P2.256: Neonatal Diabetes Mellitus with Maternal Pembrolizumab Exposure: A Complex Interplay of Genetic and Autoimmune Factors

Introduction:

Introduction:
Neonatal Diabetes Mellitus (NDM) is a rare disorder characterized by persistent hyperglycemia occurring within the first six months of life. Known causes include monogenic mutations affecting pancreatic or immune function, and less commonly, maternal autoimmune therapies. Recent evidence has linked maternal use of immune checkpoint inhibitors (ICIs), such as Pembrolizumab (anti-PD-1 therapy), to neonatal immune dysregulation. This report details a rare clinical presentation of NDM involving both a pathogenic LRBA gene mutation and maternal Pembrolizumab exposure, highlighting complex interactions between genetics and autoimmune mechanisms.

Case Description:

Case Description:
A premature male infant born at 34w4d presented with intrauterine growth restriction and persistent hyperglycemia shortly after birth. Initial glucose levels ranged from 236–345 mg/dL, necessitating intravenous insulin infusion. Maternal history was significant for Pembrolizumab (Keytruda) treatment for breast cancer during early pregnancy, resulting in maternal autoimmune hypothyroidism. An abdominal ultrasound confirmed a structurally normal pancreas, while neonatal testing revealed positive GAD65 antibodies suggestive of autoimmune diabetes. A comprehensive neonatal diabetes genetic panel identified a heterozygous deletion of exons 23-34 in the LRBA gene, classified as likely pathogenic. Hyperglycemia was managed initially with intravenous insulin; continuous subcutaneous insulin was attempted but complicated by limited subcutaneous fat. Subsequent management involved injections of diluted insulin (U10 Humalog), maintaining target glucose levels of 200–250 mg/dL.

Discussion:

Discussion:
The presented case highlights the critical diagnostic considerations involving NDM, autoimmune mechanisms, and genetics. The maternal use of Pembrolizumab during pregnancy is significant due to emerging evidence linking ICIs with neonatal immune dysfunction. Recent literature reports severe neonatal immune-mediated disorders following maternal Pembrolizumab exposure, suggesting transplacental drug transfer and subsequent immune dysregulation as potential mechanisms [1,2].
The identified LRBA gene deletion further complicates this presentation. LRBA deficiency is recognized for its association with autoimmune endocrinopathies and immune dysregulation syndromes, including NDM and infancy-onset DM [3,4,5]. Cases of LRBA mutations presenting as NDM underline the importance of comprehensive genetic testing, facilitating precise diagnosis and targeted management strategies.
Optimal management of NDM requires immediate genetic testing to establish etiology and guide therapies. Current evidence strongly advocates for rapid genetic diagnosis as it significantly influences clinical management, such as identifying infants who can benefit from sulfonylurea therapy instead of insulin [6,7,8]. Furthermore, careful management using insulin pumps or insulin injections, along with rigorous glucose monitoring, is critical due to the risks of hypoglycemia and limited fat reserves in premature neonates.

Conclusion:

Conclusion:
This case shows the challenges of diagnosis and management of NDM. Recognition of ICIs like Pembrolizumab as potential inducers, combined with genetic mutations such as LRBA, is essential for accurate diagnosis and effective intervention of neonatal autoimmune disorders. Early comprehensive genetic evaluation and personalized management strategies remain crucial for optimizing outcomes in affected neonates.