WFS1-related disorders range from Wolfram syndrome (WFS) to WFS1-related low-frequency sensory hearing loss (also known as DFNA6/14/38 low-frequency sensorineural hearing loss [LFSNHL]). WFS is a progressive neurodegenerative disorder characterized by onset of diabetes mellitus and optic atrophy before age 15 years, and typically associated with sensorineural hearing loss, progressive neurologic abnormalities (ataxia, peripheral neuropathy, dementia, psychiatric illness, and urinary tract atony), and other endocrine abnormalities. Median age at death is 30 years. WFS-like disorder is characterized by sensorineural hearing loss, diabetes mellitus, psychiatric illness, and variable optic atrophy. WFS1-related LFSNHL is characterized by congenital, nonsyndromic, slowly progressive, low-frequency (<2000 Hz) sensorineural hearing loss.
Diagnosis of WFS and WFS-related disorder is based on clinical findings and molecular genetic testing of WFS1, the only gene associated with WFS1-related disorders. WFS1-related LFSNHL is diagnosed based on audiologic findings and molecular genetic testing.
WFS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing is possible if the disease-causing mutations in the family are known. WFS-like disease and WSF1-related LFSNHL are inherited in an autosomal dominant manner. Risk to offspring of an affected individual is 50%. Prenatal testing for pregnancies at increased risk for all three phenotypes is possible if the disease-causing mutation(s) in the family are known.