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==Overview==
==Overview==
'''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]].
'''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)]].
<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==
==History and Epidemology==
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==Pathophysiology==
==Pathophysiology==
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>
[[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>
[[Image:autodominant.jpg|thumb|{{PAGENAME}} has an [[autosomal dominant]] pattern of [[inheritance]].|alt=]]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.
[[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.
*'''[[EYA1]] gene mutations'''([[BOR1]], BOS2)
*'''[[EYA1]] gene mutations'''([[BOR1]], BOS2)
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The [[symptoms]] of the following [[disorders]] can be overlapping with [[symptoms]] of Branchio-renal [[syndrome]]. comparison is important to make the relevant differential diagnosis:
The [[symptoms]] of the following [[disorders]] can be overlapping with [[symptoms]] of Branchio-renal [[syndrome]]. comparison is important to make the relevant differential diagnosis:
**Characterized by abnormalities in the facial area and head due to the maldevelopment of the skull
**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===
The most common presenting symptoms in patients with BOR syndrome is:
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 in addition to that:
<u>Otologic manifestations</u>
**Deafness- It can be sensorineural, conductive, or mixed ranging from mild hearing difficulties to marked hearing loss.
***Around 90% of the patients have underlying hearing loss.
*With more than 90% of patients have at least one of the following
***Among these hearing losses, approximately 50% of the people present with mixed hearing loss, 30% with conductive hearing loss, and 20% with sensorineural hearing loss.
**Preauricular tags
[[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/]]
**Preauricular pits
**Middle ear malformations: ossicular hypoplasia or displacement
*[[Deafness]]- (0% of the people have [[hearing loss]].
**Inner ear anomalies: with dysplasia in semicircular canals, cochlear hypoplasia, enlargement of aqueducts ( Both cochlear and vestibular)
**It can be [[sensorineural]], conductive, or mixed ranging from mild severity to marked hearing loss
**External auditory canal stenosis or malformation
**Approximately 50% of the people present with mixed [[hearing loss]]
**Lop-ear deformity
**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]]
*[[Renal Hypoplasia]] or [[agenesis]] in some cases
*ureteropelvic junction obstruction
*[[ureteropelvic]] junction [[obstruction]]
*Vesicoureteral reflux
*[[Vesicoureteral reflux]]
<u>Miscellaneous Findings</u>
<u>Miscellaneous Findings</u>
*Lacrimal duct aplasia/Hypoplasia
*[[Lacrimal duct aplasia]]/[[Hypoplasia]]
*Facial nerve palsy
*[[Facial nerve palsy]]
*Retrognathia
*[[Retrognathia]]
*MVP
*[[MVP]]
*Cleft lip/palate
*[[Cleft lip]]/[[palate]]
<br />
<br />
===Diagnotic criteria===
*Positive family history of branchial, oto, renal abnormalities is strongly suggestive of BOR syndrome.
===Diagnotic criteria based on history and physical exam===
*If no evidence of family history then clinical criteria should be used to make the diagnosis
*Positive [[family history]] of [[branchial]], [[oto]], [[renal]] abnormalities is strongly suggestive of BOR syndrome.
**Either 3 major criteria
**2 major plus 2 minor criteria
*If no evidence of family history then [[clinical]] [[criteria]] should be used to make the [[diagnosis]], Either:
**3 Major
**2 Major plus 2 Minor criteria
{| class="wikitable"
{| class="wikitable"
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|}
|}
==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
|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'''
Gene Studies
*[[Treatment]] for [[Otologic]] [[Anomalies]]
Currently, there are three known gene mutations which result in BOR syndrome. If a clinical diagnosis of BOR syndrome is made, confirmation should be attempted via sequence analysis for EYA1. If an EYA1 mutation is not found with sequence analysis, one should utilize duplication/deletion analysis for EYA1 and sequence analysis for SIX 1 and SIX 5.
**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]]
EYA1 mutation
**If the defect is mainly in the [[external ear canal]] with the [[middle ear]] intact then advise [[canaloplasty]].
About 40% of people with BOR syndrome will have an EYA1 mutation.
**[[Cosmetic]] [[procedures]] can be done if the [[patient]] [[desires]] the one. These are usually reserved for [[pinna]] [[deformities]].
EYA1 encodes for a transcription cofactor that is expressed in the metanephric mesenchyme during development of the kidneys.
**Semiannual [[examination]] is advised to keep an [[eye]] on [[hearing]] [[impairment]] or its progression.
SIX1 mutation
The SIX1 mutation is estimated to be found in 2% of BOR syndrome cases.
It encodes transcription factors that control expression of GDNF and PAX2.
The majority of patients with this mutation do not demonstrate renal malformation.
SIX5 mutation
The SIX5 mutation is present in about 2.5% of BOR syndrome cases.
Hearing may be normal in these patients.
For making diagnosis 2 out of 5 following features should be present
*Treatment for [[Renal]] Anomalies
The diagnosis of BOR/BOS syndrome is made when at least two of five features (branchial defects, hearing loss, preauricular pits, abnormalities of the part of the ear that projects from the head (pinna), and renal malformations) are present in an individual with two or more affected family members, or three features are present in an individual with no affected family members.
**Treatment usually depends upon the severity of [[renal]] [[complications]].
Evaluation of hearing function (audiological assessment), and imaging (CT or computerized tomography) of the temporal bone to identify the middle and inner ear defects, should be performed. Renal abnormality is investigated by urinalysis, renal function tests, and imaging studies such as renal ultrasonography and CT.
**[[Medical]] and [[surgical]] both types of options are available.
Molecular genetic testing for mutations in the EYA1(BOR1, BOS2), SIX5 (BOR2), and SIX1 (BOR3, BOS3) genes is available to confirm a clinical diagnosis of BOR/BOS syndrome.
**[[Temporary]] [[Dialysis]] or [[Kidney]] [[transplantation]] is the option available in the case of [[End-Stage Renal disease]].
EYA1 mutations are to be found in about 40% of people with BOR/BOS syndrome. A SIX1 mutation is estimated to be found in 4% of people with BOR/BOS syndrome and a SIX5 mutation is present in about 5% of people with BOR/BOS syndrome.
**[[Semiannual]] [[examination]] of [[kidney]]s is advised to prevent the progression of [[kidney]] [[diseases]].
Individuals with BOR may have underdeveloped (hypoplastic) or [[Renal agenesis|absent]] kidneys with resultant renal insufficiency or [[renal failure]].
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 the location of the [[embryologic]] [[Branchial arch|brancial cleft]]s.
*Treatment of [[Branchial]] Anomalies
**[[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}