RARE DISEASE
BOR syndrome
BOR syndrome
BOR syndrome
Synonyms: Branchiootorenal spectrum disorder, Branchiootorenal syndrome, Melnick-Fraser syndrome
Synonyms: Branchiootorenal spectrum disorder, Branchiootorenal syndrome, Melnick-Fraser syndrome
Synonyms: Branchiootorenal spectrum disorder, Branchiootorenal syndrome, Melnick-Fraser syndrome
Drug discovery
33
papers
On emerging therapies
Overview
Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by branchial arch anomalies (cysts/fistulae), hearing loss (conductive/sensorineural/mixed), and renal malformations ranging from hypoplasia to agenesis. Caused by mutations in EYA1 (40% of cases), SIX1, or SIX5 genes, it requires multidisciplinary management for otologic, renal, and craniofacial manifestations [1][2][5][9].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare otorhinolaryngological diseases, rare renal diseases, rare surgical maxillo-facial diseases, rare transplant-related disorders
Research Papers
33 drug discovery papers about BOR syndrome. Recent publications:
33 drug discovery papers about BOR syndrome. Recent publications:
categories:
Small molecules
cell therapies
2023-01-31 | [Branchio-oto-renal syndrome or branchio-oto syndrome: the clinical and genetic analysis in five Chinese families].
Objective: To screen the causative genes of five families with branchio-oto-renal syndrome (BORS) or branchio-oto syndrome(BOS) and to analyze the phenotypic characteristics and clinical management strategies of patients. Methods: Five families with BORS/BOR from December 2018 to September 2021 were recruited, information of patients, including family history and medical history, was collected, and genealogies were drawn. The examinations concerning audiology, nephrology, and radiology were performed on the affected individuals. Peripheral blood was obtained for DNA extraction, then next-generation sequencing technology was used to screen candidate variants associated with BORS/BOS. Based on patient's clinical results, the appropriate interventions were recommended and implemented. Results: Eight individuals were diagnosed with BOS or BORS. Of the eight patients, all had hearing loss, preauricular pits and ear malformations, and only four presented with branchial cleft fistulae or cysts. Except for two patients(5-I-2, 5-II-2) who did not undergo renal examination, the remaining six lacked renal abnormalities. Genetic analysis identified four likely pathogenic or pathogenic EYA1 variants (c.1715G>T, c.1140+1G>A, c.639G>C, c.1475+1G>C; NM_000503.6), and c.1715G>T was first reported in this study. Middle ear ossicular reconstruction was performed in 1-II-2,2-I-2 and 3-II-2, but did not yield the expected results; then hearing aids and cochlear implantation were recommended and achieved satisfactory results. Conclusions: Next-generation sequencing technology facilitates the diagnosis and genetic counseling of BORS/BOS. Hearing loss, preauricular pits, ear malformations and branchial cleft fistulae or cysts are the most common manifestations of patients in this study. Middle ear surgeries for improving hearing loss may have some limitations in BORS/BOS patients, and hearing aids and cochlear implantation can contribute to hearing gains. 目的： 筛查5个鳃耳（肾）综合征家系的致病基因，探讨其表型特征和临床诊疗情况。 方法： 招募2018年12月至2021年9月经临床诊断为鳃耳（肾）综合征的5个家系，收集家族史和病史信息，绘制家系图。对先证者及家系成员进行听力学、颞骨影像学及肾脏学检查。获取外周血提取DNA，利用二代高通量测序技术筛查鳃耳（肾）综合征分子病因。对确诊患者建议并实施相应临床干预。 结果： 5个家系共8人被诊断为鳃耳（肾）综合征。8例患者均存在听力损失、耳前瘘管和不同程度耳畸形，4例患有鳃裂瘘管或囊肿。除2例未明确肾脏表型，余6例经肾脏B超或CT检查未发现肾脏异常。基因检测确定4个致病或可能致病的EYA1基因变异（NM_000503.6：c.1715G>T；c.1140+1G>A；c.639G>C；c.1475+1G>C），其中c.1715G>T变异为首次报道。3例患者行听骨链重建术后，听力无明显改善，其中2例验配助听器或植入人工耳蜗而获得满意的听力康复效果。 结论： 二代高通量测序技术可辅助鳃耳（肾）综合征的诊断和遗传咨询。听力损失、耳前瘘管、耳畸形和鳃裂瘘管或囊肿是本研究鳃耳（肾）综合征患者的常见表型。鼓室探查听骨链重建对改善鳃耳（肾）综合征患者听力损失可能存在一定局限性，助听器和人工耳蜗植入可以帮助其实现听力康复。.
2022-04-25 | Cochlear implantation in Branchiootorenal syndrome - case report and review of the literature.
Branchiootorenal syndrome (BOR) manifests with branchial fistulae, otological anomalies and renal dysplasia. Management remains largely symptomatic. The most common consequence of BOR is mild-to-profound sensorineural, conductive or mixed hearing loss, where conventional hearing aids (HA) provide limited benefit. Cochlear implantation for BOR-associated hearing loss is an emerging treatment. Existing literature remains limited, centring around paediatric cases. This paper is the first to present a case of an adult/non-paediatric BOR patient receiving bilateral cochlear implants (CI), including pre- and postoperative objective and subjective hearing outcomes. Additionally, an overview of reported cases of cochlear implantation in BOR/BO patients is given. A review of the case patient's medical charts from initial visit at our tertiary center to latest follow-up was conducted. A search of the Medline database resulted in four papers on cochlear implantation in BOR/BO patients, forming the basis of a literature review on this topic. Excellent hearing outcomes were achieved after bilateral CI despite the patient's inner ear malformation. The case patient's outcomes were comparable to results reported for unselected adult, non-syndromic CI-recipients with normal inner ear anatomy. BOR patients experiencing insufficient benefit from conventional HA should be considered for cochlear implantation.
