Townes-Brocks Syndrome

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2021-01-18
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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 multigene 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 multigene panel that includes SALL1 and other genes of interest may also be considered. The genes included in multigene panels vary by laboratory and are likely to change 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.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of TBS. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Townes-Brocks Syndrome

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

See Table A. Genes and Databases for chromosome locus and protein.

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 used may 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. Clubfoot, 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.
  • Other. Consultation with a clinical geneticist and/or genetic counselor

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 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.