'''Branchio-oto-renal syndrome''' (also known as '''branciootorenal syndrome''', '''BOR syndrome''' or '''BOR''') is an [[autosomal dominant]] [[genetic disorder]] involving the [[kidney]]s, [[ears]], and [[neck]]. In [[ears]], it is associated with a wide number of [[defects]] ranging from [[sensorineural]], [[conductive]], or [[Hearing Loss|mixed hearing loss]] to structural defects of the [[inner ear]], [[middle ear]] and [[outer ear]] along with [[branchial fistulas]] or [[cyst]]. [[Renal]] abnormalities include the complete absence of [[kidneys]] in some cases while in others only mild [[hypoplasia]] is present. The most important differential studied is [[Branchiootic syndrome]] (BO) which has exactly the same features as BOR syndrome but the affected individuals do not have the [[kidneys]] abnormalities like in BOR syndrome. The two condition similarities some times create a hard time for researchers and sometimes they even consider them together as BOR/BO syndrome.
'''Branchio-oto-renal syndrome''' (also known as '''branciootorenal syndrome''', '''BOR syndrome''' or '''BOR, Melnick- Fraser Syndrome''') is an [[autosomal dominant]] [[genetic disorder]] involving the [[kidney]]s, [[ears]], and [[neck]]. 90% of these are due to [[inheritance]] and in 10% cases, it is acquired [[mutation]]. It is characterized by the presence of 1) [[brachial fistulae]] or [[cysts]]; 2) [[Ear malformations]] - including outer, middle or [[inner ear]]; 3) [[Renal]] [[malformations]], which can range from [[renal]] [[hypoplasia]] to renal agenesis. The most important differential studied is <u>[[Branchiootic syndrome|Branchiootic syndrome (BO)]]</u> which has exactly the same features as BOR [[syndrome]] but the affected individuals do not have the [[kidneys]] abnormalities like in BOR syndrome. The two condition similarities some times create a hard time for [[researchers]]. Sometimes they even consider them together as BOR/BO [[syndrome]].
<u>''"Branchio-"''</u> means the second [[branchial arch]], s structure that is usually present in the [[embryo]] that further gives rise to [[tissues]] on the front and the side of the neck. The abnormal development of this [[branchial arch]] leads to leads to the formation of neck masses called [[branchial cleft cysts]] which is most commonly seen in people with BO/BOR syndrome. Some people might have abnormal appearing pits or holes in the side of the [[neck]] called [[fistulae]]. They can form a connection with the [[mouth]] near the [[tonsil]]. Both branchial cleft cyst and [[fistulae]] can create problems later in life so they are usually removed during the early stages of childhood. <u>''"Oto-"''</u> refer to the ear. It has been studied that most patients with BO/BOR syndrome usually have [[hearing]] [[abnormalities]]. It can be [[sensorineural]], [[conductive]], or [[mixed]]. [[Sensorineural]] [[hearing loss]] is usually seen in the [[patients]] with abnormalities in the [[inner ear]]: [[conductive hearing loss]] is due to the defects of bones in the [[middle ear]]; [[Mixed hearing loss]] is caused by both [[inner ear]] + [[middle ear]] abnormalities. Preauricular pits ( tiny holes) and tags (an extra bit of tissue) are the other anomalies associated with the ear anomalies. <u>''"Renal"''</u> word means [[kidneys]] here; The major point to be noted here is that BO syndromes do not have [[real]] components. So BOR syndrome causes an alteration in [[kidney]] [[structure]] and [[function]]. The [[renal]] [[abnormalities]] range from mild to severe and may include one or both the [[kidneys]]. The [[renal]] abnormalities include the complete absence of [[kidneys]] in some cases while in others only mild [[hypoplasia]] is present. The most serious condition associated with [[kidneys]] is their inability to clear fluids and waste from the [[body]] which is usually given a name [[End-stage renal disease]][[(ESRD)]].
==History and Epidemology==
*Heusinger(1864) first recognized an association between [[fistulae]], [[preauricular pits]], and [[hearing]] [[impairment]][[defects]].
*Melnick et al. and Fraser et al. in 1975 defined BOR [[syndrome]] as a specific entity having an [[autosomal dominant]] [[inheritance]] pattern with maximum [[penetrance]].
*The [[incidence]] rate for BOR syndrome is around 1 in 40,000 people.
*[[Males]] and [[females]] are equally affected by this [[disorder]].