2021-05-01 | 488 Anatomical and Audiological Considerations in Branchio-otic/Branchio-oto-renal Syndrome: A Systematic Review and Narrative Synthesis
Abstract Introduction Branchio-otic/ Branchio-oto-renal syndrome (BO/BOR) is a rare autosomal dominant condition characterised by hearing loss, branchiogenic and renal anomalies. Anatomical variants, audiological outcomes and optimal management are considered. Method Systematic review and narrative synthesis. Databases searched: Medline, Pubmed, Embase, Web of Science, Cochrane Collection and ClinicalTrials.gov. No limits placed on year of publication. Results Searches identified 379 articles. Of these, 64 studies met the inclusion criteria, reporting outcomes in 503 patients from at least 104 families. In 308 patients hearing loss was categorised as sensorineural (29%), conductive (20%) and mixed (51%). Hearing outcomes were variable in terms of onset, pattern, and severity, ranging from mild to profound deafness. 43% patients presented with inner ear anomalies, 35% had middle and 36% had external ear abnormalities. In 44 studies, 58 ear operations were described. Mixed outcomes were reported in patients managed with hearing aids or middle ear surgery; however successful cochlear implantation was described in all five cases. Conclusions The anatomical and audiological profiles of patients with BO/BOR are variable. Cochlear implantation outcomes were good however the studies lacked long-term follow-up. Given the range of anatomical variants, management decisions should be made on an individual basis including full audiological and radiological assessment.
2013-06-28 | Mutational Analysis of EYA1, SIX1 and SIX5 Genes and Strategies for Management of Hearing Loss in Patients with BOR/BO Syndrome
Background Branchio-oto-renal (BOR) or branchio-otic (BO) syndrome is one of the most common forms of autosomal dominant syndromic hearing loss. Mutations in EYA1, SIX1 and SIX5 genes have been associated with BOR syndrome. In this study, clinical and genetic analyses were performed in patients with BOR/BO syndrome focusing on auditory manifestations and rehabilitation. Methods The audiologic manifestations were reviewed in 10 patients with BOR/BO syndrome. The operative findings and hearing outcome were analyzed in patients who underwent middle ear surgeries. The modality and outcome of auditory rehabilitation were evaluated. Genetic analysis was performed for EYA1, SIX1, and SIX5 genes. Results All patients presented with mixed hearing loss. Five patients underwent middle ear surgeries without successful hearing gain. Cochlear implantation performed in two patients resulted in significant hearing improvement. Genetic analysis revealed four novel EYA1 mutations and a large deletion encompassing the EYA1 gene. Conclusions Auditory rehabilitation in BOR/BO syndrome should be individually tailored keeping in mind the high failure rate after middle ear surgeries. Successful outcome can be expected with cochlear implantations in patients with BOR/BO syndrome who cannot benefit from hearing aids. The novel EYA1 mutations may add to the genotypic and phenotypic spectrum of BOR syndrome in the East Asian population.
2001-01-01 | Living renal transplantation in a child with branchio-oto-renal syndrome.
We report a case of living renal transplantation in a boy who had been undergoing continous ambulatory peritoneal dialysis (CAPD) because of end stage renal disease due to branchio-oto-renal syndrome (BOR syndrome). The coexistence of preauricular pits, hearing loss, branchial fistulae and renal anomalies is known as BOR syndrome. An 11-year-old boy had been undergoing CAPD for one year due to chronic renal failure. His medical history disclosed a slight degree of deafness, and proteinuria had been detected at three years of age. He underwent surgery for branchial cleft fistula at nine years of age, and a diagnosis of BOR syndrome was made. His family history revealed branchial clefts in both his sister and his mother. His renal function thereafter gradually deteriorated, and he underwent CAPD at ten years of age. He had several episodes of peritonitis, and therefore his parents decided to donate a kidney.His mother's renal function was slightly impaired (creatinine clearance; 72ml/min), in addition she also had a history of a branchial cleft which closed spontaneously when she was a child and complained of a slight degree of deafness. As a result, the boy's father donated his left kidney to the patient. Renal transplantation was successfully performed following the removal of the CAPD catheter, and immediate diuresis did not necessitate hemodialysis. Azathioprine, Cyclosporine A, and prednisolone were all administered for immunosuppression. The postoperative course was uneventful, and the graft has also been functioning well.
gene therapies
2026-09-01 | Abstract No: 564 A Novel De Novo EYA1 Nonsense Mutation (p.Arg361Ter) Identified by Whole-Exome Sequencing Clarifies Branchio-Oto Syndrome in a Chinese Family Presenting with Atypical Chronic Kidney Disease
Branchio-Oto syndrome (BOS) is an autosomal dominant disorder classically characterized by hearing loss, branchial defects, preauricular pits, and renal anomalies ranging from mild tubulopathy to renal hypoplasia or chronic kidney disease. However, marked phenotypic variability often leads to underdiagnosis, especially when renal involvement dominates the clinical picture while extrarenal features remain subtle. We aimed to determine the genetic etiology in a Chinese proband with suspected hereditary kidney disease and inconclusive syndromic features.
