Mutations in the Wolfram syndrome type 1 gene (WFS1) define a clinical entity of dominant low-frequency sensorineural hearing loss.

OBJECTIVE To describe low-frequency sensorineural hearing loss (LFSNHL) inherited as a dominant trait in 3 families and in 1 sporadic case. DESIGN Longitudinal clinical study from 1968 to 2001. SETTING Tertiary care hospital; field studies conducted by molecular genetic research laboratory. PARTICIPANTS Dominant LFSNHL families. INTERVENTIONS Questionnaires, serial audiograms, and interviews, correlated with molecular genetic data. OUTCOME MEASURES Symptoms, age of onset, serial audiometric data, and hearing aid use. RESULTS Low-frequency sensorineural hearing loss is typically diagnosed in the first decade and slowly progresses over decades; LFSNHL is often asymptomatic in young patients, few of whom use hearing aids. Speech perception becomes affected in later decades when patients develop high-frequency loss. Even children with a strong family history of dominant LFSNHL were not monitored routinely. Penetrance appears complete in that all individuals with a genetic mutation developed hearing loss. CONCLUSIONS Dominant LFSNHL is most commonly caused by mutations in the Wolfram syndrome type 1 gene (WFS1). Mutations in WFS1 also cause a rare recessive syndromic form of hearing loss known as Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Routine newborn hearing screening methods will not typically identify hearing loss affecting frequencies below 2000 Hz; thus, children at risk must be specifically monitored. Genetic counseling and genetic testing may be useful in the management of patients with this type of hearing loss.