Townes-Brocks Syndrome

Autosomal dominant malformation syndrome historically defined by the triad of anorectal malformation, dysplastic external ears and thumb malformations without radial involvement, with hearing loss and kidney disease of variable onset throughout life; SALL1 is the gene with a definitive association and DACT1 underlies a rare form with reduced penetrance.

Literature and regulatory information updated: 27 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Founding description and evolution of the concept

In 1972, Townes and Brocks described, in the Journal of Pediatrics, a family in which a father and five of his seven children shared imperforate anus, triphalangeal thumbs and other anomalies of the hands and feet (fused metatarsals, absent bones, supernumerary thumbs), with mild sensorineural hearing loss and lop ears, transmitted vertically, and they named the condition a hereditary syndrome of imperforate anus with hand, foot and ear anomalies [3, 4, 24]. In 1976, Reid and Turner described another family with familial anal anomaly, and in 1978 Kurnit and colleagues documented autosomal dominant transmission of a syndrome of anal, ear, renal and radial malformations, which gave rise to the acronym REAR (renal, ear, anal, radial), now regarded as a historical synonym of Townes-Brocks syndrome (TBS); Kurnit and colleagues noted the similarity of these features to the VATER association, later broadened to VACTERL [2, 3, 18, 25]. The term “radial” in the acronym is misleading in the light of current knowledge, because the thumb anomalies of TBS occur with the radius present and radial hypoplasia or aplasia has not been observed in patients with a SALL1 variant [2, 26].

In the following years the clinical description broadened. In 1982, Walpole and Hockey associated imperforate anus and hand and foot anomalies with satyr ears and sensorineural hearing loss [18]. In 1984, Monteiro de Pina-Neto described a child with sensorineural hearing loss, imperforate anus with rectovaginal fistula, hypoplastic thumb and congenital heart disease, proposing that heart disease, other ear abnormalities and internal organ anomalies be included in the spectrum of the syndrome, and suggested that the patients published by Silver and colleagues in 1972 as Holt-Oram syndrome in fact had TBS [3, 27]. Aylsworth described the syndrome in 1985 in a mother and two children, and De Vries-Van der Weerd and colleagues, in 1988, in a father and son: the son had the full spectrum (imperforate anus with prominent perineal raphe and rectoperineal fistula, triphalangeal thumb, preaxial hexadactyly, syndactyly, clinodactyly, preauricular tags, hypoplastic satyr ears, sensorineural hearing loss and urorenal anomalies), whereas the father had only limb anomalies, hearing loss and renal anomalies, without anorectal malformation; the cases of father-to-son transmission in these families and in those of Townes and Brocks, Reid and Turner and Kurnit established autosomal dominant inheritance (indirect attribution via OMIM) [3]. In 1989, a group from the Genetics Unit of the Hospital Pediátrico D. Estefânia in Lisbon published the case of a girl with imperforate anus with rectovaginal fistula, bilateral supernumerary digits on the radial side of the base of the thumb, partial cutaneous syndactyly between the 2nd and 3rd fingers of the right hand, satyr ears with ossicular deformities documented by computed tomography, ventricular septal defect (VSD) and bilateral symmetrical mixed hearing loss detected at 6 years of age; the case was apparently sporadic, but the maternal grandfather, with hearing loss, polycystic kidneys and a short proximal phalanx of the left 5th finger, might have been affected, and the authors stressed the intrafamilial variability and the diagnostic difficulty in isolated cases; it is one of the first Portuguese descriptions of the entity [3, 28]. In 1990, O'Callaghan and Young drew attention to the prominent median perineal raphe, from the anal orifice to the scrotum, and to hypoplastic 3rd toes overlapped by the 2nd and 4th, in a mother and her son; Cameron and colleagues (1991) and Ishikiriyama and colleagues (1996) raised the hypothesis of a higher frequency of intellectual disability, which later molecular reviews reduced (section 3.10) (indirect attribution via OMIM) [3]. The clinical review by Powell and Michaelis in 1999 systematised the pre-molecular phenotype [29].

1.2. Milestones of molecular discovery

Cytogenetic rearrangements pointed to band 16q12.1: Friedman and colleagues described in 1987 a father and daughter with TBS and a pericentric inversion of chromosome 16 with breakpoints at p11.2 and q12.1, and Serville and colleagues, in 1993, an infant with a reciprocal translocation t(5;16) (indirect attribution via OMIM) [3]. SALL1, the human homologue of the Drosophila spalt (sal) gene, is located in that band. In 1998, Kohlhase and colleagues identified SALL1 variants in a family with vertical transmission (two maternal half-brothers born to the same affected mother, both with imperforate anus, microtia, sensorineural hearing loss and bifid or triplicated, triphalangeal thumbs) and in a sporadic case [3], both predicted to produce a truncated protein lacking all the deoxyribonucleic acid (DNA)-binding domains, establishing SALL1 as the causal gene [30]. In 1999, the same group found variants in 9 of 23 additional families, all located 5′ of the first double zinc finger region, and observed that SALL1 mutations could produce a phenotype resembling Goldenhar syndrome [31]. In the same year, Marlin and colleagues identified the c.826C>T transition hotspot at a CpG dinucleotide and a case with a t(5;16)(p15.3;q12.1) translocation whose breakpoint lay at least 180 kb telomeric to SALL1, suggesting a position effect [32]. There followed the demonstration, by quantitative PCR, of heterozygous SALL1 deletions in patients without a point variant [33], the delineation of an 802-base-pair hotspot region in exon 2 [34], the dominant-negative mouse model [35] and the link between the truncated protein and primary cilia dysfunction [36].

The second molecular phase broadened the class. In 2013, Vodopiutz and colleagues described two sisters from a consanguineous family homozygous for SALL1 c.3160C>T p.(Arg1054Ter), with multiple congenital anomalies, central nervous system defects, cortical blindness and absent psychomotor development, whereas the heterozygotes were healthy, which established a recessive form in the same gene [5]. In 2017, Webb and colleagues identified, in a North American family, a heterozygous DACT1 nonsense variant that segregated with imperforate anus and renal, genitourinary and ear anomalies, and the form came to be called TBS type 2 (TBS2; OMIM 617466) [2, 4]. In 2023, Christians and colleagues showed that hypomorphic missense variants of DACT1 in the DVL2-interaction region cause CAKUT and features of TBS2 with reduced penetrance [13].

1.3. Current nomenclature and definition of the entities in scope

GeneReviews names the main form SALL1-related Townes-Brocks syndrome (SALL1-TBS) and defines it by the presence of suggestive findings and a heterozygous pathogenic or likely pathogenic SALL1 variant [2]. Orphanet groups TBS1 and TBS2 under ORPHA:857 and defines the disease by the triad of imperforate anus, dysplastic ears often associated with sensorineural and/or conductive hearing loss, and thumb malformations, with other signs that are mainly renal and cardiac [1]. On 20 March 2026 ClinGen classified the relationship between SALL1 and TBS type 1 as definitive [15]. For the purposes of this article, the entities in scope are: (a) TBS1, the heterozygous SALL1 form, which includes minimal presentations, the “TBS BOR-like” presentation and apparently isolated kidney disease; (b) TBS2, the heterozygous DACT1 form with reduced penetrance; (c) the multiple congenital anomalies syndrome with intellectual disability due to homozygosity for SALL1 p.(Arg1054Ter). Smith's describes TBS as a single-gene disorder that brings together many features of the VACTERL association and the facio-auriculo-vertebral spectrum, which explains its central position in the differential diagnosis of those entities [18].

The only specific guideline identified is the French National Diagnosis and Care Protocol (PNDS), drawn up by the Rare Disease Reference Centres “Surdités génétiques” and “Anomalies du développement” of the Lille University Hospital (CHU) according to the methodology of the Haute Autorité de Santé (HAS), with a text of December 2023 published in February 2024 and based on a review of 188 molecularly confirmed patients from 115 families published between 1999 and June 2023 [12]. GeneReviews states that there are no published clinical practice guidelines and bases its recommendations on the authors' experience, and the Lille group noted in 2025 the absence of an international consensus [2, 19].

2. Molecular Genetics and Pathophysiology

2.1. Genetic class: types, genes and inheritance

TBS is a syndrome with limited genetic heterogeneity. Almost all molecularly confirmed patients have a heterozygous SALL1 variant; the French PNDS stresses that, at the time of its review, only SALL1 alterations had been implicated in the classic form, and the DACT1 form accounts for a minority whose fraction has not been published [8, 12]. The biallelic SALL1 form constitutes a second inheritance pattern in the same gene and should not be treated as a classification error between sources. The following table brings together the types currently recognised, with inheritance given as autosomal dominant (AD), autosomal recessive (AR) or X-linked (XL).

2.2. The SALL1 gene and the SALL1 protein

SALL1 is located at 16q12.1 and encodes the Sal-like 1 protein, a C2H2-type zinc finger transcription factor of the SAL family [2, 7]. The protein has four conserved C2H2 double domains, a single C2H2 motif linked to the second domain and an amino-terminal C2HC motif; the glutamine-rich region, between nucleotides c.687 and c.750 of the coding sequence, participates in self-dimerisation and in heterodimerisation with the other SAL proteins [19, 40]. SALL1 is strictly nuclear, binds to heterochromatin foci and has amino-terminal and central repressor domains; it acts as a transcriptional repressor, possibly within the NuRD histone deacetylase complex [2, 7]. The gene is expressed in all affected organs, including the developing ear, limb buds and excretory organs, and is essential for invasion of the metanephric mesenchyme by the ureteric bud, which explains renal agenesis, hypoplasia and dysplasia [7, 18, 41]. In the original cloning, the deduced protein had 1306 amino acids and the messenger RNA was most abundant in kidney, brain and liver, with expression in fetal brain in neuronal populations distinct from those expressing SALL2; the gene has three exons, and the upstream region, GC-rich and lacking TATA or CAAT boxes, includes eleven binding sites for the WT1 factor (Wilms tumor 1) and one for the SIX1 factor [10]. Chai and colleagues showed, with gel-shift and reporter gene assays, that SIX1 binds directly to the SALL1 promoter and increases its expression in a dose-dependent manner, which places SALL1 downstream of one of the genes of the branchio-oto-renal (BOR) spectrum and provides a plausible biological basis for the clinical overlap between the two entities (section 6.3) (indirect attribution via OMIM) [10]. In transfected murine cells, SALL1 protein fused to green fluorescent protein (GFP) concentrated in chromocentres, aggregates of pericentromeric heterochromatin, partly overlapped with the murine homologue of heterochromatin protein 1 (HP1) and strongly repressed transcription of a reporter, without reversal by trichostatin A, a histone deacetylase inhibitor; the same team identified as a partner PIN2, an isoform of telomeric repeat-binding factor 1 (TRF1), and linked SALL1 to higher-order chromatin organisation (Netzer and colleagues, 2001, indirect attribution via OMIM) [10]. The lack of effect of trichostatin A indicates that this repression does not depend solely on inhibitor-sensitive deacetylases, which limits the hypothesis of the NuRD complex as the sole mechanism. The absence of a measurable metabolite or enzymatic activity precludes any confirmatory biochemical test [7].

2.3. Molecular mechanism: haploinsufficiency, dominant-negative effect and primary cilia

The central question of pathogenesis is the relationship between the amount of functional SALL1 protein and the phenotype. The Sall1+/− mouse does not reproduce the syndrome, whereas the Sall1-ΔZn2-10 allele, which produces a truncated protein, causes in the heterozygous state high-frequency sensorineural hearing loss, cystic renal hypoplasia and wrist bone anomalies, and in the homozygous state complete renal agenesis, exencephaly and limb and anal deformities, more severe than in the null; the truncated protein interacts with all SAL members, which supports a dominant-negative model [35]. The reference null allele, described by Nishinakamura and colleagues in 2001, showed that Sall1 is indispensable for invasion of the metanephric mesenchyme by the ureteric bud, but heterozygotes did not have the TBS phenotype; in 2008, Kiefer and colleagues found in transgenic mice that the truncated protein alone reproduces the limb anomalies, detected this protein in a B-lymphocyte line from a patient with p.(Arg276Ter) and observed ectopic activation of Nppa and Shox2 in the developing heart and limb, a sign of derepression of genes normally silenced by SAL proteins (indirect attribution via OMIM) [10]. In Drosophila, simultaneous loss of spalt and spalt-related reduced Johnston's organ, the insect's main auditory structure, with deafness demonstrated by electrophysiology, and altered testes, genitalia and antennae, which points to conservation of the function of these genes between insects and vertebrates (Si Dong and colleagues, 2003, indirect attribution via OMIM) [10]. GeneReviews summarises the dosage hypothesis at heterochromatin foci: deletion of one allele reduces functional protein to 50%; a 5′ truncation produces a protein that does not localise to the site of action but binds the other SAL proteins and displaces them to the cytoplasm, reducing functional protein below 50%; variants further 3′ retain both repressor domains and the heterochromatin localisation domain, with residual function and a milder phenotype [2]. Sensitivity to nonsense-mediated decay (NMD) modulates this effect: in fibroblasts, a TBS-causing allele, NM_002968.3:c.995del p.(Pro332HisfsTer10) (historically “995delC”), escaped NMD in a patient with a relatively severe phenotype (bilateral preaxial polydactyly, imperforate anus, rectal atresia, hypospadias and overfolded helices), whereas another variant, NM_002968.3:c.3414_3415del (historically “3414delAT”), subject to NMD, was associated with a much milder phenotype, with preaxial polydactyly and triphalangeal thumb in a single limb [3, 9, 10, 42]; the recurrent variant p.(Arg276Ter) escapes NMD and is associated with a severe phenotype [2].

