Townes-Brocks syndrome (TBS) is an autosomal dominant genetic disorder first reported by Townes and Brocks in 1972. It is classified under ICD-10 code Q87.8.
The incidence is approximately 1 in 250,000, with over 100 cases reported in the literature 1). About 50% of cases result from de novo mutations, and the remaining 50% are inherited from parents. It is also called REAR syndrome.
The causative gene is SALL1 (16q12.1), with reported mutation types including frameshift 60.5%, nonsense 33.3%, splice site 1.2%, large deletion 2.5%, and homozygous 2.5% 1). TBS type 2 (OMIM 617466) caused by DACT1 gene mutations has also been reported 2).
The incidence is approximately 1 in 250,000, with over 100 cases reported in the literature. About half of cases result from de novo mutations, so it can occur without a family history.
Based on the classification by Valikodath et al., they are organized into the following four groups.
Ocular Malformation
Coloboma: Occurs in the iris, lens, and choroidoretina. Caused by failure of embryonic fissure closure. When combined with microphthalmia, there is a risk of poor visual acuity.
Others: Anophthalmia, microphthalmia, congenital cataract, aniridia.
Innervation Disorder
Duane syndrome: Presents with impaired abduction of the eye and retraction of the globe on adduction.
Others: oculomotor, abducens, and facial nerve palsy; gustatory lacrimation (crocodile tears syndrome).
Goldenhar-like findings
Limbal dermoid: a solid tumor commonly occurring at the inferotemporal limbus. Corneal astigmatism poses a risk of amblyopia. Surgery involves lamellar keratoplasty.
Dermolipoma: found on the bulbar conjunctiva.
Other ocular findings
Optic nerve coloboma: reported as a rare finding.
Retinal vascular tortuosity and hyperopia: Reported in cases with large deletions5).
Acquired acute optic neuropathy.
If aniridia is present, involvement of PAX6 mutation is suggested. Management includes tinted glasses or contact lenses with an artificial iris, and monitoring for glaucoma and cataract is important.
Various ocular abnormalities have been reported, including coloboma (iris, chorioretinal), Duane syndrome, anophthalmia/microphthalmia, congenital cataract, limbal dermoid, aniridia, and retinal vascular tortuosity. Valikodath et al. classified these into four groups: “ocular dysgenesis,” “innervation defects,” “Goldenhar-like findings,” and “others.”
The causative gene for TBS is SALL1 (16q12.1). The SALL1 protein consists of an N-terminal transcriptional repression domain (amino acids 1–87), a glutamine/alanine-rich domain, and four C2H2 double zinc finger domains 1).
As of March 2022, the Human Gene Mutation Database (HGMD) contains 116 mutations 1). A mutation hotspot exists in the 802 bp region from nt764 to 1565 1).
| Mutation type | Frequency |
|---|---|
| Frameshift | 60.5% |
| Nonsense | 33.3% |
| Splice | 1.2% |
| Large deletion | 2.5% |
| Homozygous | 2.5% |
The inheritance pattern is autosomal dominant with nearly complete penetrance, but expressivity varies among individuals. Genetic anticipation, where symptoms become more severe in successive generations within a family, has been reported2)4).
TBS has nearly complete penetrance, so almost all individuals with the mutation develop symptoms, but expressivity varies. Even within the same family, one person may have only hearing loss while another has anal atresia, thumb anomalies, and heart disease. Genetic anticipation, where symptoms become more severe across generations, has also been reported.
A clinical diagnosis of TBS is made when all three major features are present, or when two major features plus minor features are present2).
| Classification | Findings | Frequency |
|---|---|---|
| Major | Auricular malformation | 87% |
| Major | Thumb malformation | 89% |
| Major | Anal atresia/anal stenosis | 84% |
| Secondary | Renal abnormality | Approximately 42% |
| Secondary | Congenital heart disease | Approximately 25% |
| Secondary | Hearing loss | High frequency |
| Secondary | Ophthalmic abnormalities | Case reports |
If TBS is suspected, perform the following screening tests.
