P-429: HNF4A-MODY uncovered in a patient presenting atypical Fanconi syndrome: a rare genetic intersection
A Dantas Costa-Riquetto, A C Santomauro Júnior, R Naves Mayrink Barreto Novais, E Barbosa de Oliveira Val, M G TelesAbstract
Introduction
Maturity-Onset Diabetes of the Young (MODY) comprises a heterogeneous group of monogenic disorders characterized by non-autoimmune diabetes, typically manifesting before 25 years of age and often inherited in an autosomal dominant pattern. HNF4A-MODY, a specific subtype, is caused by mutations in the hepatocyte nuclear factor 4 alpha gene, leading to impaired pancreatic β-cell function and insulin secretion.
Objectives
This study aims to characterize the clinical and genetic features of a patient with diabetes (DM) and Fanconi syndrome, identify the causative genetic mutation, and reaffirm the phenotypic spectrum of monogenic DM.
Methods
Case report.
Results
A 25-year-old eutrophic male proband was diagnosed with DM at age 22 during nephrology evaluation for hyperglycemia, reporting polyuria, polyphagia, and weight loss. Born at term without neonatal hypoglycemia, he had no family history of early-onset DM, though maternal relatives exhibited late-onset DM with overweight. Initial evaluations showed a glucose of 258 mg/dL, an HbA1c of 6.3%, preserved C-peptide, and negative autoantibodies; he received metformin until 2019, followed by gliclazide for worsening glycemic control. Medical history included hypophosphatemic rickets secondary to Fanconi syndrome (treated with calcitriol, phosphate, and potassium chloride) and prior severe hypokalemia hospitalization. Genetic testing identified the heterozygous HNF4A c.187C>T p.(Arg63Trp) variant, classified as pathogenic per ACMG guidelines.
Conclusions
The proband’s clinical presentation, characterized by early-onset DM, preserved C-peptide, negative autoantibodies, and a history of hypophosphatemic rickets due to Fanconi syndrome, suggests a potential underlying monogenic form of DM. This genetic finding elucidates the molecular basis of the patient’s phenotype, establishing a direct link between the HNF4A mutation and the co-occurrence of MODY and atypical Fanconi syndrome.