DEAFNESS, SENSORINEURAL, WITH IMPERFORATE ANUS AND THUMB ANOMALIES TOWNES-BROCKS-BRANCHIOOTORENAL-LIKE SYNDROME, INCLUDED
ANUS, IMPERFORATE, WITH HAND, FOOT, AND EAR ANOMALIES
TBS
Townes syndrome
Sensorineural deafness with imperforate anus and hypoplastic thumbs
renal-ear-anal-radial syndrome
Imperforate anus with hand, foot and ear anomalies
rear syndrome
Townes and Brocks (1972) observed a father and 5 of his 7 children who had imperforate anus, triphalangeal thumbs, and other anomalies of the hands and feet, including fusion of metatarsals, absent bones, and supernumerary thumbs. Other features ... Townes and Brocks (1972) observed a father and 5 of his 7 children who had imperforate anus, triphalangeal thumbs, and other anomalies of the hands and feet, including fusion of metatarsals, absent bones, and supernumerary thumbs. Other features included mild sensorineural deafness, and lop ears. Reid and Turner (1976) described the same syndrome. Kurnit et al. (1978) described autosomal dominant inheritance of a syndrome of anal stenosis, other anal abnormalities, deformed external ears and perceptive deafness, renal anomalies, including hypoplastic kidney, and radial dysplasia (REAR syndrome). The features are those of the VATER syndrome (192350), which has been subsequently expanded into the VACTERL syndrome (acronym for vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects). Walpole and Hockey (1982) reported cases. Monteiro de Pina-Neto (1984) reported a case in which congenital heart defect was also present and proposed that the cases of Silver et al. (1972) were instances of this syndrome rather than the Holt-Oram syndrome (142900). Aylsworth (1985) observed the Townes-Brocks syndrome in a mother and 2 children. De Vries-Van der Weerd et al. (1988) described TBS in a father and son. The son, the proband, showed the full spectrum of anomalies, including imperforate anus, prominent perineal raphe, rectoperineal fistula, triphalangeal thumb, preaxial hexadactyly, syndactyly, clinodactyly, preauricular protuberances, hypoplastic satyr ears, sensorineural hearing loss, and urorenal anomalies. In contrast, the father showed only limb anomalies, sensorineural hearing loss, and renal anomalies. Anorectal malformations, which are present in most patients with TBS, were absent in the father. Ferraz et al. (1989) reported a sporadic case. The patient's 'satyr ear' and CT scans of the deformities in the ossicles of the ear were pictured. The cardiac lesion was ventricular septal defect. At birth the girl had been noted to have type I imperforate anus with rectovaginal fistula, bilateral supernumerary digits on the radial side of the thumb base, and incomplete soft tissue syndactyly between fingers 2 and 3 on the right. Bilateral symmetric mixed deafness was discovered at age 6 years. The maternal grandfather may have been affected, since he had deafness, polycystic kidneys, and a short proximal phalanx of the left fifth finger. In a review of the Townes-Brocks syndrome, O'Callaghan and Young (1990) pointed out that patients may have a prominent midline perineal raphe extending from the site of the anal orifice to the scrotum. They pictured the feet of a mother and son, both showing hypoplastic third toes overlapped by the second and fourth toes, as well as a satyr form of lopped ear. Cameron et al. (1991) suggested that there may be an increase of mental retardation in persons with TBS. Ishikiriyama et al. (1996) also saw a boy with both TBS and mental retardation. Serville et al. (1993) listed the main features of TBS as follows: abnormal placement of the anus, anal atresia or stenosis; auricular pits, fistulas, or tags; conductive and sensorineural deafness; dysplastic ears; hypoplastic or bifid thumbs; deviation of distal phalanges of the thumbs; triphalangeal thumbs; and cardiac and renal abnormalities. They noted that neither of the patients reported by Friedman et al. (1987) had thumb anomalies, but pointed to the fact that clinical variability is known in TBS. Johnson et al. (1996) described a 3-generation family in which the grandmother and mother were thought to have Goldenhar syndrome (164210), but the birth of a grandson with typical features of TBS redirected the diagnosis to that possibility. The mother was of short stature with small ears, preauricular and tragal tags on the right and postauricular tag on the left, facial asymmetry, epibulbar dermoids bilaterally, micrognathia, and macrostomia with lateral extension more prominent on the right. The thumbs were triphalangeal with a previously removed, rudimentary, supernumerary digit that had been attached to the right thumb. Midline clefting of the uterus was reported. The anus was normal. The IQ at age 10 was 84; microcephaly was noted at the age of 24 years. The grandmother had small ears with preauricular