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International Archives of... Jan 2014Introduction Branchio-oto-renal (BOR) syndrome is an autosomal-dominant genetic condition with high penetrance and variable expressivity, with an estimated prevalence... (Review)
Review
Introduction Branchio-oto-renal (BOR) syndrome is an autosomal-dominant genetic condition with high penetrance and variable expressivity, with an estimated prevalence of 1 in 40,000. Approximately 40% of the patients with the syndrome have mutations in the gene EYA1, located at chromosomal region 8q13.3, and 5% have mutations in the gene SIX5 in chromosome region 19q13. The phenotype of this syndrome is characterized by preauricular fistulas; structural malformations of the external, middle, and inner ears; branchial fistulas; renal disorders; cleft palate; and variable type and degree of hearing loss. Aim Hearing loss is part of BOR syndrome phenotype. The aim of this study was to present a literature review on the anatomical aspects and audiological profile of BOR syndrome. Data Synthesis Thirty-four studies were selected for analysis. Some aspects when specifying the phenotype of BOR syndrome are controversial, especially those issues related to the audiological profile in which there was variability on auditory standard, hearing loss progression, and type and degree of the hearing loss. Mixed loss was the most common type of hearing loss among the studies; however, there was no consensus among studies regarding the degree of the hearing loss.
PubMed: 25992067
DOI: 10.1055/s-0033-1358659 -
The Journal of International Medical... Jul 2020Branchial cleft abnormality is a common congenital neck malformation in children, which is caused by the abnormal development of the gill sac or gill groove. It is... (Review)
Review
Branchial cleft abnormality is a common congenital neck malformation in children, which is caused by the abnormal development of the gill sac or gill groove. It is mainly manifested as a cyst in the sinus tract and fistula in the neck, as well as branchio-oto-renal syndrome (BORS). As a rare autosomal dominant genetic disease, the typical manifestations of BORS are hearing loss, abnormal branchial cleft development and renal dysplasia. In this paper, a patient was admitted to the hospital for bilateral branchial cleft fistulas combined with bilateral anterior auricular fistulas, auricular appendix, auricle dysplasia, external auditory canal stenosis, and hearing loss. The patient was diagnosed with BORS, and underwent fistulectomy of the neck and anterior ear, external auditory canal formation, and tympanoplasty. The aim of this report is to strengthen clinicians' understanding of BORS and reduce the rate of clinical missed diagnosis through our case report and literature review.
Topics: Branchial Region; Branchio-Oto-Renal Syndrome; Child; Craniofacial Abnormalities; Fistula; Humans; Pharyngeal Diseases
PubMed: 32689865
DOI: 10.1177/0300060520926363 -
Scientific Reports Jan 2022Some patients have an atypical form of branchio-oto-renal (BOR) syndrome, which does not satisfy the diagnostic criteria, despite carrying a pathogenic variant (P...
Some patients have an atypical form of branchio-oto-renal (BOR) syndrome, which does not satisfy the diagnostic criteria, despite carrying a pathogenic variant (P variant) or a likely pathogenic variant (LP variant) of a causative gene. P/LP variants phenotypic indices have yet to be determined in patients with typical and atypical BOR syndrome. We hypothesized that determining phenotypic and genetic differences between patients with typical and atypical BOR syndrome could inform such indices. Subjects were selected from among patients who underwent genetic testing to identify the cause of hearing loss. Patients were considered atypical when they had two major BOR diagnostic criteria, or two major criteria and one minor criterion; 22 typical and 16 atypical patients from 35 families were included. Genetic analysis of EYA1, SIX1, and SIX5 was conducted by direct sequencing and multiplex ligation-dependent probe amplification. EYA1 P/LP variants were detected in 25% and 86% of atypical and typical patients, respectively. Four EYA1 P/LP variants were novel. Branchial anomaly, inner ear anomaly, and mixed hearing loss were correlated with P/LP variants. Development of refined diagnostic criteria and phenotypic indices for atypical BOR syndrome will assist in effective detection of patients with P/LP variants among those with suspected BOR syndrome.
