Idiopathic Mast Cell Activation Syndrome Research Articles

Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders

BackgroundIdiopathic mast cell activation syndrome (iMCAS) is characterised by severe, episodic systemic mast cell (MC) activation and mediator-related symptoms, event-related increase in serum tryptase levels and response to MC-targeted therapies, in the absence of underlying IgE-mediated allergy or clonal MC disorder. Studies indicating its prevalence using evidence-based diagnostic criteria are currently lacking. ObjectiveThe present study aimed to assess prevalence, as well as clinical and laboratory features of patients with iMCAS. MethodsWe conducted a retrospective evaluation of the data from 703 consecutive patients (≥18 years old) who were referred to our centre based on suspected MC disorders. Patients underwent a thorough clinical work-up including patient history, allergy tests, KIT D816V mutation analysis and/or bone marrow investigation. Disease activity was prospectively assessed during follow-up visits. ResultsThirty-one cases with confirmed iMCAS were identified. Furthermore, hereditary alpha-tryptasemia was detected in three of the cases with baseline tryptase levels >8 ng/ml. The most common clinical presentation during the MCAS episodes was mucocutaneous symptoms in patients with iMCAS, especially urticaria/angioedema. However, these symptoms were less prevalent in clonal MCAS patients (p=0.015). The duration of diagnostic delay was significantly longer in iMCAS compared to cMCAS patients (p=0.02). ConclusionOverall prevalence of iMCAS was 4.4% in the entire cohort, which indicates that iMCAS is an uncommon condition. Screening suspected patients for the three diagnostic criteria and performing a comprehensive allergy work-up including laboratory tests and ultrasensitive mutation analysis of KIT D816V followed by applying recommended diagnostic algorithms is crucial for the diagnosis of iMCAS.

Predictive Value of Elevated Tryptase and Mediator Symptoms in Systemic Mastocytosis - a Single Center Experience

Background: Systemic mastocytosis (SM) is a rare clonal hematologic disorder primarily driven by the KIT D816V mutation in almost all (95%) patients. These patients most often have elevated serum tryptase levels and can present with a wide spectrum of symptoms caused by mediator release from clonal mast cell degranulation (e.g., skin rash, anaphylaxis, diarrhea, and neurocognitive symptoms). However, these symptoms are similar in other non-clonal mast cell disorders such as idiopathic mast cell activation syndrome (MCAS) and hereditary alpha-tryptasemia (HaT). As such, many patients are referred to hematology for SM work-up based on elevated serum tryptase and mediator release symptoms. We evaluated a real-world single-center experience determining whether elevated serum tryptase, mediator release symptoms, and/or a history of anaphylaxis correlated with a diagnosis of SM. Methods: We conducted a retrospective chart review of patients referred to the Mastocytosis Clinic at Huntsman Cancer Institute at the University of Utah for a year between August 2022 and July 2023. Data were collected by chart review and analyzed for disease characteristics, laboratory values, and diagnostic outcomes. Findings/Results: There were a total of 37 patients referred to us during the designated time period with either a tryptase value greater than 10.9 ug/L or abnormal mast cells found on tissue biopsy (e.g., skin, colon, etc) with or without systemic mediator release symptoms. Patients did not have to have a history of anaphylaxis to be seen. Of these, 7 patients already had a known diagnosis of SM and had bone marrow biopsy at an outside institution. Of the 30 remaining patients, 19 (63%) patients reported a history of at least one mediator release symptom, defined as pruritus, flushing, syncope, bloating, nausea, vomiting, or diarrhea. The median serum tryptase level was 17.4 ug/L. (Range 2 - 317 ug/L). KIT D816V mutation was detected in the peripheral blood by digital droplet PCR in 7 (23.3%) patients. Diagnostic bone marrow was done in 19 patients wherein 6 (31.5%) of them met the WHO diagnostic criteria for SM. Of these patients, 5 patients tested positive for KIT D816V mutation on peripheral blood and 1 patient had KIT wild type. Two patients with KIT D816V mutations did not receive bone marrow biopsy as they had no mediator release symptoms. The remaining 13 patients had a bone marrow biopsy but did not have a diagnosis consistent with SM, although some had rare scattered mast cells identified in the marrow. They were all KIT D816V mutation negative and serum tryptase ranged from 2.7 - 43 ug/L. As of the date of data analysis, 4 (30.7%) patients tested positive for HaT; serum tryptase ranged from 20 - 26 ug/L in this cohort. Conclusion: While SM can have a variety of clinical manifestations, including elevated tryptase level and mediator release symptoms, the presence of KIT D816V in the peripheral blood is a strong predictor of SM diagnosis. Persistently elevated serum tryptase without the KIT D816V mutation may suggest the likelihood of HaT, while only mediator release symptoms with normal serum tryptase and without the KIT mutation is a strong negative predictor of SM and HaT.