tags, epibulbar dermoid on the right, and micrognathia without facial asymmetry. The thumbs were triphalangeal and the great toe on the left was bifid representing syndactyly of toes 1 and 2 or absence of 2. Genitourinary abnormalities included urethrostenosis and septate uterus. The anus showed redundant skin. Height was 147 cm. The grandson was born with an imperforate anus covered by a thin membrane requiring a minor surgical procedure. The left side of the face was smaller than the right. The ears were small with overfolding of the helix more prominent on the right which showed a small preauricular tag. Other findings were epibulbar dermoid on the left, triphalangeal thumbs with ulnar deviation. Newman et al. (1997) reported a case of Townes-Brock syndrome in a male who presented at the age of 23 years with end-stage renal failure. He had severe hypertension and bilaterally small kidneys by ultrasound scan. Surgery had been performed after birth to correct anal stenosis. At that time the ears were noted to be low set with overfolded helices and bilateral preauricular tags, bilateral preaxial hexadactyly of the hands, and syndactyly of the third and fourth toes. Bilateral sensorineural deafness was noted at 3 years of age. Kohlhase et al. (1998) reported 2 half-sibs with TBS, born of the same mother. Photographs illustrated the presence of duplicated triphalangeal left thumb and duplicated triphalangeal right thumb combined with a third dysplastic thumb. Dysplastic ears were also illustrated. The affected mother displayed low birth weight and presented with imperforate anus, preauricular tags, microtia and dysplastic ears, sensorineural hearing loss, bifid right thumb, and rudimentary bifid left thumb. Her son had imperforate anus type 3 with rectoperineal fistula, microtia and dysplastic ears, sensorineural hearing loss, bifid left and distally broadened right thumb. His sister likewise showed imperforate anus type 3 with rectovaginal fistula, preauricular tags, microtia and dysplastic ears, sensorineural hearing loss, bifid triphalangeal left thumb, and triple triphalangeal right thumb. Doray et al. (1999) described 2 unrelated, apparently sporadic cases of Townes-Brocks syndrome. Surka et al. (2001) described a 3-generation family in which 7 individuals had TBS confirmed by genetic analysis (602218.0008). Cardiac anomalies seen in this family included lethal truncus arteriosus in 1 patient and a lethal complicated defect that included pulmonary valve atresia in a second. These severe cardiac anomalies had not previously been reported in a familial case of TBS. On the basis of this family and a review of the literature, Surka et al. (2001) suggested that cardiac evaluation is warranted in all patients with this disorder. The authors stated that hypoplastic thumbs were observed in 2 individuals in their family and therefore should be considered a feature of TBS. In fact, the thumb anomalies as indicated by the photographs were bilateral triphalangeal thumbs in at least 2 individuals, a right hypoplastic thumb with absent distal phalanx and left preaxial polydactyly and triphalangeal thumb in one, and left preaxial polydactyly and triphalangeal thumb in another. A severely affected child who died at the age of 3 days from cardiac malformations had bilateral preaxial polydactyly. Botzenhart et al. (2005) reported 13 unrelated families with TBS confirmed by genetic analysis. Rare phenotypic features included hypothyroidism, gastroesophageal reflux, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadia scrotalis, unilateral chorioretinal coloboma with loss of vision, Duane anomaly, dorsal hypoplasia of the corpus callosum, and umbilical hernia. Sudo et al. (2010) reported a Japanese family in which the 4-year-old female proband had bilateral preauricular tags, bilateral preaxial polydactyly, syndactyly of the right toe, overriding toes of the left foot, anteriorly placed and stenosed anus, mild bilateral sensorineural hearing loss, ventricular septal defect, and small right kidney. Her mother and her maternal uncle, grandfather, and great aunt were also affected. Her mother had right preaxial polydactyly, anterior placement of the anus, small right kidney, and mild sensorineural hearing loss, whereas her uncle had right preaxial polydactyly, imperforate anus, and mild hearing loss. Her grandfather and great aunt had only unilateral preaxial polydactyly and deafness. The proband and her mother were found to be heterozygous for a frameshift mutation in the SALL1 gene. Sudo et al. (2010) noted that there was an anticipation-like increase in severity of the phenotype with each succeeding generation in this family, and stated that similar increases in clinical severity had been observed in other TBS families, frequently in patients who inherited the disease from their mothers.
