Clinical characteristics.

SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears (overfolded superior helices and preauricular tags; frequently associated with sensorineural and/or conductive hearing impairment), and thumb malformations (duplication of the thumb [preaxial polydactyly], triphalangeal thumbs, and, rarely, hypoplasia of the thumbs) without hypoplasia of the radius. Impaired kidney function, including end-stage kidney disease (ESKD), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoureteral reflux). Foot malformations (flat feet, overlapping toes) and genitourinary malformations are common. Congenital heart disease occurs in 15% of affected individuals. Developmental delay and/or learning difficulties occur in approximately 15% of affected individuals. Rare features include growth deficiency, Duane anomaly, iris coloboma, and Chiari I malformation.

Diagnosis/testing.

The diagnosis of SALL1-TBS is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in SALL1 identified by molecular genetic testing.

Management.

Treatment of manifestations: Immediate surgical intervention for imperforate anus; stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation; standard treatment of gastroesophageal reflux; early treatment of hearing loss; surgery for severe malformations of the hands; hemodialysis and possibly kidney transplantation for ESKD; management of genitourinary anomalies per urologist or gynecologist; surgery or medical treatment by cardiologist for congenital heart defects; developmental and educational support as needed; neuropsychiatric management as needed for behavioral issues; growth hormone therapy for those with growth hormone deficiency; management of ocular issues per ophthalmologist.

Surveillance: Assess for constipation and assess growth and thyroid function at each visit; annual audiology evaluation; monitor kidney function annually in individuals with and without kidney anomalies, even if kidney function is normal on initial examination; monitor developmental progress, educational needs, and behavioral assessment annually; ophthalmology examination per ophthalmologist.

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

Evaluation of relatives at risk: Clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with SALL1-TBS in order to identify as early as possible those who would benefit from clinical evaluation and prompt initiation of treatment for kidney disease and other features of SALL1-TBS.

Pregnancy management: Consider prenatal cardiac and nephrology evaluations in pregnant women with SALL1-TBS.

Genetic counseling.

SALL1-TBS is inherited in an autosomal dominant manner. About 50% of individuals diagnosed with SALL1-TBS have the disorder as the result of a de novo pathogenic variant. Each child of an individual with SALL1-TBS has a 50% chance of inheriting the pathogenic variant. Once the SALL1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SALL1-related Townes-Brocks syndrome (SALL1-TBS) should be suspected in individuals with the following major and minor clinical features and family history.

Major features

• Imperforate anus or anal stenosis
• Dysplastic ears (overfolded superior helices, preauricular tags, microtia)
• Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius

Minor features

• Sensorineural and/or conductive hearing impairment
• Foot malformations
• Impaired kidney function with or without kidney malformations
• Genitourinary malformations
• Congenital heart disease

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SALL1-TBS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in SALL1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous SALL1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

SALL1-related Townes-Brocks syndrome (SALL1-TBS) is characterized by the triad of imperforate anus or anal stenosis, dysplastic ears (frequently associated with hearing impairment), and thumb malformations without hypoplasia of the radius. Impairment of kidney function may occur with or without structural abnormalities. Foot malformations, genitourinary malformations, and congenital heart disease are common. Of 165 affected individuals from 101 families with a SALL1 pathogenic variant, approximately 80% had the three major features or two major plus minor features, whereas 20% had a partial clinical expression [Kohlhase et al 1998, Kohlhase et al 1999, Marlin et al 1999, Kohlhase et al 2003, Borozdin et al 2006, Botzenhart et al 2007, and 30 additional reports]. The following description of the phenotypic features associated with this condition is based on these reports. Some features may be underestimated due to later onset (e.g., impaired kidney function) or incomplete physical examination.

Gastrointestinal manifestations include imperforate anus, anal stenosis, anteriorly placed anus, chronic constipation, and gastroesophageal reflux [Engels et al 2000].

Ear anomalies and hearing loss. Dysplastic ears are common, including overfolded superior helices, preauricular tags, and microtia. Congenital sensorineural and/or conductive hearing loss ranges from mild to severe. Hearing loss that is mild can worsen with age [Yan et al 2024].

Thumb malformations include preaxial polydactyly, triphalangeal thumbs, and, rarely, hypoplastic thumbs without hypoplasia of the radius.