The PNDS integrates these data into a model in which the truncated protein escapes degradation, exerts a dominant-negative effect on the other SAL proteins, activates normally repressed target genes and adopts an aberrant cytoplasmic localisation, with primary cilium anomalies and disruption of the Sonic Hedgehog (SHH) pathway [12]. Bozal-Basterra and colleagues showed that cytoplasmic truncated SALL1 interacts with the negative regulators of ciliogenesis CCP110 and CEP97, which increases the frequency and length of primary cilia and disturbs their disassembly and SHH transduction in patient fibroblasts, in a CRISPR-edited cell line and in murine embryonic fibroblasts [36]. In 2020, the same group identified LUZP1 as a partner of truncated SALL1 that accelerates its proteasomal degradation; loss of LUZP1 reduces filamentous actin, facilitates ciliogenesis and alters SHH signalling [43]. These results are preclinical and have not led to studies in humans.

SALL1 deletions provide the natural test of haploinsufficiency. Borozdin and colleagues, studying by quantitative PCR 240 patients with a clinical diagnosis of TBS without a point variant, found deletions in three families and described milder phenotypes, concluding that haploinsufficiency suffices for mild TBS but not for the severe classic form [33]. Miller and colleagues, reviewing all known truncating variants and deletions in connection with a 149 kb deletion, did not support that correlation [44]. Innoceta and colleagues described a family with autosomal dominant hearing loss and mild anal and skeletal anomalies carrying a 350 kb deletion that includes exon 1 and the upstream region, and concluded that the overall phenotype of deletions is milder, particularly in comparison with p.(Arg276Ter), with a possible higher risk of developmental delay [45]. The Lille series provided quantitative data: in the 22 people with a deletion limited to SALL1 as the morbid gene, all proportions of features were lower than in carriers of point variants (excluding p.(Arg276Ter)), with the exception of developmental delay or intellectual disability, present in 6 of 20 (30%) [19]. ClinGen assigns SALL1 a haploinsufficiency score of 1 (little evidence) and a triplosensitivity score of 0, a dosage classification that does not contradict the definitive causality of TBS [15]. Position effects complete the spectrum: the translocation with a breakpoint downstream of SALL1 and a deletion upstream of the gene described by Stevens and May suggest that regulatory alterations can cause the syndrome without altering the coding sequence [2, 32].

2.4. SALL1 variant spectrum and nomenclature

Pathogenic SALL1 variants are almost all loss-of-function or structural variants: Yan and colleagues, in a review of 166 genetically diagnosed patients and 80 pathogenic or likely pathogenic variants, found that all were loss-of-function or copy number/structural variants [46]. The PNDS counted 104 truncating variants and 11 deletions in 115 families [12]. Variants cluster in exon 2: Botzenhart and colleagues found 46 of 56 mutations between the coding region of the glutamine-rich domain and 65 base pairs 3′ of the first double zinc finger domain, delineating an 802-base-pair hotspot [34]; Yan and colleagues placed the cluster between c.764 and c.1565 [46]; and all variants in the Lille series were in exon 2, 52% (11 of 21 families) within the hotspot [19]. In 2005, Botzenhart and colleagues counted 35 known SALL1 variants, most of them 5′ of or within the first double zinc finger region [3, 40]. In the early series, the nine variants of Kohlhase and colleagues (1999) comprised two nonsense variants, one of them in three families with no known relationship, and five small deletions, with no evident phenotypic difference according to position in the gene, a conclusion that later, larger series qualified (section 2.5); Marlin and colleagues found a variant in 9 of 11 unrelated patients (5 familial and 6 sporadic), one nonsense and six frameshift, all in exon 2, and interpreted the de novo occurrence in sporadic cases as compatible with complete penetrance [10, 31, 32]. In 2000, 19 of the 20 known variants were in exon 2, 5′ of the third double zinc finger region, among nonsense variants, small insertions and deletions and one extensive intra-exonic deletion; one small deletion was associated with a phenotype distinct from TBS, which Kohlhase attributed to a possible dominant-negative effect [10, 47]. A variant in intron 2 creates an aberrant splicing site [47]. Only two of the variants in the 2007 review produced a protein lacking the glutamine-rich domain, and one of them was associated with anal, ear, hand and renal manifestations, so this domain is not required for typical TBS [34].

The recurrent variant c.826C>T p.(Arg276Ter), historically “R276X”, results from a transition at a CpG dinucleotide; Marlin and colleagues found it in six of eight variants in sporadic cases [32], Kohlhase and colleagues described in 2003 its high frequency in sporadic cases and the first familial case [48], and the review by Yan and colleagues counted it in 19 of 103 probands [46]. The PNDS writes it as “c.826T>C”, which inverts the alleles; the normalised form is the one given in the following table [9, 12]. GeneReviews warns that the variants in its table were supplied by the authors without verification by the editorial team [2], so the variants cited were normalised according to Human Genome Variation Society (HGVS) nomenclature in VariantValidator (GRCh38 assembly) on the MANE Select transcripts [9]. The SALL1 literature also has a numbering shift of its own: the two variants in the 1998 article were renumbered by the same authors in 1999 (1377delC became 1268delC and 1222C>A became 1115C>A, a difference of 109 nucleotides), and it is the 1999 numbering that matches the current transcript; the p.(Ser372Ter) change was described through two different substitutions of the same nucleotide, c.1115C>A and c.1115C>G [9, 10]. In deletions located in single-nucleotide repeats, the HGVS 3′ alignment rule shifts the position relative to the published notation (for example, “1268delC” corresponds to c.1270del) [9].

DACT1 numbering requires care: the TBS2 literature uses transcript NM_016651, whereas the MANE Select is NM_001079520.2, with a difference of 37 codons in the normalised variants; the difference matches that between the two protein lengths described for DACT1 (836 and 799 amino acids; section 2.7). The remaining missense variants of Christians and colleagues were converted in VariantValidator to the MANE transcript and are listed in the table: four from the OMIM nucleotide notation in NM_016651.6, and p.(Gly644Asp) and p.(Pro669Ala) from table 1 of the publication, which uses NM_016651.5 and GRCh37 coordinates (chr14:59113272 and chr14:59113346); the two transcript versions give the same coding notation, and the GRCh37 coordinates returned by VariantValidator match those published [9, 11, 13]. The OMIM gene entry repeats the p.(Lys630Asn) variant under two allelic numbers (.0006 and .0007) with the same patient, which corresponds to a single variant. The p.Ser371X variant, described as somatic mosaicism in a patient with complete TBS and Duane anomaly, was published without nucleotide notation and was not normalised [54].

2.5. Genotype–phenotype correlations in SALL1

For most variants, which are private to each family, there are no clinically usable correlations [2, 12]. Three correlations have support. The first concerns p.(Arg276Ter): in GeneReviews, 15 of 16 carriers (94%) had the complete triad and about 50% had heart disease [2]; the PNDS reports 10 of 20 (50%) with heart disease versus 18% in the others [12]; and Leduc and colleagues found congenital heart disease in 12 of 26 carriers (46.2%) versus 28 of 180 (15.6%) carriers of other genotypes, excluding deletions, p.(Arg276Ter) being the only variant associated with tetralogy of Fallot in the literature [19]. The second concerns position: variants in the 5′ hotspot of exon 2 are associated with a more severe phenotype than those further 3′ [2]. The third, already discussed, concerns deletions, with a phenotype that is milder on average but controversial [19, 33, 44, 45].

The analysis by Leduc and colleagues of 226 patients tested two boundaries. Carriers of variants upstream of or within the glutamine-rich region (c.1–c.750; n = 26) had, compared with those with downstream variants (n = 200), less hearing loss (45.8% versus 67.4%; p = 0.037), fewer dysplastic ears (58.3% versus 85.3%; p = 0.003) and fewer thumb malformations (50.0% versus 74.5%; p = 0.009), but more chronic renal failure (CRF; 50.0% versus 29.3%; p = 0.040); however, the upstream group was older (median age 30.5 years versus 8.0; p = 0.033) and the downstream group had more missing data, which the authors acknowledge as a source of confounding [19]. Carriers of variants upstream of the middle of the hotspot (c.1164; n = 109) had, compared with those with downstream variants (n = 117), more hearing loss (74.8% versus 55.5%; p = 0.003), more lower-limb malformations (57.9% versus 40.2%; p = 0.009) and more genital anomalies (21.3% versus 8.3%; p = 0.007), with no significant difference in CRF (37.1% versus 26.2%; p = 0.086) [19]. Wang and colleagues, in 81 patients, suggested that variants between c.1500 and c.3468 are less associated with the renal phenotype, without statistical analysis (indirect attribution via Leduc) [19]. A mechanistic hypothesis for the better renal function of downstream variants comes from the mouse with truncated Sall1 that retains the glutamine-rich region, which is less susceptible to acute kidney injury than the wild type and the null (Hirsch and colleagues, 2015, indirect attribution) [19].

Yan and colleagues described a “generational effect”: 62.5% of first-generation patients had an atypical presentation versus 14.9% of affected offspring, and the offspring had more dysplastic ears (p = 0.002), genitourinary malformations (p = 0.003), craniofacial malformations (p = 0.032) and psychomotor delay (p = 0.050) [46]. The Lille group did not confirm this effect and observed that, when de novo occurrence was proven, the index case had the triad, which points to an ascertainment bias in which parents with minimal forms are recognised only after the child's diagnosis [19]. The same observation had already been made in a three-generation Japanese family described by Sudo and colleagues in 2010: the 4-year-old proband had bilateral preauricular tags, bilateral preaxial polydactyly, toe anomalies, an anteriorly placed and stenotic anus, mild sensorineural hearing loss, VSD and a small right kidney, whereas the grandfather and great-aunt had only unilateral preaxial polydactyly and hearing loss; the authors described an anticipation-like worsening in each generation, often with maternal transmission, an interpretation that has no known molecular basis and is compatible with the same ascertainment bias (indirect attribution via OMIM) [3].

2.6. Penetrance, expressivity and mosaicism

Penetrance is described as probably complete when individuals at the mild end of the spectrum are included, with very variable expressivity within the same family [2, 12]. In family 6 of the Lille series, with three affected generations, no feature was common to all affected members; one carrier had only an anorectal malformation, moderate speech delay and strabismus, and another had no phenotypic features, although without renal or cardiac assessment [19]. The p.(Arg1054Ter) variant is the exception to complete penetrance: 11 heterozygotes had no TBS features, and the variant retains some function, with partial NMD and mutant transcript at 43% of the normal level in fibroblasts from a healthy carrier [2, 5]. Four individuals with somatic and gonadal mosaicism have been described [2, 31, 54–56]; a mosaic parent may have minimal signs, such as the 2nd and 4th toes overlapping the 3rd, or only an anteriorly placed anus [55, 56]. The Lille series did not identify somatic mosaicism [19]. De novo variants are predominantly paternal: in 16 families with 10 variants, the origin was paternal in 14 (87.5%), regardless of variant type, with mean ages at conception of 29.9 years for the father and 26.5 for the mother, without an evident paternal age effect [57, 58].

