A 22-year-old man who recently started dialysis therapy presents for a kidney transplant evaluation. A renal ultrasound at the time dialysis therapy was initiated was consistent with moderate bilateral renal hypoplasia, with both kidneys 7.5 cm in length. He also has severe bilateral hearing loss requiring hearing aids in both ears and underwent surgeries for branchial cyst repair and canaloplasty. Physical examination findings were significant for hypertension, bilateral preauricular pits (Fig 1), and surgical scars in the neck. Although his brother, 3 years older, also had bilateral deafness and preauricular pits, his renal function was normal. His father had bilateral preauricular pits, but neither renal failure nor hearing impairment. The patient’s mother, who has none of these features, wishes to be considered as a donor.
Figure 1. Bilateral preauricaular pits and hearing aids. (A) Right ear; (B) Close-up of left ear.
■What is the diagnosis based on the history and physical examination?
■Is gene analysis required for making the diagnosis?
■If the patient receives a successful renal transplant from the mother, what is the prognosis for the graft?
Discussion
What is the diagnosis based on the history and physical examination?
Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder with an estimated prevalence of 1:40,000. It affects 2% of profoundly deaf children.1 It appears to be a clinically and genetically heterogeneous multiorgan condition manifested predominantly during organogenesis. It is characterized by malformations of the outer, middle, and inner ear, along with conductive, sensorineural, or mixed hearing impairment; branchial fistulae and cysts; preauricular pits; and renal malformations.1, 2, 3, 4 Renal and urological anomalies in patients with BOR syndrome include renal agenesis, hypoplasia, and dysplasia, ureteropelvic junction obstruction, calyceal cysts and diverticula, calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux.1, 2, 3, 4 Renal histological characteristics reported in patients with BOR syndrome include glomerular hyalinization, mesangial proliferation, basement membrane splitting, dilated tubules with microcalcification, teratoid tissue in the kidney, dense deposits in the mesangium and inner basement membrane on electron microscopy, and immunoglobulin G (IgG), IgM, C3, and IgA in the mesangium on immunofluorescence.2 Approximately 6% of affected individuals progress to end-stage renal disease early in life.2 Because of the similarity of clinical features, this syndrome can be misdiagnosed as Alport syndrome.2
Is gene analysis necessary for making the diagnosis?
The diagnosis of BOR syndrome can be made by clinical criteria alone (Table 1). About 40% of patients show EYA1 gene (8q13.3) sequence variations. A minor percentage (<1.0%) of patients have SIX1 gene (14q23) sequence variations. Penetrance is high, but expressivity is incomplete and variable.1
Table 1.
Major and Minor Criteria for Diagnosis of BOR Syndrome
Major criteria
Deafness (98.5%)
Preauricular pits (84%)
Branchial anomalies (ie, cysts and clefts) (68.5%)
Renal abnormalities (38%)
Minor criteria
External ear anomalies
Middle ear anomalies
Inner ear anomalies
Preauricular tags
Other: facial asymmetry, palate abnormalities
Note: Three major or 2 major and 2 minor criteria required to diagnose BOR syndrome or 1 major criteria and an affected first-degree relative meeting criteria for BOR syndrome.
If the patient receives a successful renal transplant from the mother, what is the prognosis for the graft?
Patients with end-stage renal disease are excellent candidates for renal transplantation. Pierides et al3 reported on a 20-member BOR family. End-stage renal disease developed in 4 members at ages 36, 14, 17, and 17 years. All received renal transplants from living related unaffected donors with successful outcomes.3 Detailed renal and urological investigations are recommended before considering older genetically affected family members as donors. In this case, only routine workup is required because the mother is not expected to have BOR syndrome.
Final Diagnosis
BOR syndrome or Melnick-Fraser syndrome.
References
1. 1Kochhar A, Fischer SM, Kimberling WJ, Smith RJ. Branchio-oto-renal syndrome. Am J Med Genet A. 2007;143:1671–1678. MEDLINE
3. 3Pierides AM, Athanasiou Y, Demetriou K, Koptides M, Deltas CC. A family with the branchio-oto-renal syndrome: Clinical and genetic correlations. Nephrol Dial Transplant. 2002;17:1014–1018. MEDLINE |
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4. 4Chang EH, Menezes M, Meyer NC, et al.Branchio-oto-renal syndrome: The mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat. 2004;23:582–589.
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Case provided and authored byTausif Zar, MD, Fabio Aglieco, MD, and Kasturi V. Ranga, MD,1,21Department of Medicine, Division of Nephrology, University of Connecticut School of Medicine, Farmington; and 2Department of Medicine, Division of Transplant Medicine, Hartford Hospital, Hartford, CT.
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