Tu102 - Atypical Presentation of Hereditary Alpha Tryptasemia: The Role of a Concurrent Auto-inflammatory Gene Variant

Abstract Text: Background
Hereditary Alpha Tryptasemia (HaT) is a genetic condition that arises from increased alpha-tryptase gene copy numbers (TPSAB1). Common clinical manifestations include mast cell activation symptoms such as anaphylaxis, flushing, and urticaria, as well as less frequently, more subtle or atypical features such as arthralgias, gastrointestinal symptoms, and low-grade fevers. Variants of unknown significance (VUS) in autoinflammatory genes (NLRP3, NOD2) may contribute to the presentation variability.

Case Presentation
A 32-year-old Caucasian French Canadian male presented with a twelve-year history of recurrent fevers, intermittent diarrhea, arthralgias, and fatigue. He had persistently elevated baseline tryptase (~20 ng/mL) and exhibited classic mast cell-mediated reactions, including a rash. Extensive workup ruled-out systemic mastocytosis (negative c-KIT mutation, bone marrow biopsy), autoimmune conditions, and infections. Genetic testing confirmed HaT (duplication of alpha-tryptase coding exons in TPSAB1) and identified a VUS in two autoinflammatory genes (NLRP3, NOD2). Complete response was observed following treatment with second-generation H1-antihistamines and histamine H2 blockers. Over two years of follow-up, his arthralgias, fevers, and gastrointestinal complaints remained fluctuating but controlled, with no severe reactions.

Discussion
This case highlights how HaT can manifest predominantly with constitutional and autoinflammatory-like symptoms rather than the classic allergic or anaphylactic phenotype. The concurrent VUS emphasizes the potential genetic interplay that may influence symptom severity and expression.

Conclusion
Increased awareness of HaT’s broad spectrum of presentations is crucial for timely diagnosis and management. Exploring genetic modifiers, including autoinflammatory variants, may shed light on individualized therapeutic strategies and improve outcomes for patients with elevated tryptase and atypical clinical features.