Lower extremity findings include flat feet, clubfoot, overlapping toes (second and fourth toes overlapping third toe), syndactyly of the toes, and missing toes (typically third toe) [Surka et al 2001].

Kidney manifestations include mild malrotation, ectopia, or horseshoe kidney, renal agenesis, renal hypoplasia, polycystic kidneys, and vesicoureteral reflux. Functional impairment with or without structural abnormalities is also frequent [Botzenhart et al 2007, Stein et al 2024].

Genitourinary manifestations include hypospadias, vaginal aplasia with bifid uterus, bifid scrotum, and cryptorchidism [Botzenhart et al 2005, Botzenhart et al 2007].

Congenital heart disease is reported in 50% of persons with the common p.Arg276Ter pathogenic variant [Kohlhase et al 2003] and approximately 15% of all persons with 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.

Developmental delay and learning difficulties are reported in approximately 15% of individuals, but adults do not usually have intellectual disability. If they do, it is mild.

Behavioral problems are observed in some children with SALL1-TBS, especially attention-deficit/hyperactivity disorder.

Postnatal growth deficiency. 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 deficiency among individuals with a confirmed SALL1 pathogenic variant is not known. Growth hormone deficiency was reported in one individual with TBS [Lawrence et al 2013], suggesting this may be the cause for growth deficiency in other individuals with TBS. Growth deficiency may be secondary to chronic kidney insufficiency in some children with SALL1-TBS.

Other skeletal manifestations include rib anomalies (fused ribs, missing ribs, additional cervical ribs) and mild vertebral anomalies reported in 9% of individuals. Painful joints have been observed in several adults with SALL1-TBS [J Kohlhase, unpublished observations].

Ocular manifestations include Duane anomaly, iris coloboma, lamellar cataract, chorioretinal coloboma with loss of vision, and, rarely, microphthalmia [Valikodath et al 2020].

Central nervous system manifestations in individuals with SALL1-TBS include Chiari I malformation [J Kohlhase, unpublished observations], cranial nerve palsy (cranial nerves VI and VII), and hypoplasia of the dorsal part of the corpus callosum.

Hemifacial microsomia has been reported [Kohlhase et al 1999, Keegan et al 2001].

Congenital hypothyroidism is a rare feature of SALL1-TBS [Lawrence et al 2013, Yan et al 2024]. Note: Almost 5% of individuals with a rare disorder have been reported to have more than one molecular diagnosis [Posey et al 2017]. It is possible that rare features associated with SALL1-TBS may have an independent molecular cause.

Genotype-Phenotype Correlations

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

The most common pathogenic variant, c.826C>T (p.Arg276Ter), is associated with greater frequency (50%) and severity of congenital heart defects than other SALL1 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 toward the 5' end in exon 2 appear to be associated with a more severe outcome than pathogenic variants towards the 3' end 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, based on a limited number of individuals (nine individuals from five distinct families) with large deletions involving only SALL1 [Borozdin et al 2006, Miller et al 2012, Stevens & May 2016, Innoceta et al 2023].

Penetrance

Penetrance is likely 100%, if individuals at the mild end of the phenotypic spectrum are included. Note: One SALL1 variant, p.Arg1054Ter, was associated with a severe phenotype when present in homozygosity. Eleven individuals heterozygous for p.Arg1054Ter had no features of SALL1-TBS, but this variant was found to preserve some degree of SALL1 function.

Nomenclature

Townes-Brocks syndrome was previously referred to as REAR syndrome (for renal, ear, anal, and radial malformations) [Kurnit et al 1978].

Prevalence

Approximately 200 individuals with SALL1-TBS are reported in the medical literature. The population prevalence is not known. The prevalence of pathogenic SALL1 variants was 1:1,592 among a large cohort of individuals with monogenic kidney disease [Stein et al 2024], and 1:2,952 among individuals with hearing loss [Yan et al 2024].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SALL1-TBS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

Medications that cause renal or otic toxicity should be avoided.

Evaluation of Relatives at Risk

Molecular genetic testing for the SALL1 pathogenic variant identified in the proband is appropriate for apparently asymptomatic older and younger at-risk relatives of an individual with SALL1-TBS in order to identify as early as possible those who would benefit from clinical evaluation and prompt initiation of treatment for kidney disease and other features of SALL1-TBS.

