SAT-542 - Recurrent Pancreatic Ductal Adenocarcinoma in A Patient with Early-Onset Monogenic Diabetes

Background: Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic diabetes syndromes inherited in an autosomal dominant pattern, typically presenting with non-ketotic diabetes at a young age and accounting for 1–5% of diabetes cases. MODY4 is caused by pathogenic variants in the PDX1 homeobox gene on chromosome 13 (13q12.2), encoding a transcription factor essential for pancreatic development and regulation of genes involved in insulin synthesis and glucose sensing.

Case Presentation: A 52-year-old woman with insulin-dependent MODY4 diagnosed at age 15 due to a pathogenic PDX1 mutation was initially diagnosed with pancreatic ductal adenocarcinoma (PDAC) after groin pain prompted abdominal imaging and evaluation of elevated CA 19-9. She underwent distal pancreatectomy followed by 12 cycles of FOLFIRINOX. Five years later, routine surveillance CT abdomen and pelvis identified a sub-centimeter cystic lesion in the pancreatic head. Endoscopic ultrasound demonstrated an anechoic lesion involving the head and uncinate process, and biopsy revealed a well-differentiated neoplasm. She underwent completion pancreaticoduodenectomy, with pathology confirming well-differentiated PDAC arising in association with extensive intraductal papillary mucinous neoplasm (IPMN) with low- and high-grade dysplasia. Tumor genomic sequencing demonstrated somatic variants of strong or potential clinical significance in SMAD4, KRAS, ERCC2, and CBL.

Discussion: This case highlights potential long-term pancreatic implications of developmental monogenic diabetes, as the patient developed recurrent PDAC arising in association with IPMN after a prolonged disease-free interval. While causality cannot be inferred, coexistence of MODY4, IPMN, and recurrent malignancy raises the possibility that altered pancreatic developmental biology may influence susceptibility to later neoplastic processes. Genome-wide association data have identified a pancreatic cancer susceptibility locus at 13q12.2 near PDX1, and preclinical work supports dynamic, stage-dependent functions of PDX1 during PDAC initiation and maintenance.

Conclusion: This case underscores that pancreatic developmental forms of monogenic diabetes such as MODY4 may have implications beyond glycemic control, highlighting the need for long-term pancreatic function and further study of malignancy risk and endocrine outcomes in this population.

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