Genetic research progress in branchio-oto syndrome/ branchio-oto-renal syndrome / 中南大学学报(医学版)

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 EYA1 gene which is the most important cause of BOS/BORS. A total of 240 kinds of pathogenic variations of EYA1 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 EYA1 chromosomal fragment deletion mutations caused by non-allelic homologous recombination. EYA1 encodes a phosphatase-transactivator cooperated with transcription factors of SIX1, 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 SIX1 and SIX5 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 SIX5 gene in the pathogenesis of BORS needs further verification.

Genetic analysis of a Chinese pedigree affected with branchiootic syndrome due to a nonsense variant of EYA1 gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic basis for a Chinese pedigree suspected for branchiootic syndrome (BOS).@*METHODS@#The proband was subjected to target-capture high-throughput sequencing to detect potential variant of deafness-associated genes. Candidate variants were verified by Sanger sequencing of the family members.@*RESULTS@#The proband was found to harbor a c.1627C>T (p.Gln543Ter) nonsense variant of the EYA1 gene. Sanger sequencing confirmed that all of the 4 patients with the BOS phenotype from the pedigree have harbored the same heterozygous variant. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be pathogenic (PVS1+PS+PP3+PP4).@*CONCLUSION@#The c.1627C>T (p.Gln543Ter) variant of the EYA1 gene probably underlay the BOS phenotype in this pedigree. Above finding has provided a basis for its clinical diagnosis.

Identification and genetic analysis of new mutations in EYA1 gene of BOS syndrome / 中华耳鼻咽喉头颈外科杂志

Objective: To analyze the clinical manifestations of a patient with branchiootic syndrome(BOS) and her families and to carry out genetic testing in order to specify the biological pathogenesis. Methods: Clinical data of the patient and her families were collected. Genomic DNA in the peripheral blood of the proband and her family members was extracted. All exons of 406 deafness-related susceptible genes as well as their flanking regions were sequenced by high-throughput sequencing, and the mutation sites of the proband and her parents were validated by Sanger sequencing. Results: There were nine members in three generations, of whom four presented with hearing loss, preauricular fistula and branchial fistula which met the diagnostic criteria of BOS. Proband and her mother presented with auricle malformation and inner ear malformation. And no one had abnormalities in the kidneys of all the patients. Pedigree analysis revealed that the mode of inheritance in the family was consistent with the autosomal dominant pattern. Mutational analysis showed that all the affected patients detected a heterozygous frameshift variation c.1255delT in the EYA1 gene, which had not been reported. Genotype and phenotype were co-isolated in this family. Such a frameshift variation produced a premature termination codon, thereby causing premature termination of translation (p.C419VFS*12). ACMG identified that the mutation was pathogenic. This mutation was novel and not detected in controls. A heterozygous missense variation mutation c.403G>A(p.G135S) in EYA1 gene was also detected in three members of this family. ACMG identified that the mutation clinical significance was uncertain. However, two of whom were normal, which seemed the disease was not caused by this mutation in this family. Conclusions: A novel frameshift mutation in EYA1(c.1255delT) is the main molecular etiology of BOS in the Chinese family. This study expands the mutational spectrum of EYA1 gene. The clinical manifestations are heterogeneous among patients in this family. The diagnosis of BOS should combine gene tests with clinical phenotypes analysis.

Alterações funcionais e estruturais do complexo craniofacial na síndrome branquio-óculo-facial: relato de caso / Functional and structural alterations of the craniofacial complex in the branchio-oculo-facial syndrome: case report / Alteraciones funcionales y estructurales del complejo craneofacial en el síndrome branquio-óculo-facial: relato de caso

