Clinical Diagnosis

Branchiootorenal spectrum disorders (BOR/BOS) include branchiootorenal (BOR) syndrome and branchiootic syndrome (BOS).

Branchiootorenal (BOR) syndrome. In the absence of a family history, three or more of the following major criteria OR two major and two minor criteria (see Table 1) must be present to make the clinical diagnosis of branchiootorenal (BOR) syndrome [Chang et al 2004]:

Second branchial arch anomalies

• Branchial cleft sinus tract appearing as a pin-point opening anterior to the sternocleidomastoid muscle, usually in the lower third of the neck

• Branchial cleft cyst appearing as a palpable mass under the sternocleidomastoid muscle, usually above the level of the hyoid bone

Otologic findings

• Deafness: mild to profound in degree; conductive, sensorineural, or mixed in type (see Deafness and Hereditary Hearing Loss Overview)

• Preauricular pits

• Auricular deformity (lop-ear deformity)

• Preauricular tags

• Abnormalities of the external auditory canal: atresia or stenosis

• Middle ear abnormalities: malformation, malposition, dislocation, or fixation of the ossicles; reduction in size or malformation of the middle ear space

• Inner ear abnormalities: cochlear hypoplasia; enlargement of the cochlear and vestibular aqueducts; hypoplasia of the lateral semicircular canal [Ceruti et al 2002, Kemperman et al 2002]

Renal anomaly

• Renal agenesis, hypoplasia, dysplasia

• Uretero-pelvic junction (UPJ) obstruction

• Calyceal cyst/diverticulum

• Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux

Note: (1) Individuals with an affected family member need only one major criterion to make the diagnosis of BOR syndrome [Chang et al 2004].

Branchiootic syndrome (BOS). In the absence of structural renal anomalies, the clinical diagnosis of branchiootic syndrome (BOS) should be considered. BOS is characterized by deafness, cup-ear deformity, preauricular pits, and branchial fistulae, but the absence of renal anomalies.

Molecular Genetic Testing

Genes. Three genes are known to be associated with branchiootorenal spectrum disorders:

• EYA1

  • BOR1. Approximately 40% of individuals with BOR syndrome have mutations in EYA1 [Chang et al 2004].

  • BOS1. Although persons in many families segregating EYA1 mutations have renal abnormalities consistent with the clinical diagnosis of BOR, some affected persons in these families can have normal kidneys. In many individuals, the kidneys may not be evaluated, and when evaluated, although kidney malformations may be detected by urography, renal function is often normal [Orten et al 2008].

• SIX5

  • BOR2. Approximately 5% of individuals with BOR syndrome have mutations in SIX5 [Hoskins et al 2007].

• SIX1

  • BOR3. Two families with BOR have been reported to have mutations in SIX1 [Ruf et al 2004, Kochhar et al 2008].

  • BOS3. Seven different mutations in SIX1 have been identified in BOS kindreds [Ruf et al 2004, Ito et al 2006, Kochhar et al 2008].

Other loci

• BOR. It is likely that mutations in additional genes are causally related to the BOR syndrome phenotype.

• BOS. The BOS2 locus has been withdrawn. BOS2 was originally assigned to chromosome 1q31 based on linkage data on a large extended family in which affected individuals have branchial anomalies and hearing loss associated with commissural lip pits [Kumar et al 2000]. Subsequent studies have not confirmed this localization and re-examination of affected individuals has identified some persons with renal abnormalities [Kimberling, personal communication].

Clinical testing

• EYA1

  • Sequence analysis/mutation scanning. Note: These methods do not detect large insertions or deletions.

  • Deletion/duplication testing. Testing that detects deletions/duplications not readily identified by sequence analysis of genomic DNA. A variety of methods including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), or array CGH may be used.
    
    Mutations or deletions of EYA1 are the major cause of BOR/BOS. In approximately 10% of individuals with BOR/BOS, a chromosomal rearrangement of the EYA1 region will be present [Chang et al 2004].

• SIX5

  • Sequence analysis. Heterozygous mutations were identified in 5/95 (5.2%) unrelated individuals with BOR syndrome in whom an EYA1 or SIX1 mutation was not identified [Hoskins et al 2007]. This prevalence implies that SIX5 mutations are present in fewer than 2.5% of persons with BOR syndrome.

