BRANCHIO-OTO-RENAL (BOR) SYNDROME

Introduction. This work is devoted to the problem of embryology of the ears and kidneys. First ear and kidney abnormalities were reported in 1946 by Edith Potter’s association of crumpled and flattened ears with bilateral kidney agenesis. Ear malformations are associated with an increased frequency of clinically significant structural renal anomalies compared with the general population. These include specific multiple congenital anomaly syndromes, Townes-Brocks syndrome, branchio-oto-renal syndrome.The link can be explained by structural and functional similarities between tissues in the inner ear and in the kidney. Also, toxins that accumulate in kidney failure can damage nerves, including those in the inner ear.Goal. To study the causes, clinical manifestations of Branchio-oto-renal (BOR) syndrome. Materials and Methods. Review of modern and foreign literary sources; methods - description, analysis, abstracting.Results and discussion. Mutations in three genes, EYA1, SIX1, and SIX5, have been reported in people with BOR/BO syndrome. About 40 percent of people with this condition have a mutation in the EYA1 gene. SIX1 gene mutations are a much less common cause of the disorder. SIX5 gene mutations have been found in a small number of people with BOR syndrome, although researchers question whether mutations in this gene cause the condition. Some affected individuals originally reported to have SIX5 gene mutations were later found to have EYA1 gene mutations as well, and researchers suspect that the EYA1 gene mutations may be the actual cause of the condition in these people.The proteins produced from the EYA1, SIX1, and SIX5 genes play important roles in development before birth. The EYA1 protein interacts with several other proteins, including SIX1 and SIX5, to regulate the activity of genes involved in many aspects of embryonic development. Research suggests that these protein interactions are essential for the normal formation of many organs and tissues, including the second branchial arch, ears, and kidneys. Mutations in the EYA1, SIX1, or SIX5 gene may disrupt the proteins’ ability to interact with one another and regulate gene activity.Conclusions. The link between ear anomalies and kidney function can be explained by structural and functional similarities between tissues in the inner ear and in the kidney. Additionally, toxins that accumulate in kidney failure can damage nerves, including those in the inner ear.

P0071MOLECULAR ALTERATIONS AND THE SEARCH FOR GENETIC MODIFIERS IN BRANCHIOOTORENAL SYNDROME

Background and Aims Branchiootorenal (BOR) syndrome (MIM# 113650) is an exceedingly rare disorder of autosomal-dominant inheritance that describes the combination of branchial anomalies, structurally defective ears with associated hearing loss, and congenital anomalies of the kidney and urinary tract (CAKUT). Pathogenic variants in the developmentally important gene EYA1 have been found to underlie most instances of BOR syndrome. Given the high inter- and intrafamilial variability of phenotypic traits in BOR syndrome, renal involvement varies significantly. However, distinct somatic, genetic, or environmental factors underlying this phenomenon remain elusive. Moreover, the precise role of EYA1 in renal development and pathogenesis of BOR related kidney disease remains ill-defined. Here, we sought to investigate molecular alterations as well as genetic modifiers of renal involvement in a family segregating a previously reported (Rodríguez-Soriano et al. Pediatr Nephrol 2001) heterozygous canonical splice site variant in EYA1 (c.1698 + 1G>A, NM_000503.5). Remarkably, structural kidney anomalies led to end-stage renal disease in a two-year old boy while his father exhibited normal renal function. Method For analysis of the splice site EYA1 variant, cDNA was obtained from primary patient fibroblasts. Immunofluorescence microscopy was employed to assess the intracellular distribution of EYA1 in both patient and control fibroblasts. Semiquantitative data on cellular EYA1 abundance were obtained from immunoblotting of whole protein extracts from patient and control fibroblast cultures. As for the investigation of genetic modifiers of renal involvement in BOR syndrome, identification of candidate genes was based upon whole exome sequencing data in all four family members (the parental couple and both affected children). Analysis of variants was restricted to de novo variants and those inherited from the non-affected mother. Results The splice site EYA1 variant that was assumed to be disease-causing turned out to be pathogenic. Mutant transcript variants result from exon skipping, leading to the translation of an aberrant C-terminus. This affects the highly conserved C-terminal EYA domain that is crucial for interaction with several transcription factors (e.g., from the SIX family). In line with these findings, our imaging data demonstrate a reduced nuclear enrichment of EYA1 in the mutant case, suggesting an impaired nuclear translocation process. Immunoblotting showed an increased EYA1 abundance in mutant fibroblasts, possibly indicating compensation of gene dose effects. Data from immunofluorescence microscopy and immunoblotting are preliminary. Finally, our search for genetic modifiers of renal involvement in BOR syndrome yielded a promising candidate variant in CYP51A1 in both affected children and their mother. CYP51A1 is an essential enzyme of cholesterol synthesis and has been shown to be indispensable for embryonic development. Conclusion Here, we sought to define the molecular basis of BOR syndrome in a family segregating a canonical splice site variant in EYA1. Analysis of the splice site demonstrates pathogenicity of this very variant. Further in vitro functional analyses show reduced nuclear localization of EYA1 in mutant fibroblasts, albeit we detected an increase in EYA1 abundance. Our findings are compatible with the notion that the interaction of mutant EYA1 with various transcription factors in the cytosol is impaired, preventing nuclear translocation of the protein complex. We propose that an increase in EYA1 abundance in mutant cells constitutes a compensatory mechanism. In searching for genetic modifiers of renal involvement in BOR syndrome, we identified a candidate variant in CYP51A1. Both CYP51A1 and EYA1 are developmentally important and concurrence of pathogenic variants in both genes may impair normal renal development.