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

Pregnancy Management

Consider prenatal cardiac evaluation in pregnant women with SALL1-TBS. Impairment of kidney function can progress significantly during pregnancy and warrants a nephrology evaluation.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Mode of Inheritance

SALL1-related Townes-Brocks syndrome (SALL1-TBS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• About 50% of individuals diagnosed with SALL1-TBS have an affected family member(s) [C Graziano & G Olivucci, unpublished observations].
• About 50% of individuals diagnosed with SALL1-TBS have the disorder as the result of a de novo pathogenic variant. 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 proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [Kohlhase et al 1999, Blanck et al 2000, Devriendt et al 2002, van den Akker et al 2009]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present only in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a SALL1 pathogenic variant may be as mild as second and fourth toes overlapping the third toe [Devriendt et al 2002]. In a family with two affected sibs, a mother with presumed somatic and gonadal mosaicism (the SALL1 pathogenic variant identified in the affected sibs was not identified in maternal leukocyte DNA) was reported to have isolated anteriorly placed anus [Blanck et al 2000].
• The family history of some individuals diagnosed with SALL1-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 molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

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

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Although the penetrance of SALL1-TBS appears to be complete in heterozygous individuals, clinical expressivity can be highly variable. 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 in a heterozygous sib or the severity of manifestations.
• If the parents have not been tested for the SALL1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SALL1-TBS because of the possibility of parental gonadal mosaicism.

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

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have the SALL1 pathogenic variant, the parent's family members may be 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.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Prenatal Testing and Preimplantation Genetic Testing

Once the SALL1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Although this testing can determine if the fetus has inherited a familial SALL1 pathogenic variant, it cannot predict which manifestations will be present or the severity of manifestations, with the exception of the p.Arg276Ter pathogenic variant, which has caused a severe phenotype in all known instances. In a fetus found to have a SALL1 pathogenic variant, high-resolution ultrasound examination can be used to evaluate phenotypic manifestations (e.g., complex heart defects, preaxial polydactyly, foot malformations, and preauricular tags) [Kohlhase et al 2003].

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

SALL1 encodes Sal-like protein 1 (SALL1), a C2H2 zinc finger protein of the SAL type. 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].

Most SALL1 pathogenic variants are truncating and located in exon 2 or intron 2. However, a few families in whom larger deletions partially or completely removing SALL1 clearly result in Townes-Brocks syndrome (TBS) have been described [Borozdin et al 2006, Miller et al 2012, Innoceta et al 2023]. It remains unclear if TBS is only caused by loss of SALL1 function or also by a dominant-negative effect of truncated SALL1 proteins on the function of other SAL proteins. The recurrent p.Arg276Ter pathogenic variant was reported to escape nonsense-mediated decay and causes a severe phenotype, suggesting a dominant-negative mechanism that may be common to other SALL1 variants [Kiefer et al 2003].

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 pathogenic variant possibly leads to a truncated protein, which does not localize to the physiologic site of action but binds other SAL proteins and moves them from the nucleus to the cytoplasm. Therefore, in most instances the more severe phenotype of the 5' truncating pathogenic variants may result from a greater than 50% reduction of the functional protein at the site of action. Furthermore, truncated SALL1 might impede the function of primary cilia, since primary fibroblasts derived from SALL1-TBS exhibit a higher rate of ciliogenesis, abnormally elongated cilia, and aberrant cilia disassembly [Bozal-Basterra et al 2018].

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.

Mechanism of disease causation. Loss of function and possible dominant-negative effect of some truncating variants

SALL1-specific laboratory technical considerations. Due to the existence of a highly homologous SALL1 pseudogene (SALL1P1), capture-based gene panels may not be able to distinguish between SALL1 pathogenic variants and variants within the pseudogene.

Author History

Claudio Graziano, MD (2024-present)
Jürgen Kohlhase, MD; Center for Human Genetics (2006-2024)
Giulia Olivucci, MD (2024-present)

Revision History

• 8 August 2024 (sw) Comprehensive update posted live
• 14 January 2016 (me) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 24 January 2007 (me) Review posted live
• 17 November 2006 (jk) Original submission

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