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Genetics Home Reference: your guide to understanding genetic conditions
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Branchiootorenal syndrome

Reviewed January 2008

What is branchiootorenal syndrome?

Branchiootorenal (BOR) syndrome is a genetic condition that typically disrupts the development of tissues in the neck and causes malformations of the ears and kidneys. The signs and symptoms of this condition can vary, however.

"Branchio-" refers to the second branchial arch, which is a structure in the developing embryo that gives rise to tissues in the front and side of the neck. In people with branchiootorenal syndrome, abnormal development of the second branchial arch can result in the formation of masses in the neck called branchial cleft cysts. In some people, abnormal connections called fistulae form passages between these cysts and the surface of the neck. Fistulae can also develop between the skin of the neck and the throat, near the tonsils. Branchial cleft cysts and fistulae can cause medical problems if they become infected.

"Oto-" refers to the ear; most people with branchiootorenal syndrome have hearing loss and other ear abnormalities. The hearing loss is known as sensorineural deafness if it is caused by changes in the inner ear, and conductive deafness if it is caused by changes in the middle ear. Branchiootorenal syndrome can also involve hearing loss that results from changes in both the inner ear and the middle ear, which is called mixed hearing loss. Other ear abnormalities associated with branchiootorenal syndrome include malformations of the inner ear or middle ear and abnormally shaped outer ears (pinnae). Some affected people also have tiny holes in the skin (preauricular pits) or small flaps of skin (preauricular tags) just in front of the ear.

"Renal" refers to the kidneys; branchiootorenal syndrome causes abnormalities of kidney structure and function. These abnormalities range from mild to severe and can affect one or both kidneys. In some cases, end-stage renal disease (ESRD) develops later in life. This serious condition occurs when the kidneys become unable to filter fluids and waste products from the body effectively.

How common is branchiootorenal syndrome?

Researchers estimate that branchiootorenal syndrome affects about 1 in 40,000 people.

What genes are related to branchiootorenal syndrome?

Mutations in three genes, EYA1, SIX1, and SIX5, are known to cause branchiootorenal syndrome. About 40 percent of people with this condition have a mutation in the EYA1 gene. SIX1 and SIX5 mutations are much less common causes of the disorder.

The proteins produced from the EYA1, SIX1, and SIX5 genes play important roles in development before birth. The EYA1 protein interacts with several other proteins, including SIX1 and SIX5, to regulate the activity of genes involved in many aspects of embryonic development. Research suggests that these protein interactions are essential for the normal formation of many organs and tissues, including the second branchial arch, ears, and kidneys. Mutations in the EYA1, SIX1, or SIX5 gene often disrupt the proteins' ability to interact with one another and regulate gene activity. The resulting genetic changes affect the development of organs and tissues before birth, which leads to the characteristic features of branchiootorenal syndrome.

EYA1 and SIX1 mutations have also been found in some people with a condition known as branchiooto (BO) syndrome. This condition includes many of the same features as branchiootorenal syndrome, but affected individuals do not have kidney (renal) abnormalities. The two conditions are otherwise so similar that researchers often consider them together (BOR/BO syndrome). It is unclear why some EYA1 and SIX1 mutations are associated with kidney abnormalities and others are not.

Some people with branchiootorenal syndrome do not have an identified mutation in the EYA1, SIX1, or SIX5 gene. In these cases, the cause of the condition is unknown.

Related Gene(s)

Changes in these genes are associated with branchiootorenal syndrome.

  • EYA1
  • SIX1
  • SIX5

How do people inherit branchiootorenal syndrome?

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In about 90 percent of cases, an affected person inherits the mutation from one affected parent. The remaining cases result from new mutations in the gene, and occur in people with no history of the disorder in their family.

Where can I find information about diagnosis or management of branchiootorenal syndrome?

These resources address the diagnosis or management of branchiootorenal syndrome and may include treatment providers.