Perioperative Considerations in Patients With Mast Cell Activation Syndrome

Mast Cell Activation Syndrome (MCAS) is a hypersensitivity disorder, and subset of Mast Cell Disease, which has become increasingly recognized over the past three decades. Since the first case reports were published in the late 1980s, 1 Akin C Valent P Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010; 126 (e4): 1099-1104 Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar , 2 Roberts LJ. Carcinoid syndrome and disorders of systemic mast-cell activation including systemic mastocytosis. Endocrinol Metab Clin North Am. 1988; 17: 415-436 Abstract Full Text PDF PubMed Google Scholar significant advancements have been made to better understand MCAS characteristics and determine effective treatment strategies. With improvements in recognition and modification of diagnostic criteria, it is estimated that up to 17% of the population has MCAS, 3 Buttgereit T Gu S Carneiro-Leão L et al. Idiopathic mast cell activation syndrome is more often suspected than diagnosed – a prospective real-life study. Allergy. 2022; 77: 2794-2802 Crossref Scopus (2) Google Scholar , 4 Afrin LB Ackerley MB Bluestein LS et al. Diagnosis of mast cell activation syndrome: a global “consensus-2”. Diagnosis (Berl). 2020; 8: 137-152 Crossref PubMed Scopus (34) Google Scholar highlighting the importance of clinician education regarding this recently identified disorder. To better understand the pathophysiology of MCAS—and the pharmacologic interventions effective in its management—it is important to first begin by discussing the normal activity of mast cells.

Idiopathic mast cell activation syndrome is more often suspected than diagnosed-A prospective real-life study.

Idiopathic mast cell activation syndrome (MCAS) is characterized by three diagnostic criteria: (1) episodic mast cell (MC)-driven signs/symptoms of at least two organ systems in the absence of clonal MC expansion and definite triggers, (2) episodic increase in tryptase, and (3) response to MC-targeted treatment. Many patients believe they have MCAS, but how often this is the case remains unknown. We prospectively investigated patients with suspected MCAS (n=100) for the diagnostic criteria including baseline tryptase, KIT D816V mutation, and patient-reported outcome measures (PROMs) over the course of 12weeks. Comorbid depression and anxiety were explored with the Hospital Anxiety and Depression Scale (HADS). In 53% of our patients (80% females), suspicion of MCAS was based on self-evaluation. In total, patients reported 87 different symptoms, mostly fatigue (n=57), musculoskeletal pain/weakness (n=49), and abdominal pain (n=43), with overall high disease activity and impact. Two of 79 patients had increased tryptase (by >20% +2ng/ml) following an episode. Only 5%, with any of the PROMs used, showed complete response to MC-targeted treatment. Depression and anxiety disorders were frequent comorbidities (n=23 each), and 65 patients had pathological HADS values, which were linked to high disease impact and poor symptom control. Mast cell activation syndrome was confirmed in only 2% of patients, which implies that it is not MC activation that drives signs and symptoms in most patients with suspected MCAS. There is a high need for comprehensive research efforts aimed at the identification of the true underlying pathomechanism(s) in patients with suspected MCAS.

M076 SUCCESSFUL DESENSITIZATION FOR ANTICOAGULATION/ANTIPLATELET THERAPY IN ALLERGIC ACUTE CORONARY (KOUNIS) SYNDROME

An acute coronary syndrome from vasospasm or plaque rupture accompanying mast cell activation from allergic hypersensitivity or anaphylactoid reactions are referred to as Kounis syndrome. We describe the medically challenging treatment of a 49-year-old female with a history of idiopathic mast cell activation syndrome (MCAS) who presented during an acute cardiac event.

