Branchio-oto-renal syndrome

What is branchio-oto-renal syndrome?

Branchio-oto-renal syndrome (BOR) is a disease characterized by cervical fistula, aural fistula, and auricular anomaly, etc. (known as “branchiogenic anomalies”) associated with hearing loss and kidney deformity (congenital anomalies of the kidney and urinary tract: CAKUT*). It is considered as the same disease as brachio-oto (BO) syndrome, which does not present with kidney deformity. BOR syndrome is an autosomal dominant hereditary disease, but there are also cases without family history. Kidney deformity concurrent with hypoplastic/dysplastic kidney leads to loss of kidney function in the future, sometimes requiring dialysis and kidney transplantation.

 *Please refer to the section of “CAKUT” on this website.
 *Cervical fistula and aural fistula
Cervical fistula is a fistula (small hole) occurring along the anterior border of the neck muscle (sternocleidomastoid muscle) and may be accompanied by a small sac (cyst) filled with liquid that is connected to the small hole. Aural fistula is a small hole (fistula) occurring near the root of the ear.

Symptoms of branchio-oto-renal syndrome

・Second branchial arch anomaly: Presents with physical symptoms called branchial cleft fistula or branchial cleft cyst.
Branchial cleft fistula is a small hole situated anterior to the sternocleidomastoid muscle (neck muscle) usually in the lower one third of the neck. Branchial cleft cyst, a small sac filled with liquid that is connected to a branchial cleft fistula, is situated posterior to the sternocleidomastoid muscle and usually palpable above the hyoid bone. Second branchial arch anomalies are reported to occur in about 50% of patients with BOR syndrome.

・Hearing loss is observed in 90% or more patients, with the severity varying from mild to severe, and any of the three types, conductive, sensorineural, and mixed, can occur. Conductive hearing loss is caused by impairment of the external or middle ear, while sensorineural hearing loss occurs when there is impairment in the inner ear, cochlear nerve, or brain. Mixed hearing loss is a combination of conductive and sensorineural hearing loss.
Hearing loss associated with BOR syndrome is almost always congenital and non-progressive but can become progressive when accompanied by large vestibular aqueduct syndrome, a type of inner ear anomaly.

・Other symptoms include preauricular fistula (53%), ear deformity(38%), accessory ear(12%), meatal atresia (12%), middle ear anomalies, and inner ear anomalies.

・Kidney deformities (congenital anomalies of the kidney and urinary tract*): Kidney deformities are reported to occur in about 40% of patients with branchio-oto-renal syndrome, with hypoplastic kidney most commonly observed (29%). Other kidney deformities include hydronephrosis (14%), aplastic kidney (9%), multicystic dysplastic kidney, hydroureter, urethral stricture, and vesicoureteral reflux. about 30% of patients with concurrent kidney deformities progress to end-stage kidney disease and undergo peritoneal dialysis, hemodialysis, or kidney transplantation.

*Please refer to the section of “CAKUT” on this website.
・The frequency of concurrent intellectual disability or psychomotor retardation is not high in BOR syndrome patients. The presence of concurrent intellectual disability or psychomotor retardation may suggest another disease.

Treatment for BOR syndrome

There is currently no specific treatment for BOR syndrome. However, many patients with BOR syndrome can lead a good social life if their hearing loss and anomalies of the kidney and urinary tract are appropriately managed.


・Second branchial arch anomaly and preauricular fistula
For treatment of branchiogenic anomalies, if a preauricular fistula or cervical fistula, etc. is infected, it is initially treated with antimicrobial agents. Then, if the infection recurs repeatedly, surgical resection is performed. For auricular anomalies and auricular appendage , plastic surgery is considered for aesthetic reasons.

・Hearing loss
Many cases of hearing loss associated with BOR syndrome are detected by newborn hearing screening , etc. during the early postnatal period.

★Newborn hearing screening
Newborn hearing screening is a hearing examination performed during the neonatal period to detect the presence of hearing loss early. The current newborn hearing screening consists of two methods: OAE (otoacoustic emission) testing and ABR (automated auditory brainstem response) testing and is usually performed during the hospitalization period after birth. OAE testing examines the acoustic echo emitted by the inner ear when responding to a sound, while ABR detects the electronic response of the brain using electrodes placed on the skin surface when playing a small sound through earphones. These tests both finish within a few to 10 minutes while the baby is sleeping and do not cause any discomfort such as pain. It is estimated that about 1 to 2 out of 1000 babies are found to require early support based on the results of newborn hearing screening.

Given that hearing loss can affect speech development, early treatment initiation is desirable. There are various causes of hearing loss associated with BOR syndrome. Surgical interventions such as tympanoplasty and tympanic membrane tubing are performed for conductive hearing loss, but sufficient hearing improvement is not always achieved in some patients even after multiple surgeries. In these patients, cochlear implantation has been reported to be useful, and the use of hearing aids is also beneficial. It is important to provide the treatment that is most appropriate for each cause of hearing loss.

