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.
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