2.7. DACT1 and TBS type 2

DACT1 (Dapper 1), at 14q23.1, encodes a cytoplasmic and nuclear scaffold protein that binds Dishevelled proteins through a carboxy-terminal PDZ domain-binding motif and modulates the canonical Wnt/β-catenin pathway and the non-canonical planar cell polarity pathway; the Dact1-null mouse dies in the neonatal period with severe posterior malformations, including absent anus with a blind-ending colon and genitourinary malformations [4, 8]. The first human sequence, identified by homology with Xenopus Dapper, predicted an 836-amino-acid protein with 60% identity and complete conservation of the 28 carboxy-terminal amino acids, where the PDZ domain-binding motif lies; a second analysis predicted 799 amino acids, four coding exons spanning about 6.8 kb and seven Dapper homology domains, including a leucine zipper, a serine-rich region and the PDZ-binding domain, and initially mapped the gene to 14q22.3, a band later revised to 14q23.1 [11]. In Xenopus, Dapper binds Dishevelled, forms complexes with axin, glycogen synthase kinase 3, casein kinase I and β-catenin, inhibits activation of c-Jun N-terminal kinase (JNK) by Dishevelled, and depletion of its maternal RNA eliminates the notochord and head structures; the same homologue (Frodo) stabilises p120-catenin and relieves transcriptional repression by Kaiso, and the SESTD1 protein binds all members of the DACT family [11]. In the mouse, Dact1−/− embryos are born at a near-Mendelian ratio, but almost all die on the first day of life; the malformation is visible from embryonic day 8.25 in the primitive streak region, where the transmembrane protein VANGL2, of the planar cell polarity pathway, accumulates with abnormal distribution of E-cadherin, and Vangl2 heterozygosity corrects the recessive Dact1 phenotype, just as loss of Dact1 corrects the semidominant Vangl2 phenotype (Suriben and colleagues, 2009, indirect attribution via OMIM) [11]. Sestd1−/− mice have an identical spectrum (short tail, absent genital tubercle, anus and bladder, blind-ending colon and hydronephrotic kidneys, with neural tube defects of partial penetrance), and simultaneous loss of both genes does not worsen the picture, which indicates that SESTD1 and DACT1 act in the same VANGL2-regulating pathway (Yang and Cheyette, 2013, indirect attribution via OMIM) [11]. In the index family of Webb and colleagues, six affected individuals over three generations, the nonsense variant segregated with the disease, was absent from the population databases then available, produced a stable protein in HEK293 cells, and the mutant messenger RNA enlarged the proctodeum in Xenopus; since the truncated protein retains the coiled-coil domain required for homodimerisation, the authors proposed a dominant-negative effect through formation of non-functional dimers with the normal protein [4, 11]. Christians and colleagues, in a cohort of 209 families with CAKUT, found very rare non-silent DACT1 variants (allele frequency ≤ 0.0005) in 8 families (3.8%) versus 1.7% of controls; the seven missense variants, mostly likely pathogenic, were exclusively maternally inherited, lay in the DVL2-interaction region and reduced that binding, and loss of Dact1 impaired tubule formation in mouse IMCD cells [13]. Carriers had renal agenesis, duplex kidneys or (multi)cystic (hypo)dysplastic kidneys with hydronephrosis and TBS2 features in the skeleton, brain, distal gut and genital tract [13]. By 2024, five pathogenic or likely pathogenic DACT1 variants had been described in TBS2, mainly with external ear, genitourinary and anal anomalies and without hearing loss; none was found among the 51 variants of the Chinese hearing loss cohort or in 142 Japanese patients with CKD [6, 46]. Gene–disease evidence is limited: there is no ClinGen validity curation, and GenCC classifications are distributed across “Limited” (four submissions), “Moderate” (one) and “Supportive” (one), with a DECIPHER haploinsufficiency index of 60.74% and a pLI of 0.16 [8, 16]. Rare DACT1 missense variants have also been described as a risk factor in Chinese fetuses with neural tube defects, and Orphanet links the gene to craniorachischisis and occipital encephalocele, associations distinct from TBS2 [1, 8]. In the study by Shi and colleagues (2012), five different heterozygous missense variants occurred in 5 of 167 stillborn or aborted Chinese fetuses with severe neural tube defects, including anencephaly, and in none of 480 Han controls; without parental DNA, it was not determined whether they were inherited or de novo; two of them (p.Arg45Trp and p.Asn356Lys, in the publication's numbering) reduced planar cell polarity pathway functions in cell assays and caused morphogenetic defects in Xenopus embryos, and OMIM keeps this association as pending confirmation [11]. The five variants were published only in protein notation, p.R45W, p.D142G, p.N356K, p.V702G and p.T808K [4]. The five reference residues match isoform 1 (NP_057735.2, encoded by NM_016651.6, 836 amino acids), which indicates the publication's numbering; in the MANE transcript (NM_001079520.2, NP_001072988.1, 799 amino acids), which lacks the 37 amino acids from residue 213 of isoform 1, they correspond to p.(Arg45Trp), p.(Asp142Gly), p.(Asn319Lys), p.(Val665Gly) and p.(Thr771Lys), by comparison of the RefSeq protein sequences of the two isoforms [4, 9]. The nucleotide notation does not appear in the abstract or in OMIM, and none of the variants is registered in ClinVar; since each amino acid change may result from more than one nucleotide substitution, depending on the reference codon, the c. notation was not assigned and the protein notation is retained.

2.8. Allelic disorders, modifiers and dual diagnosis

The recessive form due to p.(Arg1054Ter) is the only established allelic disorder of SALL1; Vodopiutz and colleagues concluded that the quantity and quality of the transcript determine the phenotype and mode of inheritance and recommended detailed neurological assessment in all carriers of SALL1 variants [5]. No genetic modifiers have been identified. Almost 5% of patients with a rare disease have more than one molecular diagnosis, so rare features (for example, severe intellectual disability or involvement of an unusual organ) may have an independent cause; in the Lille review, one patient from the literature also had mosaic trisomy 8 [2, 19]. The SAL family includes SALL4, whose variants cause Duane syndrome with radial ray anomalies (Okihiro syndrome), acro-renal-ocular syndrome and a Holt-Oram-like phenotype; this is the closest functional differential and is covered in section 6 [26].

3. Clinical Spectrum and Manifestations by System

3.1. Frequency of features: what the series measure

Published frequencies depend on the period, the inclusion criterion and the mode of ascertainment. Pre-molecular series, such as those cited by the Oxford Desk Reference (sensorineural hearing loss in 71%, hand malformations in 56% and imperforate anus or fistula in 47%, without indication of the source series), included patients without genetic confirmation, some probably with differential diagnoses [41, 59]. Molecular series start from probands with the triad, which overestimates the features that prompted testing; the Lille series, recruited through the Lille University Hospital laboratory and rare disease networks, and cohorts ascertained through renal or hearing loss panels show lower proportions of the triad. The table compares the main sources.

Sources of the table: GeneReviews [2], PNDS [12] and Leduc and colleagues [19]. In the Lille series the mean age was 23.6 ± 21.8 years and in the reviewed literature 15.6 ± 17.3 years, with age missing for 114 patients; the female:male sex ratio was 0.95 overall [19]. The proportion with renal failure increases with age at observation, and a series with older patients finds more kidney disease without this reflecting a different risk. Orphanet classifies as very frequent (80–99%) abnormal pinna morphology, rectovaginal fistula, preauricular tag, preaxial polydactyly, triphalangeal thumb, anal atresia and rectoperineal fistula, frequencies inherited from clinical descriptions and not from a molecular cohort [1].

3.2. Digestive tract and anorectal region

Anorectal malformation occurs in about two thirds of patients and, in TBS, corresponds mainly to low forms: imperforate anus with perineal fistula, anteriorly placed anus and anal stenosis; in girls, rectovaginal fistula is frequent [2, 12, 18]. Smith's also reports a prominent perineal raphe and, occasionally, duodenal atresia [18]. Chronic constipation and gastro-oesophageal reflux (GOR) accompany many patients [2]. After anorectoplasty, the PNDS describes terminal constipation as frequent in the first years, with a risk of recurrent overflow faecal soiling, favoured by sphincter incompetence and by altered perception of the urge to defecate; faecal incontinence is listed among the occasional manifestations in Orphanet [1, 12]. Spinal magnetic resonance imaging (MRI) can exclude occult spinal dysraphism, which is not classically described in TBS [12].

3.3. Ear and hearing

Dysplastic ears are the most constant feature: overfolded superior helix, hypoplastic antihelix, small cup-shaped ears or large prominent ears, preauricular tags and pits, microtia and, rarely, aplasia of the pinna; the external auditory canals may be narrow or stenotic, and pretragal enchondromas occur in 36% [2, 12, 18]. Ossicular findings mainly affect the head of the malleus, which is hypoplastic, or the oval window, which is abnormally shaped, and the inner ear may show cochlear hypoplasia, semicircular canal dysplasia, aplasia or hypoplasia of the cochlear nerve or an enlarged vestibular aqueduct [12]. Hearing loss affects about two thirds of patients, is congenital or late-onset, predominantly sensorineural, bilateral and high-frequency, mild to moderate, and may worsen [12, 19]. Among 108 patients with data in the review by Yan and colleagues, more than 60% (65/108) had sensorineural hearing loss, 11.1% (12/108) conductive or mixed, 19.4% severe, 13.9% mild and 13.9% moderate, with progression documented in at least two families and in one patient followed for three years [46]. In the Lille series, hearing loss was mainly postlingual and progressive in four patients, and six ear imaging studies were generally normal, with one incus anomaly and one external auditory canal anomaly [19]. A Chinese family had middle ear malformation and bilateral enlargement of the vestibular system, not previously described [46]. The ear phenotype can appear apparently isolated: a 7-year-old boy with bilateral cup ears, normal hearing screening and renal ultrasound, whose father and grandfather had the same deformity, carried SALL1 c.1949del p.(Gly650AlafsTer46) [60].

3.4. Hands and feet

Limb anomalies affect 89% (164/184) of the patients reviewed by the PNDS [12]. In the thumb, usually bilaterally, the predominant findings are preaxial polydactyly (47%), which is a true duplication with two thumbs hypoplastic relative to the contralateral one, triphalangeal thumb (29%) and, less frequently, hypoplastic thumb (8%); the radius is always present and there is no radial club hand [12]. Smith's adds broad or bifid thumb, hypoplastic thenar eminence, distal ulnar deviation of the thumb and occasional syndactyly between the 2nd and 3rd or the 3rd and 4th fingers [18]. In the feet, involved in about half, there are talipes equinovarus (5%), pes planovalgus (4%), syndactyly of the lateral toes (15%), clinodactyly and overlapping toes (16%), with typical overlapping of the 2nd and 4th toes over the 3rd, and absence or hypoplasia of the 3rd toe [2, 12, 18]. Radiology shows pseudoepiphyses of the 2nd metacarpals, triquetral–hamate fusion, absence of the triquetrum and navicular, and fusion or shortening of the metatarsals; rib anomalies and mild vertebral anomalies occur in 9%, scoliosis is occasional and several adults report arthralgia [2, 18].

3.5. Kidney and urinary tract

Developmental anomalies of the kidney and urinary tract affect about 55% of the patients reviewed by the PNDS, with unilateral or bilateral renal hypodysplasia (32% of the anomalies described), cystic (5%) or non-cystic dysplasia, renal agenesis (5%), multicystic kidneys, vesicoureteral reflux (VUR), ectopia, horseshoe kidney, pelviureteric junction syndrome, duplex systems, bladder diverticula and posterior urethral valves [2, 12, 18]. Renal failure, present in 29% overall, is reported in about 5% of children and 30% of adults; it may be present from birth or arise in childhood or adulthood, and its severity and progression are proportional to the reduction in nephron number [12]. Cases of renal failure without a major ultrasound anomaly have been described, and normal renal imaging does not dispense with lifelong monitoring of function [7, 12, 19].

The renal natural history in adults was recognised late. Reardon and colleagues proposed in 2007 that renal failure is part of the natural history, after finding that the renal presentation had been described only once [61]. That earlier report, by Newman and colleagues in 1997, was of a man who presented at 23 years of age with end-stage kidney disease, severe hypertension and small kidneys bilaterally, with anal stenosis operated on at birth, overfolded helices, preauricular tags, bilateral preaxial hexadactyly, syndactyly of the 3rd and 4th toes and bilateral sensorineural hearing loss noted at 3 years (indirect attribution via OMIM) [3]. Faguer and colleagues described two adults diagnosed at 28 and 35 years with severe CRF and renal hypodysplasia, one of them with FSGS, and stated that regular assessment of the glomerular filtration rate (GFR) is mandatory throughout life [62]. Beaudoux and colleagues reviewed 44 genetically confirmed adults, 10 of whom had kidney disease; the median age at diagnosis of kidney disease was 30 years and at transplantation 49 years, and renal failure was discovered as an incidental finding, through gout or through recurrent pyelonephritis [63]. In the Lille series, 19 of 48 patients had CRF, including two newborns; 3 had CRF without an ultrasound anomaly and 6, mainly adults, reached end-stage kidney disease (ESKD); in the reviewed literature, 9.5% of the 56 patients with CRF progressed to ESKD [19]. The PNDS estimates ESKD with dialysis or transplantation in 8% of patients, a value that may be an underestimate [12].

