What is Branchiootorenal Spectrum Disorder?

By Danielle Ellis, B.Sc.Reviewed by Lily Ramsey, LLM

Cause and symptoms
Genetics
Epidemiology
Diagnosis and treatment 
References
Further reading

Branchiootorenal spectrum disorder (BORSD) is a group of rare autosomal dominant conditions. It is characterized by malformations of the outer, middle, and inner ear associated with hearing impairment, branchial fistulae, and renal malformations.

BORSD encompasses the phenotypes previously described separately as branchiootorenal (BOR) syndrome and branchiootic (BO) syndrome, distinguished only by the presence or absence of a renal anomaly. It is a heterogeneous disorder first described by Melnick et al. and Fraser et al.

Cause and symptoms

BORSD is a genetic condition passed down through the generations in an autosomal dominant pattern. The responsible genes are EYA1, SIX1, and SIX5.

The aberrant development of the second branchial arch in persons with BORSD can lead to branchial cleft cysts, which are neck lumps. Fistulae are anomalous holes or pits in the side of the neck, right above the collarbone, in some affected people.

Fistulae can create tunnels in the neck and exit near the tonsils in the mouth. Because branchial cleft cysts and fistulae can become infected and create health concerns, they are frequently surgically removed.

Hearing loss and other ear problems are common in patients with BOR/BO syndrome. Abnormalities in the inner ear cause sensorineural hearing loss; conductive hearing loss is caused by alterations in the middle ear's tiny bones; and mixed hearing loss is caused by a combination of the inner ear and middle ear problems.

Some patients with the condition have tiny holes in their skin or extra tissue in front of their ears. Preauricular pits (82%) and preauricular tags (13%) are the terms for these structures.

BOR syndrome affects the structure and function of the kidneys. These disorders can affect one or both kidneys, ranging from minor to severe. End-stage renal disease (ESRD) might develop later in life in certain people. When the kidneys cannot adequately filter fluids and waste items from the body, this dangerous illness develops.

The presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormalities in an affected individual, as well as individuals in the same family, might vary greatly from right to left.

Genetics

BORSD has been linked to over 200 variations in the EYA1 gene, including nonsense, missense, splice site, minor deletions, and insertions. Large deletions of one or more exons, the complete gene, or chromosomal rearrangements involving the EYA1 gene are observed in about 20% of BORSD patients. There are only a few examples of BORSD caused by SIX1 gene mutations that have been published. Most variations alter the homeodomain region, which is required for specific Six1-DNA binding.

The EYA1 gene has 18 exons and is found on chromosome 8q13.3. The SIX1 gene, the human equivalent of the Drosophila sine oculis gene, is two exons long and found on chromosome 14q23.1.

The EYA1 gene is mutated in about 40% of patients with this disorder. Mutations in the SIX1 gene are a far less common cause of the disease. In a tiny percentage of patients with BOR syndrome, SIX5 gene mutations have been discovered. The proteins generated by the EYA1, SIX1, and SIX5 genes play a vital role in prenatal development.

The EYA1 protein regulates the activity of genes involved in many stages of embryonic development by interacting with numerous other proteins, including SIX1 and SIX5. Many organs and tissues, including the second branchial arch, ears, and kidneys, are thought to require these protein interactions for optimal development.

Mutations in the EYA1, SIX1, or SIX5 genes can cause the proteins' capacity to interact and control gene activity to be disrupted. The ensuing genetic alterations impact the development of organs and tissues before birth, resulting in the BOR/BO syndrome's distinctive traits.

Epidemiology

The reported BORSD patients are mostly concentrated in wealthy countries like Japan, France, Denmark, Korea, and the United States. The frequency of BORSD in the European population is estimated to be 1/40000 and 1/50 in the population of severely deaf children. According to state-wide surveillance in Japan, about 250 people were identified with BORS in 2009–2010.

Only 7% of BORSD cases are caused by de novo pathogenic variations, consistent with earlier findings. Approximately 93% of reported BORSD patients have an affected parent. Renal anomalies were seen in around a third of BORSD patients, with the most common symptoms being renal agenesis, hypoplasia, dysplasia, and others. According to certain studies, BORSD is responsible for 2% of hereditary hearing loss.

Diagnosis and treatment

Clinical criteria are used to diagnose branchiootorenal spectrum disease. Clinical characteristics and/or heterozygous pathogenic mutations in EYA1, SIX1, or SIX5 identified on molecular genetic testing are used to confirm the diagnosis in a proband.

Treatment of manifestations includes excision of branchial cleft cysts/fistulae and canaloplasty to correct an atretic external auditory canal. Medical and surgical treatment for vesicoureteral reflux can prevent progression to ESRD. Renal transplantation may be required for ESRD in some cases. Examination of hearing loss and monitoring of renal function is also necessary. Genetic counseling can help the patients and the family understand the condition better.

References

• Masuda, M., Kanno, A., Nara, K., Mutai, H., Morisada, N., Iijima, K., Morimoto, N., Nakano, A., Sugiuchi, T., Okamoto, Y., Masuda, S., Katsunuma, S., Ogawa, K., & Matsunaga, T. (2022). Phenotype-genotype correlation in patients with typical and atypical branchio-oto-renal syndrome. Scientific reports, 12(1), 969. https://doi.org/10.1038/s41598-022-04885-w
• Biggs, K., Crundwell, G., Metcalfe, C., Muzaffar, J., Monksfield, P., & Bance, M. (2022). Anatomical and audiological considerations in branchiootorenal syndrome: A systematic review. Laryngoscope Investigative Otolaryngology. https://doi.org/10.1002/lio2.749
• List, P. G. (2021). Branchiootorenal Spectrum Disorder Panel. Gene, 1(2), 5-7. https://www.genedx.com/Resources/TIS-Files/TIS-TL57.pdf
• Chen, A., Song, J., Acke, F., Mei, L., Cai, X., Feng, Y., & He, C. (2021). Otological manifestations in branchiootorenal spectrum disorder: A systematic review and meta-analysis. Clinical genetics, 100(1), 3–13. https://doi.org/10.1111/cge.13949
• Smith, R. J. (2018). Branchiootorenal spectrum disorder. https://europepmc.org/article/nbk/nbk1380#free-full-text
• Smith RJH. Branchiootorenal Spectrum Disorder. 1999 Mar 19 [Updated 2018 Sep 6]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1380/
• Branchiootorenal/branchiootic syndrome. [Online] Medline Plus. Available at: https://medlineplus.gov/genetics/condition/branchiootorenal-branchiootic-syndrome/

Further Reading

• All Rare Disease Content
• What is a Rare Disease?
• Importance of Research into Rare Disease
• Teaching old drugs new tricks – drug repurposing for rare diseases
• What is Adenomyosis?