2026-04-11 | Prenatal phenotypic delineation of a de novo EYA1 likely pathogenic variant in branchio-oto-renal syndrome
Branchio-oto-renal (BOR; MIM 113650) syndrome is primarily linked to pathogenic variants in the EYA1 gene. Although over 200 pathogenic variants of the EYA1 gene have been reported, validation of the pathogenicity of novel variants and the aggregation of prenatal phenotypes are crucial to guide prenatal diagnosis. This study analyzed the clinical and genetic data of a fetus presenting with BOR syndrome. A de novo EYA1 gene variant was identified and the functional impact of this variant was validated using minigene splicing assays in vitro. Additionally, a systematic review of prenatal cases with EYA1 variants was conducted to summarize phenotypic frequencies. Prenatal ultrasound detected left ear anomaly, facial cyst and a persistent right umbilical vein. Genetic testing revealed a novel variant c.640-15G > A in the EYA1 gene. In vitro minigene assays demonstrated an aberrant effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was reclassified as likely pathogenic. Systematic literature review indicated that urinary system abnormalities and amniotic fluid anomalies were more prevalent in prenatal cases. This study adds a novel likely pathogenic variant to the EYA1 variant spectrum in BOR syndrome and suggests that certain prenatal ultrasound phenotypic markers might be strongly associated with EYA1-related diseases.
2025-10-10 | Case report of a novel GREB1L gene mutation in a patient with branchio-oto-renal syndrome.
Branchio-oto-renal (BOR) syndrome is an uncommon disorder inherited in an autosomal dominant manner. Its main clinical manifestations include branchial cleft cysts, anterior auricular fistula, hearing impairment, and kidney malformations. BOR syndrome is associated with heterozygous pathogenic variants including EYA1, SIX1, and SIX5. The study focused on a 13-year-old Chinese boy who presented with hearing impairment, renal malformations, and bony atresia of the right external auditory canal with microtia. The boy's clinical manifestations met the diagnostic criteria for BOR syndrome. Two of the boy's family members underwent clinical examination. However, neither displayed a phenotype associated with BOR syndrome. The boy and his two relatives provided blood samples for genomic DNA extraction, followed by Sanger sequencing. A novel mutation in the GREB1L gene was identified in the boy, but neither of his family members exhibited the same variant. Identifying a novel mutation in GREB1L offers valuable insights into the genotype-phenotype correlation of BOR syndrome, improving the precision of early diagnosis and promoting the advancement of personalized treatment strategies.
2025-08-12 | ASD with the Bor Syndrome: A Case Report
The branchio-auto-renal (BOR) syndrome that firstly described by Melnick is a syndrome with renal hypoplasia, hearing loss, and brankial arc defects.1,2 It has been seen approximately 1 in 40,000 births.3 Phenotypic anomalies that seen more than 20% of individuals with BOR syndrome are classified as major and less than 20% of individuals are classified as minor. Hearing loss and preauricular pitting are the most common clinical features. Renal anomalies (~%65), branchial cleft fistulae (~%50), lop ear deformity (~%35), and stenotic external auditory canals (~%30) are also common. Minor anomalies include preauricular tag, lacrimal duct aplasia, short palate, retrognathia, benign intracranial tumor, cleft palate, congenital hip dysplasia, euthyroid goiter, facial nerve paresis, gustatory lacrimation, non-rotation of the gastrointestinal tract, pancreatic duplication cyst, temporoparietal linear nevus.4 If the family history exists, a single major criterion is sufficient for diagnosis of BOR syndrome. Three major criteria or two major and two minor criteria are required for diagnosis without family history.5,6 The Autism Spectrum Disorder (ASD) is characterized by persistent inadequacies in communication, and repetitive, restricted, stereotypic behavior and the presence of information, and is classified as one of neurodevelopmental disorders in DSM-5.7 The twin studies that started and continued with Folstein and Rutter for the biological mechanisms of the ASD in 1977 show that autism has an important genetic component.8–13 Although because of the progress that has been made in advancing new genetic technologies, progress in investigating the genetic etiology of ASD in the last 10–15 years,14–16 the genetic cause of the majority of ASD cases (> 75%) is still unknown.
2025-02-03 | A novel EYA1 splicing mutation in a Chinese branchio-oto syndrome family with functional analysis and reproductive intervention.
Branchio-oto syndrome (BOS) is a group of autosomal dominant genetic diseases, multisystem disorders excluding renal anomalies. There are clinical heterogeneity and ethnic diversity in BOS, which reported in more studies in European populations than in Asian populations, with a prevalence rate of approximately 1/40000. As the most common disease-causing gene, the mutation types of EYA1 range from missense to various frameshift, splicing and nonsense variants. Although splicing mutations are one of the important factors in the disease, existed research has paid less attention to the novel mutations causing aberrant RNA splicing and their pathogenic mechanisms. Reproductive interventions that actively block the transmission of the disease to future generations have also not been reported. We had collected research samples from a three-generation Chinese family with BOS. Whole exome sequencing was applied for the screening of candidate causing gene. Minigene assay was performed to identify the aberrant splicing products, and molecular biology techniques were used to analyze the pathogenicity of potentially mistranslated proteins. pre-implantation genetic testing (PGT) has been employed to prevent hearing loss in this family based on SNP analysis. A novel mutation EYA1:c.1598-2AG>TA was identified by whole-exome sequencing and classified as harmful refer to ACMG's evidence. An aberrant RNA splicing was verified and suggested that might prematurely terminates the translation of EYA1 protein, through the minigene assay. The EYA1 truncated protein presented unstable and difficultly translocated to the nucleus, also impaired EYA1-SIX1 interactions in cytological experiments. PGT helped the proband give birth to a healthy boy. A novel splicing variant of EYA1 gene was identified in this study, and the potential molecular pathogenic mechanism was elucidated by several functional experiments. On basis above findings, we successfully implemented the first instance of using PGT to ensure the birth of a healthy offspring free from this genetic disorder.
