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Branchio-oto-renal Syndrome (Melnick-Fraser Syndrome)

last modified on: Thu, 09/21/2023 - 11:36

See also: Second Arch Branchial Cleft Fistula Case Example

Branchio-oto-renal (BOR) syndrome, also known as Melnick-Fraser syndrome, is characterized by an association of: 1) branchial fistulae or cysts; 2) ear malformations, which can include the inner, middle and outer ear; and 3) renal malformations, which can range in severity from renal hypoplasia to agenesis.

Inherited in an autosomal dominant fashion, each child of a parent with BOR syndrome has a 50% chance of presenting with the disease. It is thought that 90% of BOR syndrome cases are due to inheritance, while the remaining 10% of cases are due to acquired mutations. BOR displays variable expressivity, accounting for the differences in severity of symptoms among family members. Penetrance, however, is 100% (Smith 2018). Anticipation (proclivity for successive generations to present with the disease at an earlier age) does not occur.

History

  • In 1864, Heusinger was the first to recognize an association between branchial cleft fistulae, preauricular pits, and hearing impairment.
  • In 1975, Melnick et al. and Fraser et al. described BOR syndrome as a specific entity with an autosomal dominant inheritance pattern (Fraser et al. 1980).

Epidemiology

  • BOR syndrome affects about 1 in 40,000 people (Li et al. 2020).

Diagnosis

  • A family history positive for branchial, otologic, and renal malformations is suggestive of BOR syndrome.
  • If no family history of disease is known, clinical criteria can be utilized to make the diagnosis for patients with at least three major criteria. Alternatively, the diagnosis can be made for patients demonstrating two major criteria and two minor criteria (Li et al. 2020).

Major Criteria

1. Pinnae malformation

2. Hearing loss

3. Preauricular pits

4. Renal anomalies

5. Second branchial arch anomalies

6. External auditory canal stenosis

Minor Criteria

1. Preauricular tags

2. Lacrimal duct aplasia

3. Middle ear anomalies

4. Inner ear anomalies

5. Palate malformations or facial asymmetry

6. Euthyroid goiter

Phenotypic Findings

Otologic

Otologic manifestations of BOR are the most common presenting symptoms, with over 90% of people experiencing at least one of the following (Smith 2018):

  1. Deafness may present as a conductive, sensorineural, or mixed classification. The magnitude of deafness is variable, ranging from mild hearing loss to profound. Furthermore, the magnitude of hearing loss can be stable or progressive. Hearing loss is well-established as the most common single trait among those with BOR syndrome, estimated to be 89% of individuals in a study by Fraser et al. (1980). Among those with hearing loss, 50% presented with mixed, 30% with conductive, and 20% with sensorineural presentations. It was also estimated that 2% of children with profound deafness have BOR (Fraser et al. 1980).
  2. Lop-ear deformity
  3. Preauricular pits
  4. Preauricular tags
  5. External auditory canal: stenosis
  6. Middle ear: ossicular malformations, such as hypoplasia or displacement
  7. Inner ear: hypoplastic cochlea, dysplastic lateral semicircular canals, enlargement of the vestibular or cochlear aqueducts

Branchial Arch Anomalies

  1. Brancial cleft cyst.
  2. Brancial cleft sinus tract.
  3. Branchial cleft fistulae.

Renal malformations

  1. A spectrum of renal malformations is possible, from hypoplasia to agenesis.
  2. Calyceal cysts.
  3. Uretero-pelvic junction obstruction.
  4. Vesicoureteral reflux

Other associated findings

  1. Mitral valve prolapse
  2. Cleft palate
  3. Lacrimal duct aplasia
  4. Facial nerve paralysis
  5. Retrognathia

Gene Studies

  • Currently, there are three known gene mutations which result in BOR syndrome. If a clinical diagnosis of BOR syndrome is made, confirmation should be attempted via sequence analysis for EYA1. If an EYA1 mutation is not found with sequence analysis, one should utilize duplication/deletion analysis for EYA1 and sequence analysis for SIX1 and SIX5.

