Branchiootorenal Spectrum Disorder

Clinical characteristics: Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g., preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle, and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment. Congenital anomalies of the kidney and urinary tract (CAKUT) include kidney agenesis, hypoplasia, and dysplasia as well as urinary tract anomalies such as ureteropelvic junction (UPJ) obstruction, calyceal cysts and/or diverticula, and/or vesicoureteral reflux (VUR). Glomerular pathology that includes proteinuria and glomerulosclerosis has been reported. Some individuals progress to end-stage kidney disease (ESKD) depending on the severity of the kidney involvement. Diagnosis/testing: The clinical diagnosis of BORSD is established in an individual based on the presence of three or more major criteria OR two major criteria and two minor criteria OR one major criterion and a first-degree relative with BORSD. The molecular diagnosis of BORSD is established in a proband with suggestive findings and a heterozygous pathogenic variant in either EYA1 or SIX1 identified by molecular genetic testing. Management: Treatment of manifestations: Otologic considerations include canaloplasty to correct an atretic canal and/or excision of branchial cleft cysts/fistulae if they are infected, symptomatic, or cosmetically concerning. Audiologic considerations include hearing aids for individuals with mild-to-moderate sensorineural or mixed hearing loss and cochlear implantation (CI) for individuals with bilateral severe-to-profound hearing loss. All individuals with hearing loss should be enrolled in an appropriate educational program for the hearing impaired. CAKUT require (1) nephrologists to assess kidney function, control hypertension, manage proteinuria, and help in delaying progression of kidney disease when possible; and (2) urologists to perform corrective surgery (e.g., pyeloplasty) for UPJ obstruction and manage use of prophylactic antibiotics and/or surgical correction for VUR. Surveillance: Routinely scheduled follow up with the treating otolaryngologist, audiologist, speech-language pathologist, nephrologist, and urologist. Agents/circumstances to avoid: Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Individuals with CAKUT should use appropriate caution when taking medications (i.e., antibiotics and analgesics) that can impair kidney function and/or that require normal kidney physiology for their use. Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic relatives at risk for BORSD to determine if treatable and/or possibly progressive otologic and/or kidney abnormalities are present. Evaluations can include molecular genetic testing if the BORSD-related genetic alteration in the family is known or comprehensive physical examination (to include hearing evaluation and kidney imaging and function studies) if the genetic alteration in the family is not known. Genetic counseling. BORSD is inherited in an autosomal dominant manner. Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of de novo EYA1 or SIX1 pathogenic variant. Each child of an individual with BORSD has a 50% chance of having BORSD. If the BORSD-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Intrafamilial variability makes it impossible to accurately predict which manifestations of BORSD may occur and how mild or severe they will be in a fetus found to have a familial BORSD-related genetic alteration.