• SIX1

  • Sequence analysis. Heterozygous mutations were identified in 10/247 (4.0%) unrelated individuals with BOR syndrome in whom an EYA1 or SIX5 mutation was not identified [Kochhar et al 2008]. This prevalence implies that SIX1 mutations account for approximately 2% of cases of BOR syndrome.

Table 2. Summary of Molecular Genetic Testing Used in Branchiootorenal Spectrum Disorders (BOR/BOS)

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% of All BOR/BOS	Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Gene and Test Method	Test Availability
40%	EYA1	Mutation scanning	Small insertions, small deletions, missense and nonsense mutations	~100%	Clinical
		Duplication/deletion analysis 1	Partial- or whole-gene rearrangements	~100%
2.5%	SIX5	Sequence analysis	Sequence variants	~100%	Clinical
2%	SIX1	Sequence analysis	Sequence variants	~100%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

Interpretation of test results

• Failure to detect a mutation in EYA1, SIX5, or SIX1 may reflect the limited extent of the molecular genetic testing method used (for example, deletions of EYA1 are an important consideration) and does not exclude the diagnosis of BOR/BOS.

• For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/establishing the diagnosis in a proband

• Sequence analysis or mutation scanning of EYA1 should be completed in all probands with the clinical diagnosis of BOR/BOS.

• If a mutation in EYA1 is not found using either of these two methods, the following should be considered:

  • A chromosomal rearrangement that deleted a portion or all of one EYA1 allele that can be detected using a variety of tests, including quantitative PCR, real-time PCR, multiplex ligation dependent probe amplification (MLPA), array CGH or haplotype reconstruction.

  • Mutation of either SIX1 or SIX5

• The clinical phenotype may also help guide genetic testing. For example, the majority of persons reported with SIX1 mutations do not have renal malformations [Ito et al 2006, Kochhar et al 2008], while in persons with SIX5 mutations, hearing can be normal [Hoskins et al 2007].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

EYA1. Oto-facial-cervical (OFC) syndrome: two individuals with de novo deletions of the EYA1 gene and surrounding region had complex phenotypes including features of BOR syndrome [Rickard et al 2001].

SIX5. No other phenotypes are known to be associated with mutations in SIX5.

SIX1. SIX1 was considered a candidate gene for DFNA23, as the DFNA23 locus maps to chromosome 14q21-q22. However, in a purported DFNA23 family, although a mutation was found in SIX1, the individual in question also had a solitary left hypodysplastic kidney with vesicoureteral reflux and progressive renal failure consistent with the diagnosis of a branchiootorenal spectrum disorder.

Natural History

Branchiootorenal spectrum disorders include branchiootorenal (BOR) syndrome and branchiootic syndrome (BOS).

Genotype-Phenotype Correlations

A genotype-phenotype correlation has not been defined for BOR/BOS. To compare phenotype with genotype, Zhang et al [2004] grouped EYA1 mutations as inactivating (i.e., splice site mutations, insertions, nonsense mutations, and duplications and deletions of more than 3 bp) or non-inactivating (i.e., missense mutations and 3 bp deletions). Using this criterion, they showed that EYA1 inactivating mutations are not associated with a more severe phenotype (p=0.799).

Mouse mutants with a targeted deletion of Six1 display a wide range of phenotypes. When the mutant Six1 protein is not expressed, the presence of a phenotype depends on the genetic background [Xu et al 2003]. For example, deletions in Six1 in mice modify the severity of the phenotype caused by deletions in Eya1 [Li et al 2003, Xu et al 2003, Zheng et al 2003]. This type of double heterozygosity has not been described in persons with a BOR/BOS phenotype. However, of families reported with SIX1 mutations, only two have renal abnormalities, a finding that suggest that genetic background significantly affects the severity of renal defects in BOR syndrome.

Other explanations for the range of phenotypes include haploinsufficiency and dominant-negative or gain-of-function effects. Of these possibilities, when considering SIX1 and SIX5 disease-causing mutations, complex dominant-negative and/or gain-of-function mechanisms are appealing, as no inactivating mutations (i.e., splice site mutations, insertions, nonsense mutations, and duplications and deletions of more than 3 bp) have been reported in SIX1 or SIX5 families with branchiootorenal spectrum disorders [Hoskins et al 2007, Kochhar et al 2008].

