Branchiootorenal spectrum disorders are inherited as autosomal dominant genetic conditions characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae, cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis can vary greatly from one person to another, even in members of the same family.
Branchiootorenal (BOR) syndrome is characterized by pits or ear tags in front of the outer ear (preauricular pits), abnormal passages from the throat to the outside surface of the neck (branchial fistulas), branchial cysts, malformations of the outer, middle and inner ear, hearing loss and kidney (renal) abnormalities.
Individuals with bronchitic (BOS) syndrome have ear and hearing abnormalities but kidneys are not affected.
Symptoms
Most people with BOR/BOS syndrome have some type of hearing loss. The hearing loss may be due to nerve damage (sensory), blockage of sound waves (conductive), or both. The degree of hearing loss varies from mild to profound and can differ between the two ears. The deafness can be stable or progressive. Other abnormalities related to the ear that may be present include pits or outgrowths of cartilage (tags) in front of the outer ear; a cupped or small outer ear; and/or a narrow or upward slanted outer ear canal.
An abnormal passage from the throat to the outside surface of the neck (branchial fistula), and/or an opening on the side of the neck, or a mass that can be felt under the muscles on the side of the neck is often present.
The kidney abnormalities associated with BOR syndrome range from mild to very severe. In milder cases, the kidney may be unusually shaped. In more severe cases, there may be duplication of the collecting system of the kidneys and/or the absence or failure of one or both of the kidneys to form.
The symptoms and/or signs of branchio-oto-renal syndrome are consistent with underdeveloped (hypoplastic) or absent kidneys with resultant chronic kidney disease or kidney failure. Ear anomalies include extra openings in front of the ears, extra pieces of skin in front of the ears (preauricular tags), or further malformation or absence of the outer ear (pinna). Malformation or absence of the middle ear is also possible, individuals can have mild to profound hearing loss. People with BOR may also have cysts or fistulae along the sides of their neck.[rx] In some individuals and families, renal features are completely absent. The disease may then be termed Branchio-oto Syndrome (BO syndrome
Other abnormalities that have been found in association with BOR syndrome are narrowing of the tear duct in the eyes interfering with the normal flow of tears; a long narrow face; cleft palate; paralysis of certain muscles in the face; and/or a deep overbite.
Causes
BOR/BOS syndrome is caused by mutations in the EYA1(BOR1, BOS2), SIX5 (BOR2), and SIX1 (BOR3, BOS3) genes.
BOR/BOS syndrome is inherited as an autosomal dominant disorder. Dominant genetic disorders occur when one copy of a gene is abnormal and this abnormal copy results in the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Mutations in three genes, EYA1, SIX1, and SIX5, have been reported in people with BOR/BO syndrome. About 40 percent of people with this condition have a mutation in the EYA1 gene. SIX1 gene mutations are a much less common cause of the disorder. SIX5 gene mutations have been found in a small number of people with BOR syndrome, although researchers question whether mutations in this gene cause the condition. Some affected individuals originally reported to have SIX5 gene mutations were later found to have EYA1 gene mutations as well, and researchers suspect that the EYA1 gene mutations may be the actual cause of the condition in these people.
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 may 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 BOR/BO syndrome.
Diagnosis
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.
Physical Exam
Second branchial arch anomalies
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Branchial cleft sinus tract appears as a pinpoint opening anterior to the sternocleidomastoid muscle, usually in the lower third of the neck
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Branchial cleft cyst appears as a palpable mass under the sternocleidomastoid muscle, usually above the level of the hyoid bone
Otologic findings
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Deafness: mild to profound in degree; conductive, sensorineural, or mixed in type
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Preauricular pits
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Auricular malformation (lop ear, cupped ear)
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Preauricular tags
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Abnormalities of the external auditory canal: atresia or stenosis
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Middle ear abnormalities: malformation, malposition, dislocation, or fixation of the ossicles; reduction in size or malformation of the middle ear space
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Inner ear abnormalities: cochlear hypoplasia; enlargement of the cochlear and vestibular aqueducts; hypoplasia of the lateral semicircular canal [Ceruti et al 2002, Kemperman et al 2002]
Renal anomalies
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Renal agenesis, hypoplasia, dysplasia
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Ureteropelvic junction (UPJ) obstruction
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Calyceal cyst/diverticulum
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Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux
Lab test
- CT or computerized tomography – 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
Genetics Test
- Molecular genetic testing – approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
- Gene-targeted testing – requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of branchiootorenal spectrum disorder is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing, whereas those with atypical features in whom the diagnosis of branchiootorenal spectrum disorder has not been considered are more likely to be diagnosed using genomic testing. When the phenotypic and laboratory findings suggest the diagnosis of branchiootorenal spectrum disorder the use of a multigene panel is recommended.
- A multigene panel Test – including EYA1, SIX1, SIX5, and other genes of interest is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting the identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests..
- 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.
- EYA1 mutations test – are 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.
Treatment
The child with hearing impairment should undergo appropriate rehabilitation measures with annual hearing testing (audiometry). Medical attention should be sought promptly for any episode of inflammation of the middle ear (otitis media). A canaloplasty should be considered to correct an atretic external auditory canal. Medical and surgical treatment for vesicoureteral reflux may prevent progression to end-stage renal disease (ESRD).
Patients with BOR/BOS syndrome may benefit from hearing aids. When structural defects of the ear are present, surgery may be beneficial. Branchial cleft deformities have the potential to become easily infected and may require surgical treatment such as excision of the branchial cleft cyst or fistulae. Antibiotics can be given if the cyst or sinuses are infected. Also, a physician specializing in kidney problems (nephrologist) should closely monitor any renal impairment. Surgical repair may be undertaken for correctable defects. Severe kidney problems may warrant dialysis or kidney transplantation.
A semi-annual examination for hearing impairment is recommended to assess the stability of hearing loss. Semiannual examination for renal function is recommended to prevent the progression of worsening of the kidneys.
Genetic counseling is recommended for patients and their families. Another treatment is symptomatic and supportive.
References
Dr. MD Harun Ar Rashid, FCPS, MD, PhD, is a highly respected medical specialist celebrated for his exceptional clinical expertise and unwavering commitment to patient care. With advanced qualifications including FCPS, MD, and PhD, he integrates cutting-edge research with a compassionate approach to medicine, ensuring that every patient receives personalized and effective treatment. His extensive training and hands-on experience enable him to diagnose complex conditions accurately and develop innovative treatment strategies tailored to individual needs. In addition to his clinical practice, Dr. Harun Ar Rashid is dedicated to medical education and community outreach, often participating in initiatives that promote health awareness and advance medical knowledge. His career is a testament to the high standards represented by his credentials, and he continues to contribute significantly to his field, driving improvements in both patient outcomes and healthcare practices.