Cohorts ascertained through the kidney show the predominant renal presentation. In the North American laboratory analysed by Stein and colleagues, the 22 patients with a SALL1 variant had a median age of 23 years (3 months to 62 years), CKD in 91% (20/22), renal agenesis or hypoplasia in 32%, FSGS in 18% and renal cysts in 14%; only 3 (14%) had a prior diagnosis of TBS and the triad [38]. In the Japanese national cohort of Asagai and colleagues, 17 of 20 individuals from 14 families had renal hypodysplasia or dysfunction, and the final diagnosis was typical TBS in 40%, “BOR-like” TBS in 20% and non-syndromic CAKUT in 35%, with typical TBS and isolated CAKUT in the same family [6]. In a three-generation Serbian family with SALL1 p.(Tyr503Ter), all seven affected members had bilateral renal hypodysplasia and CKD, and none had the complete triad; the proband reached ESKD in adolescence and received a transplant [51]. A 10-year-old Slovenian girl was investigated for raised creatinine and diagnosed on the basis of ear tags, without anorectal or limb anomalies [39], and a Turkish family was diagnosed late without the triad, with a proband with developmental delay, renal failure and a foot anomaly carrying SALL1 c.2287dup p.(Arg763LysfsTer42) [64]. Biopsy is not useful for diagnosis; when performed, it shows non-specific FSGS, linked to nephron reduction, and dysplastic lesions [12, 50].

3.6. Genital tract

Genital anomalies predominate in males: hypospadias (22% of boys in the PNDS), cryptorchidism (6%, bilateral in half of cases), bifid scrotum and penoscrotal transposition [2, 12]. In the Lille series, 6 of 25 men (24%) had genital anomalies and no women; in the reviewed literature, 24 of 96 men (25%) versus 3 of 93 women (3.23%) [19]. In women, uterovaginal hypoplasia, bifid uterus and vaginal aplasia have been described [12, 40]. In the series of 13 families of Botzenhart and colleagues, rare features included hypothyroidism, GOR, vaginal aplasia with bifid uterus, cryptorchidism, bifid scrotum without hypospadias, unilateral chorioretinal coloboma with visual loss, Duane anomaly, dorsal hypoplasia of the corpus callosum and umbilical hernia [3, 40].

3.7. Heart

Congenital heart disease occurs in 15–20% of patients, with atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus and, more rarely, tetralogy of Fallot; lethal truncus arteriosus and pulmonary valve atresia have been described [2, 12]. The heart defects of TBS are usually not severe and are amenable to catheterisation or surgery, with the exception of the forms associated with p.(Arg276Ter) [12, 19]. In family 18 of the Lille series, with p.(Arg276Ter) inherited from the mother, a child with pulmonary atresia, VSD, major aortopulmonary collaterals, unilateral renal agenesis and cystic changes of the anterior horns of the lateral ventricles died at 3 months [19]. The family described by Surka and colleagues illustrates the clustering of heart disease in a family with a SALL1 variant: over three generations, seven people had confirmed TBS, one died with truncus arteriosus and another with complex heart disease with pulmonary valve atresia (a child died at 3 days), severe heart defects not previously described in familial cases; on the basis of this family and a literature review, the authors advocated cardiac assessment of all patients [3, 53].

3.8. Endocrine system and growth

Endocrine abnormalities affect 13–16% of patients [12, 19]. Hypothyroidism (6% in the PNDS; 5.6% in the literature reviewed by Leduc) is mainly congenital, due to thyroid dysgenesis, and detectable on newborn screening; in the Lille series four patients had hypothyroidism, sometimes subclinical [12, 19]. Short stature (4%) may result from CRF, growth hormone deficiency or poorly controlled hypothyroidism; of the seven cases with growth delay reviewed by the PNDS, two had renal failure and one had a growth hormone deficiency described as atypical [12]. Lawrence and colleagues described the first patient with growth hormone deficiency and another with hypothyroidism, both with the same variant, and argued that treatable deficiencies are underdiagnosed [52]. Exceptional cases of parathyroid hypoplasia have been described, as well as hyperuricaemia and subclinical hypothyroidism co-segregating in a Chinese family, and delayed puberty is listed among the occasional manifestations in Orphanet [1, 12, 46].

3.9. Eye and cranial nerves

Eye anomalies, excluding refractive errors, affect 12–15% of the patients reviewed [12]. Stilling-Duane anomaly, almost always type I (limited or absent abduction with normal adduction), unilateral or bilateral, has been described in 5 patients (3%), and iris or chorioretinal coloboma in 4 (2%) [12]. Lamellar cataract, congenital or acquired, microphthalmia, optic atrophy, horizontal nystagmus due to absence of the optic chiasm and epibulbar dermoids have also been described [2, 18, 34]. In the Lille series, 2 of 44 patients had Duane, 3 acquired cataract and 8 refractive errors, without colobomas or dermoids [19]. Valikodath and colleagues described a child with bilateral Duane type 1 and Möbius sequence, Marcus Gunn synkinesis, gustatory lacrimation and absent emotional tears, with bilateral absence of the abducens nerve and of the left facial nerve on MRI [65]. Cranial nerve involvement other than isolated Duane, mainly of the facial nerve, occurs in about 5% [12].

3.10. Neurodevelopment, behaviour and central nervous system

Developmental delay or learning difficulties were estimated at about 15% in GeneReviews; adults with TBS rarely have intellectual disability, and when present it is mild [2]. The more recent reviews, which excluded confounding factors (contiguous gene deletions, dual diagnosis, speech delay due to hearing loss, prematurity or neonatal resuscitation), obtained lower values: 6.5% psychomotor delay and 5% intellectual disability in the PNDS, and 8% in the literature reviewed by Leduc, with 15% (6/40) in the Lille series, generally mild to moderate [12, 19]. Speech delay associated with hearing loss had a good outcome [19]. Attention deficit hyperactivity disorder (ADHD) and other behavioural problems are described in some children [2, 12]. In the CNS, Chiari I malformation, hypoplasia of the dorsal part of the corpus callosum, agenesis of the corpus callosum and occasional microcephaly have been described [1, 2, 18].

3.11. Face and the oculo-auriculo-vertebral spectrum

Some patients have features of hemifacial microsomia or mandibular hypoplasia, and facial asymmetry was recorded in 3.9% (9/230) in the combined Leduc series [2, 18, 19]. Keegan and colleagues reviewed eight patients at the boundary between TBS and expanded-spectrum hemifacial microsomia with anal anomalies; two had the major findings of TBS, SALL1 was sequenced in four and one of them had p.(Arg276Ter), which added evidence for the hotspot and led the authors to recommend SALL1 testing in patients with overlapping features [3, 66]. Johnson and colleagues described in 1996 a three-generation family in which the grandmother and mother had been regarded as having Goldenhar syndrome (epibulbar dermoids, ear tags, micrognathia, facial asymmetry), until the birth of a grandson with typical TBS; both had triphalangeal thumbs and genitourinary anomalies (indirect attribution via OMIM) [3]. Kosaki and colleagues described a family in which expression varied between isolated external ear anomalies and Goldenhar syndrome: two sisters carrying the same SALL1 variant, one with a TBS phenotype and the other with epibulbar dermoid, bilateral microtia with canal atresia, mandibular hypoplasia, preaxial polydactyly, anteriorly placed anus and hypoplastic kidneys, and the mother, also a carrier, with dysplastic ears only [3, 18]. Figure 1 (A–E) of Smith's, on page 375 of the 8th edition, shows facial variation with large prominent ears, preauricular tags and features resembling the facio-auriculo-vertebral spectrum, imperforate anus, hypoplastic thenar eminence and thumb and hypoplastic 3rd toe [18].

3.12. Prenatal period and recessive form

The PNDS recorded prenatal involvement in 4% (6/160) of published cases, mainly intrauterine growth restriction (IUGR), renal malformations and tetralogy of Fallot, acknowledging underestimation given advances in ultrasound [12]. In the Lille series, 57% of patients had prenatal ultrasound findings (IUGR and renal, limb and cardiac malformations), which reflects recent recruitment [19]. The Spanish registry associated TBS with low birth weight [17]. In the recessive form, the two sisters homozygous for p.(Arg1054Ter) had multiple TBS-type congenital anomalies, CNS defects, cortical blindness and absent psychomotor development [5].

3.13. Phenotype of TBS type 2

In the TBS2 index family, the 20-month-old proband had imperforate anus with rectovaginal fistula, crossed fused renal ectopia, grade II VUR, a smaller right ear with an overfolded superior helix and bilateral cup ears, normal hearing and development and no thumb or radial anomaly; her brother had imperforate anus, hypospadias, crossed fused renal ectopia and VUR, the mother had spina bifida occulta, Graves' disease and cup ears, and the mother's half-sister and the maternal grandmother had severe left microtia, the grandmother also with a bifid uterus [4, 14]. In carriers of missense variants, renal anomalies predominate (agenesis, duplication, cystic dysplasia), with variable skeletal, cerebral, anorectal and genital features [13]. Among the 11 patients from 8 families of Christians and colleagues, 10 had CAKUT, 4 neurological anomalies, 4 skeletal, 1 genital and 1 distal gut anomalies; the last had caudal regression (absent coccyx, sacral dysplasia, syringohydromyelia and anorectal dysgenesis) with agenesis of the corpus callosum, hydrocephalus and agenesis of the cerebellar vermis; the variant of the initial Kurdish patient, p.(Thr330Lys) (in the literature p.(Thr367Lys)), was inherited from the unaffected mother [13, 14]. The absence of thumb anomalies and hearing loss is the main clinical element distinguishing TBS2 from TBS1 [2, 46].

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age and setting

No isolated manifestation is specific to TBS, and the diagnosis is suggested by a combination of signs, possibly in a dominant familial context [12]. In the prenatal period, suspicion arises mainly when one of the parents is affected; without a family history, ultrasound signs (IUGR, non-specific renal or cardiac malformations, club foot, rarely preaxial polydactyly) seldom lead to the diagnosis [12]. In the newborn, anorectal malformation with dysplastic ears or preauricular tags and a duplicated or triphalangeal thumb is the typical presentation; the Oxford Desk Reference recommends, in the presence of an anal anomaly, asking about visual or hearing problems, carefully examining the external ear and looking for triphalangeal or hypoplastic thumbs [67]. In the presence of an ear anomaly or facial asymmetry, triphalangeal or hypoplastic thumbs suggest TBS, and the Oxford recommends considering SALL1 testing in patients with features overlapping the oculo-auriculo-vertebral spectrum [41, 59]. In the presence of preaxial polydactyly, TBS is one of the syndromic causes to consider [68].

In childhood and adolescence, suspicion arises from progressive hearing loss with dysplastic ears, from CAKUT discovered on ultrasound or during a urinary tract infection, or from reassessment of a child operated on at birth for anorectal malformation [12]. In adults, the presentation is mainly renal: proteinuria, arterial hypertension, gout, pyelonephritis or CKD with renal hypodysplasia, often without a prior diagnosis of TBS, as shown by renal panel cohorts in which only 14% had a previous diagnosis [38, 63]. Targeted examination of the ears, thumbs and feet, questions about anorectal surgery in childhood and a three-generation pedigree (limb malformations, ear dysplasia, hearing loss, renal failure, cardiac or anorectal surgery) are often sufficient to raise the hypothesis [12, 63]. The PNDS asks the attending physician to refer to clinical genetics every patient with a malformative association of at least two systems involved, hearing loss, or early isolated renal involvement [12].

4.2. Red flags and urgent situations

The newborn with anorectal malformation needs assessment by a specialised surgical team within the first 48 hours of life, which decides the indication and timing of surgery; in high forms with rectourinary or rectogenital fistula, colostomy is performed early [12]. Refractory cyanosis with an ejection murmur at the pulmonary area suggests tetralogy of Fallot, and feeding difficulty, respiratory distress and poor weight gain after three weeks of life suggest a significant left-to-right shunt through a VSD or ductus arteriosus; these situations require immediate cardiological assessment, particularly if the patient carries p.(Arg276Ter) [12, 19]. Prenatal oligohydramnios or anhydramnios suggests severe renal involvement [12]. At any age, a rise in creatinine, new proteinuria or hypertension in a patient with TBS indicates progression of kidney disease, and pregnancy may worsen renal function [2]. Club foot requires a prompt paediatric orthopaedic appointment, without being a therapeutic emergency [12].

In the child, the signs that require hearing to be tested are absence of response to voice or noise, absence of babbling at 9 months, of words at 18 months or of word combinations at 24 months; in the adult, decreased hearing acuity, difficulty in noisy environments or complaints from relatives [12].

