Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[BOR Syndrome. Includes: Branchiootorenal Syndrome 1 (BOR1); Branchiootorenal Syndrome 2 (BOR2)]
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Author:
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Richard JH Smith, MD
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Initial Posting:
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Last Revision:
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Disease characteristics. Branchiootorenal (BOR) syndrome is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment; branchial fistulae and cysts; and renal malformations, ranging from mild renal hypoplasia to bilateral renal agenesis. The presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality may differ from right side to left side in an affected individual and also among individuals in the same family. Some individuals progress to end-stage renal disease (ESRD) later in life.
Diagnosis/testing. The diagnosis of BOR is made using clinical criteria. Molecular genetic testing of the EYA1 gene (BOR1) detects mutations in approximately 40% of individuals with the clinical diagnosis of BOR syndrome. Molecular genetic testing of the SIX5 gene (BOR2) detects mutations in 5.2% of individuals with the clinical diagnosis of BOR syndrome who do not have an EYA1 mutation. Such testing is available clinically.
Management. Management of BOR includes excision of branchial cleft cysts/fistulae, fitting with appropriate aural habilitation, and enrollment in appropriate educational programs for the hearing impaired. A canaloplasty can be considered to correct an atretic canal. Medical and surgical treatment for vesicoureteral reflux may be necessary. End-stage renal disease may require dialysis or renal transplantation. Surveillance includes semiannual examination for hearing impairment and annual audiometry to assess stability of hearing loss and semiannual/annual examination by a nephrologist if indicated.
Genetic counseling. BOR syndrome is transmitted in an autosomal dominant manner. Affected individuals have a 50% chance of transmitting the disorder to each child. Extreme clinical variability can be observed in the same family. Prenatal testing for fetuses at risk for an EYA1 mutation is clinically available for families in which the disease-causing mutation has been identified.
In the absence of a family history, three or more major criteria OR two major and two minor criteria (see Table 1) must be present to make the following clinical diagnosis of branchiootorenal (BOR) syndrome [Chang et al 2004]:
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Major Criteria
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Minor Criteria
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Second branchial arch anomalies
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External auditory canal anomalies
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Deafness
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Middle ear anomalies
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Preauricular pits
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Inner ear anomalies
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Auricular deformity
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Preauricular tags
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Renal anomalies
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Other: facial asymmetry, palate abnormalities
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Second branchial arch anomalies
Otologic findings
Renal anomaly
Note: (1) Individuals with an affected family member need only one major criterion to make the diagnosis of BOR syndrome [Chang et al 2004]. (2) In the absence of structural renal anomalies, the clinical diagnosis of branchiooto syndrome (BO syndrome) should be considered.
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Genes. Three genes are known to be associated with BOR syndrome:
EYA1 (BOR1). Approximately 40% of individuals with BOR syndrome have mutations in EYA1 [Chang et al 2004].
SIX5 (BOR2). Approximately 5.2% of individuals with BOR syndrome (who did not have identifiable mutations in EYA1 or SIX1) had mutations in SIX5 [Hoskins et al 2007].
SIX1. A very small percentage of individuals with BOR syndrome have mutations in SIX1 [Ruf et al 2004].
Other loci. It is probable that mutations in additional genes are causally related to the BOR syndrome phenotype.
Clinical uses
Clinical testing
EYA1
Mutation scanning. The complete EYA1 coding sequence is screened for allele variations by DHPLC; the specific mutation is then identified by direct sequencing. (mutation scanning does not detect large insertions or deletions, which are present in the approximately 20% of individuals* with an EYA1 mutation who have a chromosomal rearrangement.)
Deletion/duplication testing. Real-time PCR, Southern analysis, or FISH testing of EYA1. Approximately 10% of individuals* with a BOR syndrome phenotype have a large chromosomal rearrangement that can be detected with real-time PCR, or the analysis of Southern blots or FISH hybridized with probes corresponding to each of the EYA1 exons. A semi-quantitative PCR-based screen facilitates the rapid and reliable detection of many of these rearrangements [Chang et al 2004].
* Approximately 20% of individuals with EYA1 mutations, but 10% of those with a BOR phenotype, have a large chromosomal rearrangement.
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].
Research testing
Mutations of SIX1 have been implicated in a small number of individuals with BOR syndrome [Ruf et al 2004]. Testing of this gene is available on a research basis only.
Table 2
summarizes molecular genetic testing for this disorder.
