, Kohlhase J. Mosaic trisomy 8 and Townes-Brocks syndrome due to a novel SALL1 mutation in the same patient. Am J Med Genet A. 2006;140:649–51. [PubMed: 16470706]

Chapter Notes

Author Notes

Dr Kohlhase’s Web site: www.humangenetik-freiburg.de

Acknowledgments

The author's research has received funding by the Deutsche Forschungsgemeinschaft (German National Science Foundation) and the Wilhelm-Sander-Stiftung, a German non-profit research foundation.

Revision History

  • 14 January 2016 (me) Comprehensive update posted live
  • 3 May 2012 (me) Comprehensive update posted live
  • 24 January 2007 (me) Review posted to live Web site
  • 17 November 2006 (jk) Original submission
Copyright © 1993-2016, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1445PMID: 20301618

Views

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...