Branchio-oto-renal syndrome: a narrative review

Abstract

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder caused by pathogenic variants in EYA1, SIX1, or SIX5, which affect the branchial arches, auditory system, and kidneys. Diagnosis integrates clinical criteria that require major criteria such as branchial anomalies, hearing loss, or preauricular pits, as supported by genetic testing. Gene-targeted testing confirms typical BOR syndrome phenotypes, whereas comprehensive genomic testing identifies atypical cases. Management is tailored to the individual phenotypes. Kidney anomalies, the most important prognostic factor, necessitate early nephrology referral and interventions such as pyeloplasty for ureteropelvic junction obstruction or kidney replacement therapy for kidney failure. Hearing loss is addressed using hearing aids, surgical correction, or cochlear implantation, depending on the type and severity of hearing loss. Branchial anomalies, including cysts and sinuses, can be managed conservatively or surgically when symptomatic. Genetic counseling plays a critical role, given the 50% inheritance risk and the implications for family planning. Prenatal ultrasonography is recommended for detecting renal anomalies during at-risk pregnancies. Management of BOR syndrome requires a multidisciplinary approach that integrates otolaryngology, nephrology, and genetics. Advances in genomic technologies and a deeper understanding of phenotypic variability are essential for improving the outcomes of patients with BOR.

Introduction

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant genetic disorder affecting the kidneys, ears, and neck. This syndrome (OMIM 113650) is characterized by a combination of hearing loss, auricular abnormalities, branchial arch vestiges (branchial clefts, cysts, or fistulae), and kidney anomalies [1,2]. Patients with similar symptoms but without kidney anomalies are diagnosed with branchio-otic syndrome. In 1864, Heusinger discovered a connection between branchial fistulae, preauricular pits, and hearing impairments. However, the precise characteristics of what is now known as BOR syndrome were not thoroughly characterized until a century later by Melnick et al. [1] and Fraser et al. [2]. BOR syndrome is also linked to a wide range of additional clinical characteristics, including abnormalities of the shoulder, ureters, palate, and bladder, lacrimal system dysfunction, otitis media, and face, as well as several other clinical features [3]. The disease now has a variety of names owing to observations of these additional characteristics. Examples include branchio-oto-dysplasia, branchio-oto-ureteral, BOR, preauricular pits, cervical fistulae, hearing loss syndrome, and ear pits-deafness syndrome [4,5].

Prevalence

The prevalence of the BOR syndrome remains unclear. Multiple studies have been conducted to determine the incidence of hearing loss in children. A pioneering study by Fraser in 1976 [6] found that 0.15% of 3,640 children with profound hearing loss had branchial fistulae and preauricular pits (1:700,000). In 1980, Fraser et al. [7] surveyed 421 school children with profound hearing loss and found that 2% had BOR syndrome, estimating the prevalence of the condition to be 1:40,000. In 1999, Smith found that 25 out of 1,434 patients diagnosed with a genetic cause of hearing loss suffered from BOR syndrome (1.7%) [8]. Interestingly, a survey conducted by Japanese researchers found only 250 cases of BOR syndrome in Japan in the year 2009–2010, suggesting a low prevalence in far east Asia, and thus an ethnic variation [9]. Penetrance in BOR syndrome is close to 100%, with incomplete and variable expression as proven by studies with large sample sizes [5,8,10,11].

Phenotypes of BOR syndrome

Since Melnick [1] described a father and three of his six children with mixed hearing, abnormal pinna, branchial fistula, and renal anomalies in 1975, there has been increased interest in the phenotypes of BOR syndrome. This has led to a wide range of clinical presentations associated with the BOR syndrome, causing researchers to predict its heterogeneous nature. Hearing loss was the most consistent finding in patients with BOR syndrome, followed by preauricular pits, branchial fistulas, and renal abnormalities [7,12]. Chen et al. [12] in 1995 classified these phenotypes of unknown significance into major and minor phenotypes based on their occurrence. Phenotypes which were expressed in more than 20% of the patients with BOR syndrome were called “major anomalies” and those occurring in less than 20% as “minor anomalies” (Table 1).

Table 1.