  • Gene Review: Branchiootorenal Spectrum Disorders (http://www.ncbi.nlm.nih.gov/books/NBK1380)
  • Genetic Testing Registry: Branchiootorenal syndrome 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1970479)
  • Genetic Testing Registry: Melnick-Fraser syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0265234)
  • MedlinePlus Encyclopedia: Branchial cleft cyst (http://www.nlm.nih.gov/medlineplus/ency/article/001396.htm)
  • MedlinePlus Encyclopedia: End-Stage Kidney Disease (http://www.nlm.nih.gov/medlineplus/ency/article/000500.htm)

You might also find information on the diagnosis or management of branchiootorenal syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/branchiootorenal-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/branchiootorenal-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about branchiootorenal syndrome?

You may find the following resources about branchiootorenal syndrome helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for branchiootorenal syndrome?

  • BOR
  • BOR Syndrome
  • Branchiootorenal dysplasia
  • Branchio-Otorenal Dysplasia
  • Branchio-Otorenal Syndrome
  • Branchio-Oto-Renal Syndrome
  • Melnick-Fraser syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about branchiootorenal syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding branchiootorenal syndrome?

autosomal ; autosomal dominant ; branchial arch ; cell ; cysts ; dysplasia ; embryo ; embryonic ; end-stage renal disease ; ESRD ; gene ; inherited ; kidney ; mutation ; pinnae ; preauricular ; protein ; renal ; renal disease ; sensorineural ; stage ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoort VS, Schwartz CE, Smith RJ. Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat. 2004 Jun;23(6):582-9. (http://www.ncbi.nlm.nih.gov/pubmed/15146463?dopt=Abstract)
  • Gene Review: Branchiootorenal Spectrum Disorders (http://www.ncbi.nlm.nih.gov/books/NBK1380)
  • Hoskins BE, Cramer CH, Silvius D, Zou D, Raymond RM, Orten DJ, Kimberling WJ, Smith RJ, Weil D, Petit C, Otto EA, Xu PX, Hildebrandt F. Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am J Hum Genet. 2007 Apr;80(4):800-4. Epub 2007 Feb 22. (http://www.ncbi.nlm.nih.gov/pubmed/17357085?dopt=Abstract)
  • Kemperman MH, Koch SM, Joosten FB, Kumar S, Huygen PL, Cremers CW. Inner ear anomalies are frequent but nonobligatory features of the branchio-oto-renal syndrome. Arch Otolaryngol Head Neck Surg. 2002 Sep;128(9):1033-8. (http://www.ncbi.nlm.nih.gov/pubmed/12220207?dopt=Abstract)
  • Kochhar A, Fischer SM, Kimberling WJ, Smith RJ. Branchio-oto-renal syndrome. Am J Med Genet A. 2007 Jul 15;143A(14):1671-8. Review. (http://www.ncbi.nlm.nih.gov/pubmed/17238186?dopt=Abstract)
  • Ruf RG, Xu PX, Silvius D, Otto EA, Beekmann F, Muerb UT, Kumar S, Neuhaus TJ, Kemper MJ, Raymond RM Jr, Brophy PD, Berkman J, Gattas M, Hyland V, Ruf EM, Schwartz C, Chang EH, Smith RJ, Stratakis CA, Weil D, Petit C, Hildebrandt F. SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8090-5. Epub 2004 May 12. (http://www.ncbi.nlm.nih.gov/pubmed/15141091?dopt=Abstract)
  • Sanggaard KM, Rendtorff ND, Kjaer KW, Eiberg H, Johnsen T, Gimsing S, Dyrmose J, Nielsen KO, Lage K, Tranebjaerg L. Branchio-oto-renal syndrome: detection of EYA1 and SIX1 mutations in five out of six Danish families by combining linkage, MLPA and sequencing analyses. Eur J Hum Genet. 2007 Nov;15(11):1121-31. Epub 2007 Jul 18. (http://www.ncbi.nlm.nih.gov/pubmed/17637804?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: January 2008
Published: October 27, 2014