Mast cell disorders are associated with decreased cerebral blood flow and small fiber neuropathy

BackgroundMast cell disorders including hereditary alpha tryptasemia (HαT) and idiopathic mast cell activation syndrome (MCAS) can be associated with neurologic symptoms such as orthostatic intolerance, pain, and cognitive impairment. The origin of these symptoms is not well understood. ObjectiveTo characterize neurologic findings in patients with HαT and MCAS through objective measurements. MethodsPatients with a confirmed diagnosis of HαT or MCAS with neurologic symptoms were referred for standardized autonomic testing encompassing Valsalva maneuver, deep breathing, sudomotor and tilt tests with cerebral blood flow velocity (CBFv) determination, and skin biopsies for small fiber neuropathy (SFN). ResultsThere were 15 patients with HαT (age 44.4 ± 15.9 years), 16 with MCAS (34.4 ± 15.5), and 14 matched controls who were evaluated. Baseline serum tryptase level was increased in patients with HαT when compared with patients with MCAS (14.3 ± 2.5 ng/mL vs 3.8 ± 1.8; P <.001) and neurologic symptoms were similar between the 2 groups. When compared with controls, orthostatic CBFv was reduced in HαT (−24.2 ± 14.3%; P <.001) and MCAS (−20.8 ± 5.5%; P <.001). Reduced nerve fibers consistent with SFN were found in 80% of patients with HαT and 81% of those with MCAS. Mild-to-moderate dysautonomia was detected in all patients with HαT and MCAS when results of sympathetic, parasympathetic, and sudomotor tests were combined. ConclusionWe provide evidence of reduced orthostatic CBFv and SFN associated with mild-to-moderate autonomic dysfunction in patients with HαT and MCAS. Our findings suggest that comprehensive autonomic testing may be helpful to explain neurologic symptoms and guide treatment in patients with HαT and MCAS.

Children with flushing and diarrhea: Is it mast cell activation?

Mast cell activation syndromes (MCAS) are divided into 3 groups based on mast cell (MC) clonality and activation triggers. Primary MCAS diseases are due to clonal expansion and MC proliferation that are typically associated with mutations in KIT as found in mastocytosis and monoclonal mast cell activation syndrome. Secondary MC disorders are in response to allergic or other inflammatory diseases causing MC activation. Idiopathic MCAS is diagnosed when no clonal MC disease and other etiologic mechanisms have been identified.

Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine.

Mast cell activation (MCA) is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell (MC) disorders, and hereditary alpha tryptasemia (HAT). MCA-related symptoms range from mild to severe to life-threatening. The severity of MCA-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of MCs, organs affected, and the type and consequences of comorbid conditions. In severe systemic reactions, MCA is demonstrable by a substantial increase of basal serum tryptase levels above the individual’s baseline. When, in addition, the symptoms are recurrent, involve more than one organ system, and are responsive to therapy with MC-stabilizing or mediator-targeting drugs, the consensus criteria for the diagnosis of MCA syndrome (MCAS) are met. Based on the etiology of MCA, patients can further be classified as having i) primary MCAS where KIT-mutated, clonal, MCs are detected; ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or iii) idiopathic MCAS, where neither a triggering reactive state nor KIT-mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where KIT-mutated MCs, IgE-dependent allergies and sometimes HAT are detected. These patients may suffer from life-threatening anaphylaxis and are candidates for combined treatment with various types of drugs, including IgE-blocking antibodies, anti-mediator-type drugs and MC-targeting therapy. In conclusion, detailed knowledge about the etiology, underlying pathologies and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine.