4.3. Newborn screening

There is no newborn screening for TBS. Two universal newborn programmes are directly relevant: newborn hearing screening, which can identify congenital hearing loss, and screening for congenital hypothyroidism, through which the hypothyroidism of TBS, predominantly congenital, is already being treated at the time of the syndromic diagnosis [12]. A normal newborn hearing screen does not exclude later hearing loss, because hearing loss may appear later and progress [12, 19].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Suggestive findings and criteria

There are no validated formal clinical criteria. GeneReviews defines major and minor findings that suggest the disease: major findings are imperforate anus or anal stenosis, dysplastic ears (overfolded superior helix, preauricular tags, microtia) and typical thumb malformations (preaxial polydactyly, triphalangeal thumb, hypoplastic thumb) without radial hypoplasia; minor findings are sensorineural and/or conductive hearing loss, foot malformations, renal dysfunction with or without malformation, genitourinary malformations and congenital heart disease; a family history compatible with autosomal dominant transmission strengthens suspicion, but its absence does not exclude it [2]. The Oxford Desk Reference describes expression as very variable but including two or more of: bilateral ear malformation, ear tags, sensorineural hearing loss, hand malformations, imperforate anus or fistula and renal anomalies [41]. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic SALL1 variant according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP); a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [2]. The PNDS adds that, when the clinical picture and family history are highly suggestive, the absence of a causal variant does not necessarily exclude the diagnosis, because a regulatory alteration of SALL1 expression may escape current techniques [12].

Source: GeneReviews [2].

5.2. Clinical assessment and supporting investigations

Clinical and imaging assessment supports the suspicion. Hand radiography, recommended by the PNDS for the first orthopaedic appointment, shows the type of duplication or triphalangism and confirms the presence of the radius; the absence of radial hypoplasia is a diagnostic element, and its presence points to SALL4 [7, 12]. Ophthalmological examination looks for coloboma and Duane anomaly, the latter atypical in TBS and more frequent in SALL4-related disease [2, 7]. Renal ultrasound, creatinine with estimated GFR (eGFR), albuminuria and echocardiography complete the organ assessment [2, 12]. In the presence of an anal anomaly, the Oxford recommends radiographs of the spine, sacrum, pelvis and chest for the VACTERL association, lumbosacral MRI, renal ultrasound (genitourinary anomalies account for 49% of the anomalies associated with anorectal malformations) and echocardiography (27% of associated anomalies are cardiovascular), as well as endocrine referral if Pallister-Hall syndrome is suspected [67]. There is no confirmatory biochemical biomarker [7].

5.3. Molecular testing: choice and order

GeneReviews proposes two approaches. In the targeted approach, SALL1 is sequenced (missense, nonsense and splicing variants and small insertions or deletions) and, if negative, exon-level or whole-gene deletion/duplication analysis is performed; a multigene panel including SALL1, SALL4 and other genes in the differential is an alternative; SALL4 should be studied first if there is radial involvement or Duane anomaly, because patients with TBS features have SALL4 variants [2]. In the genomic approach, used in atypical phenotypes, exome or genome sequencing is performed [2]. The PNDS notes that, in current practice, SALL1 is almost always analysed within a panel for limb malformations, hearing loss or renal malformations, and that exome or genome sequencing is justified when there is doubt about a differential diagnosis; the Lille group stresses that the possibility of dual diagnosis also justifies exome or genome sequencing [12, 19]. A deletion that includes contiguous genes requires a chromosomal microarray, which is also the first prenatal test in the presence of malformations [12, 67].

5.4. Yield, sensitivity and limitations of testing

The proportion of pathogenic variants detected by each method, according to Human Gene Mutation Database (HGMD) data summarised by GeneReviews, is above 90% for sequencing and below 10% for deletion/duplication analysis [2]. These proportions describe the known mutational spectrum and are not the clinical sensitivity of the test. The diagnostic yield in patients with the complete triad has been estimated at between 58% (7 of 12 patients, Kohlhase 1999) and 75% (GeneReviews, 2007–2016 editions), and Smith's reports truncating variants in 64–83% of clinical cases [12, 18]. According to Kohlhase, cited by Yan and colleagues, about 25% of patients with typical TBS do not have a SALL1 variant; a Chinese patient with typical TBS remained without a SALL1 or DACT1 variant even after genome and HiFi long-read sequencing [46]. A negative result does not exclude the diagnosis.

The known technical limitations are as follows. The highly homologous pseudogene SALL1P1 may prevent capture-based panels from distinguishing SALL1 variants from those of the pseudogene and complicate exome interpretation [2]. Deletions and duplications require dedicated methods (quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification, MLPA, or targeted microarray); exome and genome sequencing can detect them through breakpoints or read depth, with lower sensitivity [2]. Regulatory variants and position effects, such as the downstream translocation and the upstream deletion of SALL1, are not detected by sequencing of the coding region [2, 32, 45]. Leucocyte DNA may not detect all somatic mosaicism and does not detect exclusively gonadal mosaicism [2]. In the Chinese hearing loss cohort, 150 SALL1 VUS were recorded for 7 pathogenic or likely pathogenic variants, and in the Japanese cohort the only missense variant (in exon 3, with conflicting ACMG classifications) remained of uncertain significance, which illustrates the difficulty of interpreting non-truncating variants in a gene in which all confirmed pathogenic variants are loss-of-function [6, 46].

5.5. Report content and interpretation

The report should state the gene, the reference transcript with version (NM_002968.3 for SALL1; NM_001079520.2 for DACT1, with the NM_016651 equivalent when the literature requires it), the nucleotide and protein HGVS nomenclature, zygosity, the ACMG/AMP class, the method and the limitations of the analysis (coverage of SALL1 relative to SALL1P1, whether or not copy number variants were sought) [2, 9]. For a VUS, segregation analysis in the parents is of particular value, because about half of cases are de novo and a de novo variant with confirmed parentage strengthens pathogenicity; in DACT1, transmission from mildly affected or unaffected parents is expected and does not rule out pathogenicity [2, 13]. The test does not predict the manifestations or severity in an individual, with the partial exception of p.(Arg276Ter), associated with a severe phenotype in all known cases [2, 12].

5.6. Practical algorithm

In renal agenesis, hypoplasia or dysplasia, a molecular diagnosis is possible in up to 15–20% of patients, with 5–10% having variants in PAX2, HNF1B, DSTYK, SALL1, SIX1 or EYA1 and a further 10% large genomic imbalances, which is why SALL1 should be part of CAKUT panels [69].

5.7. Prenatal and preimplantation diagnosis

The classic features are detectable from the 16th week by high-resolution and three-dimensional ultrasound; in a fetus at low a priori risk with these features, SALL1 testing establishes the diagnosis, and in a fetus with a known variant high-resolution ultrasound assesses complex heart disease, preaxial polydactyly, foot malformations and preauricular tags [2]. The PNDS describes ultrasound screening for club foot in the second trimester (detection rate of 80–90% for all aetiologies, with low positive predictive value), the difficulty of assessing the hand, which is often closed, and fetal echocardiography between 18 and 22 weeks of gestation when TBS is suspected [12]. The anorectal malformation of TBS, usually low, is rarely diagnosed before birth [12]. In France, prenatal genetic analysis (microarray or exome) is decided by the multidisciplinary prenatal diagnosis committee according to the ultrasound signs and family history [12]. Invasive prenatal diagnosis and preimplantation genetic testing (PGT) are possible when the familial variant has been identified, but do not predict the manifestations or severity [2, 12].

6. Differential Diagnosis

6.1. Comparative table

The PNDS selects as the main differentials the syndromes with at least two systems involved in common with TBS, and recognises that variable expressivity broadens the list when the presentation is isolated (hearing loss with ear dysplasia, preaxial polydactyly, CAKUT or renal failure of undetermined cause) [12]. The table brings together the differentials of GeneReviews, the PNDS and the textbooks.

6.2. SALL4 and Okihiro syndrome

Okihiro syndrome is the main differential, with a prevalence close to that of TBS and shared signs in different proportions [12]. Among 69 patients from 23 families with a SALL4 variant, 13% had the triad of Duane, radial ray defect and sensorineural hearing loss, 45% Duane and radial defects and 21% radial defects only; Duane anomaly occurred in 65%, radial ray anomaly in more than 90%, renal anomaly in 38%, heart disease in 15%, hearing loss in 16%, choanal atresia in 5% and short stature in 7% [26]. The PNDS gives the direct comparison: Duane in 50% in Okihiro syndrome (bilateral in 20%) versus 3% in TBS, cardiac conduction defects in 5% and scoliosis in 10% in SALL4-related disease; and in SALL4-related disease radial involvement is constant and reductive, although preaxial polydactyly and triphalangeal thumb may occur in 20% [12]. Smith's also describes hypoplasia of the radius and ulna, crossed renal ectopia and, occasionally, anal stenosis, preauricular tag, microtia, preaxial polydactyly and facial asymmetry, and recommends considering a 20q13.13–q13.2 microdeletion when there is intellectual disability [70]. Radial aplasia has never been observed in SALL1-related TBS, and some patients with clinical TBS had SALL4 variants, which justifies testing both genes [2, 26].

6.3. Branchio-oto-renal spectrum and the “TBS BOR-like” presentation

The BOR spectrum combines branchial arch anomalies (cysts, fistulae, clefts), sensorineural or mixed hearing loss, external ear malformations and renal malformations, with a frequency of about 1 in 40,000, due to variants in EYA1 and SIX1 [12]. Two families later diagnosed with SALL1-related TBS were initially considered to have BOR, because they had dysplastic ears with renal malformations or dysfunction and no member with the triad [2, 37]. In the family of Engels and colleagues, a father and two daughters, the daughters had dysplastic ears, hypoplastic kidneys with impaired function, GOR, hypermetropia and mild developmental delay, and the father renal dysfunction, dysplastic ears and GOR, with no anal or hand malformations in any of them; OMIM records this presentation as Townes-Brocks-branchiootorenal-like syndrome, included in entry 107480 [3, 37]. In a three-member German family, Albrecht and colleagues described preauricular tags, overfolded helices, hypospadias and renal dysfunction, with a brother with only hypospadias and infraducted 3rd toes, also without anal or hand anomalies, and regarded the picture as distinct from that of Engels (indirect attribution via OMIM) [3]. In the Japanese cohort, 20% of carriers of a SALL1 variant had a “TBS BOR-like” presentation, with only dysplastic ears and hearing loss or CAKUT, without digital or anal anomalies [6]. SIX5 is no longer considered a BOR gene and was removed from the GeneReviews differential in August 2025 [2]. Branchial anomalies and the absence of limb and anorectal anomalies point to BOR; the coexistence of a triphalangeal thumb, anteriorly placed anus or overlapping toes in a relative points to SALL1.

6.4. Oculo-auriculo-vertebral spectrum

The oculo-auriculo-vertebral spectrum shares with TBS microtia, atresia or stenosis of the external auditory canal, preauricular tags and fistulae, hearing loss and heart and renal malformations, but has craniofacial involvement, generally unilateral, that does not belong to TBS: hypoplasia of the mandible, maxilla, malar bone or zygomatic arch [12]. SALL1 variants have been described in patients with a Goldenhar-like phenotype and in families in which expression ranges from isolated external ear anomalies to Goldenhar syndrome [18, 31]. The first example was a 2-base-pair deletion, recorded in OMIM without the deleted bases (“2-bp del, nt1277”; rs1597230341), in a girl described in 1993 by Gabrielli and colleagues with features of both syndromes; the corresponding dbSNP record, normalised in VariantValidator, is NM_002968.3:c.1277_1278del p.(Arg426LysfsTer11), NC_000016.10:g.51140945_51140946del [9, 10]; in the Kosaki family, the p.(Leu419Ter) variant was of maternal origin, and the sisters also had, inherited from the unaffected father, the p.(Pro270Leu) polymorphism, with no known pathogenic role [10]. GeneReviews concludes that isolated hemifacial microsomia does not suggest TBS, but may coexist with typical findings; the Oxford recommends SALL1 testing when there is overlap [2, 59].

6.5. VACTERL association and other syndromes with anorectal malformation

The VACTERL association, with an incidence of 1.6 per 10,000 in the Oxford and a prevalence of 1 in 10,000 to 1 in 40,000 in the PNDS, is the most important differential in simplex cases with anorectal malformation, heart disease and thumb anomalies [12, 67]. To date, severe vertebral defects and tracheo-oesophageal fistula have not been observed in patients with a SALL1 variant; radial involvement belongs to VACTERL and not to TBS; and dysplastic ears and hearing loss distinguish TBS in the VACTERL differential table of the Brazilian manual Síndromes Genéticas: Reconhecer para Tratar [2, 71]. The recurrence risk for siblings and offspring in VACTERL is about 1%, versus 50% for the children of a patient with TBS, which gives the distinction direct weight in counselling [2]. The Oxford adds cat eye syndrome and Pallister-Hall syndrome as diagnoses to consider in the presence of an anal anomaly [67]. The case of Liberalesso and colleagues, of a patient from southern Brazil, shows how the features of TBS overlap with those of Goldenhar syndrome and VACTERL and how genetic testing is decisive [49].