A parent-of-origin effect does not appear to be present, as renal defects have been reported in six liveborn offspring of affected fathers and four liveborn offspring of affected mothers.

Penetrance

Based on careful clinical studies of large pedigrees, branchiootorenal spectrum disorders appear to have 100% penetrance, although expressivity is highly variable [Chang et al 2004].

Anticipation

Although anticipation (the tendency of some dominant conditions to become more severe in successive generations) has been considered by several investigators, family studies suggest that it does not occur. For example, in seven three-generation families assessed for anticipation with respect to severity of hearing loss and renal involvement, the degree of hearing loss increased in four families in successive generations, but did not in the remaining three families. Generational progression in renal disease was present in three families, but in one family, the reverse was observed.

Nomenclature

BOR syndrome is known eponymously as Melnick-Fraser syndrome. While phenotypic descriptions are applied to BOR, BOS, and even branchiootoureteral (BOU) syndrome, these clinical distinctions must be considered in light of the associated molecular genetics. Many affected persons in families segregating EYA1 mutations have clinical findings consistent with the diagnosis of BOR; however, some affected persons in these same families have clinical findings consistent with BOS or BOU [Orten et al 2008]. For this reason, these syndromes are best considered as branchiootorenal spectrum disorders.

Prevalence

The prevalence of branchiootorenal spectrum disorders is not known. In 1976, GR Fraser surveyed 3,640 children with profound hearing impairment and found only five (0.15%) with a family history of branchial fistulae and preauricular pits (1:700,000) [Fraser 1976]. Four years later, in a study by FC Fraser of 421 children in the Montreal School for the Deaf, 2% of the profoundly deaf students had BOR syndrome [Fraser et al 1980]. Using these data, Fraser et al [1980] estimated the prevalence of BOR syndrome at 1:40,000. The true prevalence is probably somewhere between these extremes.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a branchiootorenal spectrum disorder (BOR/BOS), the following evaluations are recommended:

• Second branchial arch anomalies. Cervical examination for fistulae; computed tomography of the neck if a mass is palpable under the sternocleidomastoid muscle above the level of the hyoid bone

• Otologic findings

  • A complete assessment of auditory acuity using ABR, emission testing, and pure tone audiometry (see Deafness and Hereditary Hearing Loss Overview)

  • Computed tomography of the temporal bones, especially if the hearing impairment fluctuates or is progressive

• Renal anomalies. Renal ultrasound examination and/or excretory urography (intravenous pyelography); tests of renal function: BUN and creatinine; urinanalysis

Treatment of Manifestations

Second branchial arch anomalies. Excision of branchial cleft cysts/fistulae

Otologic anomalies

• Fitting with appropriate aural habilitation as indicated

• Enrollment in an appropriate educational program for the hearing impaired

• A canaloplasty can be considered to correct an atretic canal; however, in individuals with BOR/BOS, associated middle ear anomalies such as a facial nerve overriding the oval window can preclude a successful result. The status of the middle ear can be evaluated preoperatively by obtaining thin-cut CT images of the temporal bones in both the axial and coronal planes.

Renal anomalies

• Urologic and renal abnormalities should be treated in the standard manner.

• If renal anomalies (such as vesicoureteral reflux) are present, medical and surgical treatment may prevent progression to end-stage renal disease.

• If end-stage renal disease develops, renal transplantation should be considered.

Surveillance

Otologic anomalies

• Semiannual examination by a physician who is familiar with hereditary hearing impairment

• Annual audiometry to assess stability of hearing loss (more frequent if fluctuation or progression is described by the affected individual)

Renal anomalies. Semiannual/annual examination by a nephrologist and/or urologist if indicated, based on level of renal function and type of renal and/or collecting system malformation

Agents/Circumstances to Avoid

Individuals with renal abnormalities should use appropriate caution when taking medications (i.e., antibiotics and analgesics) that can impair renal function or require normal renal physiology for clearance.

Testing of Relatives at Risk

Relatives at risk for BOR/BOS should be screened to determine if a treatable and/or possibly progressive otologic and/or renal abnormality is present.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

The branchiootorenal spectrum disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 90% of individuals diagnosed with branchiootorenal spectrum disorders have an affected parent.