==Pathophysiology==
[[File:Genetic work up .png|thumb|558x558px|Different gene mutations involved in the pathogenesis of BOR syndrome.[https://radiologykey.com/wp-content/uploads/2015/12/B9780323081764001130_t0015.png]]]
BOR results from the mutation of the [[EYA1 gene]].<ref>{{OMIM|113650}}</ref> <ref>[http://www.genetests.com/servlet/access?db=geneclinics&site=gt&id=8888891&key=QKsO4q7nnt6jd&gry=&fcn=y&fw=2fkb&filename=/profiles/bor/index.html Branchiootorenal syndrome from Gene Reviews]</ref>
"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 BOR/BO syndrome, abnormal development of the second branchial arch can result in the formation of masses in the neck called branchial cleft cysts. Some affected people have abnormal holes or pits called fistulae in the side of the neck just above the collarbone. Fistulae can form tunnels into the neck, exiting in the mouth near the tonsil. Branchial cleft cysts and fistulae can cause health problems if they become infected, so they are often removed surgically.
[[Image:autodominant.jpg|thumb|337x337px| Autosomal dominant pattern of inheritance observed in BOR Syndrome.[https://en.wikipedia.org/wiki/Branchio-oto-renal_syndrome#/media/File:Autosomal_dominant_-_en.svg]]]90% of BOR syndromes result from [[inheritance]] and 10% of the cases are thought to be the [[result]] of [[Acquired disorder|acquired mutations]]. Branciootorenal syndrome has an [[Autosomal dominant inheritance]] pattern with variable expressivity as a result of which the same family members express the different levels of severity of the [[disease]]. It also shows a 100% [[penetrance]]. The mutations in the genes - [[SIX1]], [[EYA1 gene|EYA1]], and [[SIX5]] play a major role in the causation of BOR syndrome. Out of these, [[EYA1 gene]] mutations play a major role (40%) followed by the [[SIX1|SIX1 gene]], and [[SIX5]] [[gene]] [[mutation]] is only found in a small number of people suffering from BOR syndrome.
"Oto-" and "-otic" refer to the ear; most people with BOR/BO syndrome have hearing loss and other ear abnormalities. The hearing loss can be sensorineural, meaning it is caused by abnormalities in the inner ear; conductive, meaning it results from changes in the small bones in the middle ear; or mixed, meaning it is caused by a combination of the inner ear and middle ear abnormalities. Some affected people have tiny holes in the skin or extra bits of tissue just in front of the ear. These are called preauricular pits and preauricular tags, respectively.
"Renal" refers to the kidneys; BOR syndrome (but not BO 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.
==Pathophysiology==
*'''[[EYA1]] gene mutations'''([[BOR1]], BOS2)
**About 40% of people are having [[EYA1]] mutation.
**This usually encodes for [[transcription factors]] in the metanephric mesenchyme.
*[[SIX1]] Gene mutation (BOR3, BOS3)
**Found in less than 5% of the cases
**This [[gene]] mainly encodes the [[Transcription factor|transcription factors]] that control the expression of [[PAX1|PAX]] and [[GDNF]].
**The [[Renal|renal malformation]] is not associated with this [[mutation]]
*[[SIX5]] Gene mutation (BOR2)
**It is seen in 2-3 percent of cases with BOR syndrome.
**[[Hearing]] is not impaired with this [[mutation]].
The [[proteins]] produced from these [[genes]] play a major role in the development before birth. Interaction of [[EYA1]] protein with [[SIX5]] and [[SIX1]] modulates the [[genes]] involved in embryonic development. These interactions also play a major role in the development of the [[ear]], [[kidneys]], and [[second branchial arch]]. The latter organs are mainly involved in the Branciootorenal syndrome.
==Differentiating Branchio-oto-renal syndrome from other Diseases==
BOR results from the mutation of the [[EYA1 gene]].<ref>{{OMIM|113650}}</ref> <ref>[http://www.genetests.com/servlet/access?db=geneclinics&site=gt&id=8888891&key=QKsO4q7nnt6jd&gry=&fcn=y&fw=2fkb&filename=/profiles/bor/index.html Branchiootorenal syndrome from Gene Reviews]</ref>
The [[symptoms]] of the following [[disorders]] can be overlapping with [[symptoms]] of Branchio-renal [[syndrome]]. comparison is important to make the relevant differential diagnosis:
[[Image:autodominant.jpg|thumb|none|{{PAGENAME}} has an autosomal dominant pattern of inheritance.]]
**Characterized by abnormalities in the [[facial]] area and head due to the [[maldevelopment]] of the [[skull]]
==Diagnosis==
==Diagnosis==
===Gene Studies===
There are 3 main [[gene]] [[mutations]] studied so far that results in the causation of [[BOR syndrome]].