Second branchial cleft fistula in a child with genetically confirmed branchio-oto-renal (BOR) syndrome

Branchial cleft anomalies constitute 32% to 45% of all neck pathologies in the pediatric population. These disorders may be a part of a branchio-oto-renal syndrome (Melnick-Fraser syndrome), characterized by branchial arch abnormalities, preauricular pits, hearing impairment, and various types of renal anomalies. Usually, the treatment of a branchial fistula does not necessarily require extensive diagnostics. However, in patients with a congenital branchial cleft fistula associated with ear anomalies recognized during a physical examination, and history of hearing loss or similar findings in other relatives, the additional analysis should be carried out to eliminate the possibility of BOR syndrome. The aim of this study is to present a rare case of a male patient presenting complete second branchial cleft fistula, diagnosed as having BOR syndrome.

Case report of a novel mutation of the EYA1 gene in a patient with branchio-oto-renal syndrome

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disorder characterized by the coexistence of branchial cysts or fistulae, external ear malformation with pre-auricular pits or tags, hearing impairment and renal malformations. However, the presence of the main features varies in affected families. Here, we present a 16-year-old boy admitted to the Department of Nephrology at the Pediatric Clinic, University Clinical Center of Kosovo, Pristina, Republic of Kosovo because of severe renal insufficiency diagnosed 6 years ago, which progressed to end-stage renal failure. Clinical examination on readmission showed a pale, lethargic and edematous child, with auricular deformity, pre-auricular tags and pits as well as bilateral branchial fistulae. Laboratory tests revealed high blood urea nitrogen (BUN) 15.96 mmol/L and serum creatinine 633.0 µmol/L; low glomerular filtration rate (GFR) 12 mL/min./ 1.73 m2 and massive proteinuria 4+. Abdominal ultrasound showed bilateral kidney hypoplasia. A novel mutation of the EYA1 gene was confirmed. Daily hemodialysis is continuing until renal transplantation is done. This case is presented to increase awareness among general practitioners to consider BOR syndrome or other renal abnormalities in patients with branchial fistula and/ or external ear anomalies or similar findings in other family members.

Branchio-oto-renal syndrome

Branchio-oto-renal (BOR) syndrome involves branchial arch fistulas or cysts, ear malformations with hearing loss, and anomalies of the kidney. BOR syndrome is inherited in an autosomal dominant trait and is caused in most cases by mutations in the EYA1 gene. A few families with gene mutations in SIX1 or SIX5 have also been described. The variability of clinical symptoms is wide. Renal involvement is observed in the majority of cases ranging from mild anomalies (e.g. dilation or duplication of the urinary tract) to severe hypodysplasia of the kidneys which eventually lead to renal failure. Branchio-otic syndrome (BOS) is characterized by branchial arch and ear anomalies without detectable renal pathology. BOR and BOS can be seen within the same family.