MON-212 Diagnostic Complexity In Pediatric Diabetes: A Case Involving A Rare PPP1R3A Variant

Abstract Disclosure: S. Jung: None. Background: PPP1R3A encodes the glycogen-targeting subunit of protein phosphatase 1, a key regulator of glycogen storage in skeletal muscle. While variants in this gene have been associated with altered glycogen metabolism, their role in pancreatic β-cell function and diabetes remains unclear. We present a case illustrating the diagnostic challenges posed by identifying a rare variant of uncertain significance (VUS) in pediatric diabetes. Case: A 5-year-old boy presented with a one-week history of polydipsia and polyuria. His height was 120 cm (80th percentile) and weight 25 kg (86th percentile). Laboratory evaluation showed an HbA1c of 10.7% without diabetic ketoacidosis. He was started on NPH and regular insulin but demonstrated marked insulin sensitivity, allowing rapid dose reduction. Autoimmune markers (GAD antibody, insulin antibody) were negative, but anti-IA2 antibody was positive (19.15 U/mL; cutoff ≥ 2 U/mL). Fasting serum C-peptide was 1.08 ng/mL, and 24-hour urinary C-peptide was 7.13 nmol/day, indicating preserved endogenous insulin secretion. Family history revealed progressively earlier-onset diabetes on the paternal side: grandmother diagnosed at 45 (with complications), aunt in her 20s, uncle in his 30s, and father at 34, currently on oral hypoglycemic agents. On the maternal side, the grandfather was diagnosed in his 50s, but the mother remains normoglycemic. Genetic testing identified a heterozygous p.Glu17Asp variant in PPP1R3A, classified as a VUS, inherited from the unaffected mother. Discussion: This case highlights the diagnostic complexity when clinical, familial, and genetic data are inconsistent. Although the patient’s preserved β-cell function and paternal family history suggested monogenic diabetes, the maternally inherited PPP1R3A VUS does not explain the pattern and could be incidental. Anti-IA2 antibody positivity adds autoimmune overlap, further complicating interpretation. This case suggests the uncertain contribution of rare PPP1R3A variants in pediatric diabetes and demonstrates the importance of cautious integration of genetic findings within clinical context. Conclusion: This case illustrates the limitations of genetic testing in pediatric diabetes and the need for careful follow-up, family counseling, and further research to clarify the clinical relevance of rare variants like those in PPP1R3A, ultimately improving diagnostic accuracy. Presentation: Monday, July 14, 2025