Objetivo: Descrever características clínicas, alterações funcionais e estruturais de complexo craniofacial de sujeito com síndrome branquio-óculo-facial. Método: Paciente de 13 anos e 3 meses, respiradora oral com perda auditiva condutiva de grau moderadamente severo em ambas as orelhas, diagnosticada com síndrome branquio-óculo-facial, apresentou: fissura labiopalatina transforame bilateral completa corrigida por labioplastia e palatoplastia primárias, assimetria facial, fístula em região anterior de palato duro, atresia maxilar transversa, dentinogênese imperfeita, trespasse horizontal negativo, oclusão Classe I de Angle e mordida aberta anterior e lateral bilateralmente, desvio severo da linha média superior para a esquerda, incisivo lateral superior permanente semi-erupcionado por vestibular do canino superior decíduo do lado esquerdo, retenção prolongada do segundo molar inferior decíduo direito, apinhamento dentário inferior, hipotonia e posicionamento inadequado de língua, ausência de vedamento labial em repouso, deglutição adaptada, alteração na mobilidade de lábios, bochechas e palato mole com escape de ar nasal na fala, caracterizando disfunção velofaríngea. Sujeitos com fissura lábiopalatina podem apresentar grande variedade de alterações na produção dos fones. Paciente apresenta crescimento deficiente da maxila que, como relatado na literatura, pode alterar o desenvolvimento do terço médio da face com repercussão na oclusão dentária, fala e formato do nariz. Conclusão: As alterações clínicas funcionais e estruturais relatadas são na maioria do complexo craniofacial, demonstrando a importância da otorrinolaringologia, fonoaudiologia e odontologia na terapêutica interdisciplinar dos pacientes com a síndrome.

Introduction: Branchio-Oculo-Facial Syndrome (BOFS) is a rare autosomal disease with variable expression, dependent on genetic mutations, whose phenotype is characterized by ocular, hearing and craniofacial alterations. Purpose: describe the clinical features, the functional and structural alterations in the craniofacial complex of a subject with branchio-oculo-facial syndrome. Method: A 13-year and 3-month-old girl, with moderately severe conductive bilateral hearing loss diagnosed with BOFS, presented: bilateral cleft lip and palate treated by labioplasty and palatoplasty, facial asymmetry, anterior maxillary fistula, transverse maxillary atresia, imperfect dentinogenesis, negative horizontal trespass, Angle Class I bilateral, anterior and lateral open bite on both sides, severe left superior midline deviation, eruption by vestibular of the superior canine on the left side, prolonged retention of the second inferior molar right deciduous, lower dental crowding, hypotonia and inadequate tongue positioning, absence of labial resting at rest, adapted swallowing, alteration in mobility of lips, cheeks and palate with nasal air exhaust in speech, characterizing velopharyngeal dysfunction. There are few publications of BOFS, given its rarity. Subjects with cleft lip and palate may present a wide variety of changes in the production of headphones. Patient presents deficient growth of the maxilla which, as reported in the literature, may alter the development of the middle third of the face with repercussion in dental occlusion, speech and nose shape. Conclusion: The functional and structural clinical alterations reported are the majority of the craniofacial complex, demonstrating the importance of otorhinolaryngology, speech therapy and orthodontics in the interdisciplinary therapy of patients with BOFS.

Introducción: El síndrome branquio-oculo-facial (BOFS) es una enfermedad autosómica rara con expresión variable, dependiente de las mutaciones genéticas, caracterizada por alteraciones oculares, auriculares y craneofaciales. Propósito: describir características clínicas, alteraciones funcionales y estructurales del complejo craneofacial de un sujeto con BOFS. Método: Niña de 13 años y 3 meses de edad, con pérdida de audición conductiva moderadamente grave bilateralmente diagnosticada con SBOF, presentó: paladar y labio hendido bilateral tratado por labioplastia y palatoplastia primarias, asimetría facial, fístula maxilar anterior, atresia maxilar transversal, dentinogénesis imperfecta, traspaso horizontal negativo, clase I de Angle bilateral, mordida abierta anterior y lateral bilateralmente, desviación severa de la línea media superior izquierda, erupción vestibular del canino superior del lado izquierdo, retención prolongada del segundo molar inferior derecho deciduo, apiñamiento dental, hipotonía e inadecuada colocación de la lengua, ausencia de sello labial en reposo, deglución adaptada, alteración de movilidad de labios, mejillas y velo del paladar con escape de aire nasal y disfunción velofaríngea Hay pocas publicaciones de BOFS, dada su rareza. Los sujetos con labio y paladar hendido pueden presentar una gran variedad de cambios en la producción de auriculares. El paciente presenta crecimiento deficiente del maxilar que, según se informa en la literatura, puede alterar el desarrollo del tercio medio de la cara con repercusión en la oclusión dental, habla y la forma de la nariz. Conclusión: Alteraciones clínicas funcionales y estructurales la mayoría del complejo craniofacial. Eso demuestra la importancia de otorrinolaringología, fonoaudiología y odontología en la terapia interdisciplinaria de pacientes con SBOF.;Introdução: A Síndrome Branquio-Óculo-Facial é uma doença autossômica rara com expressão variável, dependente das mutações genéticas, cujo fenótipo caracteriza-se por alterações oculares, auriculares e craniofaciais.