Furniss et al. (2007) reported a heterozygous mutation in the SALL1 gene (995delC; 602218.0011) in a patient with a relatively severe form of Townes-Brocks syndrome. The patient had bilateral preaxial polydactyly, imperforate anus, rectal atresia, hypospadias, and overfolded ... Furniss et al. (2007) reported a heterozygous mutation in the SALL1 gene (995delC; 602218.0011) in a patient with a relatively severe form of Townes-Brocks syndrome. The patient had bilateral preaxial polydactyly, imperforate anus, rectal atresia, hypospadias, and overfolded helices. The mutation was found to be resistant to nonsense-mediated decay. Furniss et al. (2007) concluded that the phenotype was caused by a truncated SALL1 protein acting in a dominant-negative manner. These findings were in contrast to another SALL1 mutation (602218.0012) that did undergo nonsense-mediated decay and was associated with a milder phenotype of Townes-Brocks syndrome.
In 2 half-sibs with TBS, born of the same mother, and a sporadic TBS patient, Kohlhase et al. (1998) identified 2 different heterozygous mutations in the SALL1 gene (602218.0001; 602218.0002).
In a father and 2 daughters ... In 2 half-sibs with TBS, born of the same mother, and a sporadic TBS patient, Kohlhase et al. (1998) identified 2 different heterozygous mutations in the SALL1 gene (602218.0001; 602218.0002). In a father and 2 daughters with features overlapping those of Townes-Brocks syndrome and branchiootorenal syndrome (113650), Engels et al. (2000) identified a mutation in the SALL1 gene (602218.0007). The daughters had dysplastic ears, hypoplastic kidneys with impaired renal function, gastroesophageal reflux, hypermetropia, and mild developmental delay. The father showed impaired renal function, dysplastic ears, and gastroesophageal reflux. None of the affected family members had anal or hand malformations. Engels et al. (2000) considered this family to demonstrate phenotypic overlap between the 2 conditions. In 3 members of a nonconsanguineous German family who had only some features of Townes-Brocks syndrome, Albrecht et al. (2004) identified a mutation in the SALL1 gene (602218.0009). Characteristic features of TBS included preauricular tags, overfolded helices, hypospadias, and impaired renal function; 1 brother had only hypospadias and underriding third toes. None of the affected family members had the characteristic anal or hand malformations of TBS. Albrecht et al. (2004) considered the disorder in their patients to be different from that described by Engels et al. (2000). Powell and Michaelis (1999) reviewed the clinical features and molecular basis of Townes-Brocks syndrome. Botzenhart et al. (2005) stated that 35 mutations had been identified in the SALL1 gene. Most mutations occur 5-prime to or within the region encoding the first double zinc finger. Kosaki et al. (2007) analyzed the SALL1 gene in 2 sisters, 1 with a Townes-Brocks syndrome phenotype and the other exhibiting features of Goldenhar syndrome (see hemifacial microsomia, 164210), and identified heterozygosity for a mutation (L419X; 602218.0010). Their mother, who had dysplastic external ears but was otherwise normal, also carried the mutation. The authors noted that Johnson et al. (1996) had previously reported an affected family member with a Goldenhar syndrome-like phenotype in a 3-generation TBS family.
Townes-Brocks syndrome (TBS) is diagnosed clinically based on the presence of the following:...