small molecules
2025-11-03 | First-line treatment with low-dose ruxolitinib, pirfenidone, and low-dose calcineurin inhibitors leads to significant improvement in patients with bronchiolitis obliterans syndrome after allogeneic transplantation
Abstract Introduction Bronchiolitis obliterans syndrome ( BOS ) is a clinical syndrome characterized by new-onset persistent airflow limitation after hematopoietic stem cell transplantation ( HSCT ), which is one of the leading causes of late deaths after HSCT, severely restricting the ability of patients to perform their daily activities and reducing their quality of life. Traditional treatments for BOS rely on glucocorticoids combined with FAM regimens ( fluticasone + azithromycin + montelukast ) and calmodulin phosphatase inhibitors ( CNIs ), but they have limited efficacy with an even lower overall remission rate ( ORR ) and poor prognosis once progression to steroid-refractory cGVHD (SR-cGVHD) is achieved. Therefore, there is an urgent need to explore new treatments and strategies. Methods A retrospective analysis of 14 patients, 11 males and 3 females, with a median age of 19 years (7-54 years), who underwent hematopoietic stem cell transplantation combined with BOS at Henan Cancer Hospital from 2018 to 2025, including 6 cases of mild BOS, 3 cases of moderate BOS, 5 cases of severe BOS, Among them, 6 cases of mild, 3 cases of moderate, and 5 cases of severe BOS were treated with low-dose rucotinib ( 5 mg qd po) combined with piroxicam (200 mg tid po), small-dose CNI (half of the effective therapeutic concentration), and FAM first-line treatment. Patients' lung function was assessed at one and three months after treatment, with first-second forced expiratory volume (FEV1) as the primary study endpoint, and secondary endpoints including best-remission rate (BOR) at three months, no recurrence rate (NRM) at 1 year, overall survival (OS) at 1 year, and treatment-related adverse events. Results After three months of treatment, no patients had worsened according to the NIH scale. 35.7% (5 patients) had stable disease, 14.5% (2 patients) achieved partial remission (PR), and 50.0% (7 patients) achieved complete remission (CR).In terms of lung function, FEV1 improved in 85% of patients, with the largest improvement being 27.5% and the smallest only 2.6%. Only two patients showed a decrease in FEV1 (both patients had severe BOS). the 3-month best-remission rate was 64.5%, the 1-year NRM rate was 7.1% ± 6.9%, and the 1-year OS was 92.9% ± 6.9%. In terms of safety, no serious pulmonary infections occurred and no hematologic adverse events were observed. Conclusions In conclusion, the first-line treatment of BOS patients with low-dose ruxolitinib in combination with pirfenidone, low-dose CNI, and FAM had better efficacy and safety, and improved the overall survival of patients.Keywords Low-dose ruxolitinib, pirfenidone, low-dose calcineurin inhibitors, bronchiolitis obliterans syndrome, allogeneic transplantation
2024-12-26 | IPSC-induced podocytes from a BORS patient with EYA1 gene mutation showed glucocorticoid-resistant and cytoskeletal rearrangement
The primary cause of branchio-oto-renal syndrome (BORS) is mutations in the EYA1 gene. This study aimed to explore the impact and underlying mechanisms of EYA1 mutations on podocyte injury. We collected clinical and genetic data from a 4-year-old girl diagnosed with BORS and her family. Induced pluripotent stem cells (iPSC) were derived from peripheral blood mononuclear cells of both the patient and healthy individuals, which were differentiated into podocytes in vitro. RNA-seq was used to analyze differentially expressed genes in both groups. Here, the proband, along with his brother and mother, exhibited symptoms of BORS. WES analysis identified a heterozygous splicing variant at the EYA1 locus: c.1050 + 5G > A, inherited from his mother. The proband was initially glucocorticoid-resistant. After tacrolimus treatment, his urine protein/creatinine ratio significantly improved. Compared to healthy individuals, patient-derived podocytes displayed increased motility and pronounced cytoskeletal rearrangement. Dexamethasone was ineffective in ameliorating the pathological damage induced by puromycin aminonucleoside in patient-derived podocytes. RNA-Seq results indicated significant downregulation of cell adhesion molecule signaling pathway expression in patient-derived podocytes compared to healthy controls. In BORS patients with EYA1 mutations, podocytes exhibit cytoskeletal reorganization and enhanced motility in vitro while showing resistance to steroid treatment-indicating a unique damage response that warrants further investigation.
2024-01-02 | Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.
Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.
2014-04-22 | The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase
Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is posttranslationally modified by ubiquitin and that its ubiquitination level is self-limited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decrease Eya1 ubiquitination. Conversely, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1+/−; Wnt9b+/− mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and they further suggest that dysregulation of this novel axis contributes to tumorigenesis.