Phenotypic manifestations of BOR syndrome

	Otological	Branchial	Renal	Others
Common anomalies >20%	Hearing loss	Preauricular pits	Renal anomalies
	Pinnae deformities	Branchial fistulae
	External auditory canal stenosis
Uncommon anomalies <20%	Facial nerve paresis	Preauricular tag		Lacrimal duct aplasia
				Short palate
				Retrognathia
				Benign intracranial tumor
				Cleft palate
				Congenital hip dysplasia
				Euthyroid goiter
				Gustatory lacrimation
				Nonrotation of gastrointestinal tract
				Pancreatic duplication cyst
				Temporoparietal linear nevus

BOR, branchio-oto-renal.

Otologic anomalies

Hearing loss is the most common entity in BOR syndrome, ranging from 46% to 99% of patients [13,14]. The most common type of hearing loss reported is the mixed type (51%), followed by sensorineural and conductive hearing losses at 29% and 20%, respectively [15]. In a review of 248 probands, the level of hearing loss varied from mild, moderate, and severe to profound, in descending order of occurrence [16]. Hearing loss in BOR syndrome can be stable, progressive, or even fluctuating [15,17,18]. Almost all patients were afflicted bilaterally, albeit asymmetrically [19]. The second most common otologic anomaly was preauricular deformity. In a review of 295 patients, Chen et al. [12] found that preauricular pit was the most common anomaly, followed by the preauricular fistula, preauricular tags, and preauricular sinus. These anomalies were bilateral in most cases, except for preauricular tags [19].

A wide variety of external ear deformities, including ankylotia, microtia, low-set ears, and constricted ears, have been described in the literature. In the middle ear, ossicular anomalies, otitis media with effusion, a patulous eustachian tube, and an underdeveloped tympanic cavity may have been responsible for the reported conductive hearing loss. The inner ear is mostly associated with cochlear hypoplasia, enlarged vestibular aqueduct, dysplastic vestibule, and cochlear aplasia [15,19]. A comprehensive list of the reported otological manifestations is provided in Table 2.

Table 2.

A comprehensive list of reported otologic manifestations in patients with BOR syndrome

External ear	Middle ear	Inner ear
Ankylotia	Ossicular abnormality	Cochlear hypoplasia /dysplasia
Cup shaped pinna	Underdeveloped tympanic cavity	Mondini deformity
Microtia	Absent oval window	Semicircular canal abnormality
Lop ears	Cholesteatoma	Dilated vestibule
Low set ears	Otitis media with effusion	Enlarged vestibular aqueduct
Protruding ears	Patulous eustachian tube	Common cavity deformity
	Middle ear epidermal cyst	Internal acoustic meatus abnormality
	Tympanic membrane perforation	Enlarged endolymphatic duct/sac
	Absent/poorly mastoid pneumatization	Cochlear nerve hypoplasia
	Absent Köerner septum	Facial nerve abnormality
	Hypoplastic/enlarged/absent antrum
	Tympanic plate defect
	Large emissary vein
	Sclerotic mastoid

BOR, branchio-oto-renal.

Since the advent of computed tomography and magnetic resonance imaging, various radiological findings have been attributed to BOR syndrome, especially those involving the inner and middle ears. The heterogeneity of the radiological findings without a characteristic anatomical abnormality pushed inner and middle ear lesions to minor diagnostic criteria proposed by Chang et al. [14]. Since then, multiple studies have been conducted to identify the characteristic radiological findings of BOR syndrome. Hypoplasia and dysplasia of the cochlea were the most consistent findings, followed by enlarged vestibular aqueduct, vestibular sac, ossicular anomalies, and a small middle ear cavity [20]. Propst et al. [21] in their study identified hypoplastic apical turn of the cochlea, deviated facial nerve to medial aspect of cochlea, funnel-shaped internal auditory canal, and patulous eustachian tube as the easily recognizable features of BOR syndrome [21].

Robson [22] and Hsu et al. [23] then identified an imaging marker where the basal turn is tapered with hypoplastic middle and apical turns displaced antero-medially named the “unwound” or “offset” cochlea. However, this finding was later found to be consistent with BOR syndrome with EYA1 pathogenic variant only. In BOR syndrome with SIX1 pathogenic variant, a distinctive protuberance of the apical part of cochlea called the “thorny” apical turn has been described [24,25].