DiagnosisClinical DiagnosisTownes-Brocks syndrome (TBS) is diagnosed clinically based on the presence of the following:Imperforate anus Dysplastic ears (overfolded superior helices, microtia) Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without shortening of the radius In the two most recent studies [Botzenhart et al 2005, Botzenhart et al 2007] of 61 persons with novel SALL1 mutations (not including the most common mutation, p.Arg276X [c.826C>T]), 84% had anal anomalies, 89% hand anomalies, and 87% ear anomalies; 67% had the characteristic triad. In persons who show only two typical malformations, presence of additional anomalies commonly seen in TBS (e.g., renal malformations, hearing loss, heart defects) (see Clinical Description) can lead to the diagnosis.Molecular Genetic TestingGene. SALL1 is the only gene in which mutations are known to cause Townes-Brocks syndrome. Clinical testing Sequence analysis/mutation scanning. Direct sequencing of the complete SALL1 coding region (exons 1 through 3) has detected mutations 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 and mutation scanning of the entire gene can have similar detection frequencies; however, detection rates for mutation scanning may vary considerably among laboratories based on the specific protocol used.Deletion/duplication testing. Quantitative real-time PCR using amplicons within the SALL1 introns and/or exons as well as within regions 5' and 3' of the transcription unit identified three different deletions in three patients [Borozdin et al 2006]: Deletion of part of exon 2, intron 2 and exon 3; Deletion of the entire SALL1 coding region; and A larger deletion including several neighboring genes. Sequence analysis/mutation scanning and deletion/duplication testing together identify a causative SALL1 mutation or deletion in approximately 70% of persons with the classic triad of malformations as described by Kohlhase et al [1999].Table 1. Summary of Molecular Genetic Testing Used in Townes-Brocks SyndromeView in own windowGene SymbolTest MethodsMutations DetectedMutation Detection Frequency by Gene and Test Method 1Test AvailabilitySALL1Sequence analysis / mutation scanning Sequence variants 2<70% Clinical Deletion / duplication analysis 3Exonic, multiexonic, or whole-gene deletions <5% 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To establish the diagnosis in a proband with typical thumb, anal, and ear malformations Perform cardiac evaluation, ophthalmologic examination, and renal ultrasound examination in addition to a routine physical examination. Check for renal impairment by routine laboratory tests even if the kidneys appear normal on ultrasound. Perform hand/forearm x-ray investigations to evaluate for involvement of the radius. If at least two out of three classic major TBS features (anal, ear, and typical thumb malformations) are found, SALL1 molecular genetic testing is suggested as the first step. Presence of additional minor features (i.e., those commonly observed in TBS) increases the likelihood of finding a SALL1 mutation. Atypical features (i.e., not yet reported to occur with SALL1 mutations) may decrease the SALL1 mutation detection rate, but currently it does not seem possible to determine which atypical features (with the exception of concomitant involvement of the radius) are true negative predictors of a SALL1 mutation. 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. In a few individuals, complete overlap exists between Okihiro syndrome and TBS [Kohlhase et al 2002; Borozdin et al 2004; Kohlhase, personal communication]. In those individuals, both SALL1 and SALL4 molecular genetic testing should be considered. See Differential Diagnosis, Okihiro syndrome and SALL4-Related Disorders.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo other distinct phenotypes are known to be associated with SALL1 mutations.
In addition to the clinical features described in Diagnosis, the clinical manifestations of Townes-Brocks Syndrome may include the following:...
Natural HistoryIn addition to the clinical features described in Diagnosis, the clinical manifestations of Townes-Brocks Syndrome may include the following:Eyes. Microphthalmia (rare), iris coloboma, lamellar cataract, chorioretinal coloboma with loss of vision Kidneys. Renal agenesis, renal hypoplasia, polycystic kidneys; functional impairment with or without structural abnormalities (42% of cases) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007] Hearing. Congenital sensorineural and/or conductive hearing loss ranging from mild to severe. Hearing loss that is mild may worsen with age (65% of cases). Heart. Congenital heart disease occurs in 50% of persons with the common p.Arg276X mutation [Kohlhase et al 2003] and 12%-25% of persons with other SALL1 mutations [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]. Gastrointestinal. Anal stenosis, chronic constipation, gastroesophageal reflux [Engels et al 2000] Face. Hemifacial microsomia [Kohlhase et al 1999, Keegan et al 2001] Lower extremities. Club foot, overlapping toes (II and IV over III), syndactyly of toes, missing toes (III) (52% of cases) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007] Genitourinary. Hypospadias, vaginal aplasia with bifid uterus, bifid scrotum, cryptorchidism (36% of cases) [Surka et al 2001, Botzenhart et al 2005, Botzenhart et al 2007] Central nervous systemIntellectual 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 Skeletal. Rib anomalies (fused ribs, missing ribs, additional cervical ribs), mild vertebral anomalies (9% of cases). Painful joints have been observed in several adults with TBS [Kohlhase, unpublished observations.Endocrine. Congenital hypothyroidism (rare) 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 mutation-positive individuals is not known.
