Branchiootorenal Syndrome 1

A number sign (#) is used with this entry because branchiootorenal syndrome-1 (BOR1) is caused by heterozygous mutation in the EYA1 gene (601653) on chromosome 8q13.

Description

Branchiootorenal syndrome is an autosomal dominant disorder characterized by sensorineural, conductive, or mixed hearing loss, structural defects of the outer, middle, and inner ear, branchial fistulas or cysts, and renal abnormalities ranging from mild hypoplasia to complete absence. Reduced penetrance and variable expressivity has been observed (Fraser et al., 1978).

Genetic Heterogeneity of Branchiootorenal Syndrome

See also BOR2 (610896), caused by mutation in the SIX5 gene (600963) on chromosome 19q13. Sanchez-Valle et al. (2010) stated that approximately 40% of patients with BOR have mutations in the EYA1 gene and 5% have mutations in the SIX5 gene.

See also branchiootic (BO) syndrome-1 (BOS1; 602588) and the otofaciocervical syndrome (OFC; 166780), allelic disorders showing overlapping phenotypes but without renal anomalies. See also 600257 for a discussion of the BOR-Duane-hydrocephalus contiguous gene syndrome as described by Vincent et al. (1994).

Although Melnick et al. (1978) maintained that the BOR syndrome is distinct from the BO syndrome because in the latter condition renal anomaly is absent and deafness is not a constant feature, Cremers and Fikkers-van Noord (1980) concluded that the 2 syndromes are in fact a single entity.

Clinical Features

Melnick et al. (1975, 1976) described a family in which the father and 3 of 6 living children (a son and 2 daughters) had mixed hearing loss associated with a Mondini-type cochlear malformation (hypoplasia of cochlear apex shown by tomography) and stapes fixation, cup-shaped, anteverted pinnae, bilateral prehelical pits, bilateral branchial cleft fistulas, and bilateral renal dysplasia with anomalies of the collecting system. The father and affected son also had aplasia of the lacrimal ducts. A fourth child, who died at 5 months of age, was said to have had branchial cleft fistulas and bilateral polycystic kidneys. Conditions in the same nosoembryologic community were discussed. Fitch and Srolovitz (1976) reported a woman with preauricular pits, cervical fistulas, and partial deafness who gave birth to 2 children with preauricular pits and severe renal dysgenesis.

Fraser et al. (1978) reported a kindred with the BOR syndrome. Clinical features included preauricular pits, branchial fistulas, sensorineural, conductive, or mixed hearing loss, lacrimal stenosis, and malformed external ears. Radiographic studies showed hypoplastic and malformed external ear canals, ossicles, and cochlea. Radiographic studies of the urinary tract showed minor anomalies, including partially distorted pelvicalyceal systems, narrow pelviureteric junctions, and renal dysplasia. Not all features were expressed in those affected. Fraser et al. (1978) also provided a review of previously reported cases.

Carmi et al. (1983) observed a man with the BOR syndrome and crossed renal ectopia who fathered 3 children born with bilateral renal agenesis and the Potter syndrome. Preisch et al. (1985) reported affected father, son, and daughter. The father and daughter showed unilateral tearing with eating, i.e., gustatory lacrimation. Another family reportedly showed the same phenomenon. Gustatory lacrimation, sometimes described as 'crocodile tears,' was noted by Gorlin (1976) to have been observed in over 100 cases but never in multiple members of families. Most cases are unilateral and often follow facial trauma or surgery but can occur as a congenital defect in innervation.

Fraser et al. (1983) reported 2 families in which the propositi had bilateral sensorineural hearing loss, preauricular pit or tag, and duplication of the ureters or bifid renal pelvises. Other relatives had 1 or more of these anomalies in a pattern suggesting autosomal dominant inheritance with reduced penetrance and variable expressivity. Fraser et al. (1983) suggested the term 'branchiootoureteral syndrome.'

Heimler and Lieber (1986) described a large, 4-generation kindred with branchiootorenal syndrome containing 16 individuals with confirmed manifestations of the disorder. Of these, only 4 had abnormalities in all 3 systems, whereas 7 had branchial arch and/or hearing defects but no reported renal abnormalities. However, because only 1 of these individuals had undergone detailed renal evaluation, it is possible that the incidents of renal defects in this kindred was higher than reported.