Kidney anomalies

Kidney anomalies in patients with BOR syndrome are poorly understood. In a review of published articles on BOR syndrome, only 10% of the articles were published in nephrology journals, and the rest were in genetic and otolaryngology-related journals [26]. The majority of the phenotypic descriptions of kidney anomalies in BOR syndrome have been performed morphologically to describe overt conditions such as kidney agenesis and kidney hypoplasia [12]. In the absence of gross kidney deformities with the presence of ear and branchial symptoms, authors of yesteryear have erroneously labelled this condition BOR, branchio-oto, or branchio-oto-ureteral syndrome [27,28]. In 1978, Melnick et al. [27] described two families that were described as having branchio-oto; however, a detailed reanalysis by Fraser showed some degree of kidney involvement that was previously reported as normal [2,27]. Moreover, a genetic study on BOR and branchio-oto syndrome showed that they are alleles of the same EYA1 gene [29].

This could be due to the nature of the kidney tissue, which might have extremely high gene expression, leading to a wide variety of clinical presentations [30]. Kidney abnormalities range from mild symptoms to severe illness, with some patients progressing to chronic kidney disease due to persistent kidney dysfunction and, ultimately, end-stage kidney disease (ESKD). The natural history and timeline of progression to chronic kidney disease in patients with BOR syndrome remain unclear. Structural kidney abnormalities occur in approximately 66% of patients, with kidney hypoplasia, dysplasia, and agenesis among the most frequently reported findings [8]. Other abnormalities include caliectasis, hydronephrosis, pelviectasis, a prominent collecting system, and vesicoureteral reflux [12]. Tubular and glomerular regions are also affected in BOR syndrome, including sclerosis, mesangial proliferation, and tubular injury. However, studies on these conditions are limited, despite evidence that kidney insufficiency and proteinuria in BOR syndrome lead to ESKD and kidney failure. It is possible that kidney involvement in BOR syndrome is underestimated, as it can be insidious and takes many years to diagnose [31].

Kidney involvement in BOR syndrome may present early in life, with cases of premature kidney failure reported in both childhood and young adulthood. Approximately 40% of individuals with BOR syndrome experience clinically significant decline in kidney function, often occurring over time [26]. The onset of kidney disease is highly variable, ranging from infancy to adulthood. Kidney impairment is most commonly identified in childhood or adolescence, with many patients who progress to severe disease reaching ESKD during the mid-teen years (approximately 14–17 years) [26,32]. Infants with congenital kidney agenesis or severe kidney dysplasia may present with kidney failure early in life, whereas individuals with milder phenotypes may maintain preserved kidney function into adulthood, with gradual deterioration.

Overall, approximately 6%–10% of patients with BOR syndrome progress to ESKD, requiring dialysis or kidney transplantation [26]. The risk of progression is markedly increased in patients with bilateral kidney hypoplasia, severe dysplasia, or other major structural abnormalities. Notably, there is substantial phenotypic variability even among affected members of the same family carrying identical pathogenic variants, with wide differences in both the severity and timing of remission [7,12]. Wang et al. [33] showed an increased association between ear anomalies and kidney pathology and advocated kidney ultrasonography in children who presented with ear findings. Furthermore, when BOR syndrome is suspected based on hearing loss or otologic abnormalities, early and comprehensive evaluation for kidney involvement is essential [8]. This assessment should include serum kidney function tests, urinalysis, and kidney ultrasonography to identify potential structural or functional abnormalities [32].

Branchial and other anomalies

Commonly observed branchial anomalies include branchial cleft sinuses that open at the anterior margin of the sternocleidomastoid muscle and branchial cleft cysts [3]. Other reported anomalies in BOR syndrome are vast and include conditions such as retrognathia, cleft palate, bifid uvula, and lacrimal duct aplasia [9,12].

