title: EYA1-related disorders: two clinical cases and a literature review.
abstract: OBJECTIVE
  To delineate the diagnostic and rehabilitative aspects of syndromes that have overlapping features, we present the cases of two unrelated Caucasian males affected by hearing impairment, preauricular pits and cervical fistulae. Specific findings that are helpful in the diagnosis and management of EYA1-related disorders are highlighted.
  
  
  METHODS
  Genetic, otologic, imaging, eye and renal evaluations were conducted to achieve a detailed and comprehensive assessment, leading to the most accurate diagnosis and appropriate treatment. A literature review was also carried out.
  
  
  RESULTS
  Diagnostic criteria indicated that the two patients were affected by BOS1 (Branchio-Otic Syndrome 1). We also identified a novel sporadic missense mutation in the EYA1 gene: p.G533R (c.1597G>A, NM_000503.4), a highly conserved, heterozygotic amino acid substitution. In the other case, we identified the p.X593QextX6 (c.1777T>A, NM_000503.4) substitution. Both variants lead to isoform 1 (EYA1B and EYA1C) which is composed of 592 amino acids. Clinical and in silico evidence suggests a pathogenic role for the new mutations. Imaging evaluation revealed a complex pathology, characterized by external, inner and middle ear malformations, without renal anomalies.
  
  
  CONCLUSIONS
  Our results demonstrate the importance of considering the imaging evaluation and the complete DNA sequencing of the EYA1 gene for the differential diagnosis of deafness and related branchio-oto-renal disorders.
authors.affiliation: Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Via Giustiniani, 2, Padua, Italy. Electronic address: alessandro.castiglione@unipd.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Castiglione
authors.affiliation: Unit of Medical Genetics, IRCCS, "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy. Electronic address: s.melchionda@operapadrepio.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Melchionda
authors.affiliation: Unit of Medical Genetics, IRCCS, "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy. Electronic address: m.carella@operapadrepio.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Carella
authors.affiliation: Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Via Giustiniani, 2, Padua, Italy. Electronic address: patrizia.trevisi@unipd.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Trevisi
authors.affiliation: Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Via Giustiniani, 2, Padua, Italy. Electronic address: roberto.bovo@sanita.padova.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bovo
authors.affiliation: Neuroradiologic Unit, University of Padua, Via Giustiniani, 2, Padua, Italy. Electronic address: renzo.manara@sanita.padova.it.
authors.forename: Renzo
authors.initials: R
authors.lastname: Manara
authors.affiliation: Department of Neurosciences, Operative Unit of Otolaryngology and Otosurgery, University of Padua, Via Giustiniani, 2, Padua, Italy. Electronic address: alessandromartini@unipd.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Martini
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001301:Audiometry, Pure-Tone; D019280:Branchio-Oto-Renal Syndrome / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D007758:Ear, Inner / Q000002:abnormalities / Q000000981:diagnostic imaging; D004432:Ear, Middle / Q000002:abnormalities / Q000000981:diagnostic imaging; D005091:Exons; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D011859:Radiography; D017422:Sequence Analysis, DNA
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases
keywords: Branchio-otic; Branchio-oto-renal; Branchio-oto-ureteral; EYA1 mutations; Hearing loss; Oto-Facio-Cervical