★Refer to the following website about cochlear implantation:
The website of the Oto-Rhino-Laryngological Society of Japan(http://www.jibika.or.jp/citizens/hochouki/naiji.html)

・Kidney deformities
Treatment options for kidney deformities are also mainly symptomatic. Hydronephrosis* due to ureteropelvic junction stenosis*and vesicoureteral reflux* etc. sometimes require surgery. The severity of renal dysfunction is different among individual patients; there are patients with normal kidney function, those only requiring drug therapy with angiotensin converting enzyme inhibitor and angiotensin II receptor blocker, etc. which are a type of antihypertensive agents with kidney protective effect, and those with severe hypoplasia or dysplasia of the kidneys, which may progress to end-stage kidney disease in the future, requiring kidney replacement therapy such as hemodialysis, peritoneal dialysis, or kidney transplantation. The prognosis of BOR syndrome is considered depending on the severity of kidney deformities, and early detection of and therapeutic intervention for kidney symptoms are desirable. Therefore, when BOR syndrome is suspected based on symptoms such as dysplastic ear, hearing loss, or cervical fistula, it is desirable to perform detailed examinations including echography.

・Genetic counseling
Since 90% of BOR syndrome cases are familial, genetic counseling is important for patients with BOR syndrome. Genetic counseling is performed by a clinical geneticist or a genetic counselor to solve worries, anxiety, or questions, etc. of patients with a hereditary disease or their family about heredity. During a genetic counseling session, accurate medical information based on scientific grounds is communicated and explained in an easily comprehensible manner, and at the same time, psychological, social, and other support is provided to help the patient and family solve their problems by themselves utilizing medical technology and information. BOR syndrome is an autosomal dominant hereditary condition, and the chance that a child of the patient will develop BOR syndrome is 50%. However, symptoms and severity may be different among siblings (brothers and sisters) with the same genetic abnormality. For example, there are some cases in which one of brothers with BOR syndrome has kidney deformities, while the other does not. Definitive diagnosis by genetic testing is highly useful in determining treatment strategy for the patient. Genetic testing can be performed on blood samples.

Q&A

1. What is the approximate number of patients with this disease?

According to a survey conducted by the research group supported by the Ministry of Health, Labour and Welfare, Japan in 2010, the estimated number of patients (number of people receiving medical treatment) in Japan is about 250.

2. In whom is this disease common?

There is no gender difference. BOR syndrome is often noticed early after birth through symptoms including hearing loss, cervical fistula, aural fistula, and auricular abnormality. Kidney deformities may be noticed early after birth if they are severe or otherwise, may be found in adulthood by medical checkup. If cervical fistula, aural fistula, or hearing loss is present without any other significant diseases, BOR syndrome should be suspected, and it is recommended to receive a kidney test (e.g., ultrasound imaging).

3. Is the cause of this disease known?

A gene is like a blueprint of a protein made in the body. It is estimated that mutations (the use of the word “abnormality” is avoided in genetic counseling) in the EYA1 gene on chromosome 8 cause BOR syndrome in about 40% of patients. In some patients, mutations in the SIX1 gene on chromosome 14 cause this disease. Since the proteins made by the EYA1 and SIX1 genes are combined together in the body, mutations in either of these genes cause almost the same symptoms.

4. Is this disease hereditary?

BOR syndrome is an autosomal dominant hereditary disease. Therefore, if one of the parents is affected by this disease, the chance of a child being affected would be 50%. However, even if neither parent is affected, the child may be affected due to newly generated mutations in a gene (de novo mutations).

5. What is the clinical course of this disease?

Many patients become aware of having this disease by a diagnosis of hearing loss based on newborn hearing screening, etc. As untreated hearing difficulty may slow language acquisition or result in the necessity to communicate in sign language, attention is needed. Kidney deformities are often noticed for the first time by renal dysfunction found by kidney echography or blood test, but advanced kidney disease may require dialysis or kidney transplantation. If hearing loss and kidney disease are properly managed and treated, patients can have the same lifestyle as healthy people.

6. What precautions are required in everyday life?

Hearing loss should be treated at a specialized hospital with a pediatric otolaryngologist specialized in hearing loss, and language training should be given, as appropriate. In addition, as the symptoms of some types of inner ear anomalies may be affected by an impact on the head, attention should be paid to avoid this. Patients with kidney problems should consume adequate water and a necessary amount of salt based on their individual condition under the guidance of a kidney specialist.
*Please refer to the section of “CAKUT” on this website.

Documents and links related to this disease

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