Genetic insights into BOR syndrome

BOR syndrome is a genetically complex condition that primarily affects the branchial arches, ears, and kidneys. The disorder is primarily associated with pathogenic variants in EYA1, SIX1, or SIX5 genes, and, to a lesser extent, SALL1 gene. This gene encodes transcription factors or interactors essential for embryonic development, particularly in the craniofacial and auditory systems (Table 3) [8,19,34-37].

Table 3.

The genes responsible for BOR syndrome

Gene	Prevalence	Phenotypic correlation
EYA1	40%–75% [34]	1. Half of patients have moderate to severe mixed hearing loss [19]
Chromosome 8q13.3		2. Structural otologic anomalies are more common and severe [19]
		3. Higher incidence of branchial anomalies, preauricular pits, ear anomalies [35]
SIX1	2% [8]	1. >60% patients have profound sensorineural hearing loss [19]
Chromosome 14q23.1		2. Majority of patients do not exhibit renal abnormalities [36]
		3. Higher incidence of atypical BOR [35]
SIX5	0%–3.1% [35]	1. Hearing may be normal [37]
Chromosome 19q13.32
Unknown	>50% [8]

BOR, branchio-oto-renal.

EYA1 is the most frequently mutated gene in BOR syndrome, accounting for approximately 40% of the cases, including inherited and sporadic forms. Located on chromosome 8q13.3, EYA1 spans 18 exons and encodes a 592-amino acid protein [11,38]. This protein contains a highly conserved EYA homologous region (EYA domain) at the C-terminus and a proline/serine/threonine-rich transactivation domain at the N-terminus [29,38]. Functionally, EYA1 acts as a phosphatase-transactivator, forming a complex with SIX proteins to regulate gene expression that is critical for the development of cranial sensory and branchial arch-derived organs [29]. More than 237 pathogenic variants have been identified in EYA1, including frameshift, nonsense, missense, splice site pathogenic variants, and large deletions, with the majority disrupting the EYA domain and impairing protein-protein interactions [14,39,40]. Hearing loss is present in 92%–94% of patients with EYA1 pathogenic variants, predominantly as mixed-type hearing loss. Severity ranges from moderate to severe, and progression is uncommon [8]. Studies in knockout mice have suggested that EYA1 haploinsufficiency underpins the variability in clinical phenotypes [9,41]. Recent advances in sequencing technologies have identified recurrent large deletions in chromosome 8q13.3 encompassing EYA1, mediated by retroviral sequence blocks, which are associated with more severe phenotypes [42].

SIX1 is the second most commonly implicated gene in BOR syndrome and accounts for approximately 2% of all cases. SIX1 is located on chromosome 14q23.1 and encodes a transcription factor with a conserved SIX domain and a homeodomain required for DNA binding and protein interactions [42]. The SIX1-EYA1 complex plays a pivotal role in regulating cell proliferation and differentiation during embryogenesis, particularly in the inner ear and branchial arches [36,43]. To date, more than 13 pathogenic variants in SIX1 have been identified, primarily in the SIX domain and homeodomain. These pathogenic variants disrupt the formation of the SIX1-EYA1 complex or impair DNA binding, leading to clinical manifestations [36]. Approximately 82.5% of patients with SIX1 pathogenic variants experience hearing loss, predominantly sensorineural hearing loss (90%), with profound hearing loss reported in 60% of the cases. The progression of hearing loss is observed in some patients with significant intrafamilial variability [19].

SIX5 pathogenic variants are less frequently associated with BOR syndrome. Located on chromosome 19q13.32, SIX5 encodes a transcription factor homologous to SIX1 that contains an additional activation domain at its C-terminal [37]. SIX5 interacts with EYA1 to regulate transcription; however, its contribution to BOR syndrome is debatable. Functional studies in mice have shown only ocular phenotypes, suggesting a minor role in BOR syndrome [44]. However, few studies have reported SIX5 pathogenic variants in patients with otological and kidney abnormalities [45,46].

