Mast cell activation syndrome (MCAS) is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome. Whether MCAS is a primary syndrome or exists as a constellation of symptoms in the context of known inflammatory, allergic, or clonal disorders associated with systemic mast cell activation is not well understood. More importantly, the underlying mechanisms and pathways that lead to mast cell activation in MCAS patients remain to be elucidated. Here we summarize the known literature, identify gaps in knowledge, and highlight research needs. Covered topics include contextualization of MCAS and MCAS-like endotypes and related diagnostic evaluations; mechanistic research; management of typical and refractory symptoms; and MCAS-specific education for patients and health care providers.

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Hereditary alpha-tryptasemia (HαT) is an autosomal dominant disorder estimated to affect 5% of the population. High baseline tryptase level is a consistent finding, but there is a great variability of clinic manifestations, including no symptoms at all. We describe a case of HαT in a 5 years 8 months old girl manifesting with idiopathic anaphylaxis and elevated baseline tryptase level. As more cases of HαT are described, a better understanding of the clinical phenotype will be acquired.

To provide an overview on the current understanding of genetic variability in human tryptases and summarize the literature demonstrating the differential impact of mature tryptases on mast cell-mediated reactions and associated clinical phenotypes.
It is becoming increasingly recognized that tryptase gene composition, and in particular the common genetic trait hereditary alpha-tryptasemia (HαT), impacts clinical allergy. HαT has consistently been associated with clonal mast cell disorders (MCD) and has also been associated with more frequent anaphylaxis among these patients, and patients in whom no allergic trigger can be found, specifically idiopathic anaphylaxis. Additionally, more severe anaphylaxis among Hymenoptera venom allergy patients has been linked to HαT in both retrospective and prospective studies. An increased relative number of α-tryptase-encoding gene copies, even in the absence of HαT, has also been associated with systemic mastocytosis and has been shown to positively correlate with the severity of mast cell-mediated reactions to vibration and food. These findings may be due to increased generation of α/β-tryptase heterotetramers and differences in their enzymatic activity relative to β-tryptase homotetramers. HαT is a naturally occurring overexpression model of α-tryptase in humans. Increased relative α-tryptase expression modifies immediate hypersensitivity symptoms and is associated with more frequent and severe mast cell-mediated reactions, ostensibly due to increased α/β-tryptase heterotetramer production.

UNASSIGNED: Hereditary alpha-tryptasemia (HαT) is associated with elevated basal serum tryptase (bST) and is associated with a higher risk of severe anaphylactic reactions in patients with clonal mast cell disorders or IgE-mediated Hymenoptera venom-induced anaphylaxis. The consequence of this genetic trait remains to be determined in other allergic diseases and food allergy in particular.
UNASSIGNED: Here, we describe three cases of peanut allergy among siblings from a single family of four: two of them were associated with HαT, and the third one was associated with the tryptase wild-type genotype.
UNASSIGNED: TPSAB1/TPSB2 genotypes were determined by digital PCR. After the case description, we provided a review of the literature regarding bST levels and tryptase genotypes in anaphylaxis, with a particular focus on food allergy.
UNASSIGNED: Compared to the sibling with the conventional tryptase genotype, the two siblings with HαT presented a lower peanut threshold at the initial oral food challenge, higher peanut skin prick test reactivity, higher levels of specific IgE to peanut, Ara h 2, and Ara h 6, and a lower IgG4/IgE ratio after 10 years of oral immunotherapy.
UNASSIGNED: The tryptase genotype and HαT status might modify the clinical presentation and biological features of food allergy.

The current article aims to provide a comprehensive update on diagnostic criteria for mast cell activation syndrome (MCAS), addressing challenges in diagnosing and classifying MCAS and its variants.
In recent years, there has been a significant increase in our knowledge regarding the underlying mechanisms responsible for the activation of mast cells (MCs) in various pathological conditions. Furthermore, a set of criteria and a classification for MCASs have been established. MCAS is characterized by the presence of typical clinical symptoms, a substantial elevation in serum tryptase levels during an attack compared to the patient\'s baseline tryptase levels, and a response to MC mediator-targeting therapy. In this report, a thorough examination was conducted on the contemporary literature relating to MCAS, with a focus on comparing the specificity, sensitivity, and robustness of MCAS-related parameters within proposals for diagnosing and classifying MCAS and its variants. Moreover, the significance of employing specific consensus criteria in the assessment and categorization of MCAS in individual patients was underscored, due to the escalating occurrence of patients receiving a misdiagnosis of MCAS based on nonspecific criteria.

Our knowledge of biology and mast cell (MC) function, as well as disorders associated with the pathologic activation of MCs, has evolved over the last few decades. Anaphylaxis, mast cell activation syndrome (MCAS), and mastocytosis are interrelated yet distinct conditions within the spectrum of mast cell activation disorders. Nevertheless, all three conditions can co-exist in one and the same patient, as pathologic MC activation is the key finding in all three. When mediator release is excessive and involves multiple systems, anaphylaxis and MCAS may occur. Furthermore, mastocytosis is a clonal disorder of MCs and often presents with anaphylaxis and MCAS. Nevertheless, in some cases, even the proliferative and accumulative features of MCs in mastocytosis can account for symptoms and disease progression. In each case, diagnosis can be only made when the diagnostic consensus criteria are fulfilled. The current article aims to provide a concise clinical update and pinpoint the main difficulties in diagnosing these puzzling disorders of MCs in medical practice.

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Mastocytosis is characterized by expansion and activation of clonally aberrant mast cells (MCs) in one or more organ systems. Inappropriate MC activation is a key finding in both allergy and mastocytosis; therefore, symptoms in both conditions show some degree of overlap. When mediator release is excessive and involves multiple systems, anaphylaxis may occur. In mastocytosis, the prevalence of atopy is similar to those of the general population, whereas the incidence of anaphylaxis is significantly higher. The purpose of this review is to discuss features of allergy and anaphylaxis as well as the principles of managing MC mediator release symptoms in mastocytosis.

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