Clinical Guidance

Clinically actionable genotype-phenotype correlations for EYA1 and SIX1 are limited, as both genes exhibit high interfamilial variability and intrafamilial variability, sometimes even for the same pathogenic variant . However, the following correlations with the involved gene have been observed:

• EYA1 pathogenic variants are associated with the specific "unwound cochlea" cochlear malformation or offset cochlear turns (measurable by turn angle ratio [TAR] on CT or MRI; TAR 0.476), which are seen in 100% of individuals with an EYA1 pathogenic variant and is considered diagnostic for EYA1-related BORSD .

• SIX1 pathogenic variants are always associated with hearing loss, which can be sensorineural or mixed .

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"

Penetrance

Based on clinical studies of large pedigrees, BORSD appears to have 100% penetrance; however, intrafamilial variability and interfamilial variability are high .

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"

Diagnostic Criteria

The clinical diagnostic criteria for branchiootorenal spectrum disorder (BORSD) outlined by remain clinically useful and supported by subsequent studies .

Suggestive Findings

Branchiootorenal spectrum disorder (BORSD) should be suspected in probands with the following major and minor diagnostic criteria and family history.

Major diagnostic criteria

• Second branchial arch anomalies

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"

Differential Diagnosis

At the time of this writing, Online Mendelian Inheritance in Man (OMIM) lists more than 700 entries for syndromic forms of hearing loss. Although branchiootorenal spectrum disorder (BORSD) has a distinctive phenotype that is readily appreciated when segregating in large families, the diagnosis can be difficult to establish in small families. Possible considerations in a differential diagnosis are shown in .

Table 2.

Genes of Interest in the Differential Diagnosis of Branchiootorenal Spectrum Disorder

Gene(s) | Disorder | MOI | Features of Disorder

Overlapping w/BORSD | Distinguishing from BORSD

CHD7 | CHD7 disorder (incl CHARGE syndrome) | AD | Hearing loss, external/middle/inner ear anomalies, kidney anomalies | Coloboma, choanal atresia, genital hypoplasia, developmental delay

COL4A3

COL4A4

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"

Management Guidelines

No consensus clinical practice guidelines for branchiootorenal spectrum disorder (BORSD) have been published. The following recommendations are based on the authors' personal experience managing individuals with BORSD.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with BORSD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Branchiootorenal Spectrum Disorder: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

External auditory canal

| Otoscopic exam to assess external auditory canal tympanic membrane | For anomalies such as atresia or stenosis

Second branchial arch

| Physical exam of neck for sinus tracts, cysts, /or fistulae | • Consider imaging study (CT or MRI) of neck if a mass is palpable under sternocleidomastoid muscle.

• It may be helpful to obtain a fistulogram by using a contrast agent to visualize the path of the tract connecting the skin on the neck to the tonsillar fossa.

Hearing loss

| Complete assessment of auditory acuity using ABR testing, OAE testing, pure-tone audiometry1 | If hearing impairment fluctuates or is progressive, perform temporal bone imaging using CT /or MRI of temporal bones to determine if vestibular aqueduct is enlarged.2

Kidneys

| • Kidney ultrasound exam to detect agenesis, hypoplasia, dysplasia

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"

Clinical Guidance

Hearing loss. Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important for persons with mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises, particularly secondary to earbud use. The headphone safety feature built into most smartphones can be set to a maximum limit of 75 decibels (dB). Headphone/earbud safety features can be found in the phone settings menu:

• In iPhones, under Settings Sounds Haptics Headphone Safety

• In Android phones, under Settings Sounds Vibrations Volume Media volume limit

Also see these general resources on noise reduction:

• 6 Simple Ways to Check If Your Headphones Are Too Loud

• How Do I Prevent Hearing Loss from Loud Noise?

Anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing has led some providers to recommend avoiding activities such as weightlifting and contact sports ; however, evidence is insufficient to support the claim that avoiding these activities will decrease the risk of overall hearing loss progression .

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in are recommended.

Table 5.

Branchiootorenal Spectrum Disorder: Recommended Surveillance

System/Concern | Evaluation | Frequency

Hearing loss

| Serial audiometry to survey for progression of hearing loss based on symptoms reported by affected person | At each visit

Exam by physician familiar w/BORSD | • Annually

• More frequently if fluctuation or progression of hearing loss is described by affected person

CAKUT

| Eval of kidney function | Annually1

BORSD = branchiootorenal spectrum disorder

1. For individuals with CAKUT, it is recommended that kidney function be evaluated at least annually, especially if the CAKUT involves unilateral kidney dysplasia. Follow up as recommended by a pediatric nephologist is essential for detecting potential complications and for monitoring the long-term effects of kidney abnormalities.

Source: GeneReviews — "Branchiootorenal Spectrum Disorder"