View source for Branchio-oto-renal syndrome

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{{CMG}} {{AE}} {{Shivam Singla}}

{{SK}} Branchiootorenal dysplasia; Melnick-Fraser syndrome; Branchio oto renal syndrome; BOR syndrome Branchio Oto Renal Syndrome; Melnick Fraser Syndrome; Branchio-Otorenal Syndrome; Dysplasia, Branchiootorenal; BOR Syndrome; Branchio-Otorenal Dysplasia; Branchiootorenal Syndrome 2; Branchiootorenal Syndrome 1; Branchio-Oculo-Facial Syndrome; Branchio Oculo Facial Syndrome; Branchial Clefts with Characteristic Facies, Growth Retardation, Imperforate Nasolacrimal Duct, and Premature Aging; Lip Pseudocleft-Hemangiomatous Branchial Cyst Syndrome; Lip Pseudocleft Hemangiomatous Branchial Cyst Syndrome; Hemangiomatous Branchial Clefts-Lip Pseudocleft Syndrome; Hemangiomatous Branchial Clefts Lip Pseudocleft Syndrome; Lee Root Fenske Syndrome; BOF Syndrome; Syndrome, BOF; Branchiooculofacial Syndrome

==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]].

<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> 

[[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)
**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==

The [[symptoms]] of the following [[disorders]] can be overlapping with [[symptoms]] of Branchio-renal [[syndrome]]. comparison is important to make the relevant differential diagnosis:

*<u>The [[oculo]]-[[auriculo]]-[[vertebral]] spectrum</u>
**Characterized by physical features involving [[Jaw]], [[mouth]], [[ears]], [[eyes]], and [[bones]] of the [[spinal column]]
**One side of the [[body]] is more affected as compared to the other side of the body
*<u>Branchio-oculofacial syndrome</u>  
**Rare [[autosomal]] [[dominant]] disorder
**Most commonly - [[growth delay]], [[abnormal sinuses]], unusual facial appearance, and/or premature [[aging]]
**less commonly - graying of [[hair]], high arched [[palate]], [[abnormal teeth]], and [[cyst]] under the [[skin]] of the [[scalp]] can be found
*[[Townes-Brocks syndrome|<u>Towns Brocks syndrome</u>]] 
**Rare [[genetic]] [[disorder]]
**[[Deafness]] or [[hearing loss]]
**Associated [[ear]], [[hand]], and [[foot]] anomalies
**No [[anal]] opening
*[[Treacher Collins syndrome|<u>Treacher Collins syndrome</u>]] 
**Characterized by abnormalities in the [[facial]] area and head due to the [[maldevelopment]] of the [[skull]]

==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
*[[SIX 1]] ( 4% of the patients)
*[[SIX 5]] ( 5% of the patients)

[[File: Preauricular fistula in BOR Syndrome.png|thumb|BOR an [[autosomal dominant]] [[disorder]] characterized by the presence of branchial [[fistulae]], external [[ear]] [[malformation]] with [[hearing]] [[defects]] along with [[renal]] abnormalities.]]

===History and Symptoms===
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|266x266px|'''Preauricular pitting and skin tag in BOR syndrome.''']]

*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
*Middle ear malformations: ossicular hypoplasia or displacement
*Inner ear anomalies: dysplasia in semicircular canals, cochlear hypoplasia, enlargement of aqueducts
*External auditory canal stenosis or malformation
*Lop-ear deformity


<u>Branchial Arch menifestations</u>

*Branchial cleft cyst, fistulae, sinus tract.

 
<u>Renal malformations</u>

*Renal Hypoplasia or agenesis in some cases
*ureteropelvic junction obstruction
*Vesicoureteral reflux


<u>Miscellaneous Findings</u>

*Lacrimal duct aplasia/Hypoplasia
*Facial nerve palsy
*Retrognathia
*MVP
*Cleft lip/palate

<br />

===Diagnotic criteria based on history and physical exam===

*Positive family history of branchial, oto, renal abnormalities is strongly suggestive of BOR syndrome.

*If no evidence of family history then clinical criteria should be used to make the diagnosis
**Either 3 major criteria
**2 major plus 2 minor criteria

{| class="wikitable"
|+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

{| class="wikitable"
|-
!Ear Evaluation!!Renal Evaluation!!Branchial Arch evaluation!!Genetic counsel
|-
|Tone Audiometry||Renal US||Fistulogram||History taking
|-
|Emission testing||BUN||Computed tomography(CT)||Autosomal Dominant pattern
|-
|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 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 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 stability or progression.

*Treatment for Renal Anomalies
**Treatment usually depends upon the severity of renal complications.
**Medical and surgical both types of options are available are the options available.
**Temporary Dialysis or Kidney transplantation is the option available in the case of End-Stage Renal disease.
**Semiannual examination of kidneys is advised to prevent the progression of kidney diseases.

*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.

==References==
{{reflist|2}}

{{Phakomatoses and other congenital malformations not elsewhere classified}} 

[[Category:Disease]]
[[Category:Nephrology]]
[[Category:Genetic disorders]]

[[fr:Syndrome branchio-oto-rénal]]

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