Pathogenic variants in SALL1, which are primarily associated with Townes-Brocks syndrome, have been identified in rare cases of BOR syndrome-like phenotypes. Townes-Brocks syndrome, also known as REAR (Renal-Ear-Anal-Radial) syndrome, is a very rare genetic disorder characterized by a tetrad of anorectal malformations (e.g., imperforate anus), dysplastic ears (often with hearing loss), thumb abnormalities (e.g., triphalangeal thumbs), and kidney abnormalities (structural or functional) [47,48]. It is inherited in an autosomal dominant pattern, typically caused by pathogenic variants in the SALL1 gene, though the severity varies significantly among affected individuals. SALL1, located on chromosome 16q12.1, encodes zinc-finger transcription factors that are essential for DNA binding and organogenesis [49]. Reportedly, truncated SALL1 proteins disrupt cilia formation and function, which may explain the associated hearing loss and other features [50]. Only two patients with BOR syndrome with SALL1 pathogenic variants have been reported, both presenting with bilateral sensorineural hearing loss and external ear anomalies [48].

Another branchial arch syndrome that should be considered in the differential diagnosis is branchio-oculo-facial syndrome (BOFS). BOFS is an important branchial-arch disorder in the differential diagnosis of BOR spectrum disorders, but it is regarded as a distinct clinical entity from the branchio-otic/BOR spectrum in clinical nosology and comparative phenotyping studies [51,52]. In contrast to BOR spectrum disorders classically associated with loci on chromosome 16q12 (e.g., the EYA1 region), BOFS is primarily caused by heterozygous pathogenic variants in TFAP2A gene [53,54]. TFAP2A maps to chromosome 6p24.3, consistent with curated and primary molecular data supporting TFAP2A-related BOFS rather than a 16q12 locus [53,54].

Diagnosis of BOR syndrome

A patient can be suspected of having BOR syndrome based on the major and minor criteria proposed by Chang et al. (Table 4) [14]. In the absence of affected family members, two or more major criteria or two major and two minor criteria were present. However, if affected family members are present, a major criterion is sufficient for making a diagnosis. However, further genetic testing is required to confirm diagnosis of BOR syndrome. Gene-targeted testing analyzes specific genes attributed to BOR syndrome and its differentials. This test can be used when typical phenotypes of BOR syndrome are present. There is another exhaustive test called “Comprehensive genomic testing” which identifies and analyzes almost the entire sequences of exons and genomes. This is used when there are no attributable or atypical presentations of BOR syndrome [8,34,35].

Table 4.

The criteria for diagnosing BOR syndrome

Major	Minor
Branchial anomalies	External ear anomalies
Deafness	Middle ear anomalies
Preauricular pits	Inner ear anomalies
Renal anomalies	Preauricular tags
	Other: facial asymmetry, palate abnormalities

BOR, branchio-oto-renal.

Management of BOR syndrome

Owing to the variable nature of the phenotypic manifestations of BOR syndrome, a predetermined treatment strategy cannot be implemented. The management of BOR syndrome needs to be tailored to specific conditions or affected subsites.

Kidney anomalies

Kidney manifestations need to be addressed at the earliest as they are the gravest and determine the prognosis of patients with BOR syndrome. These patients should be referred to a nephrologist or pediatrician at the earliest for a thorough evaluation of kidney function. Patients with hydronephrosis due to ureteropelvic junction obstruction or vesicoureteral reflux require surgical pyeloplasty and reflux correction.

Bilateral agenesis is extremely fatal, and treatment options remain experimental [55]. Patients with unilateral kidney agenesis, dysplasia and parenchymal kidney anomalies are routinely followed up, and preventive measures to control proteinuria, hypertension and infection are implemented [56]. This is vital as the kidney function worsens at a slow pace and most end-stage kidney failures occur in adulthood [57]. Finally, kidney replacement therapy or transplantation should be considered in patients with end-stage kidney failure (Fig. 1).

Fig. 1.

Proposed renal and urinary tract surveillance algorithm in BOR spectrum disorder. BOR, branchio-oto-renal; BP, blood pressure; eGFR, estimated glomerular filtration rate; UPJ, ureteropelvic junction; VUR, vesicoureteral reflux.