Prenatal diagnosis of a case with Branchi-oto-renal syndrome / 中华医学遗传学杂志

OBJECTIVE@#To carry out prenatal diagnosis for a women with Branchio-oto-renal syndrome by using chromosomal microarray analysis (CMA).@*METHODS@#Peripheral blood chromosomal karyotyping and CMA were used to analyze the gravida with an abnormal phenotype. Pathological copy number variants (CNVs) were validated in other members of the family members and her fetus.@*RESULTS@#The gravida and her daughter both had Branchio-oto-renal syndrome and a 8q13.3 microdeletion encompassing the EYA1 gene. The same microdeletion was also found in the fetus. No phenotypic or genotypic anomaly was found with other members of the family.@*CONCLUSION@#Mutation of the EYA1 gene probably underlies the Branchio-oto-renal syndrome in this family, which is consistent with an autosomal dominant inheritance.

Renal Failure with Branchio-Oto-Renal Syndrome / 대한내과학회지

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder that is characterized by preauricular pits, branchial fistula, branchial cyst, hearing impairment, and kidney anomalies. Hearing impairment is the single most common feature of BOR syndrome, affecting 89% of patients. Preauricular pits (77%), kidney anomalies (66%), branchial fistula (63%), external auditory canal anomalies (41%) are also common. For most patients, BOR syndrome does not affect life expectancy. The major life-threatening feature of this condition is kidney dysfunction, which occurs with about 6% of kidney anomalies. Therefore, once BOR syndrome is recognized in a patient, careful evaluation to detect renal anomalies and treatment of any kidney involvement are necessary. No case reports of BOR syndrome involving adult-onset end-stage kidney disease have been published in the Korean medical literature. We report a case of end-stage kidney disease in a 19-year-old male patient with BOR syndrome, together with a review of the pertinent literature.

Anesthetic management of a patient with branchio-oto-renal syndrome

Branchio-oto-renal syndrome (BOR) is a rare autosomal dominant disorder. The features include branchial cysts, hearing loss, ear malformation, preauricular pits, retrognathia, congenital heart disease, and renal abnormalities. However, anesthetic management of these patients has seldom been reported. We report a case in which general anesthesia was performed for dental treatment in a patient with BOR. Airway management, renal function, and hemodynamic changes can be of critical concern during anesthetic management. A 13-year-old girl diagnosed with BOR had severe right hearing loss, right external ear malformation, renal abnormalities, and postoperative patent ductus arteriosus (PDA). Dental extraction under general anesthesia was scheduled for a supernumerary tooth. The procedure was completed with sufficient urine volume, adequate airway management, and stable hemodynamics.

Nuevas manifestaciones orales del síndrome branquio-óculo-facial: Caso clínico / New oral manifestations of Branchio-oculo-facial syndrome: Case report

El síndrome branquio-óculo-facial es una condición autosómica dominante con expresividad variable y que afecta particularmente las estructuras de la cara y cuello por un desarrollo inadecuado del primero y segundo arco branquial; presenta malformaciones de los ojos y oídos, con características faciales distintivas. Está asociado con alteraciones en el gen TFAP2A. Se presenta una paciente de 9 años con fenotipo de síndrome branquio-óculo-facial y la presencia de dos nuevas manifestaciones orales, la úvula bifida y la lengua con hendidura central parcial, no descritas hasta ahora en esta condición clínica.

The branchio-oculo-facial syndrome is a dominant autosomic condition with variable expressivity that affects particularly the facial and neck structures by an inadequate development of the first and second branchial arch. It is characterized by malformations of eyes and ears, with distinct facial characteristics. It is associated with alterations in TFAP2A gene. We present a patient with 9 years of age with phenotype of the branchio-oculo-facial syndrome and the presence of 2 new oral manifestations, the bifid uvula and the tongue with partial central cleft, not yet described in this clinical condition.

Anatomical Changes and Audiological Profile in Branchio-oto-renal Syndrome: A Literature 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...

A Case of Branchio-Otic Syndrome / 대한이비인후과학회지

Branchio-oto-renal (BOR) syndrome is a clinically heterogeneous autosomal dominant form of syndromic hearing loss characterized by variable hearing impairment, malformations of the pinnae, the presence of branchial arch remnants, and various renal abnormalities. BOR syndrome is caused by mutations in EYA1 and SIX1, which are critical to organogenesis and are expressed together in developing otic, branchial, and renal tissue. Branchio-otic (BO) syndrome comprises branchial fistulas and preauricular pits, but lacks renal anomalies. We present a case of BO syndrome in 30year-old man with a review of the literature.