It is necessary to differentiate from VACTERL association, Goldenhar syndrome, Okihiro syndrome, BOR syndrome, and STAR syndrome.
There is no curative treatment for TBS; symptomatic treatment for each complication through a multidisciplinary approach is fundamental.
Renal abnormalities are observed in approximately 42% of cases and can lead to progressive renal dysfunction. Since hereditary focal segmental glomerulosclerosis (FSGS) is resistant to immunosuppressive therapy, management of proteinuria with ARBs (e.g., valsartan 40 mg) is central 3).
When end-stage renal failure occurs, dialysis or kidney transplantation is considered. Successful kidney transplantation has been reported in 5 cases, but rejection was observed in 2 of them 1).
For kidney damage caused by hereditary focal segmental glomerulosclerosis, immunosuppressive therapy is ineffective, so proteinuria is managed with ARBs (such as valsartan). If end-stage renal failure occurs, dialysis or kidney transplantation are options, but rejection after transplantation has also been reported. Regular assessment of kidney function is important to prevent early renal failure (average age 23).
SALL1 is a transcription factor highly expressed in the brain, liver, and kidneys, and plays an important role in the development of the kidneys, limbs, and auditory organs through the regulation of PAX8, GDNF, and FOXD1 1). It represses transcription through interaction with the NuRD deacetylase complex 3).
SALL1 mutations cause disease through a dual mechanism.
Dominant Negative (DN) Effect
NMD-escape mutations: When nonsense-mediated mRNA decay (NMD) is avoided, truncated proteins are produced. These interact with wild-type SALL1 and inhibit normal function1)5).
Increased expression: The c.694C>T mutation increases expression to about 320% of wild-type, leading to accumulation of abnormal protein3).
Typical TBS phenotype is observed.
Haploinsufficiency
NMD-mediated decay mutations and large deletions: When mutant mRNA is degraded by NMD, only 50% of the wild-type protein is produced5).
Reduced expression: The c.3175C>T mutation reduces expression to about 25% of wild-type levels3).
Results in a mild TBS phenotype (only 30% present with the classic triad).
The severity hierarchy is as follows:
SALL1 mutations promote degradation of LUZP1 via CCP110/CEP97 impairment, leading to dysfunction of primary cilia1)4). This pathway is also involved in the regulation of the sonic hedgehog pathway and contributes to the pathology of polycystic kidney disease and hearing loss.
SALL1 is involved in maintaining synaptopodin, stress fiber formation, and migration ability in podocytes. SALL1 mutations cause focal segmental glomerulosclerosis through podocyte injury, progressing to chronic kidney disease 3).
There is a correlation between mutation site and severity of kidney injury. Mutations in the aa65–448 region (group A) lead to renal failure at an average age of 23 years, whereas mutations in the aa500–1000 region (groups C/D) show no renal function abnormalities 1).
Ocular abnormalities reflect the involvement of SALL1 in the development of the midbrain and cranial nerves. As congenital cranial dysinnervation disorders (CCDDs), Duane syndrome and facial nerve palsy occur.
Liang et al. (2025) reported a functional analysis of SALL1 mutations in podocytes for focal segmental glomerulosclerosis identified in two children with Townes-Brocks syndrome. In nonsense-mediated mRNA decay escape mutations, accumulation of abnormal proteins caused abnormal localization in the nucleus and cytoplasm, demonstrating a direct mechanism of podocyte dysfunction 3).
Wang et al. (2023) used AlphaFold structure prediction to analyze conformational changes in the SALL1 protein, demonstrating its utility in predicting the pathological significance of mutations 1).
Chi et al. (2024) reported via molecular docking that truncated proteins interact with wild-type SALL1 through the alpha helix of the glutamine-rich domain, causing steric hindrance 2).
Episignatures (DNA methylation patterns) are being investigated as diagnostic aids for TBS 5). Additionally, reactivation of SALL1 in podocytes has been suggested as a potential future target for renal protective therapy 3).