As kidney function may deteriorate insidiously over time and hearing loss can be progressive, individuals with BOR syndrome require lifelong, systematic follow-up [8]. Kidney and urinary tract surveillance is of particular importance, as decline in kidney function is often asymptomatic. Routine screening is recommended at least annually, with increased frequency every 3–6 months in patients demonstrating evidence of kidney impairment [58,59]. Follow-up evaluations should include blood tests to assess estimated glomerular filtration rate via serum creatinine, urine analysis for proteinuria or microalbuminuria, and regular blood pressure measurements, given the role of hypertension in accelerating kidney damage. Periodic kidney ultrasonography is also indicated to monitor structural abnormalities and to assess for progression of hydronephrosis (Fig. 1) [58,59].

Otological anomalies

The use of hearing aids is recommended for pre-lingual patients with hearing impairments before definitive treatment can be done [9]. Treatment may include a hearing aid, surgery, or a combination of both. Pinna deformities and preauricular pits can be surgically amended. Canalplasty can be performed for conductive or mixed hearing loss due to a stenotic or atretic external ear canal if the concomitant middle ear structures are functional [8,15,41]. If the middle ear is abnormal and has a poor Jahrsdoerfer score, a bone-anchored hearing aid should be considered [41]. In the presence of middle ear pathology, surgeries such as mastoidectomy, ossiculoplasty, tympanoplasty or grommet insertion can be appropriately done [15]. However, many authors have found that audiological outcomes after middle ear surgery are poor and postulate that this is likely due to the presence of an enlarged vestibular aqueduct, which acts as a third window loss [60].

In the presence of sensorineural hearing loss, cochlear implantation can be considered after evaluating the temporal bone and the status of the cochlear nerve using high-resolution imaging [15,61]. Regular pure-tone audiometry should be performed to assess the degree and progression of hearing loss [8]. Because middle ear conditions such as otitis media may affect the hearing disproportionately in individuals with BOR syndrome compared with the general population, prompt diagnosis and treatment are essential. Affected children may be screened audiologically every 6 months to a year, and adults every 1–2 years. When indicated, the suitability and effectiveness of hearing rehabilitation strategies, including hearing aids or cochlear implantation, should be considered [8,15].

Branchial anomalies

Branchial anomalies such as branchial cleft cyst or sinus can be managed with supportive treatment and antibiotics can be administered in cases of infection. If cysts and sinuses present with recurrent infection or if patients worry about cosmesis, they can be surgically excised [8,9].

Nasolacrimal duct abnormalities

Nasolacrimal duct abnormalities, including lacrimal duct aplasia or hypoplasia, have been described in BOR spectrum disorder and may present clinically with epiphora due to absent or hypoplastic tear drainage pathways [8]. Accordingly, at routine follow-up visits, patients should be screened for recurrent eye discharge, epiphora, or periocular inflammation suggestive of impaired tear drainage, and those with persistent or recurrent symptoms, particularly when associated with infection, should be referred for ophthalmologic assessment and management [8,62].

Genetic counseling

The unpredictable occurrence and severity of the phenotypic manifestations of BOR syndrome warrant genetic counseling. This empowers families afflicted with BOR syndrome with the knowledge about their condition and expectations. More than 90% of the individuals with BOR syndrome have at least one parent with the disease. However, less than 10% of the cases occur as de novo pathogenic variants [8,12]. The risk of a child inheriting the condition from a parent afflicted with BOR syndrome is 50% [8,9]. In case of de novo pathogenic variants, there is a low theoretical risk of subsequent siblings developing BOR syndrome because of germline mosaicism [8,9]. Parents with BOR syndrome who are planning to have children must be counselled about the possible risks to their offspring. For affected pregnant parents, prenatal ultrasound, which can be performed as early as 11 weeks of gestation is recommended to detect any possible kidney anomalies that may be addressed early [8,56].

Conclusions

BOR syndrome exhibits variable otological, branchial, and kidney manifestations due to pathogenic variants in EYA1, SIX1, or SIX5, underscoring the need for early multidisciplinary assessment. Tailored management including kidney surveillance, otological interventions, and genetic counseling is critical for optimizing patient outcomes and family planning. Continued advances in genomic diagnostics and phenotypic characterization will enhance prognosis and guide personalized care.

Funding Statement

This work was supported by the Yonsei Fellowship, funded by Youn Jae Lee (JIS).

Data availability statement

Data sharing is not applicable as no new data were created or analyzed in this study.