• A proband with a branchiootorenal spectrum disorder may have the disorder as the result of a de novo mutation. Approximately 10% of cases are caused by de novo mutations.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and renal anomalies. An apparently negative family history cannot be confirmed until appropriate evaluation of the parents has been performed.

Note: Although most individuals diagnosed with a branchiootorenal spectrum disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the proband's parents.

• If a parent is diagnosed with a branchiootorenal spectrum disorder, the risk to each sib is 50%.

• Disease severity cannot be accurately predicted and is extremely variable even within the same family.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

• If a disease-causing mutation cannot be detected in the DNA extracted from leukocytes of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband

• Each child of an affected individual has a 50% chance of having a branchiootorenal spectrum disorder.

• Disease severity cannot be accurately predicted and is extremely variable even within the same family.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA baking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for a branchiootorenal spectrum disorder caused by an EYA1 mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

No laboratories offering molecular genetic testing for prenatal diagnosis of branchiootorenal spectrum disorders caused by mutations in SIX1 or SIX5 are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see .

Fetal ultrasound examination. For fetuses at increased risk for BOR syndrome, prenatal ultrasound examination at 16-17 weeks' gestation should be considered for evaluation of significant renal malformations and/or oligohydramnios.

While requests for prenatal testing for significant medical conditions such as bilateral renal agenesis are generally accepted, requests for prenatal testing for conditions such as BOR syndrome may be more problematic. Variable expressivity makes it impossible to accurately predict which manifestations of BOR syndrome may occur and how mild or severe they will be. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

The vertebrate Eya gene family comprises four transcriptional activators that interact with other proteins in a conserved regulatory hierarchy to ensure normal embryologic development. The structure of these proteins includes a highly conserved 271-amino acid carboxy terminus called the eya-homologous region (eyaHR) and a more divergent proline-serine-threonine (PST)-rich (34%-41%) transactivation domain at the amino terminus (eya variable region, eyaVR) [Zhang et al 2004].

Studies in Drosophila indicate that the eyaHR mediates interactions with the gene products of so (sine oculis) and dac (dachshund), and that expression of both eya and so is initiated by ey (eyeless). The vertebrate orthologues of so are members of the Six gene family and similarly bind with Eya proteins, inducing nuclear translocation of the resultant protein complex. Amino terminal transcriptional activation has been demonstrated for the Drosophila eya and murine Eya1-3 gene products, an additional indication that Eya interactions and pathways are conserved across species.

Expression of Eya genes is present in a wide variety of tissues early in embryogenesis, and although each gene has a unique expression pattern, extensive overlap exists. For example, murine studies have shown that Eya1, Eya2, and Eya4 are all expressed in the presomitic mesoderm and head mesenchyme, but only Eya1 and Eya4 are expressed in the otic vesicle [Wayne et al 2001]. Eya3 expression is restricted to craniofacial and branchial arch mesenchyme in regions underlying or surrounding the Eya1-, Eya2-, or Eya4-expressing cranial placodes.

Six1 functions as both a transactivator and a transcriptional repressor, depending on its cofactors [Silver et al 2003, Bricaud & Collazo 2006].

Literature Cited

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Published Statements and Policies Regarding Genetic Testing

1. American College of Medical Genetics (2002) Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel (pdf).
2. American College of Medical Genetics (2000) Statement on universal newborn hearing screening (pdf)

Author Notes

Web: Pendred/BOR Home Page

Acknowledgments

The original preparation of this manuscript was supported in part by grants 1RO1DC02842 and 1RO1DC03544. (RJHS)

Author History

Glenn E Green, MD; Arizona Health Sciences Center (1999-2001)

Sai D Prasad; University of Iowa (1999-2001)

Richard JH Smith, MD (1999-present)

Revision History

• 27 August 2009 (me) Comprehensive update posted live

• 27 March 2008 (cd) Revision: sequence analaysis for BOR2-related SIX5 available clinically

• 24 March 2006 (cd) Revision: prenatal testing for EYA1 mutations available

• 24 January 2006 (me) Comprehensive update posted to live Web site

• 30 October 2003 (me) Comprehensive update posted to live Web site

• 28 November 2001 (me) Comprehensive update posted to live Web site

• 19 March 1999 (pb) Review posted to live Web site

• 6 January 1999 (rjhs) Original submission