A Case of Branchio-Oto-Renal Syndrome / 대한이비인후과학회지

The branchio-oto-renal (BOR) syndrome is a clinically and genetically heterogeneous disease entity which is characterized by the association of preauricular pits, branchial cleft anomaly, hearing loss and various renal anomalies. The incidence of BOR syndrome is approximately 1 : 40,000 and its genetic pattern of transmission is autosomal dominant. Hearing loss is the most common feature of BOR syndrome and is reported in almost 90% of affected individuals. EYA1, the human homologue of the Drosophila eyes absent gene, has been shown to cause BOR syndrome. We report, with a review of literatures, a female patient with BOR syndrome.

Síndrome branquio-oto-renal: relato de caso / Branchiootorenal syndrome (BOR): case report

Introdução: A Síndrome Branquio-Otorrenal é uma doença autossômica dominante de expressividade variável e alta, porém provavelmente de penetrância incompleta. Manifesta-se através de anormalidades do segundo arco branquial (fossetas pré-auriculares, fístulas ou cistos branquiais, entre outras) associadoa anormalidades renais (desde hipoplasia até agenesia renal). Objetivo: Nosso objetivo com o presente relato de caso é estimular a investigação precoce nas alterações renais em pacientes com defeitos otorrinolaringológicos, o que implica melhor prognóstico e qualidade de vida para os acometidos. Relatode caso: Relatamos a evolução de um caso de Síndrome Branquio-Otorrenal em paciente acompanhada há13 anos no ambulatório de nefrologia da Faculdade de Medicina de Marília. A paciente em questão apresenta anormalidades como fístula pré-auricular e fenda branquial, além de hipoacusia do tipo mista,com a concomitância de anormalidades renais. Discussão: Discutimos o diagnóstico a partir da pacienterelatada, bem como as manifestações da síndrome e o tratamento apropriado. Conclusão: Concluímos que o diagnóstico é simples de ser realizado, e sua detecção precoce propicia menor morbi-mortalidade.

Introduction: Branchiootorenal Syndrome (BOR) is an autosomal dominant disease with a high and variable expression, but probably with an incomplete penetrance. It manifests itself through the second branchial arch abnormalities (pre-auricular pits, branchial fistulae or cysts) associated with renal abnormalities (ranging from renal agenesis to hypoplasia). Objective: Our goal is to stimulate early investigation of renal changes in patients with ear and neck defects implying in a better prognosis and quality of life for those affected by BOR. Case report: We report a case of branchiootorenal syndrome development in a patient followed up for 13 years at the nephrology outpatient clinic of the Faculdade de Medicina de Marília). The patient presented with abnormalities that consisted in pre-auricular andbranchial clefts, mixed hearing loss, and renal defect. Discussion: We discuss the diagnosis as well as the manifestations of the syndrome and the appropriate treatment. Conclusion: We conclude that the diagnosis is simple to perform, and its early detection provides less morbidity and mortality.

Síndrome brânquio-óculo-facial (BOFS) e cardiopatias congênitas / Síndrome branquio-óculo facial (BOFS) y cardiopatías congénitas / Branchio-oculo-facial syndrome (BOFS) and congenital heart defects

Relatamos aqui o caso de um menino com 43 dias de vida, apresentando síndrome brânquio-óculo-facial (BOFS) e cardiopatia congênita. Na avaliação clínica, ele possuía retardo de crescimento, pregas epicânticas, fendas palpebrais pequenas, telecanto, base nasal alargada, fenda labial falsa (pseudocleft), micrognatia, orelhas displásicas e rotadas posteriormente, fendas branquiais, pescoço curto e alado, mamilo extranumerário, hipotonia e reflexos tendinosos profundos diminuídos. A ecocardiografia verificou presença de um defeito do septo atrioventricular completo do tipo A e persistência do canal arterial. Essa descrição fortalece a possibilidade de que defeitos cardíacos congênitos possam fazer parte do espectro de anormalidades observado na BOFS.

We report the case of a 43-day-old boy with branchio-oculo-facial syndrome (BOFS) and congenital heart defect. On clinical examination, he presented growth retardation, epicanthal folds, small palpebral fissures, telecanthus, broadened nasal bridge, lip pseudocleft, micrognathia, dysplastic and posteriorly-rotated ears, branchial clefts, short and webbed neck, supernumerary nipple, hypotonia and decreased deep tendon reflexes. Echocardiography showed the presence of a type-A complete atrioventricular septal defect and patent ductus arteriosus. This description strengthens the possibility of congenital heart defects being part of the spectrum of anomalies seen in BOFS.

