Endocrine Abstracts

Wolfram Syndrome (WS) is a rare neurodegenerative disorder associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Two subtypes, WFS 1 and WFS 2, with autosomal recessive inheritance, are linked to pathogenic variants in the WFS 1 and CISD 2 genes, respectively.WFS1 codes for wolframin. This protein plays a central role in insulin signaling. We present a 49-year-old male with brittle diabetes since age 20 . His background included temporal-lobe epilepsy, cataracts, proliferative retinopathy, peripheral neuropathy, intellectual disability and IgA deficiency. His brother had unclassified diabetes and passed away at age 30. His sister remains unaffected. Over years multiple investigations had failed to classify his diabetes. A glucagon-stimulation-test, a sulphonylurea-challenge and low C-peptide confirmed insulin deficiency. He had negative autoantibodies and negative MODY screening. Genetic testing revealed no pathogenic variants in suphonylurea- receptor or potassium-channel-subunit genes. He had multiple presentations with hypo- and hyperglycaemia. His diabetes was challenging as he was exquisitely insulin sensitive. As the behavior of his diabetes was atypical, we performed whole exome sequencing (WES). This revealed two variants of uncertain significance in WFS 1 gene (c; ²⁶⁵⁴C>T and c; ¹⁵⁹⁷C>T). These variants have been associated with WS when inherited in a compound heterozygous state. We believe his diabetes is linked to the WFS 1 variants identified but parental segregation analysis will be performed to establish phase. Our patient has partial WS phenotype including diabetes mellitus, peripheral neuropathy, epilepsy and cataracts. This case highlights the clinical utility of WES in practice and demonstrates a thorough, systematic workup to define diabetes subtypes.