Branchio-oto-renal syndrome

Otologic findings are the most consistent feature, reported in more than 90% of affected individuals. Hearing loss can be conductive (33%), sensorineural (29%), or mixed (52%), ranging from mild to profound. It is non-progressive in approximately 70% of cases and progressive in 30%. Branchial arch anomalies, including preauricular pits and branchial cleft sinuses or cysts, are nearly as prevalent, making them vital diagnostic indicators during clinical evaluation. Congenital anomalies of the kidney and urinary tract () are present in 67% of individuals and comprise renal agenesis (29%), hypoplasia (19%), dysplasia (14%), ureteropelvic junction obstruction (10%), calyceal cyst or diverticulum (10%), and vesicoureteral reflux. Glomerular pathology with proteinuria and glomerulosclerosis has been reported, and some individuals progress to end-stage kidney disease. Structural anomalies are congenital; progressive hearing loss typically begins during childhood or adolescence. Extreme interfamilial and intrafamilial variability is observed, with severity ranging from isolated preauricular pits to bilateral renal agenesis causing perinatal death.

The estimated prevalence is approximately 1/40,000.

BORS is caused by heterozygous germline pathogenic variants in EYA1 (~46% of affected individuals) and SIX1 (~15%). The proteins encoded by these genes form a tightly regulated transcriptional complex essential for organ development, particularly of the ear, kidneys, and branchial arches. Loss-of-function variants in EYA1 or SIX1 disrupting this complex impair morphogenesis, cell proliferation, and cellular fate specification. In approximately 39% of clinically diagnosed individuals, no pathogenic variant is present in either EYA1 or SIX1, suggesting the possible involvement of additional genes.

BORS is inherited in an autosomal dominant manner. The recurrence risk for offspring of an affected individual is 50%. Prenatal molecular testing is available once the familial pathogenic variant has been identified.

The clinical diagnosis is established using the . Temporal bone CT or MRI demonstrates inner-ear anomalies, including offset cochlear turns (turn angle ratio <0.476), cochlear hypoplasia, enlarged vestibular aqueduct, hypoplasia of the lateral semicircular canal, or widening of the internal auditory canal. Renal ultrasound, DMSA scintigraphy, and excretory urography are used to detect .

Main differential diagnoses include:

• CHD7 disorder (including ): hearing loss with external, middle, and inner ear anomalies and kidney anomalies overlapping with BORS, but additionally featuring coloboma, choanal atresia, genital hypoplasia, and developmental delay.
• SALL1-related Townes-Brocks syndrome: ear anomalies, hearing loss, and kidney anomalies overlapping with BORS, but additionally featuring thumb malformations, imperforate anus, and cardiac defects.
• : sensorineural hearing loss with progressive glomerulonephritis and ocular anomalies; lacks the branchial arch features that define BORS.

• Establishing the molecular diagnosis confirms the clinical suspicion and provides the basis for genetic counselling of the affected individual and the family.
• Molecular diagnosis is a prerequisite for tailored medical care and condition-specific surveillance, including serial audiometry to monitor progressive hearing loss and periodic evaluations of kidney function.
• Once the familial pathogenic variant has been identified, predictive testing of at-risk relatives is technically possible and allows clarification of variant status in asymptomatic family members.

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• Fraser FC, Sproule JR, Halal F. Frequency of the branchio-oto-renal (BOR) syndrome in children with profound hearing loss. Am J Med Genet. 1980;7(3):341-9. doi:10.1002/ajmg.1320070316. PMID:.
• Cho SH, Jeong SH, Choi WH, Lee SY. Genomic landscape of branchio-oto-renal syndrome through whole-genome sequencing: a single rare disease center experience in South Korea. Int J Mol Sci. 2024;25(15):8149. doi:10.3390/ijms25158149. PMID:; PMCID:PMC11311636.