North Texas Research Forum 2026
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Division
North Texas
Hospital
Medical City Fort Worth
Specialty
Family Medicine
Document Type
Presentation
Publication Date
2026
Keywords
diabetes, maturity-onset diabetes of the young, MODY, diabetes mellitus, type 2, case reports
Disciplines
Endocrinology, Diabetes, and Metabolism | Family Medicine | Medicine and Health Sciences
Abstract
BACKGROUND: Monogenic diabetes accounts for approximately 1–5% of diabetes cases and is frequently misclassified. Maturity-onset diabetes of the young (MODY) includes 14 subtypes with distinct pathophysiology and therapeutic implications. Digenic MODY, caused by pathogenic variants in more than one MODY gene, occurs in well under 1% of cases and poses unique diagnostic and management challenges. We report the first known case of concurrent HNF1A (MODY3) and PDX1 (MODY4) mutations, highlighting important clinical and therapeutic considerations.
CASE PRESENTATION: A 19-year-old male with digenic MODY due to MODY3 (HNF1A) and MODY4 (PDX1) mutations presented for team-based adult outpatient diabetes management following transition from pediatric care. He had a BMI of 26.70 kg/m2 and reported instances of polydipsia, polyuria, and nocturia, but denied any visual changes, fatigue, dizziness, nausea, vomiting, or diarrhea. Genetic testing was performed at a tertiary hospital, establishing the dual mutation diagnosis. He was previously treated with basal-bolus insulin, but he reported poor compliance and therapy discontinuation due to access barriers. He was also not on insulin at the time of presentation. Initial laboratory evaluation demonstrated a hemoglobin A1c of 12.7%, SCr of 0.84, eGFR of >120, and a UACR of 4. Given uncertainty regarding beta-cell reserve in the setting of a concurrent PDX1 mutation, treatment was initiated with metformin (500 mg orally once daily) and low-dose basal–bolus insulin (insulin aspart 3 units subcutaneously three times daily with meals and insulin glargine 8 units subcutaneously once daily). At his one-month follow-up appointment, reported home glucose monitoring revealed a fasting glucose value of 110-120 mg/dL, pre-lunch values of 120-130 mg/dL, pre-dinner values of 160-170 mg/dL, and bedtime values of 130-140 mg/dL. With his stable glucose trends and patient preference for reduction in insulin burden, metformin increased to 500 mg orally twice daily and continued his low basal insulin.
DISCUSSION: This case represents the first reported instance of concurrent MODY3 and MODY4 mutations, illustrating how dual transcription factor defects can modify expected phenotypes and treatment responses. While MODY3 typically responds to sulfonylureas, the presence of a PDX1 mutation and marked hyperglycemia raised concern for limited beta-cell reserve, supporting early insulin initiation. Despite severe hyperglycemia, the patient achieved rapid improvement on low-dose insulin, suggesting preserved insulin sensitivity with impaired insulin production. This case adds to the limited literature on digenic MODY and underscores the importance of individualized, genotype-informed management to avoid misclassification and optimize outcomes.
Original Publisher
HCA Healthcare Graduate Medical Education
Recommended Citation
Lambert-Johnson, Shay-Kay; Doan, Matthew; and Wesling, Megan, "Concurrent HNF1A (MODY3) and PDXI (MODY4) Variants in a Young Adult and Critical Therapeutic Implications" (2026). North Texas Research Forum 2026. 83.
https://scholarlycommons.hcahealthcare.com/northtexas2026/83