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1. In individuals with a BOR syndrome phenotype
2. Detection rate of 5.2% in individuals without detectable mutations in EYA1 and SIX1 genes 3. Direct DNA methods may include mutation analysis, mutation scanning, sequence analysis, or other means of molecular genetic testing to detect a genetic alteration associated with BOR syndrome. |
Interpretation of test results. Failure to detect an EYA1 or SIX5 mutation may reflect only the limited extent of the mutation screen and thus does not exclude the diagnosis of BOR syndrome.
Branchiooto (BO) syndrome. BO can be caused by allelic variants of EYA1. The BO syndrome is characterized by deafness, cup-ear deformity, preauricular pits, and branchial fistulae, but absence of renal anomalies. In two families with BO syndrome and mutations in EYA1, affected individuals had sensorineural (25%), mixed (66%), or conductive (9%) hearing loss; branchial fistulae (100%); preauricular pits (80%); and cup-ear deformity (60%) [Abdelhak et al 1997 , Hum Mol Genet ; Vincent et al 1997 ; Chang et al 2004].
Additional loci for BO syndrome are (1) BOS2 (1q31) [Kumar et al 2000] and (2) BOS3 (14q23.1-24.3) [Ruf et al 2003]. The gene for BOS2 has not been cloned but in the BOS3 interval on chromosome 14, three different mutations in SIX1 have been identified in four BO/BOR kindreds [Ruf et al 2004]. In two of these kindreds the BO phenotype segregates with a missense mutation of SIX1 (p.Tyr129Cys , p.Arg110Trp) and in one kindred in which the phenotype included renal anomalies, an amino acid deletion (p.Glu133del) was present. The remaining family segregates p.Arg110Trp with the disease phenotype, but renal studies were not done [Ruf et al 2004].
Phenotypic differences probably reflect genetic background, protein-protein interactions (EYA1 and SIX1 are part of a complex protein network), or the level of clinical investigation. For example, one individual with a deletion of the entire EYA1 gene and BO syndrome has been reported [Haan et al 1989 , Kalatzis et al 1996], and in two families with BO syndrome, mutations have been identified in exons 4 and 9 [Abdelhak et al 1997 , Hum Mol Genet ; Vincent et al 1997]. However, most mutations in EYA1 are associated with BOR syndrome.
In the large extended family with BO syndrome linked to BOS2 (1q31), affected individuals have branchial anomalies and hearing loss associated with commissural lip pits [Kumar et al 2000] (see Differential Diagnosis .)
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].
The presence, severity, and type of branchial arch, otologic, audiologic, and renal abnormality may differ from right side to left side in an affected individual and between individuals in the same family.
Second branchial arch anomalies include the following:
Otologic findings, found in more than 90% of individuals with BOR syndrome [Chen et al 1995 , Chang et al 2004], include the following:
Renal anomalies. Renal malformations can be unilateral or bilateral and can occur in any combination. The most severe malformations result in pregnancy loss (since bilateral renal agenesis can end in miscarriage) or neonatal death; end-stage renal disease (ESRD) later in life may necessitate dialysis or transplantation [Widdershoven et al 1983 , Heimler & Lieber 1986 , Ni et al 1994].
Although renal anomalies are common, the true prevalence is difficult to establish because not all affected individuals undergo intravenous pyelography or renal ultrasonography. In a study in which 21 affected individuals had one of these two tests, renal anomalies were noted in 67% [Chen et al 1995 , Chang et al 2004] and included the following:
Other findings [Chen et al 1995 , Chang et al 2004]
The following are the findings in the four families segregating SIX1 mutations:
A genotype-phenotype correlation has not been defined for BOR/BO syndrome. To compare phenotype with genotype, Zhang and colleagues (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). They showed that EYA1 inactivating mutations are not associated with a more severe phenotype (p=0.799).
A parent-of-origin effect does not appear to be present, as renal defects have been reported in six liveborn offspring of affected fathers [Cremers & Fikkers-Van Noord 1980 , Carmi et al 1983 , Widdershoven et al 1983 , Greenberg et al 1988] and four liveborn offspring of affected mothers [Fitch & Srolovitz 1976 , Cremers & Fikkers-Van Noord 1980 , Widdershoven et al 1983 , Chitayat et al 1992].
In studies of large pedigrees, the phenotype appears to have 100% penetrance, although expressivity is highly variable [Chen et al 1995 , Chang et al 2004].
Although several investigators have raised the possibility of anticipation (the tendency of some dominant conditions to become more severe in successive generations), this phenomenon has not been confirmed in family studies. 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 [Chen et al 1995].
