Branchiootic Syndrome 1

A number sign (#) is used with this entry because of evidence that some cases of the branchiootic (BO) syndrome (BOS1) are due to mutations in the EYA1 gene (601653) on chromosome 8q13.

Anterior segment anomalies with or without cataract is also caused by heterozygous mutation in the EYA1 gene.

Description

Individuals with the BO syndrome are affected by the same branchial and otic anomalies as those seen in individuals with the branchiootorenal syndrome (see BOR1, 113650), but lack renal anomalies (Vincent et al., 1997).

Although Melnick et al. (1978) maintained that the BO syndrome is distinct from the BOR syndrome because of the lack of renal anomalies and variable presence of deafness in the former, Cremers and Fikkers-van Noord (1980) suggested that the 2 syndromes represent a single entity.

See 113600 for a discussion of branchial cleft anomalies, which may be related.

Genetic Heterogeneity of Branchiootic Syndrome

See also BOS2 (120502), which maps to chromosome 1, and BOS3 (608389), which maps to 14q23 and is caused by mutations in the SIX1 gene (601205).

Clinical Features

Fourman and Fourman (1955) described a large multigenerational family in which 17 members had preauricular pits, 12 of whom also had mild to severe sensorineural hearing loss. Among family members without preauricular pits, 3 had hearing loss: one of these individuals had a branchial pit. Some reported onset of hearing loss in childhood, whereas others had onset beginning at about age 20 years. Audiograms showed both high and low tone loss, usually high tone more than low. There was no evidence of vestibular disorder. The authors suggested that ear pits, deafness, and branchial fistulae were independent effects of a single dominant gene with incomplete penetrance.

Wildervanck (1962) reported a family in which 14 members had either deformed auricles, marginal pits, or preauricular appendages. Two had a moderate conductive deafness: bilateral in 1 and unilateral in the other. The mode of inheritance was dominant with full penetration. Wildervanck (1962) suggested this was a different syndrome from that described by Fourman and Fourman (1955). McLaurin et al. (1966) reported a kindred with branchial anomalies and associated hearing impairment similar to the kindred described by Wildervanck (1962). Brusis (1974) reported a kindred similar to the one described by Fourman and Fourman (1955).

Vincent et al. (1997) reported 2 families with the BO syndrome. Clinical features included branchial cervical fistulae, cup-shaped pinnae, preauricular pits, and sensorineural, conductive, or mixed hearing loss. There was no evidence of renal anomalies.

Spruijt et al. (2006) reported an infant with severe obstructive sleep apnea caused by laryngomalacia, pharyngomalacia, glossoptosis, and tracheobronchomalacia. He also had bilateral branchial fistulae and ear anomalies, including ear pits, simple helices, and slight cup-shaped and low-set left ear. The features suggested BO syndrome. Other findings included micro- and retrognathia, but kidneys and hearing were normal. Surgical intervention improved the upper airway obstruction, but mild delay and mental and motor development were observed at age 11 months. His mildly affected mother showed mild retrognathia, left-sided branchial neck fistula, left-sided preauricular pit, and right-sided branchial cyst in the neck. Kidney ultrasound and hearing were normal. Both mother and son were heterozygous for a truncating mutation in the EYA1 gene (601653.0015). Spruijt et al. (2006) emphasized the phenotypic variability of BO syndrome associated with EYA1 mutations.

Cytogenetics

Haan et al. (1989) reported a complex inherited rearrangement of chromosome 8q associated with both trichorhinophalangeal syndrome (TRPS1; 190350) and the BOS syndrome in an affected Australian family showing features of both disorders. Preauricular pits or branchial sinuses were present in all 8 members studied in detail; 7 of these had deafness, the exception being the youngest. Three breakpoints in 8q were identified, resulting in dir ins(8)(q24.11q13.3q21.13). One of them was consistent with the previously assigned location of the TRPS1 locus on 8q24. Haan et al. (1989) concluded that the BOS syndrome is caused by mutation at either 8q13.3 or 8q21.13.

Gu et al. (1996) made use of a cell line from one of the affected members of the family reported by Haan et al. (1989). YACs spanning the BO interval from D8S543 to D8S541 were used as fluorescence in situ hybridization probes. In addition to the cytogenetically defined direct insertion of material from 8q13.3-q21.13 into 8q24.11, a previously unidentified deletion of just under 1 megabase was found in 8q13.3. These data narrowed the most likely location of the BO gene to a region between D8S543 and D8S279.

Kalatzis et al. (1996) likewise used the cell line first described by Haan et al. (1989) and identified an associated deletion by fluorescence in situ hybridization analysis of the 8q translocation breakpoint. The generation of a YAC contig and the isolation of overlapping recombinant P1 and lambda phage clones from the region allowed further characterization of the deletion. Its size was estimated to be between 470 and 650 kb, and it was flanked by the polymorphic markers D8S1060 and D8S1807.

Mapping

Vincent et al. (1997) analyzed 2 large independent families in which each of the 8 affected members presented exclusively with BO syndrome. In both families, linkage analysis mapped the causative gene to the same region on chromosome 8q13.3.

Genetic Heterogeneity

Stratakis et al. (1998) excluded linkage to 8q13.3 in a large family with presumed autosomal dominant BO syndrome spanning 4 generations. Ear pits were present in all 15 patients, whereas hearing loss and other branchial arch anomalies were present in 40% and 20%, respectively. None of the affected members had renal abnormalities or lacrimal duct stenosis.

Molecular Genetics

Vincent et al. (1997) demonstrated a 2-bp insertion in the EYA1 gene (601653.0003) in 1 of 2 families with BO syndrome. In the other family, they detected an 8-bp deletion (601653.0004).

Spruijt et al. (2006) identified a heterozygous mutation in the EYA1 gene (601653.0014) in an infant with a variant form of BO syndrome.

Anterior Segment Anomalies with or without Cataract

Azuma et al. (2000) examined genomic DNA isolated from patients with various types of developmental eye anomalies for EYA1 mutations by use of PCR-SSCP and sequencing. They identified 3 novel missense mutations in patients who had congenital cataracts and ocular anterior segment anomalies (see, e.g., 601653.0008-601653.0009).