Hepatocyte Nuclear Factor 4 Alpha (HNF4A)-related maturity-onset diabetes of the young (MODY) constitutes approximately 5% to 10% of all MODY cases (1); however, the literature documents only around 20 instances of HNF4A-MODY in China. HNF4A-MODY has demonstrated responsiveness to sulfonylureas (2), and GLP-1 receptor agonists (GLP-1RAs) have proven effective in achieving satisfactory glycemic control in select cases (3, 4). Nevertheless, treatment modalities remain insufficiently characterized due to insufficient research (5). Limited studies have explored the long-term management of patients diagnosed with HNF4A-MODY.

Here, we report a case from China involving a new de novo variant of HNF4A. The patient had been using insulin for up to 25 years before receiving a genetic diagnosis.

At the age of 13, the patent’s parents discovered that he had significantly elevated fasting blood glucose levels (320.4 mg/dL) accompanied by weight loss. He was subsequently diagnosed with type 1 diabetes and began insulin therapy. During this period, he experienced multiple hypoglycemic episodes. At a routine follow-up at age 21, another physician observed that his pancreatic islet function remained preserved, with negative results for diabetes-related antibodies. Consequently, his diagnosis was revised to type 2 diabetes, and the antihyperglycemic therapy was added in metformin and acarbose. At the age of 38, the patient sought consultation due to an increased daily insulin requirement and inadequate glycemic control. Before the current consultation, the patient’s insulin dosage had gradually increased to 80 units per day; however, glycemic control remained unsatisfactory, as indicated by an HbA1c level of 9.6% ( Figure 1 ).

The patient was born with a birth weight of 4,300 g; however, there was no relevant medical record indicating neonatal hypoglycemia. Additionally, the family reported no history of diabetes. At 21 years of age, the patient had a body mass index (BMI) of 24.5 kg/m²; at 38 years of age, the BMI increased to 28.4 kg/m². His blood pressure was recorded at 145/90 mmHg. Laboratory tests for serum lipid levels, uric acid, diabetic autoimmune antibodies, urinary microalbumin creatinine ratio, and thyroid function, including antibodies, were all within normal ranges. Fasting and postprandial C-peptide levels were measured at ages 13, 21, and 38 years ( Figure 1 ). A carotid ultrasound indicated the presence of atherosclerosis, and a fundoscopic examination revealed scattered macular hemorrhages in both eyes.

The HNF4A gene encodes HNF4α, a member of the nuclear receptor superfamily of ligand-dependent transcription factors, which play a crucial role in regulating pancreatic insulin secretion (2). HNF4A-MODY accounts for approximately 5% to 10% of all MODY cases; however, it is infrequently observed in the Chinese population (6, 7). We reviewed the literature and identified 23 mutations in the HNF4A gene among Chinese patients ( Figure 3 ). The majority of these mutations are localized within the DNA binding domain (DBD) and ligand binding domain (LBD) regions. Notably, the R91H mutation in this patient is located in the highly conserved DBD region of HNF4α (8) ( Figure 3 ).

This case emphasizes that spontaneous HNF4A-MODY is highly susceptible to misdiagnosis as either type 1 or type 2 diabetes mellitus. Currently, there are recommended tools for screening the clinical risk for MODY, such as the AACM strategy, which includes the age of onset, autoantibody to islet antigen, C-peptide and metabolic syndrome (9), and the MODY probability calculator (10). However, these tools have demonstrated inadequate efficacy in distinguishing MODY cases (11). Moreover, epidemiological research has indicated that de novo mutations in the MODY genes may occur more frequently than previously estimated (12). In individuals suspected of having MODY, characterized by clinical indicators such as macrosomia, early onset, absence of obesity, non-insulin dependence, and negative diabetic autoimmune antibodies—regardless of family history—a genetic assessment should be considered.

There is a paucity of research investigating the long-term follow-up and management strategies for patients diagnosed with HNF4A-MODY. Prolonged follow-up of this patient indicated a gradual decline in pancreatic function associated with HNF4A-MODY. Sulfonylureas are recognized as the standard first-line therapy for HNF4A-MODY (2). Due to the patient’s obesity, we kept metformin in the treatment regimen. Additionally, we gradually reduced the insulin dosage and avoided sulfonylurea medications that stimulate insulin secretion, in order to avoid the risk of atherosclerotic cardiovascular disease (ASCVD) associated with weight gain. It is reasonable to hypothesize that patients with HNF4A-MODY may respond positively to meglitinides and GLP-1RAs; however, there is currently no empirical evidence to support this hypothesis. While glycemic control and the progression of complications can be effectively managed in HNF4A-MODY patients receiving long-term insulin therapy, the potential risks of hypoglycemic episodes, obesity, and atherosclerosis remain significant concerns. Furthermore, the shift to GLP-1RA treatment in individuals with HNF4A-MODY continues to exhibit beneficial outcomes, even after an extended period of disease progression.

In summary, we have identified a novel de novo heterozygous missense mutation in the HNF4A gene in a Chinese patient diagnosed with MODY. This finding contributes to the existing mutation spectrum associated with HNF4A. This case highlights the susceptibility of spontaneous HNF4A-MODY to misdiagnosis, as well as the prolonged decline in pancreatic function characteristic of this condition. Notably, transitioning to GLP-1RA treatment in individuals with HNF4A-MODY continues to demonstrate positive outcomes, even after an extended disease duration.