Expanding the phenotype of Wolfram syndrome: adult presentation with a novel WFS1 variant

Abstract Wolfram syndrome type 1 (WS1) is a rare autosomal recessive disorder involving diabetes mellitus, optic atrophy, and neurodegeneration, caused by biallelic WFS1 mutations. Though typically diagnosed in childhood, adult-onset cases may be missed due to variable symptom onset. We describe a 38-year-old woman with early-onset insulin-requiring, autoantibody-negative diabetes, progressive visual loss due to optic atrophy, bilateral sensorineural hearing loss, secondary amenorrhea with hyperprolactinemia, and arginine-vasopressin (AVP) deficiency. Magnetic resonance imaging (MRI) demonstrated atrophy of the optic nerves/chiasm and cerebellum. Genetic testing revealed a novel homozygous exon 8 WFS1 loss-of-function variant, which was classified as pathogenic. This case underscores the need for heightened clinical suspicion, imaging-based markers, and timely genetic testing to diagnose Wolfram syndrome in adult patients and to guide their management and eligibility for emerging trials.