6.6. Fanconi anaemia, CHARGE syndrome and renal differentials

Fanconi anaemia may present as a malformation syndrome in 60% of patients, with involvement of the thumbs (hypoplastic, absent, bifid or triphalangeal) and of the radius in one third, IUGR of prenatal onset, microcephaly and bone marrow failure, with autosomal recessive inheritance and FANCA involved in about 60% of cases; the prevalence in France is estimated at 1 in 300,000 [12]. CHARGE syndrome (frequency of about 1 in 15,000, due to CHD7) shares hearing loss with dysplastic ears, heart disease, renal malformation and anorectal malformation, but has coloboma, choanal atresia, severe semicircular canal hypoplasia and olfactory bulb anomalies [12]. In isolated adult renal presentation, the differential is that of monogenic CAKUT (PAX2, HNF1B, EYA1, SIX1, DSTYK, GATA3, PBX1) and that of FSGS secondary to nephron reduction; targeted examination of the ears, hands and feet and a renal panel including SALL1 resolve most cases [38, 69, 73]. The homonymy with “Townes” in the 4q deletion syndrome, proposed by Townes and colleagues in 1967, is a source of error in literature searches [74].

7. Treatment and Risk Management Strategies

7.1. General principles

There is no specific treatment for TBS, nor any medicine that is authorised or in clinical development; treatment is symptomatic and surgical, delivered by a multidisciplinary team, with surveillance for late-onset manifestations [2, 7, 12]. The PNDS stresses that the diagnosis and treatment of each system involved do not differ from those of an isolated malformation of the same type and refers to the French protocols for isolated anorectal malformations, major ear aplasia, chronic kidney disease in children and radial club hand; multidisciplinary follow-up at a reference or competence centre is considered indispensable [12]. The interventions and medicines discussed below have been studied in the corresponding isolated conditions and apply to TBS by analogy, which is indicated in each case.

7.2. Anorectal malformation and bowel management

Once the anatomical form has been confirmed, high forms are operated on within the first 48 hours of life and low forms, which predominate in TBS, with more or less delay depending on tolerance; anorectoplasty mobilises the fistulous tract, possibly resects it, and brings the rectum to the centre of the sphincter complex, and the colostomy, when present, is closed a few weeks later [12]. GeneReviews classifies imperforate anus as an indication for immediate surgical intervention [2]. In forms with a rectourinary or rectogenital fistula, a colostomy is performed and, later, contrast study of the distal segment to define the level of the rectal pouch and the anatomy of the fistula [12]. All patients should be followed at a specialised centre (in France, the MAREP network), because terminal constipation is frequent in the first postoperative years, with overflow faecal soiling; treatment is multidisciplinary, with dietary intervention to improve stool consistency, psychological support and perineal–sphincter retraining from 6 years of age, and is intensified during the period of acquisition of continence, with scheduled toileting, an oral laxative and/or triggering of defecation with a rectal laxative [12]. Transition to adult services should take place only when there is functional, psychological and social stability, and therapeutic education accompanies the child until the end of adolescence [12].

For constipation, GeneReviews indicates stool softeners, prokinetics, osmotic agents or laxatives as needed, without naming medicines or doses [2]. The 2026 joint guideline of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN/NASPGHAN), which replaces that of 2014, makes polyethylene glycol (PEG, macrogol) the only treatment with a strong recommendation and treats impaction with high-dose PEG or enemas, but excludes from its scope children with underlying organic disease; its application to constipation after anorectal malformation is an extrapolation [75]. Table 10 of that guideline presents typical doses as contextual reference, to be prescribed according to national formularies [75].

Source of doses: Gordon and colleagues, Table 10 [75]. In advanced CKD, magnesium hydroxide and phosphate enemas carry a risk of magnesium and phosphate overload; the sources consulted make no specific recommendations for TBS, and the choice should be reviewed with nephrology when GFR is reduced. One sachet of Movicol® contains 186.87 mg (8.125 mmol) of sodium, which is relevant in hypertension and CKD [76].

7.3. Hands and feet

Orthopaedic assessment is carried out shortly after birth for club foot and at around 3 months for minor thumb or foot anomalies, with anteroposterior radiographs of both hands for the first appointment [12]. Preaxial polydactyly is classified using the Wassel scale (type I, bifid distal phalanx; II, duplicated distal phalanx; III, bifid proximal phalanx; IV, duplicated proximal phalanx; V, bifid metacarpal; VI, duplicated metacarpal; VII, triphalangism), triphalangeal thumb using the Buck-Gramko classification (six types, from rudimentary to associated with polydactyly) and thumb hypoplasia using the Blauth classification (type I, slight shortening, to type V, total aplasia, with subtypes IIIA and IIIB according to the presence of the carpometacarpal joint) [12].

Source of the table: PNDS [12]. GeneReviews cites removal of supernumerary thumbs as an example of surgery for severe hand malformations [2]. Occupational therapy assesses autonomy, grip, dexterity and strength and contributes to postoperative rehabilitation and the adaptation of implements [12].

7.4. Hearing and external ear

Early treatment of significant hearing loss, typically with hearing aids, is the GeneReviews recommendation [2]. The PNDS gives details: a conventional air-conduction hearing aid is recommended for every child with permanent bilateral hearing loss with a mean threshold above 40 dB, is unilateral if the hearing loss is unilateral and bilateral from the outset if it is bilateral, and may be offered in mild hearing loss depending on its impact; a cochlear implant is indicated in severe to profound bilateral sensorineural hearing loss according to HAS criteria [12]. When malformation of the pinna precludes air conduction, a bone-conduction hearing aid is used, on a softband from 3 months in bilateral hearing loss and bilaterally before entry into preschool education; between 5 and 12 years, percutaneous or active magnetic implants may be offered [12]. Surgical reconstruction of an absent canal or of the ossicular chain is not offered to children in France, because of the risk of an unstable canal and poor hearing results, whereas canaloplasty of a partially stenosed canal may be performed [12]. Reconstruction of the pinna depends on the child's motivation: reconstruction with costal cartilage is offered from 9–10 years, with alternatives in high-density porous polyethylene or a silicone prosthesis; the PNDS summary refers to pinna surgery classically from 8–10 years [12]. Speech therapy should begin early, with different goals in prelingual and postlingual hearing loss, and audiologists should have paediatric experience [12].

7.5. Kidney and urinary tract

Treatment of CKD in TBS has no specific features and follows the general recommendations for CKD in children and adults, including nephroprotection, conservative treatment, peritoneal dialysis or haemodialysis and transplantation from a deceased or living donor [12]. Continuous monitoring of renal function is the basis of treatment, and urological complications are treated without specific features [2, 12]. A living related donor should be tested for the recipient's SALL1 variant before donation, because a carrier with a minimal phenotype may have reduced nephron reserve [12, 38].

No medicine has been studied in TBS nephropathy. Renin–angiotensin system blockade and sodium–glucose cotransporter 2 inhibitors (SGLT2i) are used by analogy with proteinuric CKD of other causes, as in the case of Tsunoda and colleagues, in which the patient received losartan 25 mg daily from 16 years of age and empagliflozin 10 mg daily from 26 [50]. There is no TBS-specific guideline dose for these medicines; the dose given is that of the label, and use in TBS is off-label, with the exception of empagliflozin in adults with CKD, whose indication covers CKD in general [78, 79].

In a child with TBS and CKD, losartan has a paediatric indication for hypertension from 6 years of age, and dose selection differs between the US (by weight: starting dose 0.7 mg/kg once daily up to 50 mg; doses > 1.4 mg/kg or > 100 mg/day not studied) and Portugal (by weight bands: 20–50 kg 25 mg/day, exceptionally up to 50 mg; > 50 kg 50 mg/day, exceptionally up to 100 mg) [80, 81]. Empagliflozin is not authorised for paediatric CKD [78, 79]. In women of childbearing age, the PNDS asks for review of the compatibility of treatments with pregnancy before contraception is stopped [12].

7.6. Heart

Heart defects are treated according to the usual indications, by surgery or medical treatment [2]. An ASD may close spontaneously up to about 4 years of age; thereafter, if the shunt is significant, it is closed by catheterisation in most cases or by surgery with a patch in large, ostium primum or sinus venosus forms; late closure in adults is associated with atrial arrhythmias, mainly flutter [12]. A large haemodynamically significant ductus arteriosus is closed with a percutaneous device or, in unfavourable anatomy or prematurity, by surgical ligation; a persistent VSD with a large shunt is closed by surgery with cardiopulmonary bypass, classically before 1 year when there is pulmonary hypertension, or by catheterisation depending on anatomy and weight [12]. Regular tetralogy of Fallot is repaired between 4 and 6 months, with possible neonatal palliation in severe cyanotic forms, and some patients need pulmonary valve replacement in adulthood [12]. In adolescence, cardiovascular exercise rehabilitation is an option when there is functional impact [12].

7.7. Endocrine system and growth

Congenital hypothyroidism is identified by newborn screening and treated early with levothyroxine; later-onset hypothyroidism is treated in the same way [12]. Growth delay is treated according to its cause: treatment of CRF, adjustment of levothyroxine or growth hormone when there is a documented deficiency [2, 12]. There is no TBS-specific guideline dose, and the reference doses are those of the labels; levothyroxine is adjusted according to thyroid-stimulating hormone (TSH), and somatropin is recombinant growth hormone (GH).

The patient of Lawrence and colleagues was the first with growth hormone deficiency described in TBS, and the authors advocate an active search for treatable deficiencies [52]. In a child with TBS and CKD, the somatropin indication for growth delay in chronic renal insufficiency, present in the European label, allows treatment without requiring GH deficiency [85]. In bilateral cryptorchidism or posterior hypospadias, the PNDS asks for a neonatal hormonal assessment before 36 hours of life (testosterone, dihydrotestosterone, Δ4-androstenedione, dehydroepiandrosterone sulfate, dehydroepiandrosterone, corticotrophin and anti-Müllerian hormone), karyotype with SRY testing by fluorescence in situ hybridisation, referral to paediatric endocrinology and possibly hormonal kinetics during minipuberty [12].

7.8. Gastro-oesophageal reflux

GOR is treated by the gastroenterologist according to the usual indications [2]. When a proton pump inhibitor is used, the reference doses are those of the label.

The US and Portuguese labels differ in the minimum age range (1 year, with a 5 to < 10 kg band in the US) and in the maximum paediatric dose (40 mg in Portugal for > 20 kg) [87, 88].

7.9. Eye, genital tract and other interventions

Stilling-Duane anomaly has the usual strabismus treatment: screening for and treatment of amblyopia, correction of refractive errors and surgery to recentre the eye in large-angle deviations, head turn greater than 10–15° or marked retraction, without the possibility of improving abduction [12]. Colobomas are not treatable; for iris colobomas cosmetic contact lenses or tinted lenses may be used for photophobia, and chorioretinal colobomas may be complicated by retinal detachment, which is treated [12]. In cryptorchidism, the child is referred to paediatric surgery if the testes have not descended by 6 months, with orchidopexy at around 12 months; in posterior hypospadias, surgical timing is discussed at a multidisciplinary meeting of the reference centres for disorders of genital development and may be deferred to obtain the child's consent [12]. GeneReviews refers genitourinary anomalies to urology and gynaecology [2].

Neurodevelopment requires educational and developmental support, with neuropsychiatric referral for behavioural problems [2]. The PNDS assigns to the physical and rehabilitation medicine physician the assessment of functional impact, coordination of therapists and surveillance of the spine when there are lower-limb anomalies or head tilt of ocular cause; psychological support is offered at the disclosure of the diagnosis, in the following period and throughout follow-up, for the parents, the patient and siblings; and therapeutic education programmes address leisure and occupational activities and the use of auditory rehabilitation [12]. GeneReviews recommends support from patient organisations and social services [2].

7.10. Agents to avoid

GeneReviews recommends avoiding nephrotoxic and ototoxic medicines, without listing examples [2]. The Portuguese losartan label documents that the combination of angiotensin II antagonists or diuretics with NSAIDs may worsen renal function, including acute kidney injury and hyperkalaemia, particularly with pre-existing reduced renal function [81]. The GeneReviews on SALL4-related disease recommends, for an analogous reason, avoiding medicines that affect the kidney when renal function is reduced and the inner ear when there is hearing loss [26]. The sources consulted do not include a validated TBS-specific list of ototoxic agents, and the decision should follow the label of each medicine and the patient's renal and auditory function.