Relatamos en este estudio el caso de un niño con 43 días de vida, que presentaba síndrome branquio óculo facial (BOFS) y cardiopatía congénita. En la evaluación clínica, revelaba retardo de crecimiento, pliegues epicánticos, hendiduras palpebrales pequeñas, telecanto, base nasal ensanchada, hendidura labial falsa (pseudocleft), micrognatia, orejas displásicas y rotadas posteriormente, hendiduras branquiales, cuello corto y alado, pezón extranumerario, hipotonía y reflejos tendinosos profundos diminuidos. La ecocardiografía verificó la presencia de un defecto del septo atrioventricular completo del tipo A y conducto arterial persistente. Dicha descripción fortalece la posibilidad de que defectos cardiacos congénitos puedan forman parte del espectro de anormalidades observado en la BOFS.

A Case of Branchio-oculo-facial Syndrome

Branchio-oculo-facial syndrome (BOFS) is a rare, autosomal dominant disorder. It is characterized by distinct craniofacial abnormalities including abnormal location of the ears, aplastic cervical skin lesions, malformed auricles, conductive hearing loss, ocular abnormalities, and cleft lip and palate. Herein, we describe a case of BOFS with persistent aplasia cutis of the neck in a 5-year-old girl.

Branchio-Oto-Renal Syndrome / 대한피부과학회지

Branchio-oto-renal (BOR) syndrome is a rare congenital anomaly that is characterized by preauricular pits, branchial fistula and hearing impairment and it is often combined with renal anomalies. BOR syndrome is inherited in an autosomal dominant mode and the mutations of two genes, EYA1 and SIX1, have been identified. We experienced a case of a 14-year-old female who complained of bilateral neck openings and hearing loss that were found at birth the girl's family had a familial tendency for these features. A skin biopsy from the cervical lesion showed the characteristic features of branchial fistula. We report here on a case of BOR syndrome and we review the relevant literature.

Branchio-oto-renal syndrome.

Branchio-oto-renal syndrome (Melnick-Fraser syndrome) is a rare autosomal dominant disorder characterized by syndromic association of branchial cysts or fistulae along with external, middle & inner ear malformations and renal anomalies. Authors are reporting a 19 year male patient, who presented with profound deafness & low set "lop-ear" with right sided preauricular pit. USG abdomen revealed agenesis of the left kidney.

Síndrome brânquio-otorrenal: um importante alerta / Branchio-oto-renal syndrome: an important warning

A síndrome brânquio-otorrenal (SBOR) é uma doença autossômica dominante, provocada por mutações em genes da organogênese humana, principalmente o gene EYA 1. Sua incidência é de 1 em 40.000 recém-nascidos vivos. As manifestações clínicas da SBOR decorrem de transtorno genético e envolvem perda auditiva de condução, neurossensorial ou mista, malformações da orelha externa, média e interna, cistos ou fístulas branquiais e anomalias renais que podem variar de hipoplasia a agenesia renal. O diagnóstico clínico da SBOR se baseia na presença de critérios clínicos. A genética molecular é de grande valor para a confirmação do diagnóstico e para estabelecer o diagnóstico pré-natal. Testes audiométricos completos e exames renais apurados são indicados a fim de mensurar com precisão a extensão dos danos causados pela doença. Sua ampla variabilidade clínica sugere, na literatura, que os diferentes fenótipos dessa síndrome representam, na realidade, grupos heterogêneos de doenças, que fazem diagnóstico diferencial, principalmente, com a síndrome brânquio-otorrenal. O tratamento se limita a reparar os danos causados pela doença, podendo estar indicado o uso de próteses auriculares ou intervenções cirúrgicas otológicas e renais, a fim de melhorar a qualidade de vida dos pacientes. O aconselhamento genético é a melhor forma de prevenção, sendo fundamental no tratamento.

Branchio-oculo-facial syndrome.

Branchio-oculo-facial syndrome (BOFS) is a very rare autosomal dominant disorder with incomplete penetrance and variable expression; with phenotypic variation ranging from mild to severe forms, involving eye, ear, oral and craniofacial structure. We report three members of one family, showing great variability in its phenotypic expression and review the recent literature.