2014-01-29 | BOR-Syndrome-Associated Eya1 Mutations Lead to Enhanced Proteasomal Degradation of Eya1 Protein
Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.
cell therapies
2023-01-31 | [Branchio-oto-renal syndrome or branchio-oto syndrome: the clinical and genetic analysis in five Chinese families].
Objective: To screen the causative genes of five families with branchio-oto-renal syndrome (BORS) or branchio-oto syndrome(BOS) and to analyze the phenotypic characteristics and clinical management strategies of patients. Methods: Five families with BORS/BOR from December 2018 to September 2021 were recruited, information of patients, including family history and medical history, was collected, and genealogies were drawn. The examinations concerning audiology, nephrology, and radiology were performed on the affected individuals. Peripheral blood was obtained for DNA extraction, then next-generation sequencing technology was used to screen candidate variants associated with BORS/BOS. Based on patient's clinical results, the appropriate interventions were recommended and implemented. Results: Eight individuals were diagnosed with BOS or BORS. Of the eight patients, all had hearing loss, preauricular pits and ear malformations, and only four presented with branchial cleft fistulae or cysts. Except for two patients(5-I-2, 5-II-2) who did not undergo renal examination, the remaining six lacked renal abnormalities. Genetic analysis identified four likely pathogenic or pathogenic EYA1 variants (c.1715G>T, c.1140+1G>A, c.639G>C, c.1475+1G>C; NM_000503.6), and c.1715G>T was first reported in this study. Middle ear ossicular reconstruction was performed in 1-II-2,2-I-2 and 3-II-2, but did not yield the expected results; then hearing aids and cochlear implantation were recommended and achieved satisfactory results. Conclusions: Next-generation sequencing technology facilitates the diagnosis and genetic counseling of BORS/BOS. Hearing loss, preauricular pits, ear malformations and branchial cleft fistulae or cysts are the most common manifestations of patients in this study. Middle ear surgeries for improving hearing loss may have some limitations in BORS/BOS patients, and hearing aids and cochlear implantation can contribute to hearing gains. 目的： 筛查5个鳃耳（肾）综合征家系的致病基因，探讨其表型特征和临床诊疗情况。 方法： 招募2018年12月至2021年9月经临床诊断为鳃耳（肾）综合征的5个家系，收集家族史和病史信息，绘制家系图。对先证者及家系成员进行听力学、颞骨影像学及肾脏学检查。获取外周血提取DNA，利用二代高通量测序技术筛查鳃耳（肾）综合征分子病因。对确诊患者建议并实施相应临床干预。 结果： 5个家系共8人被诊断为鳃耳（肾）综合征。8例患者均存在听力损失、耳前瘘管和不同程度耳畸形，4例患有鳃裂瘘管或囊肿。除2例未明确肾脏表型，余6例经肾脏B超或CT检查未发现肾脏异常。基因检测确定4个致病或可能致病的EYA1基因变异（NM_000503.6：c.1715G>T；c.1140+1G>A；c.639G>C；c.1475+1G>C），其中c.1715G>T变异为首次报道。3例患者行听骨链重建术后，听力无明显改善，其中2例验配助听器或植入人工耳蜗而获得满意的听力康复效果。 结论： 二代高通量测序技术可辅助鳃耳（肾）综合征的诊断和遗传咨询。听力损失、耳前瘘管、耳畸形和鳃裂瘘管或囊肿是本研究鳃耳（肾）综合征患者的常见表型。鼓室探查听骨链重建对改善鳃耳（肾）综合征患者听力损失可能存在一定局限性，助听器和人工耳蜗植入可以帮助其实现听力康复。.
2022-04-25 | Cochlear implantation in Branchiootorenal syndrome - case report and review of the literature.
Branchiootorenal syndrome (BOR) manifests with branchial fistulae, otological anomalies and renal dysplasia. Management remains largely symptomatic. The most common consequence of BOR is mild-to-profound sensorineural, conductive or mixed hearing loss, where conventional hearing aids (HA) provide limited benefit. Cochlear implantation for BOR-associated hearing loss is an emerging treatment. Existing literature remains limited, centring around paediatric cases. This paper is the first to present a case of an adult/non-paediatric BOR patient receiving bilateral cochlear implants (CI), including pre- and postoperative objective and subjective hearing outcomes. Additionally, an overview of reported cases of cochlear implantation in BOR/BO patients is given. A review of the case patient's medical charts from initial visit at our tertiary center to latest follow-up was conducted. A search of the Medline database resulted in four papers on cochlear implantation in BOR/BO patients, forming the basis of a literature review on this topic. Excellent hearing outcomes were achieved after bilateral CI despite the patient's inner ear malformation. The case patient's outcomes were comparable to results reported for unselected adult, non-syndromic CI-recipients with normal inner ear anatomy. BOR patients experiencing insufficient benefit from conventional HA should be considered for cochlear implantation.
2021-05-01 | 488 Anatomical and Audiological Considerations in Branchio-otic/Branchio-oto-renal Syndrome: A Systematic Review and Narrative Synthesis
Abstract Introduction Branchio-otic/ Branchio-oto-renal syndrome (BO/BOR) is a rare autosomal dominant condition characterised by hearing loss, branchiogenic and renal anomalies. Anatomical variants, audiological outcomes and optimal management are considered. Method Systematic review and narrative synthesis. Databases searched: Medline, Pubmed, Embase, Web of Science, Cochrane Collection and ClinicalTrials.gov. No limits placed on year of publication. Results Searches identified 379 articles. Of these, 64 studies met the inclusion criteria, reporting outcomes in 503 patients from at least 104 families. In 308 patients hearing loss was categorised as sensorineural (29%), conductive (20%) and mixed (51%). Hearing outcomes were variable in terms of onset, pattern, and severity, ranging from mild to profound deafness. 43% patients presented with inner ear anomalies, 35% had middle and 36% had external ear abnormalities. In 44 studies, 58 ear operations were described. Mixed outcomes were reported in patients managed with hearing aids or middle ear surgery; however successful cochlear implantation was described in all five cases. Conclusions The anatomical and audiological profiles of patients with BO/BOR are variable. Cochlear implantation outcomes were good however the studies lacked long-term follow-up. Given the range of anatomical variants, management decisions should be made on an individual basis including full audiological and radiological assessment.