Legius et al. (1990) described father and son with a branchial cleft syndrome mixing characteristics of the BOR syndrome with those of the branchiooculofacial syndrome (BOFS; 113620). The 2 subjects showed several anomalies common to both syndromes, namely, abnormally shaped ears with deafness, cervical fistulas, preauricular ear pits, and lacrimal duct stenosis. Unilateral renal hypoplasia and dysplasia in the son were typical of the BOR syndrome. On the other hand, cleft palate and mild 'mental problems' in the father, and bilateral microphthalmia and high-arched palate in the son were more characteristic of BOFS. Neither the father nor the son showed the usual findings of BOFS, such as lip 'pseudoclefts,' abnormal nose, premature graying, or skin abnormalities. The father had been operated on for arteria lusoria (left subclavian artery passing behind the esophagus) causing dysphagia. He had also had unexplained atrial fibrillation. Lin et al. (1992) concluded that the patients of Legius et al. (1990) indeed had the BOF syndrome and that this entity is distinct from the BOR syndrome. Legius and Fryns (1992) remained dubious of a distinction.

Chitayat et al. (1992) made the diagnosis of BOR syndrome in a woman who had had 2 pregnancies complicated by oligohydramnios due to renal hypoplasia and agenesis. Both babies died neonatally of pulmonary hypoplasia. Histopathology of the temporal bones of the second child showed marked immaturity of the middle ear cleft, ossicles, facial nerve and canal, and cochlear nerve. The mother's renal ultrasound study was normal although intravenous pyelography indicated renal hypoplasia. The mother had a hearing problem first recognized at age 5 when abnormality of the right ossicular mass and antral region was found. A preauricular pit on the right in the mother was pictured.

Chen et al. (1995) described 45 individuals with the BOR syndrome, highlighting differences and similarities to findings reported by others. Characteristic temporal bone findings included hypoplasia of the cochlea, which was four-fifths of normal size with only 2 turns, dilation of the vestibular aqueduct, bulbous internal auditory canals, deep posterior fossa, and acutely angled promontories. They pictured a 3-generation family with various manifestations.

Graham and Allanson (1999) described a 14-month-old girl with unilateral congenital cholesteatoma (604183) and anomalies of the facial nerve, in addition to the branchial arch, otic, and renal malformations that comprise the BOR syndrome. The mother also had the BOR syndrome and unilateral duplication of the facial nerve. This was said to be the first study of a BOR patient with congenital cholesteatoma and the second family in which cholesteatoma and anomalies of the facial nerve were described in patients with BO/BOR syndrome.

In the branchiootorenal syndrome, renal defects, which are estimated to be severe in only 6% of patients, can include collecting system duplication, hypoplasia, cystic dysplasia, hydronephrosis, and agenesis (Izzedine et al., 2004).

Olavarrieta et al. (2008) reported an unusual Spanish family in which the male proband had BOR1 syndrome, associated with a heterozygous de novo mutation in the EYA1 gene (601653.0015), and Stickler syndrome type I (STL1; 108300), associated with a heterozygous mutation in the COL2A1 gene (120140). The patient's mother and brother, both of whom had Stickler syndrome and the COL2A1 mutation, did not carry the EYA1 mutation. All 3 patients had myopia, vitreous anomaly, and flat face, characteristic of Stickler syndrome; the brothers had cleft palate. The proband also had branchial fistulas, preauricular pits, renal agenesis, and mixed hearing loss consistent with BOR1 syndrome. The brother with Stickler syndrome had conductive hearing loss due to infection and surgery. Olavarrieta et al. (2008) emphasized that both disorders show phenotypic variability as well as overlapping features, which can complicate a precise diagnosis. Thorough clinical evaluation is necessary to identify coexisting genetic syndromes in the same patient.

Diagnosis

Chang et al. (2004) sought to refine the clinical diagnosis of the BOR syndrome by analyzing phenotypic data from families segregating EYA1 disease-causing mutations. They presented diagnostic criteria in the form of a list of major and minor criteria and suggested that an affected individual must have at least 3 major criteria, 2 major criteria and at least 2 minor criteria, or 1 major criterion and an affected first-degree relative meeting criteria for BOR syndrome. Major criteria included branchial anomalies, deafness, preauricular pits, and renal anomalies.

Mapping

Kumar et al. (1992) found linkage to genetic markers on chromosome 8q in a 4-generation family with BOR syndrome (maximum lod score of 4.0 at theta = 0.05 with marker D8S165). By multipoint analysis in 2 affected BOR families, Smith et al. (1992) found linkage to a marker telomeric to 8q12-q13 (maximum lod score of 3.79 at theta = 0.084). The diagnosis of BOR syndrome was based on the presence of at least 2 of the following features: preauricular pits, lop-ear deformity, branchial fistulas, hearing loss, and renal anomalies.

