Endocrine Abstracts

JOINT3986

Introduction: The Paired Box Gene 4 (PAX4) encodes a transcription factor crucial for pancreatic beta-cell development and maintenance in a differentiated state. PAX4 mutations have been identified as a cause of maturity-onset diabetes of the young (MODY), and also in ketosis prone diabetes. MODY diagnosis requires a high clinical suspicion, encompassing a group of rare monogenic forms of diabetes. We report a novel variant of PAX4 in a 29-year-old female which appears to be pathogenic.

Case report: A 29-year-old female was referred to Endocrinology for diabetes. At diagnosis, four years ago, our patient had a BMI 31.1kg/m² and was asymptomatic. Several random glucose tests were above 200mg/dL, and her HbA1c was 7.1%. Metformin 2000mg/day was started. She had no other significant medical history or medications. Her family history was notable for diabetes (DM), including both her parents, who were treated with oral antidiabetics, one of her sisters diagnosed at 30 years, and the other sister diagnosed at 18 years during pregnancy, who was treated with insulin due to chronic kidney disease. Additionally, all of her grandparents had DM, as did seven out of nine of her father ‘s siblings, and two out of five of her mother’s siblings. On presentation to our clinic, she had no symptoms, no physical examination alterations, including acanthosis nigricans or other skin abnormalities, and no DM-related complications. Following lifestyle modification, her BMI reduced to 23.3kg/m² and her A1c improved to 5.3%. Further testing revealed a normal C-peptide (2.69ng/mL, reference 1.10-4.40) paired with a normal glucose of 76mg/dL, negative auto-antibodies (anti-insulin, anti-ICA, anti-IA2 and anti-GAD). Exeter Diabetes Calculator ® revealed a 75.5% chance of having MODY. Next-generation sequencing for MODY identified a heterozygous mutation (NM_001366110.1(PAX4):c.1022G>A, p.(Trp341*)) in the PAX4 gene, resulting in a stop codon in the 341st position, classified as a variant of uncertain significance. Metformin was suspended and her A1c remained at 5.3%. Her family members were referred for genetic testing.

Conclusions: PAX4 variants are rare, and individuals affected have had clinical presentations and diagnoses ranging from ketosis-prone DM, to T1DM, T2DM and PAX4-MODY. Given our patient’s family history and early onset of diabetes, PAX4-MODY is highly suspected. Genetic testing is increasingly available and should be done to allow for a better understanding of atypical types of DM and to improve patient management.