BOR syndrome is known eponymously as Melnick-Fraser syndrome. Phenotypic descriptions include branchiooto syndrome (BO) and branchiootoureteral (BOU) syndrome, in addition to BOR syndrome.
The prevalence of BOR syndrome 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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
The extreme clinical variability associated with BOR syndrome has suggested to many investigators that the phenotype represents a heterogeneous group of diseases. In support of this possibility, three different conditions have been described:
BO syndrome. Melnick et al (1978) described three families, one with features of BOR syndrome and two with only cup-shaped pinnae and branchial arch fistulae. Neither the renal abnormalities nor the hearing impairment expected with BOR syndrome was present in the latter families; these individuals were classified as having BO syndrome.
BOU (branchiootoureteral syndrome. The issue became more complicated when FC Fraser et al (1983) reevaluated intravenous pyelograms previously interpreted as normal in individuals with BO syndrome (deafness, cup-ear deformity, preauricular pits, branchial fistulae) and documented duplication of the collecting system and bifid renal pelvesin three of four "normal" studies. Whether BOU syndrome is part of the spectrum of BOR syndrome or a separate disorder has not yet been clarified.
BO-like syndrome. In two large families with BO-like syndrome, linkage to the EYA1 region of chromosome 8q has been excluded [Kumar, Marres et al 1998 ; Stratakis et al 1998]. Although these data can be interpreted as confirming heterogeneity, in neither of these families is the phenotype classic for BOR syndrome.
BOF (branchiooculofacial) syndrome. Affected individuals have bilateral postauricular and cervical branchial sinus defects with hemangiomas, cleft lip with or without cleft palate, nasolacrimal duct obstruction, low set ears with posterior rotation, nasal malformation with a broad bridge and flattened tip, and occasionally, prematurely grey hair [Trummer et al 2002]. Inheritance is autosomal dominant.
To establish the extent of disease in an individual diagnosed with branchiootorenal (BOR) syndrome, 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
Renal anomalies. Renal ultrasound examination and/or excretory urography (intravenous pyelography); tests of renal function: BUN and creatinine; urinanalysis
Second branchial arch anomalies. Excision of branchial cleft cysts/fistulae
Otologic anomalies
Renal anomalies
Otologic anomalies
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
Individuals with BOR syndrome and 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.
Relatives at risk for BOR syndrome should be screened to determine if a treatable and/or possibly progressive otologic and/or renal abnormality is present.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
BOR syndrome is inherited in an autosomal dominant manner.
Parents of a proband
Note: Although most individuals diagnosed with BOR syndrome 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
Offspring of a proband
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 found to be affected, his or her family members are at risk.
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 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.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. 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 particularly if the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk for BOR syndrome caused by an EYA1 mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 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 BOR syndrome 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
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Fetal ultrasound examination. For fetuses at increased risk, 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 may be more problematic. Variable expressivity makes it impossible to accurately predict which manifestations of BOR 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
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Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Locus Name | Gene Symbol | Chromosomal Locus | Protein Name |
BOR1/BOS1 | EYA1 | 8q13.3 | Eyes absent homolog 1 |
BOR2 | SIX5 | 19q13.3 | Homeobox protein SIX5 |
BOR3/BOS3 | SIX1 | 14q23 | Homeobox protein SIX1 |
BOS2 | Unknown | 1q31 | Unknown |
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Data are compiled from the following standard references: Gene symbol from HUGO;
chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
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Gene Symbol | Locus Specific | Entrez Gene | HGMD |
EYA1 | |||
SIX5 | |||
SIX1 |
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For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
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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 [Abdelhak et al 1997 , Nat Genet].
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 [Abdelhak et al 1997 , Hum Mol Genet].
EYA1
Normal allelic variants:
EYA1 consists of 16 coding exons that extend over 156 kb. It has at least three alternatively spliced transcripts that differ only in their 5' regions
(EYA1A,
EYA1B,
EYA1C).
These 5' exons (exon -1 and the 3' end of exon 1) produce an open reading frame (ORF) that could add more than 156 amino acids to the amino terminal of
EYA1; however, it is not known whether this sequence is translated. The seventeen introns of
EYA1 vary in size from 0.1 to 27.5 kb [Abdelhak et al 1997 ,
Hum Mol Genet]. Numerous polymorphisms of
EYA1 have been reported [Abdelhak et al 1997 ,
Hum Mol Genet
; Abdelhak et al 1997 ,
Nat Genet]. When allelic variants are discovered, it is not always clear whether they are disease causing. Since mutations in
EYA1 are not found in 60% of people with a BOR syndrome phenotype, caution must be used when interpreting the effect of