Topics: Branchio-Oto-Renal Syndrome; Female; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Male; Nuclear Proteins; Pedigree; Phenotype; Protein Tyrosine Phosphatases
PubMed: 35046468
DOI: 10.1038/s41598-022-04885-w -
AJNR. American Journal of Neuroradiology Feb 2022Temporal bone imaging plays an important role in the work-up of branchio-oto-renal syndrome. Previous reports have suggested that the unwound or offset cochlea is a...
BACKGROUND AND PURPOSE
Temporal bone imaging plays an important role in the work-up of branchio-oto-renal syndrome. Previous reports have suggested that the unwound or offset cochlea is a highly characteristic marker for branchio-oto-renal syndrome. Our goals were to examine the prevalence of this finding in a branchio-oto-renal syndrome cohort and analyze genetic-phenotypic associations not previously established.
MATERIALS AND METHODS
This multicenter retrospective study included 38 ears in 19 unrelated individuals with clinically diagnosed branchio-oto-renal syndrome and confirmed mutations in the or genes. Two blinded neuroradiologists independently reviewed and documented temporal bone imaging findings in 13 categories for each ear. Imaging phenotypes were correlated with genotypes.
RESULTS
There was excellent interrater agreement for all 13 phenotypic categories (κ ≥ 0.80). Of these, 9 categories showed statistically significant differences between patients with -branchio-oto-renal syndrome and -branchio-oto-renal syndrome. Cochlear offset was present in 100% of patients with -branchio-oto-renal syndrome, but in only 1 ear (12.5%) among patients with -branchio-oto-renal syndrome. A short thorny appearance of the cochlear apical turn was observed in most patients with -branchio-oto-renal syndrome.
CONCLUSIONS
An offset cochlea is associated with the -branchio-oto-renal syndrome genotype. The -branchio-oto-renal syndrome genotype is associated with a different cochlear phenotype that almost always is without offset and has a short thorny tip as the apical turn. Therefore, cochlear offset is not a characteristic marker for all patients with branchio-oto-renal syndrome. The lack of a cochlear offset in a patient with clinically suspected branchio-oto-renal syndrome does not exclude the diagnosis and, in fact, may be predictive of the genotype.
Topics: Branchio-Oto-Renal Syndrome; Cochlea; Genetic Association Studies; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Protein Tyrosine Phosphatases; Retrospective Studies
PubMed: 35058298
DOI: 10.3174/ajnr.A7396 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Jan 2022Branchio-oto syndrome (BOS)/branchio-oto-renal syndrome (BORS) is a kind of autosomal dominant heterogeneous disorder. These diseases are mainly characterized by hearing...
Branchio-oto syndrome (BOS)/branchio-oto-renal syndrome (BORS) is a kind of autosomal dominant heterogeneous disorder. These diseases are mainly characterized by hearing impairment and abnormal phenotype of ears, accompanied by renal malformation and branchial cleft anomalies including cyst or fistula, with an incidence of 1/40 000 in human population. Otic anormalies are one of the most obvious clinical manifestations of BOS/BORS, including deformities of external, middle, inner ears and hearing loss with conductive, sensorineural or mix, ranging from mild to profound loss. Temporal bone imaging could assist in the diagnosis of middle ear and inner ear malformations for clinicians. Multiple methods including direct sequencing combined with next generation sequencing (NGS), multiplex ligation-dependent probe amplification (MLPA), or array-based comparative genomic hybridization (aCGH) can effectively screen and identify pathogenic genes and/or variation types of BOS/BORS. About 40% of patients with BOS/BORS carry aberrations of gene which is the most important cause of BOS/BORS. A total of 240 kinds of pathogenic variations of have been reported in different populations so far, including frameshift, nonsense, missense, aberrant splicing, deletion and complex rearrangements. Human Endogenous Retroviral sequences (HERVs) may play an important role in mediating chromosomal fragment deletion mutations caused by non-allelic homologous recombination. encodes a phosphatase-transactivator cooperated with transcription factors of , participates in cranial sensory neurogenesis and development of branchial arch-derived organs, then regulates the morphological and functional differentiation of the outer ear, middle ear and inner ear toward normal tissues. In addition, pathogenic mutations of and genes can also cause BOS/BORS. Variations of these genes mentioned above may cause disease by destroying the bindings between SIX1-EYA1, SIX5-EYA1 or SIX1-DNA. However, the role of gene in the pathogenesis of BORS needs further verification.