No genotype-phenotype correlations have been made for the majority of mutations, most of which are private....
Genotype-Phenotype CorrelationsNo genotype-phenotype correlations have been made for the majority of mutations, most of which are private.The most common mutation and the only mutation found in more than two families is c.826C>T (p.276X), 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 mutation is associated with greater frequency (50%) and severity of congenital heart defects than other mutations. Fifteen of 16 heterozygotes for the mutation showed the characteristic triad of anal, thumb, and ear malformations (94%), indicating that the mutation is associated with a more severe phenotype.In general, mutations within the hotspot region that is more 5' in exon 2 seem to be associated with a more severe outcome than mutations further 3' in exon 2. In addition, the phenotype associated with deletions of SALL1 seems to be milder than that associated with mutations in the hotspot region, but only three families with deletions have been reported to date [Borozdin et al 2006].
No other distinct phenotypes are associated with SALL1 mutations, but 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....
Differential DiagnosisNo other distinct phenotypes are associated with SALL1 mutations, but 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 mutations 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 mutation, it may occur in individuals with a SALL1 mutation 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, complete overlap exists between Okihiro syndrome and TBS [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 mutation [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 mutation [Kohlhase, unpublished data], their presence points toward a SALL4 mutation, even if all other features suggest TBS. Branchiootorenal (BOR) syndrome. In two families eventually determined to have SALL1 mutations, 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 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 SALL1 mutations [Kohlhase, unpublished data]. Sib and offspring recurrence risks for VACTERL association are estimated at approximately 1%. A recent review summarizes current information on VACTERL association [Shaw-Smith 2006]. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Townes-Brocks syndrome (TBS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with Townes-Brocks syndrome (TBS), the following evaluations are recommended:Heart. Baseline evaluation by a cardiologist including an echocardiogram Kidneys. Renal ultrasound examination and routine laboratory tests for renal function Hearing. Hearing evaluation as soon as the diagnosis of TBS is suspected (see Deafness and Hereditary Hearing Loss Overview) Treatment of ManifestationsImperforate anus. Immediate surgical intervention is required. Thumb malformations. Severe malformations of the hands may require surgery, e.g., removal of additional thumbs. Heart defects. Severe congenital heart defects may require surgery if functionally relevant. Renal. Function impairment requires continuous monitoring, hemodialysis, and possibly kidney transplantation. Hearing loss. Significant impairment requires early treatment, mostly with hearing aids (see Deafness and Hereditary Hearing Loss Overview). SurveillanceRenal 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.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSALL116q12.1Sal-like protein 1SALL1 homepage - Mendelian genesSALL1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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) View in own window 107480TOWNES-BROCKS SYNDROME; TBS 602218SAL-LIKE 1; SALL1Normal allelic variants. SALL1 occupies about 14.1 kb (start codon to stop codon). It contains three exons (all coding) and two introns. The genomic sequence is available at www.ncbi.nlm.nih.gov (accession number NC_000016.8); 29 different non-pathogenic polymorphisms are currently known [Bohm et al 2006]. Pathologic allelic variants. All reported and confirmed mutations are truncating and positioned 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]. Forty-six out of the 56 known SALL1 mutations are 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 hotspot 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 seems likely that the mutations 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 point mutations).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 orthologue 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 homologue 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 mutations (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 mutations 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 mutation 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.Arg276X mutation 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 with a TBS-causing mutation. 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 mutations 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. Mutations further 3' in SALL1 likely result in milder phenotypes than the 5' mutations [Blanck et al 2000, Botzenhart et al 2005]. If some of those mutations 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 the pathogenesis seems 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 hypothetical 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 TBS-causing SALL1 mutations 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 mutations did not appear milder than the phenotypes resulting from other mutations [Kohlhase et al 1999, Botzenhart et al 2007].Interestingly, 47 of 57 (82.5%) smaller mutations 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 mutations 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 point mutations 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.