Hearing loss is an etiologically diverse condition with many disease-related complications and major clinical, social, and quality of life implications. As the rate of acquired hearing loss secondary to environmental causes decreases and improvements in the diagnosis of abnormalities occur, the significance of genetic factors that lead to deafness increases. Advancements in molecular biology have led to improved detection and earlier intervention in patients with hearing loss. Subsequently, earlier implementation of educational services and cochlear implant technology in patients with profound hearing loss now results in superior communication skills and enhanced language development. The aim of this review is to provide a comprehensive framework underlying the causes of hearing impairment and to detail the clinical management for patients with hereditary hearing loss. Genet Med 2007:9(7): 393-408.

Branchio-oto-renal syndrome, a phenotype consisting of hearing loss, auricular malformations, branchial arch remnants, and renal anomalies is now recognized as one of the more common forms of autosomal dominant syndromic hearing impairment. Three loci known to be associated with the BOR phenotype have been identified and two genes that act in a regulatory network have been cloned, EYA1 and SIX1. EYA1 and SIX1 are homologous to genes involved in Drosophila eye development, eyes absent gene (eya), and sine oculis (so), respectively. EYA1, a transcriptional co-activator has a conserved, 271-amino acid, C-terminal known as the Eya Domain (ED). SIX1 has two highly conserved domains; a homeodomain (HD) and a specific Six-domain (SD) whose products function as transcription factors with specific DNA-binding activity that are crucial for protein-protein interaction. To determine the molecular basis for the organ defects that occur in BOR syndrome, many studies have focused on the effects of mutations to EYA and effects of mutations of the EYA-SIX regulatory system. However, over 60% of BOR syndrome patients do not have known mutations in EYA1 and relatively little is known about mutations to SIX1. Further evaluation of SIX1 and its related target genes may provide a better understanding of the pathophysiology of BOR syndrome and offer greater clues to the disease mechanisms.

Branchio-oto-renal syndrome (BOR) is a clinically heterogeneous autosomal dominant form

Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration.

Background While obesity increases risk and negatively impacts survival for many malignancies, the prognostic implications in squamous cell carcinoma (SCC) of the oral tongue, a disease often associated with pre-diagnosis weight loss, are unknown. Methods Patients with T1–T2 oral tongue SCC underwent curative-intent resection in this single-institution study. All patients underwent nutritional assessment prior to surgery. Body mass index (BMI) was calculated from measured height and weight and categorized as obese (≥30 kg/m2), overweight (25 to 29.9 kg/m2), or normal (18.5 to 24.9 kg/m2). Clinical outcomes including disease specific survival (DSS), recurrence free survival (RFS), and overall survival (OS), were compared by BMI group using Cox regression. Results From 2000–2009, 155 patients (90 men, 65 women) of median age 57 (range 18 to 86) were included. Baseline characteristics were similar by BMI group. Obesity was significantly associated with adverse DSS compared with normal weight in univariable (hazard ratio [HR] = 2.65, 95% confidence interval [CI], 1.07 to 6.59; P = .04) and multivariable analyses (HR = 5.01; 95% CI, 1.69 to 14.81; P = .004). A consistent association was seen between obesity and worse RFS (HR =1.87; 95% CI, .90 to 3.88) and between obesity and worse OS (HR=2.03; 95% CI, .88 to 4.65) though without reaching statistical significance (P = .09 and P = .10 respectively) in multivariable analyses. Conclusions In this retrospective study, obesity was an adverse independent prognostic variable. This association may not have been previously appreciated due to confounding by multiple factors including pre-diagnosis weight loss.