Topics: Branchio-Oto-Renal Syndrome; Chromosome Deletion; Comparative Genomic Hybridization; Genetic Research; Homeodomain Proteins; Humans; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Pedigree; Protein Tyrosine Phosphatases
PubMed: 35545373
DOI: 10.11817/j.issn.1672-7347.2022.210251 -
Frontiers in Genetics 2021Branchio-oto-renal syndrome (BOR) and branchio-oto syndrome (BOS) are rare autosomal dominant disorders defined by varying combinations of branchial, otic, and renal...
Branchio-oto-renal syndrome (BOR) and branchio-oto syndrome (BOS) are rare autosomal dominant disorders defined by varying combinations of branchial, otic, and renal anomalies. Here, we characterized the clinical features and genetic etiology of BOR/BOS in several Chinese families and then explored the genotypes and phenotypes of BOR/BOS-related genes, as well as the outcomes of auditory rehabilitation in different modalities. Probands and all affected family members underwent detailed clinical examinations. Their DNA was subjected to whole-exome sequencing to explore the underlying molecular etiology of BOR/BOS; candidate variants were validated using Sanger sequencing and interpreted in accordance with the American College of Medical Genetics guidelines. In addition, a literature review concerning and alterations was performed to explore the genotypes and phenotypes of BOR/BOS-related genes. Genetic testing identified the novel deletion (c.1425delC, p(Asp476Thrfs*4); NM_000,503.6), a nonsense variant (c.889C > T, p(Arg297*)), and two splicing variants in the gene (c.1050+1G > T and c.1140+1G > A); it also identified one novel missense variant in the gene (c.316G > A, p(Val106Met); NM_005,982.4). All cases exhibited a degree of phenotypic variability between or within families. Middle ear surgeries for improving bone-conduction component hearing loss had unsuccessful outcomes; cochlear implantation (CI) contributed to hearing gains. This is the first report of BOR/BOS caused by the variant in China. Our findings increase the numbers of known and variants. They also emphasize the usefulness of genetic testing in the diagnosis and prevention of BOR/BOS while demonstrating that CI for auditory rehabilitation is a feasible option in some BOR/BOS patients.
PubMed: 34868248
DOI: 10.3389/fgene.2021.765433 -
AJNR. American Journal of Neuroradiology Nov 2022An "unwound" or "offset" cochlea has been described as a characteristic imaging feature in patients with branchio-oto-renal syndrome, and recently recognized to be...
BACKGROUND AND PURPOSE
An "unwound" or "offset" cochlea has been described as a characteristic imaging feature in patients with branchio-oto-renal syndrome, and recently recognized to be associated in particular to those with gene mutations. Determination of this feature has traditionally relied on subjective visual assessment. Our aim was to establish an objective assessment method for cochlear offset (the cochlear turn alignment ratio) and determine an optimal cutoff turn alignment ratio value that separates individuals with -branchio-oto-renal syndrome from those with -branchio-oto-renal syndrome and healthy controls.
MATERIALS AND METHODS
Temporal bone CT or MR imaging from 40 individuals with branchio-oto-renal syndrome and 40 controls was retrospectively reviewed. Cochlear offset was determined visually by 2 independent blinded readers and then quantitatively via a standardized technique yielding the cochlear turn alignment ratio. The turn alignment ratio values were compared between cochleae qualitatively assessed as "not offset" and "offset." Receiver operating characteristic analysis was used to determine the ability of the turn alignment ratio to differentiate between these populations and an optimal cutoff turn alignment ratio value. Cochlear offset and turn alignment ratio values were analyzed for each branchio-oto-renal syndrome genotype subpopulation and for controls.