Idiopathic mast cell activation syndrome and radiation therapy: a case study, literature review, and discussion of mast cell disorders and radiotherapy

BackgroundMast Cell Activation Syndrome (MCAS) is classified as an idiopathic mast cell disorder where inconsistent or unknown triggers release inflammatory mediators and cause a constellation of symptoms. Studies demonstrate mast cells increase histamine, tryptase, and inflammatory cytokine expression following ionizing radiation. Additionally, there are cases of cutaneous mastocytosis developing within the initial radiation field suggesting mast cells play a role in local tissue reactions. Literature is sparse on radiation induced toxicity in patients with mast cell disorders.Case presentationA 62 year old female patient with a history of MCAS received breast conservation therapy for invasive lobular carcinoma of the left breast initially AJCC 7th Stage IIB, pT3 pN0 M0. The patient underwent external beam radiotherapy (EBRT) and received 4500 cGy to the left whole breast, followed by a 1000 cGy boost to the lumpectomy cavity. She developed grade 1 radiation dermatitis. Two years later she progressed distantly and received stereotactic body radiation therapy to a lumbar vertebrae lesion to a dose of 2400 cGy in a single fraction. She developed no in-field dermatologic or systemic flare in her MCAS symptoms during radiation therapy.ConclusionsTo our knowledge there are no reported cases in the literature of patients diagnosed with MCAS or other idiopathic mast cell disorders undergoing radiation therapy. Idiopathic mast cell disorders such as MCAS and primary mast cell disorders alike should not be considered a contraindication to treatment with EBRT. This patient population appears to tolerate treatment without systemic flares in symptoms.

Clinical response to omalizumab in patients with hereditary α-tryptasemia

Hereditary α-tryptasemia (HαT) is a genetic trait that results from increased TPSAB1 copy number encoding α-tryptase and is characterized by elevated basal serum tryptase (BST) levels of 8 ng/mL or higher with variably expressed clinical symptoms. 1 Lyons J.J. Hereditary alpha tryptasemia: genotyping and associated clinical features. Immunol Allergy Clin North Am. 2018; 38: 483-495 Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar In addition to multisystem issues that involve gastrointestinal, connective tissue, and neurologic systems, many individuals with HαT report symptoms associated with mast cell activation, such as chronic spontaneous urticaria and, less commonly, allergic asthma. Increasing α-tryptase gene dosage at TPSAB1 is associated with greater symptom severity 2 Lyons J.J. Yu X. Hughes J.D. et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016; 48: 1564-1569 Crossref PubMed Scopus (195) Google Scholar and increasing amounts of αβ-tryptase heterotetramers, which have unique enzymatic properties that may contribute to these symptoms. 3 Le Q.T. Lyons J.J. Naranjo A.N. Olivera A. Lazarus R.A. Metcalfe D.D. et al. Impact of naturally forming human alpha/beta-tryptase heterotetramers in the pathogenesis of hereditary alpha-tryptasemia. http://Doi:10.1084/jem.20190701 Google Scholar Multiple individuals in our cohorts with HαT have uncontrolled chronic spontaneous urticaria or asthma symptoms, which led to an on-label indication for treatment with the monoclonal anti-IgE antibody omalizumab, which binds to free IgE and reduces the expression of FcεRI on mast cells and basophils. 4 Beck L.A. Marcotte G.V. MacGlashan D. Togias A. Saini S. Omalizumab-induced reductions in mast cell Fce psilon RI expression and function. J Allergy Clin Immunol. 2004; 114: 527-530 Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar ,5 Broesby-Olsen S. Vestergaard H. Mortz C.G. et al. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: efficacy and safety observations. Allergy. 2018; 73: 230-238 Crossref PubMed Scopus (72) Google Scholar Despite the strong effect observed on symptoms of mast cell mediator release among patients with chronic spontaneous urticaria and systemic mastocytosis, a recent open-label cohort study found only modest benefit in patients identified as having idiopathic mast cell activation syndrome, with 6 of 14 having minimal to no response to omalizumab and 7 of 14 having no durable response. 6 Lemal R. Fouquet G. Terriou L. et al. Omalizumab therapy for mast cell-mediator symptoms in patients with ISM, CM, MMAS, and MCAS. http://doi:10.1016/j.jaip.2019.03.039 Google Scholar Given that many of the symptoms associated with HαT are often attributed to mast cell activation, we examined which of the symptoms commonly reported in these patients respond to this specific mast cell–targeted therapy and by inference suggest which symptoms may be more directly related to mast cells bearing heterotetrameric tryptase in these patients.

