Wolfram syndrome 1 is an autosomal recessive disorder often commencing as insulin dependent diabetes, but with inherent progressive ultimately fatal neurodegeneration. We report two pediatric cases, referred as unregulated insulin dependent diabetes mellitus, initially misdiagnosed as type 1 diabetes, in whom whole exome sequencing confirmed the clinical diagnosis of Wolfram syndrome with novel Wolfram syndrome gene 1 variants. An 11-year-old Asian male refugee with presumed type 1 diabetes since the age of 6 years, acknowledged progressive visual decline the last 6 months, but only after ophthalmological evaluation revealing bilateral optic atrophy, confirmed by optical coherence tomography and retinal nerve fiber layer thinning, leading to genetic testing and revealing a novel homozygous missense variant (c.1598C>T, p.Pro533Leu). A 15-year-old male with severely progressive autism spectrum disorder since the age of 3 years, and poorly regulated presumed type 1 diabetes since the age of 9 years, had signs of a progressive neurodegenerative disorder at presentation. Bilateral optic nerve pallor and sensorineural hearing loss were documented. Genetic testing revealed the pathogenic Wolfram syndrome gene 1 variant c.1523_1524delTA; p.Tyr508CysfsTer34 (frameshift deletion) in trans with the previously undescribed missense variant c.497T>C; p.Leu166Pro, reclassified now as likely pathogenic. Both cases highlight the importance of ophthalmological evaluation in the early diagnostic workup of pediatric insulin dependent diabetes when autoimmunity is not confirmed. Although not mandated by current guidelines, early ophthalmologic assessment, at least in insulin dependent diabetes with non-previously established autoimmunity, can enable timely diagnosis of Wolfram syndrome, enabling prompt multidisciplinary intervention and potential enrollment in emerging disease-modifying therapies.

Novel mutation

Ophthalmological examination

Optic atrophy

Wolfram syndrome

WFS1 gene

© 2025 The Author(s). Published by Elsevier Masson SAS.