The most common [[gene]] [[mutations]] are:
*[[EYA1]]( 40% of the patients), along with other 2 gene mutations those seen less commonly are
*[[SIX1]] ( 4% of the patients)
*[[SIX5]] ( 5% of the patients)
[[File: Preauricular fistula in BOR Syndrome.png|thumb|'''BOR Syndrome an [[Autosomal Dominant]] [[disorder]] showing branchial [[fistulae]]''',
https://pubmed.ncbi.nlm.nih.gov/28289595/]]
===History and Symptoms===
===History and Symptoms===
Individuals with BOR may have underdeveloped (hypoplastic) or [[Renal agenesis|absent]] kidneys with resultant renal insufficiency or [[renal failure]].
The most common presenting [[symptoms]] in [[patients]] with BOR syndrome is:
<u>Otologic manifestations</u>
*With more than 90% of patients have at least one of the following
[[File: Preauricular pitting and skin tag in BOR syndrome.png|thumb|262x262px|'''Preauricular pitting and skin tag in BOR syndrome.''', https://pubmed.ncbi.nlm.nih.gov/28289595/]]
*[[Deafness]]- (0% of the people have [[hearing loss]].
**It can be [[sensorineural]], conductive, or mixed ranging from mild severity to marked hearing loss
**Approximately 50% of the people present with mixed [[hearing loss]]
**30% with [[conductive hearing loss]]
**20% with [[sensorineural hearing loss]]
*[[Preauricular tags]]
*[[Preauricular pits]]
*[[File:Branchio-oto-renal Syndrome.png|thumb|'''Branchio-oto-renal Syndrome- Facial abnormalities and Renal biopsy slides associated with focal glomerulosclerosis.''', https://pubmed.ncbi.nlm.nih.gov/23506628/]][[Middle ear]] [[malformations]]: [[ossicular]] [[hypoplasia]] or displacement
*[[Inner ear]] [[anomalies]]: [[dysplasia]] in [[semicircular canals]], [[cochlear hypoplasia]], [[enlargement]] of [[aqueducts|aqueducts.]]
*[[External]] [[auditory canal]] [[stenosis]] or [[malformation]]
*Most Important component in managing a [[patient]] with Branchio-oto-renal syndrome is the evaluation of involved [[organs]] carefully. The following table shows the [[organs]] needed to be evaluated and what a medical practitioner needs to focus on while managing the [[patient]] of BOR syndrome
|Temporal CT||Creatinine||MRI if mass palpated||50% chnace of transmission to child
|-
|Annual Auditory evaluation||Annual nephrology evaluation||MRI if tracts observed||Prental testing
|-
|Auditory Brainstem Response||Annual urology evaluation||Example||Positive family history
|}
'''Treatment'''
*[[Treatment]] for [[Otologic]] [[Anomalies]]
**In the case of [[hearing impairment]] get the [[patient]] evaluated for the type of [[hearing loss]] and give them the [[hearing aid]] or [[cochlear implant]]
**If the defect is mainly in the [[external ear canal]] with the [[middle ear]] intact then advise [[canaloplasty]].
**[[Cosmetic]] [[procedures]] can be done if the [[patient]] [[desires]] the one. These are usually reserved for [[pinna]] [[deformities]].
**Semiannual [[examination]] is advised to keep an [[eye]] on [[hearing]] [[impairment]] or its progression.
*Treatment for [[Renal]] Anomalies
**Treatment usually depends upon the severity of [[renal]] [[complications]].
**[[Medical]] and [[surgical]] both types of options are available.
**[[Temporary]] [[Dialysis]] or [[Kidney]] [[transplantation]] is the option available in the case of [[End-Stage Renal disease]].
**[[Semiannual]] [[examination]] of [[kidney]]s is advised to prevent the progression of [[kidney]] [[diseases]].
Ear anomalies include extra openings in front of the [[ears]] (preauricular pits), extra pieces of [[skin]] in front of the ears (preauricular [[Acrochordon|tags]]), or further malformation or absence of the outer ear ([[pinna (anatomy)|pinna]]). Malformation or absence of the [[middle ear]] is also possible. Individuals can have mild to profound hearing loss, which can either be sensorineural, conductive, or mixed. People with BOR may also have cysts or [[fistula]]e along the sides of their neck corresponding to
*Treatment of [[Branchial]] Anomalies
the location of the embryologic [[Branchial arch|brancial cleft]]s.