7.11. Pregnancy, lactation, perioperative care and transition

In pregnant women with TBS, GeneReviews recommends prenatal cardiac assessment and nephrological assessment, because renal function may worsen significantly during pregnancy [2]. Before contraception is stopped, the PNDS asks for an appointment with each specialist following the patient and a summary preconception consultation with obstetrics; heart disease, renal failure or sequelae of anorectal malformation justify follow-up in a level III maternity unit; perineal assessment after anorectal surgery helps to decide the mode of delivery; and the levothyroxine dose is increased in the first trimester [12]. The US label quantifies the increase at 12.5–25 µg/day with TSH every 4 weeks, and the Portuguese label asks for TSH in each trimester [82, 83]. Losartan is contraindicated in the second and third trimesters and should be replaced before conception whenever possible; empagliflozin carries fetal risk in the second and third trimesters and is not recommended during breastfeeding; macrogol has negligible systemic exposure [76, 79, 81]. A 2024 report describes anaesthesia for urgent caesarean section in a patient with TBS, and another, from 2009, the follow-up of a case in which airway management conditions improved with age; the content of these reports is not summarised in the bibliographic databases [89, 90]. In the perioperative setting, empagliflozin should be withheld at least 3 days before surgery or prolonged fasting, and ear imaging in young children may require sedation or general anaesthesia [12, 79]. Transition to adult services is a critical point in anorectal malformation and CKD, because kidney disease progresses mainly in young adulthood [12, 63].

7.12. Comparative regulatory status

No medicine has an indication for TBS in the US, the EU, Portugal or Brazil [2, 7]. The table summarises the status of the supportive medicines with doses cited; for Brazil, the registration status in the open data of the Brazilian Health Regulatory Agency (ANVISA) is given.

7.13. Clinical trials and limits of the evidence

A ClinicalTrials.gov search on 27 October 2026 found no registered studies for “Townes-Brocks” or for SALL1; the EU Clinical Trials Register was not searched, and a negative search does not prove that no studies exist [91]. The available therapeutic evidence comes from trials in analogous conditions.

EMPA-KIDNEY included adults with CKD of various causes and does not allow the effect in congenital renal hypodysplasia or in children to be estimated; the 28% relative reduction corresponds to an absolute difference of 3.8 percentage points over about two years, in a population with a mean eGFR of 37.3 ml/min/1.73 m² [78]. The constipation guideline excludes organic constipation, and its extrapolation to constipation after anorectal malformation has not been validated [75]. There are no comparisons between these trials and no data from patients with TBS.

7.14. Developments in the last 12 months

Between October 2025 and October 2026, the developments were classificatory, observational and case reports, with no trials or regulatory procedures. In terms of classification, ClinGen assigned definitive validity to SALL1–TBS1 on 20 March 2026 [15], and GeneReviews removed SIX5 from the BOR differential in August 2025 [2]. The observational studies were the French series of 49 patients with a review of 207 cases and genotype–phenotype correlations [19], the Japanese renal cohort with 20% “BOR-like” presentations and 35% non-syndromic CAKUT [6] and the estimate of the frequency of predicted pathogenic variants in six CAKUT genes in gnomAD [73]. The case reports included the Serbian family with renal hypodysplasia over three generations [51], late diagnosis in a Turkish family [64], serial renal biopsies with progression of FSGS [50], TBS with isolated familial cup ears [60] and a Chinese family with triplets with anal atresia and rectovaginal fistula due to SALL1 c.757C>T p.(Gln253Ter) [92]. The ESPGHAN/NASPGHAN constipation guideline, published in 2026, is the only new therapeutic document applicable by extrapolation [75]. The work on primary cilia and SHH points to potential targets, but remains preclinical [36, 43].

7.15. Recommendations of the sources and divergences

GeneReviews and the PNDS agree on the multidisciplinary approach, early anorectal surgery, early auditory rehabilitation, lifelong renal surveillance regardless of initial imaging, initial cardiac and ophthalmological assessment and cascade testing of relatives [2, 12]. The main divergences concern frequency and scope. For hearing, GeneReviews proposes annual assessment, and the PNDS six-monthly ear, nose and throat (ENT) appointments in the first years and annual thereafter, with audiometry repeated at least once a year when normal [2, 12]. For the kidney, GeneReviews proposes annual renal function in all patients; the PNDS proposes annual blood pressure and growth, annual albuminuria and urinary creatinine in the summary table (every 1 to 5 years in the text), creatinine and eGFR at a frequency depending on function and ultrasound every 2 years in the summary table (every 2 to 5 years in children in the text) [2, 12]. For the thyroid, GeneReviews proposes assessment of thyroid function at each visit, the PNDS TSH every 6 months from 2 years of age and annually in adults, and the table published by the Lille group annual TSH, whose usefulness the authors consider should be re-evaluated [2, 12, 19]. GeneReviews also proposes screening for behavioural problems from 12 months, which the PNDS integrates into developmental follow-up [2, 12]. The frequencies adopted in section 11 follow the PNDS, as it is the only formal guideline, with the GeneReviews alternative indicated.

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

TBS1 is transmitted in an autosomal dominant manner, and each child of an affected person has a 50% probability of inheriting the variant, whatever the sex of the parent and of the child [2, 12]. About half of probands have an affected relative and about half have a de novo variant; in the PNDS review, 43 of 75 cases were inherited and 32 de novo [2, 12]. Expressivity is very variable, and the test result does not predict the manifestations or severity in a child, with the partial exception of p.(Arg276Ter), associated with a severe phenotype and with heart disease in about half of carriers [2, 19]. In TBS2, reduced penetrance means that apparently healthy carriers, mainly mothers, transmit the variant to affected children [4, 13]. In the recessive form due to p.(Arg1054Ter), the risk for each pregnancy of a carrier couple is 25%, and heterozygotes are healthy [2, 5].

Sources of the table: GeneReviews [2], Liberalesso and colleagues (risk of 1–5%, indirect attribution) [49], Christians and colleagues [13] and Vodopiutz and colleagues [5].

8.2. Parental testing, mosaicism and minimal forms

In a simplex case, testing of both parents is recommended; if the variant is found in neither and parentage is confirmed, the variant is de novo or there is parental gonadal (or somatic and gonadal) mosaicism [2]. Four individuals with somatic and gonadal mosaicism have been described, and the mosaic parent may have only minimal signs, such as the 2nd and 4th toes overlapping the 3rd, or an isolated anteriorly placed anus in a mother without a variant detectable in leucocyte DNA and with two affected children [2, 55, 56]. A patient with somatic mosaicism for p.Ser371X had complete TBS with Duane anomaly, which shows that mosaicism does not necessarily imply a mild phenotype [54]. The variant has been published only in protein notation; residue Ser371 exists in the MANE transcript (NM_002968.3), but there are two substitutions at the same nucleotide that create a stop codon, c.1112C>A and c.1112C>G, both described as p.(Ser371Ter) in VariantValidator [9]. ClinVar records c.1112C>G as pathogenic (VCV 1704095) from a clinical submission with no link to this patient, so it does not allow a choice between the two, and the protein notation is retained [54, 93]. An apparently negative family history may result from failure to recognise minimal forms, and only molecular testing of the parents confirms it [2]. Targeted examination of the parents (ears, thumbs, feet, perineal region, audiogram, renal ultrasound and creatinine) is part of the assessment [12].

8.3. Cascade testing

Testing for the familial variant is indicated in at-risk, asymptomatic, older and younger relatives, in order to start clinical assessment and treatment of kidney disease early [2]. The PNDS bases the information given to the family on the French bioethics law of 7 July 2011, which makes it mandatory when the disease allows preventive measures, and lists those measures: screening for renal involvement and nephroprotection, screening for hearing loss and monitoring of language development [12]. The patient may inform relatives or ask the geneticist to contact them; diagnosis in relatives is made at a genetics clinic with informed consent, clinical examination and targeted testing for the variant [12]. Before kidney donation by a relative, the absence of the variant should be confirmed [12, 38].

8.4. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis and PGT are possible only if the variant has been identified in one member of the couple or in a child; in France, eligibility is discussed at a multidisciplinary prenatal diagnosis centre (CPDPN), taking into account prenatal signs, available treatments, family history and the literature [12]. Professionals and families may have different perspectives on the use of these tests in a disease with such variable expressivity [2]. When one member of the couple has TBS, closer ultrasound surveillance may be offered to detect IUGR and severe renal or cardiac malformations, in liaison with a CPDPN, and fetal echocardiography between 18 and 22 weeks [12]. Heart disease in 46.2% of carriers of p.(Arg276Ter) makes fetal echocardiography particularly relevant in those families [19]. Diagnosis by chorionic villus sampling or amniocentesis is also mentioned by the British charity Contact [94].

8.5. Counselling, minors and psychological support

The risk and the prenatal and preimplantation options should be discussed before pregnancy, and counselling should be offered to affected or at-risk young adults [2]. Testing of asymptomatic at-risk minors has a direct benefit, because auditory and renal surveillance changes management, which distinguishes it from adult-onset diseases without possible prevention [2, 12]. The PNDS pays attention to the disclosure of the diagnosis, which should be made by a professional familiar with the syndrome, possibly with a psychologist or nurse, following the HAS guide on disclosure of chronic disease; it describes the impact of prenatal, neonatal or late disclosure, the guilt associated with transmission and the role of the psychologist in family reorganisation and in any decision on termination of pregnancy for medical reasons [12]. Counselling should address the 50% risk, the variability of expression, the impossibility of predicting severity and the late-onset manifestations (hearing loss and kidney disease) that justify lifelong surveillance [12, 19].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The population prevalence of TBS is unknown [2, 95]. The only population-based value comes from the Spanish Collaborative Study of Congenital Malformations (ECEMC): between April 1976 and June 1997, 6 cases were identified among 25,967 malformed newborns out of 1,431,368 live births under surveillance, which gives a minimum frequency of 0.42 per 100,000 live births [17]. This is a hospital-based malformation registry, without molecular confirmation and limited to cases recognisable at birth, so it measures a minimum and not prevalence; Orphanet classifies it as a birth prevalence of 1–9 per 1,000,000 in Spain, and its estimate for Europe, in the same class, has not been validated [1]. The value of 1 in 250,000 live births in Smith's and the PNDS and that of 1 in 238,000 cited by Stein and colleagues are roundings of the same Spanish data [12, 18, 38]. The number of published patients (about 200 with molecular confirmation in GeneReviews and the PNDS; 254 in the combined Leduc series) measures the literature and not the population [2, 12, 19]. The page of the British charity Contact, last revised in 2008, refers to about 100 published patients, a figure since exceeded [94].

Cohorts ascertained through genetic panels give yields and not prevalences. In a US commercial laboratory, 22 pathogenic or likely pathogenic SALL1 variants were found in 35,044 samples from a 385-gene renal panel, i.e. 1 in 1592 patients tested and 1 in 342 of patients with an identified monogenic kidney disease [38]. In the China Deafness Genetics Consortium, with 20,666 unrelated cases of disabling hearing loss (greater than 40 dB) recruited in 31 provinces and 7258 controls, 7 families with a pathogenic SALL1 variant were identified (1 in 2952), none with a prior diagnosis of TBS [2, 46]. In the Japanese national cohort of 1108 families with CKD or mild urinary abnormalities tested between 2010 and November 2024, 14 families (20 individuals) had a SALL1 variant, with a median age at diagnosis of 16 years [6]. In the general population, Huang and Savige estimated in gnomAD v2.1.1 a frequency of predicted pathogenic variants of between 1 in 249 and 1 in 1263 for the set of six CAKUT genes (HNF1B, SALL1, EYA1, PBX1, GATA3, PAX2), more than half missense; this is an aggregate value, not specific to SALL1, and incomplete penetrance prevents its conversion into disease prevalence [73]. All these data suggest that TBS is underdiagnosed, particularly in renal and auditory presentations, without allowing a validated estimate.