2013-06-28 | Mutational Analysis of EYA1, SIX1 and SIX5 Genes and Strategies for Management of Hearing Loss in Patients with BOR/BO Syndrome
Background Branchio-oto-renal (BOR) or branchio-otic (BO) syndrome is one of the most common forms of autosomal dominant syndromic hearing loss. Mutations in EYA1, SIX1 and SIX5 genes have been associated with BOR syndrome. In this study, clinical and genetic analyses were performed in patients with BOR/BO syndrome focusing on auditory manifestations and rehabilitation. Methods The audiologic manifestations were reviewed in 10 patients with BOR/BO syndrome. The operative findings and hearing outcome were analyzed in patients who underwent middle ear surgeries. The modality and outcome of auditory rehabilitation were evaluated. Genetic analysis was performed for EYA1, SIX1, and SIX5 genes. Results All patients presented with mixed hearing loss. Five patients underwent middle ear surgeries without successful hearing gain. Cochlear implantation performed in two patients resulted in significant hearing improvement. Genetic analysis revealed four novel EYA1 mutations and a large deletion encompassing the EYA1 gene. Conclusions Auditory rehabilitation in BOR/BO syndrome should be individually tailored keeping in mind the high failure rate after middle ear surgeries. Successful outcome can be expected with cochlear implantations in patients with BOR/BO syndrome who cannot benefit from hearing aids. The novel EYA1 mutations may add to the genotypic and phenotypic spectrum of BOR syndrome in the East Asian population.
2001-01-01 | Living renal transplantation in a child with branchio-oto-renal syndrome.
We report a case of living renal transplantation in a boy who had been undergoing continous ambulatory peritoneal dialysis (CAPD) because of end stage renal disease due to branchio-oto-renal syndrome (BOR syndrome). The coexistence of preauricular pits, hearing loss, branchial fistulae and renal anomalies is known as BOR syndrome. An 11-year-old boy had been undergoing CAPD for one year due to chronic renal failure. His medical history disclosed a slight degree of deafness, and proteinuria had been detected at three years of age. He underwent surgery for branchial cleft fistula at nine years of age, and a diagnosis of BOR syndrome was made. His family history revealed branchial clefts in both his sister and his mother. His renal function thereafter gradually deteriorated, and he underwent CAPD at ten years of age. He had several episodes of peritonitis, and therefore his parents decided to donate a kidney.His mother's renal function was slightly impaired (creatinine clearance; 72ml/min), in addition she also had a history of a branchial cleft which closed spontaneously when she was a child and complained of a slight degree of deafness. As a result, the boy's father donated his left kidney to the patient. Renal transplantation was successfully performed following the removal of the CAPD catheter, and immediate diuresis did not necessitate hemodialysis. Azathioprine, Cyclosporine A, and prednisolone were all administered for immunosuppression. The postoperative course was uneventful, and the graft has also been functioning well.
gene therapies
2026-09-01 | Abstract No: 564 A Novel De Novo EYA1 Nonsense Mutation (p.Arg361Ter) Identified by Whole-Exome Sequencing Clarifies Branchio-Oto Syndrome in a Chinese Family Presenting with Atypical Chronic Kidney Disease
Branchio-Oto syndrome (BOS) is an autosomal dominant disorder classically characterized by hearing loss, branchial defects, preauricular pits, and renal anomalies ranging from mild tubulopathy to renal hypoplasia or chronic kidney disease. However, marked phenotypic variability often leads to underdiagnosis, especially when renal involvement dominates the clinical picture while extrarenal features remain subtle. We aimed to determine the genetic etiology in a Chinese proband with suspected hereditary kidney disease and inconclusive syndromic features.
2026-04-11 | Prenatal phenotypic delineation of a de novo EYA1 likely pathogenic variant in branchio-oto-renal syndrome
Branchio-oto-renal (BOR; MIM 113650) syndrome is primarily linked to pathogenic variants in the EYA1 gene. Although over 200 pathogenic variants of the EYA1 gene have been reported, validation of the pathogenicity of novel variants and the aggregation of prenatal phenotypes are crucial to guide prenatal diagnosis. This study analyzed the clinical and genetic data of a fetus presenting with BOR syndrome. A de novo EYA1 gene variant was identified and the functional impact of this variant was validated using minigene splicing assays in vitro. Additionally, a systematic review of prenatal cases with EYA1 variants was conducted to summarize phenotypic frequencies. Prenatal ultrasound detected left ear anomaly, facial cyst and a persistent right umbilical vein. Genetic testing revealed a novel variant c.640-15G > A in the EYA1 gene. In vitro minigene assays demonstrated an aberrant effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was reclassified as likely pathogenic. Systematic literature review indicated that urinary system abnormalities and amniotic fluid anomalies were more prevalent in prenatal cases. This study adds a novel likely pathogenic variant to the EYA1 variant spectrum in BOR syndrome and suggests that certain prenatal ultrasound phenotypic markers might be strongly associated with EYA1-related diseases.
