Authors: Elif Duygu Topan , Hilal Bektas Uysal

Abstract

Background: Wolfram syndrome type 1 is a rare, autosomal recessive neurodegenerative disorder caused by pathogenic variants in the WFS1 gene. It is classically characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness, but its clinical spectrum is highly heterogeneous. Delayed recognition is common, especially when features are misattributed to diabetes complications.

Case Report: We present a 39-year-old man with insulin-dependent diabetes mellitus since adolescence, who developed progressive multisystem involvement including optic atrophy, neurogenic bladder with end-stage renal disease, psychiatric manifestations, and neurological complications. Despite early diabetes onset, Wolfram syndrome was not suspected until late in the disease course. Genetic analysis revealed a homozygous missense variant in WFS1 (c.1672C>T; p.Arg558Cys), previously described as a founder mutation and classified as pathogenic according to the criteria of the American College of Medical Genetics and Genomics. The patient exhibited an incomplete phenotype, with optic atrophy and suspected central diabetes insipidus, but without documented sensorineural hearing loss. Despite multidisciplinary supportive care, the disease followed a relentlessly progressive course and the patient died due to multisystem failure.

Conclusion: This case highlights the diagnostic challenges of Wolfram syndrome in adulthood, where overlapping features with diabetic complications may obscure recognition. Early genetic testing in patients with juvenile-onset diabetes and optic atrophy is critical for timely diagnosis, comprehensive surveillance, and appropriate counseling. Reporting adult-onset cases with founder variants contributes to expanding the clinical spectrum and emphasizes the importance of multidisciplinary management in this rare but devastating disorder.

Keywords: Wolfram syndrome type 1; WFS1 mutation; founder variant; adult-onset; optic atrophy