Mastocytosis presenting as insect anaphylaxis: gender differences and natural history Purpose of the review Currently, there is strong evidence about an association between hymenoptera venom anaphylaxis (HVA) and mastocytosis. This review is focused on the most relevant clinical and biological features of systemic mastocytosis associated with HVA. Recent findings HVA is a relatively common complication that modifies the natural course of patients with mastocytosis, particularly men with indolent systemic mastocytosis without skin lesions (ISMs−) in whom HVA can be the presenting symptom in up to around one-half of the cases. Patients with ISMs− associated with HVA are typically males with cardiovascular symptoms in the absence of itching, urticaria, and angioedema during anaphylaxis. Noteworthy, ISMs− is characterized by a low bone marrow mast cell load and a low risk for disease progression. Early and more recent studies support that specific venom immunotherapy (VIT) is a well-tolerated and effective treatment in patients with mastocytosis. Summary VIT should be given life-long to all patients with mastocytosis and proven immunoglobulin E (IgE)-mediated HVA. In patients with negative venom skin test and undetectable IgE antibodies, additional studies such as component-based allergy testing might contribute to confirm an IgE-mediated mechanism of anaphylaxis in some cases, thus providing the indication of VIT. Correspondence to Iván Alvarez-Twose, MD, PhD, Instituto de Estudios de Mastocitosis de Castilla La Mancha (CLMast), Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Ctra. Cobisa S/N, Toledo 45071, Spain. Tel.: +34925269336;. e-mail: ivana@sescam.jccm.es Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.