EYA1 mutation

  • About 40% of people with BOR syndrome will have an EYA1 mutation (Chen et al. 2022).
  • EYA1 encodes for a transcription cofactor that is expressed in the metanephric mesenchyme during development of the kidneys.

SIX1 mutation

  • The SIX1 mutation is estimated to be found in 2% of BOR syndrome cases (Masuda et al. 2022).
  • It encodes transcription factors that control expression of GDNF and PAX2.
  • The majority of patients with this mutation do not demonstrate renal malformation.

SIX5 mutation

  • The SIX5 mutation is present in around 0-3.1% of BOR syndrome cases (Masuda et al. 2022).
  • Hearing may be normal in these patients.

Management

Otologic Evaluation

  • Testing should include ABR, pure tone audiometry, and emission testing.
  • Imaging of the temporal bones with a CT scan is warranted.
  • An annual auditory evaluation should be suggested.

 Branchial Arch Evaluation

  • Physical examination followed by computed tomography (CT), fistulogram, or magnetic resonance imaging (MRI) if masses are palpated or tracts are observed.

Renal Evaluation

  • Renal ultrasound
  • BUN and creatinine
  • Patients should follow-up with nephrology and urology annually.

Genetic counseling

  • It is important that patients affected with BOR realize that there is a 50% chance of transmission to each child due to autosomal dominant inheritance (Smith 2018).
  • Prenatal testing for BOR is available for those with a positive family history.

Treatment

Otologic anomalies

  • Detect hearing impairment, use appropriate auditory treatment as indicated by severity of loss, such as hearing aid or cochlear implant.
  • If the middle ear is intact with a stenotic external canal, consider a canaloplasty.
  • Consider cosmetic procedures for pinna deformities.

Branchial anomalies

  • Excision of cyst, fistula, or sinus, with full-length dissection of the tract and tonsillectomy.

Renal anomalies

  • Treatment depends on the severity of renal complications, but both surgical and medical management should be utilized.
  • Renal transplantation may be considered if end-stage renal disease develops.

References

Amer I, Falzon A, Choudhury N, Ghufoor K. Branchiootic syndrome-a clinic case report and review of the literature. J Pediatr Surg. 2012;47:1604-1606.

Chen A, Francis M, Ni L, Cremers C, Kimberling W, Sato Y, Phelps P, Bellman S, Wagner M, Pembrey M, Smith RJ. Phenotypic manifestations of branchiootorenal syndrome. Am J Med Genet. 1995;58:365-370.

Chang EH, Menezes M, Meyer NC, Cucci RA, Vervoot VS, Schwartz CE, Smith RJ. Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat. 2004;23:582-9.

Fraser FC, Sproule JR, Halal F. Frequency of the brancio-oto-renal (BOR) syndrome in children with profound hearing loss. Am J Med Genet. 1980;7:341-349.

Kochhar A, Fischer SM, Kimberling WJ, et al. Branchio-oto-renal syndrome. Am J Med Genet. 2007;15(143A(14)):1671-8

Li HX, Zhou P, Tong M, Zheng Y. Branchial cleft fistula to branchio-oto-renal syndrome: A case report and literature review. J Int Med Res. 2020;48(7):300060520926363. doi:10.1177/0300060520926363

Chen A, Ling J, Feng Y. Genetic research progress in branchio-oto syndrome/ branchio-oto-renal syndrome. 鳃耳综合征/鳃耳肾综合征的遗传学研究进展. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2022;47(1):129-138. doi:10.11817/j.issn.1672-7347.2022.210251

Masuda M, Kanno A, Nara K, et al. Phenotype-genotype correlation in patients with typical and atypical branchio-oto-renal syndrome. Sci Rep. 2022;12(1):969. Published 2022 Jan 19. doi:10.1038/s41598-022-04885-w

Smith RJH. Branchiootorenal Spectrum Disorder. 1999 Mar 19 [Updated 2018 Sep 6]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1380/