Townes-Brocks Syndrome

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Article initiated by:

Robert Thomas, Samiksha Fouzdar Jain, MD

All contributors:

S. Grace Prakalapakorn, MD, MPH, Samiksha Fouzdar Jain, MD, Andrew R. Lee, MD

Assigned editor:

Andrew R. Lee, MD

Review:

Assigned status Up to Date

 by Andrew R. Lee, MD on October 30, 2024.

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Disease Entity

Townes-Brocks Syndrome ICD-10-CM Q87.8

Disease

Townes-Brocks Syndrome (TBS) was first reported by Townes and Brocks in 1972 . They described it as a hereditary syndrome of imperforate anus with hand, foot, and ear anomalies. Since that time, additional discoveries have been made about the syndrome. Today, it is considered a rare autosomal dominant condition characterized by imperforate anus, ear dysplasia, and thumb and foot malformations. In addition to these, 42% of patients have renal anomalies and 25% of patients have congenital heart disease.

Ophthalmic Manifestations

Numerous ophthalmic manifestations of Townes-Brocks syndrome have been reported in the literature and have been described and grouped into the following four categories by Valikodath et. al.:

1. Defects of globe formation
   • Iris / lens / chorioretinal coloboma
   • Anophthalmia
   • Microphthalmia
   • Congenital cataract
   • Aniridia
2. Innervational disorders
   • Duane syndrome
   • Oculomotor, abducens, and facial nerve palsy
   • Gustatory lacrimation
3. Goldenhar-like features
   • Epibulbar dermoid
   • Lipodermoid
4. Miscellaneous
   • Absent optic chiasm
   • Acquired acute optic neuropathy

Etiolopathogenesis

TBS is caused by mutations in SALL1, a gene mapped to chromosome 16q12.1. SALL1 is a human gene related to the developmental regulator SAL of Drosophila melanogaster. This gene contains instructions for making proteins in the formation of tissues and organs before birth. Mutations in this gene lead to aberrant development and the previously described malformations. Most of the mutations are located between the glutamine-rich domain and the first double zinc finger domain within exon 2. Pathogenic variants within this region that occur towards the 5' end in exon 2 appear to be associated with a more severe outcome than pathogenic variants towards the 3' in exon 2. The penetrance of these mutations is most likely complete, but the expressivity is highly variable. In all, over 70 nonsense, frameshift, and splice mutations have been identified in causing TBS like phenotypes. A clear delineation has not yet been determined for the role of SALL1 and ocular abnormalities specifically. Because it has been associated with congenital cranial nerve dysinnervation disorders such as Duane syndrome, Marcus Gunn jaw winking, Möbius sequence, and gustatory lacrimation, SALL1 is elucidated to have an important role in the development of the midbrain nuclei and/or peripheral nerves of the oculomotor, trigeminal, abducens, and facial nerves.

Demographics

The prevalence is unknown. This could be partly due to the clinical overlap with VACTERL association which could lead to overestimation of TBS prevalence. Martínez-Frías estimated the prevalence at 1:250,000.

Genetics

TBS follows an autosomal dominant pattern of inheritance and about 50% of cases are de novo.

Other Names

• Anal-ear-renal-radial malformation syndrome
• Deafness-imperforate anus-hypoplastic thumbs syndrome
• Imperforate anus-hand and foot anomalies syndrome
• Renal-ear-anal-radial syndrome (REAR)
• Sensorineural deafness-imperforate anus-hypoplastic thumbs syndrome
• Townes syndrome

Diagnosis

The diagnosis of TBS is based on clinical findings. If those findings are inconclusive, identification of a heterozygous SALL1 pathogenic variant on molecular genetic testing establishes the diagnosis .

Major features:

1. Imperforate anus or anal stenosis in 84%
2. Dysplastic ears in 87% (overfolded superior helices, microtia)
3. Typical thumb malformations in 89% (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius

Minor features:

1. Sensorineural and/or conductive hearing impairment
2. Foot malformations
3. Renal impairment with or without renal malformations
4. Genitourinary malformations
5. Congenital heart disease

Differential diagnosis

• VACTERL association
• Goldenhar syndrome
• Okihiro syndrome (Duane-radial ray syndrome)
• Branchiootorenal (BOR) syndrome.
• STAR syndrome

Management

Management of TBS is highly variable due to the phenotypic variability of the disease. Treatment may include surgical intervention for imperforate anus, early treatment of hearing loss, surgery for severe malformations of the hands, hemodialysis and possibly kidney transplantation for end-stage renal disease, and surgery or medical treatment by a cardiologist for congenital heart defects. Management of ophthalmic diseases is dependent upon the type of disease.

Prognosis

The physical prognosis depends on the severity of the phenotypic signs exhibited. Many individuals diagnosed with Townes-Brocks Syndrome live a normal lifespan.