RESULTS
The turn alignment ratio can accurately differentiate between cochleae with and without an offset (< .001). The optimal cutoff value separating these populations was 0.476 (sensitivity = 1, specificity = 0.986, = 0.986). All except 1 cochlea among the -branchio-oto-renal syndrome subset and all with unknown genotype branchio-oto-renal syndrome had a cochlear offset and a turn alignment ratio of <0.476. All except 1 cochlea among the -branchio-oto-renal syndrome subset and all controls had no offset and a turn alignment ratio of >0.476.
CONCLUSIONS
There is a statistically significant difference in turn alignment ratios between offset and nonoffset cochleae, with an optimal cutoff of 0.476. This cutoff value allows excellent separation of -branchio-oto-renal syndrome from -branchio-oto-renal syndrome and from individuals without branchio-oto-renal syndrome or sensorineural hearing loss. The turn alignment ratio is a reliable and objective metric that can aid in the imaging evaluation of branchio-oto-renal syndrome.
Topics: Humans; Branchio-Oto-Renal Syndrome; Retrospective Studies; Protein Tyrosine Phosphatases; Intracellular Signaling Peptides and Proteins; Nuclear Proteins; Cochlea; Mutation; Homeodomain Proteins
PubMed: 36175083
DOI: 10.3174/ajnr.A7653 -
Indian Journal of Otolaryngology and... Sep 2007Branchio-oto-renal syndrome (Melnick-Fraser Syndrome) is a rare Autosomal Dominant disorder characterized by the syndromic association of branchial cysts or fistulae...
Branchio-oto-renal syndrome (Melnick-Fraser Syndrome) is a rare Autosomal Dominant disorder characterized by the syndromic association of branchial cysts or fistulae along with external, middle & inner malformations and renal anomalies. Incomplete penetrance and variable expressivity are common with the phenotypic variation ranging from mild to severe forms & consisting of various eye, ear, oral and craniofacial abnormalities. Mutations in the EYA1 gene on chromosomal site 8q13.3 are identified as the primary cause of BOR syndrome. We present a 3year old child with BOR syndrome, who came to us with bilateral low set, malformed ears & profound cochlear hearing loss along with bilateral branchial fistulae & unilateral renal agenesis. This child underwent successful cochlear implantation recently. The clinical presentation, pre-operative investigations, intra-operative findings & post-op habilitation status are presented with special highlights on the unique facial nerve course along with middle and inner ear anomalies which posed a surgical challenge during cochlear implantation.
PubMed: 23120453
DOI: 10.1007/s12070-007-0081-7 -
International Journal of Pediatric... Jul 2017Branchio-oto-renal (BOR) syndrome is an autosomal dominant genetic disorder characterized by second branchial arch anomalies, hearing impairment, and renal...
INTRODUCTION
Branchio-oto-renal (BOR) syndrome is an autosomal dominant genetic disorder characterized by second branchial arch anomalies, hearing impairment, and renal malformations. Pathogenic mutations have been discovered in several genes such as EYA1, SIX5, and SIX1. However, nearly half of those affected reveal no pathogenic variant by traditional genetic testing.
METHODS AND MATERIALS
Whole Exome sequencing and/or Sanger sequencing performed in 10 unrelated families from Turkey, Iran, Ecuador, and USA with BOR syndrome in this study.
RESULTS
We identified causative DNA variants in six families including novel c.525delT, c.979T > C, and c.1768delG and a previously reported c.1779A > T variants in EYA1. Two large heterozygous deletions involving EYA1 were detected in additional two families. Whole exome sequencing did not reveal a causative variant in the remaining four families.
CONCLUSIONS
A variety of DNA changes including large deletions underlie BOR syndrome in different populations, which can be detected with comprehensive genetic testing.
Topics: Adult; Branchio-Oto-Renal Syndrome; Child, Preschool; Ecuador; Female; Humans; Intracellular Signaling Peptides and Proteins; Iran; Male; Mutation; Nuclear Proteins; Pedigree; Protein Tyrosine Phosphatases; Sequence Analysis, DNA; Turkey; United States
PubMed: 28583505
DOI: 10.1016/j.ijporl.2017.04.037