**[[Cyst]] gets easily infected so [[antibiotics]] can be used in the initial [[management]].
**Usually the [[Branchial]] anomalies requires the [[invasive]] [[treatment]] approach
**If there is the presence of [[cyst]]/[[fistula]] or [[sinus tract]] then those should be excised
***Usually [[complete dissection]] of the tract and tonsillectomy is also done along with.
Branchio-oto-renal syndrome (also known as branciootorenal syndrome, BOR syndrome or BOR, Melnick- Fraser Syndrome) is an autosomal dominantgenetic disorder involving the kidneys, ears, and neck. 90% of these are due to inheritance and in 10% cases, it is acquired mutation. It is characterized by the presence of 1) brachial fistulae or cysts; 2) Ear malformations - including outer, middle or inner ear; 3) Renalmalformations, which can range from renalhypoplasia to renal agenesis. The most important differential studied is Branchiootic syndrome (BO) which has exactly the same features as BOR syndrome but the affected individuals do not have the kidneys abnormalities like in BOR syndrome. The two condition similarities some times create a hard time for researchers. Sometimes they even consider them together as BOR/BO syndrome.
"Branchio-" means the second branchial arch, s structure that is usually present in the embryo that further gives rise to tissues on the front and the side of the neck. The abnormal development of this branchial arch leads to leads to the formation of neck masses called branchial cleft cysts which is most commonly seen in people with BO/BOR syndrome. Some people might have abnormal appearing pits or holes in the side of the neck called fistulae. They can form a connection with the mouth near the tonsil. Both branchial cleft cyst and fistulae can create problems later in life so they are usually removed during the early stages of childhood. "Oto-" refer to the ear. It has been studied that most patients with BO/BOR syndrome usually have hearingabnormalities. It can be sensorineural, conductive, or mixed. Sensorineuralhearing loss is usually seen in the patients with abnormalities in the inner ear: conductive hearing loss is due to the defects of bones in the middle ear; Mixed hearing loss is caused by both inner ear + middle ear abnormalities. Preauricular pits ( tiny holes) and tags (an extra bit of tissue) are the other anomalies associated with the ear anomalies. "Renal" word means kidneys here; The major point to be noted here is that BO syndromes do not have real components. So BOR syndrome causes an alteration in kidneystructure and function. The renalabnormalities range from mild to severe and may include one or both the kidneys. The renal abnormalities include the complete absence of kidneys in some cases while in others only mild hypoplasia is present. The most serious condition associated with kidneys is their inability to clear fluids and waste from the body which is usually given a name End-stage renal disease(ESRD).
Autosomal dominant pattern of inheritance observed in BOR Syndrome.[2]
90% of BOR syndromes result from inheritance and 10% of the cases are thought to be the result of acquired mutations. Branciootorenal syndrome has an Autosomal dominant inheritance pattern with variable expressivity as a result of which the same family members express the different levels of severity of the disease. It also shows a 100% penetrance. The mutations in the genes - SIX1, EYA1, and SIX5 play a major role in the causation of BOR syndrome. Out of these, EYA1 gene mutations play a major role (40%) followed by the SIX1 gene, and SIX5genemutation is only found in a small number of people suffering from BOR syndrome.
The proteins produced from these genes play a major role in the development before birth. Interaction of EYA1 protein with SIX5 and SIX1 modulates the genes involved in embryonic development. These interactions also play a major role in the development of the ear, kidneys, and second branchial arch. The latter organs are mainly involved in the Branciootorenal syndrome.
Differentiating Branchio-oto-renal syndrome from other Diseases
The symptoms of the following disorders can be overlapping with symptoms of Branchio-renal syndrome. comparison is important to make the relevant differential diagnosis:
If no evidence of family history then clinicalcriteria should be used to make the diagnosis, Either:
3 Major
2 Major plus 2 Minor criteria
Diagnostic criteria for BOR Syndrome ( 2 major /or 2 major + 2 minor)
MAJOR CRITERIA
MINOR CRITERIA
Hearing loss
Middle ear anomalies
Renal anomlies
Inner ear anomalies
2nd Branchial arch anomlies
Euthyroid goiter
Pinnae malformation
Preauricular tags
Preauricular pits
Lacrimal duct aplasia
External auditory canal anomlies
Facial asymmetry/palate abnormalities
Management and Treatment
Management
Most Important component in managing a patient with Branchio-oto-renal syndrome is the evaluation of involved organs carefully. The following table shows the organs needed to be evaluated and what a medical practitioner needs to focus on while managing the patient of BOR syndrome
![[1]](https://radiologykey.com/wp-content/uploads/2015/12/B9780323081764001130_t0015.png){kind=link}
![[2]](https://en.wikipedia.org/wiki/Branchio-oto-renal_syndrome#/media/File:Autosomal_dominant_-_en.svg){kind=link}