Branchiootorenal Syndrome
Pei-Shan Lee, MD, MBA,
A boy was born at term to a 28-year-old primiparous mother via cesarean delivery secondary to failed induction for oligohydramnios. The mother had had good prenatal care and an unremarkable pregnancy, except for borderline fetal pelviectasis on ultrasonography that had resolved.
On initial examination, the neonate was noted to have bilateral preauricular pits and concern for branchial cleft remnants—a 1-cm cyst with fistula on the left side, and a 0.5-cm skin tag with fistula on the right side (Figure). Both sinuses expressed clear secretions. During the birth hospitalization, the neonate had failed the screening brainstem auditory evoked response test of the left ear.
Discussions with the family revealed variable combinations of branchial cleft anomalies, ear pits, and differing degrees of hearing loss in the neonate’s father, paternal grandmother, paternal great-uncle, and paternal great-great-grandfather. Given the visible malformations seen on the patient and the strong family history, branchiootorenal (BOR) syndrome or branchiootic syndrome (BOS) was suspected.
The patient was discharged on the third day of life with referrals to an audiologist for further hearing examination and an otorhinolaryngologist for branchial cleft anomalies. Renal ultrasonography was not repeated, given that the renal dilation had resolved on the latest prenatal ultrasonogram.
The patient was seen by an audiologist at 1 month of age, at which time he was found to have severe sensorineural hearing loss of the left ear and was eventually fitted with a hearing aid. His primary care provider obtained serial renal ultrasonograms that showed bilateral hydronephrosis 4 days after birth, mild left hydronephrosis at 2 months of age, and resolved hydronephrosis at 3 months of age. The patient was evaluated by an otorhinolaryngologist and was found to have no abnormalities of the tympanic membrane or middle ear.
A genetics specialist found the patient to have features consistent with BOR syndrome: mild facial asymmetry, ear pits, branchial arch remnants, left-sided sensorineural hearing loss, and renal pelviectasis.
NEXT: Discussion
Discussion. Branchiootorenal spectrum disorders include BOR syndrome (also known as Melnick-Fraser syndrome) and BOS (which has the same characteristics as BOR but no renal involvement). BOR/BOS is characterized by hearing impairment (sensorineural, conductive, or mixed), preauricular pits, malformations of the ear (outer, middle, and/or inner), unilateral or bilateral branchial anomalies (cysts, sinuses, or fistulas), and asymptomatic to severe renal anomalies where approximately 6% of patients progress to end-stage renal disease (ESRD).1-5 The hearing impairment may be congenital and nonprogressive or may develop over time. Less common abnormalities include preauricular tags; lacrimal duct obstruction; facial nerve paralysis; facial anomalies such as bifid uvula, cleft palate, a narrow face with high arched palate and a deep overbite, and facial or mandibular asymmetry.2,4
There is extreme variability in the presence and severity of BOR characteristics even among affected individuals in the same family, given incomplete penetrance, which can make diagnosis difficult.1,2,4 Thus, a careful history is important when an infant, child, or adult displays a mixture of these findings. The major morbidities are deafness (as seen in our patient’s paternal great-great-grandfather), cleft palate (as seen in the paternal grandmother), and ESRD (which was not affected this family). The prevalence of BOR syndrome is unknown but is estimated to be between 1 in 40,000 and 1 in 700,000.2,4
A diagnosis of BOR/BOS can be given if 1 of 3 scenarios are met clinically: At least 3 major criteria, at least 2 major and 2 minor criteria, or 1 major criteria in the setting of an affected first-degree family member (Table).3-5
BOR/BOS has an autosomal dominant inheritance pattern but has highly variable expressivity. While most cases are familial, 10% are caused by de novo mutations.4 A mutation in EYA1 on the long arm of chromosome 8 is present in 40% of individuals with BOR/BOS,3,4 and more than 160 disease-causing mutations of this gene have been identified.6 Mutations have also been seen in SIX5 and SIX1.7,8 Approximately 50% of patients do not have a recognizable genetic mutation.2,4 Molecular genetic testing of EYA1, SIX5, and SIX1 is available; however, because testing does not change management, it is not usually warranted. It could, however, be used for prenatal screening and diagnosis in families with BOR/BOS.
Management of BOR/BOS includes evaluation every 6 months for hearing impairment and yearly audiometry to assess the stability of hearing loss, as well as hearing aids and enrolling the patient in appropriate hearing-impaired programs.
Surgery can be considered for management of preauricular pits and fistulas, since they can become infected, and medical or surgical management by a nephrologist/urologist is indicated if renal involvement is present.
It is important to avoid the use of nephrotoxic and ototoxic medications. Patients should be screened for vesicoureteral reflux and treated appropriately to avoid urinary tract infections and renal scarring. Relatives should be screened for hearing loss and renal impairment.
NEXT: Outcome of the Case
Outcome of the case. The patient had been doing well and had met all developmental milestones at the 12-month well-child visit. His case is being followed closely by an audiologist, and annual appointments with a nephrologists and semiannual appointments with an otorhinolaryngologist have been scheduled. The otorhinolaryngologist will evaluate the boy for removal of the preauricular pits and fistulas after the age of 1 year. The patient has adapted to the use of a hearing aid.
References:- Annear NMP, Gale DP, Loughlin S, Dorkins HR, Maxwell PH. End-stage renal failure associated with congenital deafness. NDT Plus. 2008;1(3):171-175.
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