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Background

Although the association of branchial, otic and renal anomalies was reported by physicians as early as the 19th century, it was not until Melnick and Fraser described kindreds segregating autosomal dominant hearing loss, pinnae deformity, bilateral preauricular pits, bilateral cleft fistulae and bilateral renal dysplasia that branchio-oto renal (BOR) dysplasia was recognized as a syndrome.(Melnick, Bixler et al. 1975; Melnick, Bixler et al. 1976; Fraser, Ling et al. 1978)  Multiple family studies have shown that incomplete penetrance and variable expressivity are common, with phenotypic variation between families and also within families.  The estimated prevalence of BOR syndrome is 1:40,000 and it affects 2% of profoundly deaf children.(Fraser, Sproule et al. 1980)

In a study of 45 patients, Chen et al listed the common phenotypic features (incidence >20%) as hearing loss (93%), preauricular pits or tags (82%), renal anomalies (67%), branchial fistulae (49%), pinnae deformity (36%) and external auditory canal stenosis (29%).  The severity of hearing loss ranged from mild to profound and was conductive, sensorineural and mixed.  In addition to external auditory canal stenosis atresia occurs.  Middle ear anomalies can include malformation, malposition, dislocation or fixation of the ossicles, and reduction in size or malformation of the middle ear cavity.  Inner ear malformations include cochlear hypoplasia, enlargement of the cochlear and vestibular aqueducts, and hypoplasia of the lateral semicircular canal.(Chen, Francis et al. 1995)   Renal anomalies range from hypoplasia to aplasia, either unilaterally or bilaterally.  Anomalies of the collecting system affect the ureter, calyx and renal pelvis.(Fraser, Ayme et al. 1983; Heimler and Lieber 1986; Konig, Fuchs et al. 1994)

     Genetics

            In 1997, Abdelhak et al identified mutations in a novel gene called EYA1 in seven patients with BOR syndrome.(Abdelhak, Kalatzis et al. 1997)   EYA1 is the human homologue of the Drosophila eyes absent gene (Bonini, Leiserson et al. 1993) and belongs to a family of genes that also includes EYA2, EYA3, and EYA4.  The gene is composed of 17 exons that span 156kb of genomic DNA and encode a 559-amino acid protein.  The eya homologous region (eyaHR) from exons 9-16 of EYA1 is highly conserved within the EYA gene family and is the site of the majority of BOR mutations.  Mutations in EYA1 also cause branchio-otic syndrome (BO).(Vincent, Kalatzis et al. 1997; Rickard, Boxer et al. 2000; Vervoort, Smith et al. 2002)

Functional Analysis

            Abdelhak et al used northern blot analysis of fetal and adult tissue to shown that Eya1 is selectively expressed in the fetus, specifically during embryonic days 11-17, and not in the adult.  In situ hybridization was used to demonstrate selective expression in the ear, kidney, and sympathetic chain, findings consistent with the BOR disease phenotype.(Abdelhak, Kalatzis et al. 1997)

 Diagnosing BOR Syndrome

            The wide spectrum of phenotypic findings associated with EYA1 mutations can make the diagnosis of BOR syndrome difficult.  An additional problem is genetic heterogeneity – mutations in other genes cause a similar phenotype.  These constraints make mutation screening of EYA1 a valuable clinical test.  However, the sensitivity of mutation screening to detect disease-causing allele variants of EYA1 is technique dependent.  For example, direct sequencing-based techniques have a high probability of detecting substitutions and small insertions or deletions, but will not identify large deletions, duplications and chromosomal rearrangements.  These changes will be associated with a “false negative” result secondary to amplification of the opposite, normal allele.  We believe that approximately 20-25% of EYA1 mutations in persons with BOR syndrome fall into this category. 

Differential Diagnostic Considerations

Branchio-otic syndrome (BOS) [OMIM #602588] - An autosomal dominant disorder with a variable phenotype that can include branchial anomalies, preauricular pits and hearing loss but specifically excludes renal anomalies.  Six BO families have been reported with EYA1 mutations(Vincent, Kalatzis et al. 1997; Rickard, Boxer et al. 2000; Vervoort, Smith et al. 2002) , and in two BO families, linkage to 8q13 has been excluded.(Kumar, Marres et al. 1998; Stratakis, Lin et al. 1998)

Branchiootoureteral syndrome (BOU) - An autosomal dominant disorder described in two families with branchial and otologic findings of BOR syndrome but with renal abnormalities limited to duplication of the collecting system and bifid renal pelves.(Fraser, Ayme et al. 1983)

Branchiooculofacial syndrome (BOFS) - An autosomal dominant disorder with a variable phenotype that includes postauricular cervical branchial defects, supra-auricular defects, colobomata, cataracts, deafness, scalp cysts, pseudoclefts, cleft lip and/or palate, kidney abnormalities and premature graying of hair.(McCool and Weaver 1994; Lin, Gorlin et al. 1995)   Lin et al found no EYA1 mutations in five BOFS patients.(Lin, Semina et al. 2000)

Otofaciocervical syndrome (OFC) [OMIM #166780] - An autosomal dominant disorder with a variable phenotype that includes hearing loss, ear pits, cervical fistulae, hypoplasia of the cervical musculature (sloping shoulders), facial abnormalities, short stature and mild developmental delay.  No patients with OFC have been reported with point mutations in EYA1 but in two patients de novo deletions the entire gene and surrounding region was found.(Rickard, Boxer et al. 2000; Rickard, Parker et al. 2001)

Looking Ahead

            Although EYA1 mutations cause BOR syndrome, in a large percentage of persons with a BOR phenotype, EYA1 mutations will not be found.  This finding may reflect the stringency with which we make the diagnosis of BOR as well as the limitations of the mutation screening strategy that is employed.  Genetic heterogeneity also complicates clinical diagnosis.  Identifying interacting partners with EYA1 may clarify some of these issues.