SAT-538 - Coexistence of HNF1B-MODY5 and Autoimmune Type 1 Diabetes

Background: HNF1B-related diabetes (MODY5) is a monogenic disorder characterized by impaired insulin secretion and extra-pancreatic manifestations. Type 1 diabetes (T1D) reflects immune-mediated β-cell destruction and is supported by islet autoantibodies and marked insulin deficiency. Contemporary diagnostic algorithms of MODY often prioritize genetic testing in individuals with negative autoantibodies and preserved C-peptide. Coexistence of monogenic β-cell dysfunction with autoimmune diabetes is uncommon but clinically consequential, particularly when associated with multisystem manifestations.

Case: A 39-year-old woman with T1D diagnosed at age 14 presented for ongoing management. Her initial presentation was diabetic ketoacidosis (DKA), requiring ICU admission and initiation of insulin therapy. Over subsequent years, she developed intermittent transaminitis and later a persistent mild cholestatic pattern with progressive pruritus. Anti-mitochondrial antibodies were negative; MRI/MRCP demonstrated no biliary abnormalities; and serial transient elastography showed no hepatic fibrosis. Concurrent evaluation revealed mild right pelvicalyceal dilatation, two stable simple renal cysts, and chronic asymptomatic hypomagnesemia. Given this constellation of extra-pancreatic findings, genetic testing identified a heterozygous whole-gene deletion encompassing all coding exons of HNF1B, consistent with MODY5. This raised the possibility of diabetes misclassification; however, β-cell reserve was absent with undetectable fasting and stimulated C-peptide, and autoimmune evaluation demonstrated persistent GAD65 autoantibody positivity (with negative ICA, IAA, IA-2, and ZnT8), supporting autoimmune T1D with coexisting HNF1B-MODY5. The patient continued hybrid closed-loop insulin pump therapy with excellent glycemic control (A1c 6.0%, time-in-range 78%). Cholestasis has biochemically resolved, though pruritus persists; renal function remains preserved with improved proteinuria on low-dose ACE inhibition.

Conclusion: This case illustrates rare coexistence of HNF1B-MODY5 and autoimmune T1D, underscoring the importance of genetic evaluation in individuals with diabetes and atypical extra-pancreatic features, even when autoimmune markers are present. Notably, the patient exhibited isolated GAD65 positivity, an autoantibody pattern often associated with slower progression, yet presented with severe insulin deficiency manifesting as DKA and persistent absolute insulinopenia. Biologically, this raises the possibility that baseline β-cell vulnerability from HNF1B deficiency may influence the clinical expression and timeline of autoimmunity of T1D, a hypothesis warranting further study.

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