9.2. Geographical distribution and populations studied

TBS has been described in all regions studied, with no known founder variant; the recurrent variant p.(Arg276Ter) results from independent mutations at a CpG dinucleotide and not from a founder effect [32, 48]. In the US, the most extensive data come from the renal panel cohort of Stein and colleagues and the TBS2 index family of Webb and colleagues [4, 38]. In Europe, the main series are the French Lille series (49 patients from 22 families, recruited through the AnDDI-Rares, ERN ITHACA and ERN CRANIO networks), the multicentre series of the Kohlhase group that established the mutational spectrum, the Spanish registry and the family reports from Serbia and Slovenia [17, 19, 31, 34, 39, 51]. In Asia, the cohorts from China and Japan provided data from ascertainment through hearing loss and kidney disease, with recent Chinese, Japanese and Turkish cases [6, 46, 50, 64, 92]. In Portugal, the source identified is the case published in 1989 by the Genetics Unit of the Hospital Pediátrico D. Estefânia, with VSD, ossicular anomalies and a possibly affected maternal grandfather [3, 28]. In Brazil, Monteiro de Pina-Neto described in 1984 a child whose picture broadened the spectrum to heart disease [27], and Liberalesso and colleagues published in 2017 a case from Curitiba with SALL1 c.824T>G p.(Leu275Ter) [49]; the Brazilian manual Síndromes Genéticas: Reconhecer para Tratar includes TBS in the VACTERL differential [71]. The sources consulted do not include series or frequency estimates from Portugal or Brazil, which does not demonstrate the absence of published data.

9.3. Sex and special populations

The sex ratio is close to 1 (0.95 female:male in the combined Leduc series), but genital anomalies predominate in males (25% versus 3% in the reviewed literature) and rectovaginal fistula is specific to girls [2, 19]. The Spanish registry associated TBS with low birth weight [17]. Adults are an under-recognised population: generally without intellectual disability, with arthralgia in several cases and with CKD that appears late, the median age at diagnosis of kidney disease being 30 years [2, 63]. Pregnancy in a woman with TBS requires nephrological and cardiac assessment and, if there are anorectal sequelae, perineal assessment [2, 12]. The living related kidney donor is a particular population, because of the possibility of being a carrier with a minimal phenotype [12, 38].

9.4. Reference networks and patient organisations

In Europe, the relevant networks are ERN ITHACA, for malformation syndromes and intellectual disability, ERN CRANIO, for craniofacial and ear anomalies, ERNICA, for congenital digestive malformations including anorectal malformations, and ERKNet, for rare kidney diseases; ERN ITHACA and ERN CRANIO took part in recruitment for the Lille series [19–23]. In France, the PNDS was drawn up by the “Surdités génétiques” and “Anomalies du développement” Reference Centres of the Lille University Hospital, and anorectal malformation is followed by the MAREP network [12].

There is no French organisation dedicated to TBS, and the PNDS lists organisations by system involved: TintaMARre (anorectal malformations), ASSEDEA (limb malformations), UNANIMES (deaf and hard-of-hearing people), AIRG-France (genetic kidney diseases), Alliance Maladies Rares and the Maladies Rares Info Service [12]. The Townes-Brocks Syndrome International Support Network is a voluntary, non-profit online support network for affected people and their families, listed by the National Organization for Rare Disorders (NORD) [96]. In the United Kingdom, Contact states that there is no specific support group and offers its helpline and a closed family group [94]. GeneReviews refers to MedlinePlus and to US deaf associations (Alexander Graham Bell Association for the Deaf and Hard of Hearing, American Society for Deaf Children, National Association of the Deaf) and to the National Eye Institute in case of low vision [2]. Orphanet maintains the ORPHA:857 page [1]. The sources consulted do not identify TBS-specific organisations in Portugal or Brazil.

10. Illustrative Clinical Case

10.1. Progressive kidney disease in an adult with the complete triad (Tsunoda and colleagues, 2026)

Tsunoda and colleagues described, in Kidney Medicine, a 27-year-old Japanese man in whom TBS had been suspected at birth because of the complete triad: ear malformations, low imperforate anus and deformities of the fingers and toes; no structural renal anomalies were detected at that time [50]. At school screening he had transient proteinuria and, at 16 years, persistent proteinuria, with height 163.0 cm, weight 72.0 kg and body mass index (BMI) 27.09 kg/m², urinary protein/creatinine ratio 0.41 g/g, serum creatinine 1.13 mg/dl (eGFR 109.7 ml/min/1.73 m²) and proteinuria 0.39 g/24 h [50]. Examination showed a triphalangeal right thumb, bilateral fusion of the 4th and 5th metacarpals, overlapping of the 5th toe over the 4th with fusion of the 4th and 5th metatarsals, and pinna malformation with a cochlear implant for sensorineural hearing loss; computed tomography (CT) measured the right kidney at 98 mm and the left at 82 mm, small for his body size [50]. After genetic counselling, the family declined testing, because of anxiety about the future [50].

The first renal biopsy, at 16 years, showed 20 glomeruli, two with global sclerosis and one with FSGS of the perihilar variant, non-specific mesangial immunofluorescence (IgA, IgM and C3 1+) and no well-defined deposits on electron microscopy [50]. The patient started losartan 25 mg daily; at 24 years proteinuria exceeded 3.0 g/g, and empagliflozin 10 mg, started at 26 years, did not reduce it [50]. At 27 years, with height 165.1 cm, weight 89.8 kg (BMI 32.94 kg/m²) and hepatic steatosis, the protein/creatinine ratio was 1.37 g/g, creatinine 1.78 mg/dl (eGFR 40.1 ml/min/1.73 m²) and proteinuria 1.92 g/24 h; the second biopsy showed 20 glomeruli, four with global sclerosis and three with FSGS (two perihilar and one not otherwise specified), progression of interstitial fibrosis and tubular atrophy, microaneurysms and hyalinosis [50]. Genetic testing, accepted at this point, identified SALL1 NM_002968.3:c.845del p.(Leu282CysfsTer4) in the heterozygous state, absent in both parents and not registered in ClinVar; there was no history of hearing loss, renal dysfunction or congenital anomalies in the grandparents or the older brother, and targeted reassessment found no other extrarenal findings [50]. With the angiotensin receptor blocker and the SGLT2i and weight reduction to 74.0 kg the following year, the protein/creatinine ratio was 1.86 g/g, creatinine 1.65 mg/dl and eGFR 43.1 ml/min/1.73 m², stable [50].

The authors propose that congenital renal hypoplasia, with fewer nephrons, obesity-associated hyperfiltration and impaired podocyte repair, since SALL1 is re-expressed in injured podocytes, converged in FSGS, and recommend weight control [50]. Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC13101585/figure/fig1/) shows the photographs and radiographs of the hands and feet, the renal CT, the pinna with the cochlear implant, the electropherogram of the variant and the pedigree; Figure 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC13101585/figure/fig2/) shows the two biopsies with Masson's trichrome, periodic acid–Schiff and methenamine silver, with the microaneurysms and hyalinosis of the second biopsy and the electron microscopy [50].

The case illustrates three clinical points: the complete triad did not guarantee molecular diagnosis or early renal surveillance; ultrasound or CT without an evident structural anomaly does not exclude a nephron reduction with progression; and FSGS corresponds, according to the PNDS, to non-specific lesions linked to nephron reduction. The management in the report is not routine: losartan and empagliflozin were used by analogy with proteinuric CKD, without a trial in TBS, and the PNDS considers renal biopsy unnecessary for diagnosis [12, 78]. The initial refusal of genetic testing delayed molecular diagnosis and the study of the parents, which showed a de novo variant, with a 50% risk for the patient's offspring and a recurrence risk that is low, but not zero because of gonadal mosaicism, for other children of the parents [2, 50].

10.2. Brazilian case with a variant in the hotspot (Liberalesso and colleagues, 2017)

Liberalesso and colleagues described a 5-year-old boy from Curitiba, born at 38.5 weeks weighing 2.735 kg, length 48 cm and head circumference 34.5 cm, Apgar 9/10, with anal atresia corrected by posterior sagittal anorectoplasty on the 2nd day of life and 10 days in neonatal intensive care; a brother had ADHD and a cousin imperforate anus [49]. At 5 years he had developmental and speech delay, hyperactivity and aggressiveness treated with antipsychotics since 4 years of age, short stature, left microtia with agenesis of the helix, bilateral preauricular tags and low-set ears, a bifid right thumb and a long finger-like left thumb, preaxial polydactyly with ulnar deviation, overlapping toes, hypospadias, ASD, grade II VUR with reduced distal urethral calibre and a rudimentary rib at T12; renal function, renal scintigraphy and ultrasound were normal, brainstem auditory evoked potentials showed moderate bilateral hearing loss, and brain CT and MRI and the electroencephalogram were normal [49]. The SALL1 variant NM_002968.3:c.824T>G p.(Leu275Ter) was identified, in the exon 2 hotspot, one codon before p.(Arg276Ter) [9, 49]. Normal renal function at 5 years does not dispense with the lifelong renal surveillance recommended by the sources [2, 12].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The prognosis is very variable and depends on the severity of the manifestations and their functional, social and psychological impact; life expectancy depends mainly on the severity of the cardiac and renal malformations [12]. The heart defects of TBS are usually not severe and are treatable by catheterisation or surgery, and repair of regular tetralogy of Fallot between 4 and 6 months has a good long-term prognosis; the exceptions are the complex heart defects associated with p.(Arg276Ter), as in the child in the Lille series who died at 3 months [12, 19]. The British charity Contact states that many patients have a normal lifespan, although severe cardiac and renal problems may be life-threatening [94]. The sources consulted do not present survival curves or mortality estimates.

The renal prognosis is the main long-term determinant and is still poorly described [12]. Renal failure occurs in about 5% of children and 30% of adults, progresses according to the nephron reduction, and ESKD with dialysis or transplantation was recorded in 8% of the patients reviewed by the PNDS, in 6 of 49 patients in the Lille series and in 9.5% of the 56 patients in the literature with CRF [12, 19]. In the 10 adults with kidney disease reviewed by Beaudoux and colleagues, the median age was 30 years at diagnosis of kidney disease and 49 years at transplantation [63]. These values come from published patients, with short follow-up and ascertainment bias, and do not constitute lifetime risks; the absence of kidney disease in a child does not indicate that the risk is zero. The developmental prognosis depends mainly on the severity and earliness of hearing loss, which condition language acquisition and the educational and social pathway; intellectual disability is uncommon and, when present, generally mild, and most adults do not have intellectual disability [2, 12, 19]. The function of the operated thumb is generally good, but the reconstructed thumb is never identical to the contralateral one and may develop clinodactyly with growth [12]. Faecal continence after anorectal malformation varies from patient to patient and over time, which justifies follow-up into adulthood [12].

11.2. Initial assessment after diagnosis

11.3. Surveillance

The frequencies follow the PNDS, with the GeneReviews alternative indicated where it differs (see 7.15).

Renal surveillance applies to all patients, even with a normal initial renal ultrasound, because CRF may arise without a structural anomaly and late diagnosis in adulthood is frequent [2, 12, 19]. Carrier relatives identified through cascade testing enter the same auditory and renal surveillance programme [2].

12. Summary and Concluding Remarks

Townes-Brocks syndrome is an autosomal dominant malformation syndrome caused, in the great majority of cases, by truncating variants or deletions of SALL1, a zinc finger transcriptional repressor essential for development of the kidney, ear, limbs and anorectal region. The triad of anorectal malformation, dysplastic ears and thumb malformations with the radius present defines the classic form, but it is complete in fewer than half of patients in recent series, and the spectrum includes minimal presentations, the “BOR-like” form and apparently isolated kidney disease. The truncated protein appears to act through a dominant-negative effect and through disruption of primary cilia, and the recurrent variant p.(Arg276Ter) is associated with a severe phenotype and with heart disease in about half of carriers; deletions of the gene are associated, on average, with milder phenotypes. DACT1 underlies a form with reduced penetrance centred on CAKUT, without thumb anomalies, and homozygosity for SALL1 p.(Arg1054Ter) causes a severe recessive form.

The diagnosis is molecular, by sequencing of SALL1 with deletion analysis or by a panel with SALL4, which should be studied first when there is radial involvement or Duane anomaly; the pseudogene SALL1P1, regulatory variants and mosaicism limit sensitivity, and a negative result does not exclude the diagnosis in the presence of a highly suggestive clinical picture. The main differential includes SALL4-related disease, the branchio-oto-renal spectrum, the oculo-auriculo-vertebral spectrum and the VACTERL association, the distinction from which changes the recurrence risk from about 1% to 50%.

There is no specific treatment. Anorectal and hand surgery, auditory rehabilitation, treatment of heart defects and thyroid replacement follow the practices for the corresponding isolated malformations, and the 2023–2024 French PNDS is the only specific guideline. Hearing loss and kidney disease may appear or worsen at any age, and lifelong audiological, renal and thyroid surveillance, also applied to carrier relatives, is the measure with the greatest impact on prognosis. Nephroprotective medicines are used by analogy with other CKD, without trials in the syndrome, and the developments of the last 12 months were observational. Population prevalence data, prospective cohorts of renal and auditory natural history, and series from Portugal and Brazil are lacking.

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