2025-10-10 | Case report of a novel GREB1L gene mutation in a patient with branchio-oto-renal syndrome.
Branchio-oto-renal (BOR) syndrome is an uncommon disorder inherited in an autosomal dominant manner. Its main clinical manifestations include branchial cleft cysts, anterior auricular fistula, hearing impairment, and kidney malformations. BOR syndrome is associated with heterozygous pathogenic variants including EYA1, SIX1, and SIX5. The study focused on a 13-year-old Chinese boy who presented with hearing impairment, renal malformations, and bony atresia of the right external auditory canal with microtia. The boy's clinical manifestations met the diagnostic criteria for BOR syndrome. Two of the boy's family members underwent clinical examination. However, neither displayed a phenotype associated with BOR syndrome. The boy and his two relatives provided blood samples for genomic DNA extraction, followed by Sanger sequencing. A novel mutation in the GREB1L gene was identified in the boy, but neither of his family members exhibited the same variant. Identifying a novel mutation in GREB1L offers valuable insights into the genotype-phenotype correlation of BOR syndrome, improving the precision of early diagnosis and promoting the advancement of personalized treatment strategies.
2025-08-12 | ASD with the Bor Syndrome: A Case Report
The branchio-auto-renal (BOR) syndrome that firstly described by Melnick is a syndrome with renal hypoplasia, hearing loss, and brankial arc defects.1,2 It has been seen approximately 1 in 40,000 births.3 Phenotypic anomalies that seen more than 20% of individuals with BOR syndrome are classified as major and less than 20% of individuals are classified as minor. Hearing loss and preauricular pitting are the most common clinical features. Renal anomalies (~%65), branchial cleft fistulae (~%50), lop ear deformity (~%35), and stenotic external auditory canals (~%30) are also common. Minor anomalies include preauricular tag, lacrimal duct aplasia, short palate, retrognathia, benign intracranial tumor, cleft palate, congenital hip dysplasia, euthyroid goiter, facial nerve paresis, gustatory lacrimation, non-rotation of the gastrointestinal tract, pancreatic duplication cyst, temporoparietal linear nevus.4 If the family history exists, a single major criterion is sufficient for diagnosis of BOR syndrome. Three major criteria or two major and two minor criteria are required for diagnosis without family history.5,6 The Autism Spectrum Disorder (ASD) is characterized by persistent inadequacies in communication, and repetitive, restricted, stereotypic behavior and the presence of information, and is classified as one of neurodevelopmental disorders in DSM-5.7 The twin studies that started and continued with Folstein and Rutter for the biological mechanisms of the ASD in 1977 show that autism has an important genetic component.8–13 Although because of the progress that has been made in advancing new genetic technologies, progress in investigating the genetic etiology of ASD in the last 10–15 years,14–16 the genetic cause of the majority of ASD cases (> 75%) is still unknown.
2025-02-03 | A novel EYA1 splicing mutation in a Chinese branchio-oto syndrome family with functional analysis and reproductive intervention.
Branchio-oto syndrome (BOS) is a group of autosomal dominant genetic diseases, multisystem disorders excluding renal anomalies. There are clinical heterogeneity and ethnic diversity in BOS, which reported in more studies in European populations than in Asian populations, with a prevalence rate of approximately 1/40000. As the most common disease-causing gene, the mutation types of EYA1 range from missense to various frameshift, splicing and nonsense variants. Although splicing mutations are one of the important factors in the disease, existed research has paid less attention to the novel mutations causing aberrant RNA splicing and their pathogenic mechanisms. Reproductive interventions that actively block the transmission of the disease to future generations have also not been reported. We had collected research samples from a three-generation Chinese family with BOS. Whole exome sequencing was applied for the screening of candidate causing gene. Minigene assay was performed to identify the aberrant splicing products, and molecular biology techniques were used to analyze the pathogenicity of potentially mistranslated proteins. pre-implantation genetic testing (PGT) has been employed to prevent hearing loss in this family based on SNP analysis. A novel mutation EYA1:c.1598-2AG>TA was identified by whole-exome sequencing and classified as harmful refer to ACMG's evidence. An aberrant RNA splicing was verified and suggested that might prematurely terminates the translation of EYA1 protein, through the minigene assay. The EYA1 truncated protein presented unstable and difficultly translocated to the nucleus, also impaired EYA1-SIX1 interactions in cytological experiments. PGT helped the proband give birth to a healthy boy. A novel splicing variant of EYA1 gene was identified in this study, and the potential molecular pathogenic mechanism was elucidated by several functional experiments. On basis above findings, we successfully implemented the first instance of using PGT to ensure the birth of a healthy offspring free from this genetic disorder.
