D1.394 - Functional AOC1 variants associated with reduced diamine oxidase activity mimicking multiple drug hypersensitivity and mast cell disorders

Histamine intolerance results from impaired histamine degradation and may present with heterogeneous multisystem manifestations. Diamine oxidase (DAO), encoded by AOC1, is the main extracellular histamine-metabolizing enzyme. Reduced DAO activity can clinically overlap with mast cell activation and multiple drug hypersensitivity, frequently leading to misdiagnosis and inappropriate drug labeling.

We report a 44-year-old woman with parental consanguinity presenting with inducible urticaria, oral allergy syndrome, gastrointestinal intolerance, dysautonomia, neuropathy, and recurrent angioedema following multiple structurally unrelated drugs. Baseline serum tryptase was normal (6.7 µg/L). Serum DAO activity and histamine degradation capacity were assessed using a radio extraction assay. Targeted genetic analysis of AOC1 was performed.

Serum DAO activity was reduced (8.7 U/mL) with moderately impaired histamine degradation (63 HDU). Genetic testing identified two reduced-function AOC1 variants: c.47C>T (p.Thr16Met) and c.1990C>G (p.His664Asp). The absence of biochemical evidence of mast cell activation, combined with reduced DAO activity and functional genetic variants, supported histamine intolerance secondary to genetically determined DAO deficiency. Clinical improvement was observed with antihistamines and a low-histamine diet.

This case highlights the importance of integrating clinical phenotype, enzymatic assessment, and genetic testing in patients with complex multisystem symptoms suggestive of drug hypersensitivity or mast cell disorders. Correlating functional AOC1 variants with quantified enzymatic impairment supports a precision-medicine approach and may prevent misdiagnosis, unnecessary investigations, and inappropriate long-term drug avoidance.