Wang et al. (1994), who referred to this disorder alternatively as the 'Melnick-Fraser syndrome,' used multipoint linkage analysis based on microsatellite markers (Weissenbach et al., 1992) to map the BOR locus to a 6-cM region of 8q flanked by D8S543 and D8S84. Ni et al. (1994) concluded that BOR is flanked by D8S530 and D8S279. Based on multipoint analysis using a set of 13 polymorphic markers from the BOR region in 2 large, clinically well-characterized families, Kumar et al. (1996) concluded that the BOR locus is within a 2-cM region between markers D8S543 and D8S530. They identified YACs that map in the critical region and characterized them by fluorescence in situ hybridization and pulsed field gel electrophoresis.

Molecular Genetics

In patients with the BOR syndrome, Abdelhak et al. (1997) identified a large deletion and 7 different mutations in the EYA1 gene (see, e.g., 601653.0001; 601653.0002).

Rickard et al. (2000) studied 32 individuals with BOR syndrome or an overlapping phenotype. Eighteen of the cases had what the authors classified as classic BOR syndrome, exhibiting at least 3 of the major features: hearing loss, branchial defects, ear pits, and renal anomalies. Twelve cases had 1 or 2 major clinical features and were designated as having an atypical form of the condition. Two cases had otofaciocervical syndrome (166780). Mutations in the EYA1 gene were found in 11 of 18 cases of classic BOR syndrome (see, e.g., 601653.0011). There were no apparent clinical differences between those with and those without EYA1 mutations. No mutations were detected in any subjects with atypical BOR syndrome or OFC syndrome.

Vervoort et al. (2002) noted that in up to one-half of reported cases of BOR syndrome, EYA1 screening was negative, suggesting genetic heterogeneity. Using SSCP and direct sequencing, they screened the coding region of the EYA1 gene in a panel of BOR families linked to chromosome 8. Only 1 point mutation in 5 probands was detected. However, using Southern blot analysis, complex rearrangements such as inversions and large deletions were identified in the other 4 patients. Vervoort et al. (2002) concluded that more complex rearrangements may have been missed in earlier studies, which commonly used only SSCP and sequencing for mutation detection.

Chang et al. (2004) stated that 51 different mutations in the EYA1 gene had been associated with the BOR syndrome. There was no single common mutation; the majority of mutations were unique to individual families. About 20% of cases had complex rearrangements of EYA1.

Orten et al. (2008) identified 70 different EYA1 mutations in 89 of 435 families with BOR or a related phenotype. EYA1 mutations were found in 76 (31%) of 248 families fitting established clinical criteria for BOR and 13 (7%) of 187 families with a questionable BOR phenotype. Most of the mutations were private, and there were no apparent genotype/phenotype correlations.

Stockley et al. (2009) identified EYA1 mutations (see, e.g., 601653.0016) in 14 (82%) of 17 unrelated probands with BOR syndrome. De novo mutations were confirmed in 45% of the patients.

Cytogenetics

Sanchez-Valle et al. (2010) reported 3 unrelated patients with variable manifestations of BOR syndrome associated with heterozygous nonrecurrent genomic deletions of chromosome 8q13 including the EYA1 gene and other genes. Two of the deletions were proven to occur de novo. All patients had a clinical diagnosis of BOR, including ear and facial anomalies, hearing loss, and renal anomalies or dysfunction. Two had mild developmental delay and 1 had severe developmental delay. The deletions ranged in size from 2.7 to 8.7 Mb, and involved at least 6 genes in addition to EYA1; the patient with the most severe phenotype had the largest deletion. Although all had short stature, none had the typical facies or musculoskeletal features characteristic of otofaciocervical syndrome.

Population Genetics

Fraser et al. (1980) suggested that the frequency of the BOR syndrome may be higher than generally realized. Among 421 white children in Montreal schools for the deaf, 19 (4.5%) of 421 deaf children had preauricular pits, compared to 0.7% of newborn white infants. The BOR syndrome was identified in 4 of the 9 families that agreed to family investigations, including audiograms and intravenous pyelograms. The authors estimated that 6% of heterozygotes have severe renal dysplasia and that a preauricular pit at birth suggests that the child has at least 1 chance in 200 of severe hearing loss. Fraser et al. (1980) estimated the frequency of the BOR syndrome to be 1 in 40,000.