small molecules
2025-11-03 | First-line treatment with low-dose ruxolitinib, pirfenidone, and low-dose calcineurin inhibitors leads to significant improvement in patients with bronchiolitis obliterans syndrome after allogeneic transplantation
Abstract Introduction Bronchiolitis obliterans syndrome ( BOS ) is a clinical syndrome characterized by new-onset persistent airflow limitation after hematopoietic stem cell transplantation ( HSCT ), which is one of the leading causes of late deaths after HSCT, severely restricting the ability of patients to perform their daily activities and reducing their quality of life. Traditional treatments for BOS rely on glucocorticoids combined with FAM regimens ( fluticasone + azithromycin + montelukast ) and calmodulin phosphatase inhibitors ( CNIs ), but they have limited efficacy with an even lower overall remission rate ( ORR ) and poor prognosis once progression to steroid-refractory cGVHD (SR-cGVHD) is achieved. Therefore, there is an urgent need to explore new treatments and strategies. Methods A retrospective analysis of 14 patients, 11 males and 3 females, with a median age of 19 years (7-54 years), who underwent hematopoietic stem cell transplantation combined with BOS at Henan Cancer Hospital from 2018 to 2025, including 6 cases of mild BOS, 3 cases of moderate BOS, 5 cases of severe BOS, Among them, 6 cases of mild, 3 cases of moderate, and 5 cases of severe BOS were treated with low-dose rucotinib ( 5 mg qd po) combined with piroxicam (200 mg tid po), small-dose CNI (half of the effective therapeutic concentration), and FAM first-line treatment. Patients' lung function was assessed at one and three months after treatment, with first-second forced expiratory volume (FEV1) as the primary study endpoint, and secondary endpoints including best-remission rate (BOR) at three months, no recurrence rate (NRM) at 1 year, overall survival (OS) at 1 year, and treatment-related adverse events. Results After three months of treatment, no patients had worsened according to the NIH scale. 35.7% (5 patients) had stable disease, 14.5% (2 patients) achieved partial remission (PR), and 50.0% (7 patients) achieved complete remission (CR).In terms of lung function, FEV1 improved in 85% of patients, with the largest improvement being 27.5% and the smallest only 2.6%. Only two patients showed a decrease in FEV1 (both patients had severe BOS). the 3-month best-remission rate was 64.5%, the 1-year NRM rate was 7.1% ± 6.9%, and the 1-year OS was 92.9% ± 6.9%. In terms of safety, no serious pulmonary infections occurred and no hematologic adverse events were observed. Conclusions In conclusion, the first-line treatment of BOS patients with low-dose ruxolitinib in combination with pirfenidone, low-dose CNI, and FAM had better efficacy and safety, and improved the overall survival of patients.Keywords Low-dose ruxolitinib, pirfenidone, low-dose calcineurin inhibitors, bronchiolitis obliterans syndrome, allogeneic transplantation
2024-12-26 | IPSC-induced podocytes from a BORS patient with EYA1 gene mutation showed glucocorticoid-resistant and cytoskeletal rearrangement
The primary cause of branchio-oto-renal syndrome (BORS) is mutations in the EYA1 gene. This study aimed to explore the impact and underlying mechanisms of EYA1 mutations on podocyte injury. We collected clinical and genetic data from a 4-year-old girl diagnosed with BORS and her family. Induced pluripotent stem cells (iPSC) were derived from peripheral blood mononuclear cells of both the patient and healthy individuals, which were differentiated into podocytes in vitro. RNA-seq was used to analyze differentially expressed genes in both groups. Here, the proband, along with his brother and mother, exhibited symptoms of BORS. WES analysis identified a heterozygous splicing variant at the EYA1 locus: c.1050 + 5G > A, inherited from his mother. The proband was initially glucocorticoid-resistant. After tacrolimus treatment, his urine protein/creatinine ratio significantly improved. Compared to healthy individuals, patient-derived podocytes displayed increased motility and pronounced cytoskeletal rearrangement. Dexamethasone was ineffective in ameliorating the pathological damage induced by puromycin aminonucleoside in patient-derived podocytes. RNA-Seq results indicated significant downregulation of cell adhesion molecule signaling pathway expression in patient-derived podocytes compared to healthy controls. In BORS patients with EYA1 mutations, podocytes exhibit cytoskeletal reorganization and enhanced motility in vitro while showing resistance to steroid treatment-indicating a unique damage response that warrants further investigation.
2024-01-02 | Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.
Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.
2014-04-22 | The Canonical Wnt Signal Restricts the Glycogen Synthase Kinase 3/Fbw7-Dependent Ubiquitination and Degradation of Eya1 Phosphatase
Haploinsufficiency of Eya1 causes the branchio-oto-renal (BOR) syndrome, and abnormally high levels of Eya1 are linked to breast cancer progression and poor prognosis. Therefore, regulation of Eya1 activity is key to its tissue-specific functions and oncogenic activities. Here, we show that Eya1 is posttranslationally modified by ubiquitin and that its ubiquitination level is self-limited to prevent premature degradation. Eya1 has an evolutionarily conserved CDC4 phosphodegron (CPD) signal, a target site of glycogen synthase kinase 3 (GSK3) kinase and Fbw7 ubiquitin ligase, which is required for Eya1 ubiquitination. Genetic deletion of Fbw7 and pharmacological inhibition of GSK3 significantly decrease Eya1 ubiquitination. Conversely, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the canonical Wnt signal suppresses Eya1 ubiquitination. Compound Eya1+/−; Wnt9b+/− mutants exhibit an increased penetrance of renal defect, indicating that they function in the same genetic pathway in vivo. Together, these findings reveal that the canonical Wnt and PI3K/Akt signal pathways restrain the GSK3/Fbw7-dependent Eya1 ubiquitination, and they further suggest that dysregulation of this novel axis contributes to tumorigenesis.
2014-01-29 | BOR-Syndrome-Associated Eya1 Mutations Lead to Enhanced Proteasomal Degradation of Eya1 Protein
Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1.
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