Branchio-Oto-Renal (BOR) syndrome is a rare, congenital disorder that affects the development of tissues in the neck, ears, and kidneys. It is a condition present from birth, defined by a distinct set of physical anomalies. The syndrome is estimated to affect approximately 1 in 40,000 individuals in the pediatric population. BOR syndrome is also known by the historical name Melnick-Fraser syndrome, honoring the researchers who described it.
The Three Primary System Manifestations
The characteristic name of the syndrome, Branchio-Oto-Renal, directly indicates the three main bodily systems involved: the branchial apparatus, the otologic (ear) system, and the renal (kidney) system. The physical features and functional impairments vary widely, even among affected individuals within the same family, a phenomenon known as variable expressivity.
Branchial Anomalies
The branchial anomalies relate to defects arising from the embryonic branchial arches, which contribute to the formation of the head and neck. These defects typically manifest as branchial cleft cysts or fistulae along the side of the neck. A cyst is a fluid-filled sac, while a fistula is an abnormal tract that may connect the pharynx to the skin surface. These malformations can become infected or cause drainage, often requiring surgical excision.
Otologic Anomalies
Ear malformations and hearing impairment are the most common features of BOR syndrome, with over 90% of affected individuals experiencing some form of hearing loss. Hearing loss can be conductive, sensorineural, or a combination of both, known as mixed hearing loss. Conductive loss results from problems in the outer or middle ear, while sensorineural loss involves the inner ear structures or the auditory nerve. The severity of the hearing impairment ranges from mild to profound.
External ear anomalies are frequent and include preauricular pits, which are small depressions located just in front of the ear. Malformations can also affect the internal structures, such as hypoplasia or displacement of the middle ear ossicles, or dysplasia of the cochlea and semicircular canals in the inner ear. These structural abnormalities contribute to the varying degrees and types of hearing loss seen in the syndrome.
Renal Anomalies
The renal involvement in BOR syndrome presents a wide spectrum of congenital anomalies of the kidney and urinary tract. These issues can range from mild structural anomalies to severe functional defects. Mild manifestations include renal hypoplasia, where the kidney is underdeveloped and small, or the presence of cysts.
More severe presentations include renal agenesis, which is the complete absence of one or both kidneys, a condition that can be life-threatening if bilateral. Kidney issues may progress over time, potentially leading to chronic kidney disease or end-stage renal disease later in life.
Genetic Cause and Inheritance
BOR syndrome is the result of mutations in genes that play a role in the embryonic development of the branchial arches, ears, and kidneys. The primary gene implicated is EYA1 (Eyes Absent Homolog 1), with mutations in this gene accounting for approximately 40% of clinically diagnosed cases. The EYA1 gene product is a transcription coactivator that interacts with proteins produced by the SIX1 and SIX5 genes, which are also associated with the syndrome in a smaller proportion of cases.
These genes encode proteins that are necessary for the activation of other genes during the formation of tissues before birth. When a mutation occurs, the altered protein disrupts the normal developmental process, leading to the characteristic malformations of BOR syndrome.
BOR syndrome follows an Autosomal Dominant inheritance pattern, meaning a person needs only one copy of the altered gene to have the condition. An affected individual has a 50% chance of passing the genetic mutation to each of their children. While the syndrome has high penetrance, the expressivity is highly variable. This variable expressivity explains why some family members with the same mutation may have only mild preauricular pits, while others have profound hearing loss and severe kidney failure.
Diagnosis and Symptom Management
The identification of BOR syndrome often begins with a clinical suspicion based on the presence of the characteristic features. Diagnosis is typically established by meeting specific clinical criteria, which often require a combination of major features and a positive family history:
- Branchial anomalies
- Hearing loss
- Preauricular pits
- Renal anomalies
Confirmatory diagnosis relies on molecular genetic testing to identify a pathogenic variant in the EYA1, SIX1, or SIX5 genes. However, a detectable genetic mutation is found in only about half of all clinically diagnosed patients, meaning a negative genetic test does not entirely rule out the syndrome. Diagnostic tools are used to assess the extent of the manifestations, including audiograms to determine the type and severity of hearing loss, and renal ultrasounds to detect kidney and urinary tract abnormalities.
Management of BOR syndrome is multidisciplinary and tailored to the individual’s specific symptoms. Hearing loss is addressed with audiological interventions, such as hearing aids or cochlear implants. Individuals with hearing impairment also benefit from specialized educational programs. Branchial cysts and fistulae are usually monitored and surgically removed if they become symptomatic or infected. Kidney anomalies require long-term management by a nephrologist, involving monitoring function, controlling blood pressure, and managing proteinuria. For individuals who progress to end-stage renal disease, treatment may involve dialysis or a kidney transplant.