A review of the dermatologic symptoms of idiopathic mast cell activation syndrome

Since the first reported cases in 2007, idiopathic mast cell activation syndrome has been increasingly recognized. Understanding of the cutaneous manifestations of this condition is imperative for dermatologists given the substantial clinical heterogeneity in its presentation and high estimated prevalence. A review of PubMed® and SCOPUS® databases was performed in order to investigate the most common dermatologic manifestations of idiopathic mast cell activation syndrome. Evidence to date suggests that flushing, pruritus, and clotting dysfunction or bleeding disorder are the most frequently observed dermatologic symptoms in idiopathic mast cell activation syndrome, while dermatographism has been identified as a common finding in patients as well. Mast cell activation syndromes have also been linked to connective tissue disorders, including an Ehlers-Danlos Syndrome-like phenotype possibly mediated by matrix metalloproteinases and tryptase released by mast cells. Current literature regarding dermatologic manifestations of idiopathic mast cell activation syndrome is limited by the heterogeneity of studies including clinical descriptions, inconsistency of diagnostic criteria implemented, and a paucity of literature available. This work provides a guide for dermatologists to strengthen diagnostic acuity for idiopathic mast cell activation syndrome, therefore contributing toward a goal of helping patients to receive timely, effective, and targeted therapy. J Drugs Dermatol. 2019;18(2):162-168.

Frequency of clonal mast cell diseases among patients presenting with anaphylaxis: A prospective study in 178 patients from 5 tertiary centers in Spain

Mast cell activation syndromes (MCAS) encompass a heterogeneous group of disorders characterized by clinical symptoms secondary to the systemic effects of mediators released by mast cells (MCs) on their activation, including anaphylaxis. MCAS can be classified into 3 categories:1,2 (1) primary (monoclonal) MCAS, which includes symptomatic patients with systemic mastocytosis (SM) and those in whom clonal MCs and up to 2 minor SM criteria are found but SM cannot be diagnosed; (2) secondary MCAS; and (3) idiopathic MCAS.

Higher prevalence of vertebral fractures in systemic mastocytosis, but not in cutaneous mastocytosis and idiopathic mast cell activation syndrome

To describe osteoporosis (OP) and fragility fractures in mast cell disorders (MCDs). We retrospectively analyzed data concerning all successive patients with systemic mastocytosis (SM), cutaneous mastocytosis (CM), and mast cell activation syndromes (MCAS) diagnosed in our mastocytosis expert center between 2004 and 2015. We collected data concerning demographic profiles, clinical signs of MCD, osteoporosis, fractures, densitometry, and biological assessment of MCD. We compared CM and MCAS patients with SM patients with regard to the characteristics of OP and fragility fractures. We assessed 89 SM patients, 20 CM patients, and 20 MCAS patients. Osteoporosis was less frequent in CM (15.0%) and MCAS (10.0%) than in SM (44.9%). Similarly, fractures were less frequent in non-SM MCDs, respectively 5.0%, 5.0%, and 28.1%. SM patients displayed high prevalence of vertebral fractures (22.5%), mostly multiple. Conversely, in non-SM patients, vertebral fractures appeared to be uncommon (5%) and more frequently associated with risk factors for osteoporosis. SM is associated with multiple vertebral osteoporotic fractures, whereas CM and MCAS do not appear to be associated with this phenotype.

Highly sensitive assays are mandatory for the differential diagnosis of patients presenting with symptoms of mast cell activation: diagnostic work-up of 38 patients

Mastocytosis is a heterogeneous disease caused by excessive mast cell (MC) proliferation. Diagnosis of systemic mastocytosis (SM) is based on the presence of major and minor criteria defined by the World Health Organization. Symptoms of MC activation can also occur in patients without SM or without allergic or inflammatory disease. These MC activation syndromes (MCAS) can be divided into primary (monoclonal) MCAS (MMAS) vs. secondary and idiopathic MCAS. In this single center study, the diagnostic work-up of 38 patients with a clinical suspicion of SM and/or with elevated basic tryptase levels is presented. Clinical symptoms, biochemical parameters, results of bone marrow investigation, flow cytometric immunophenotyping, and molecular analysis were retrospectively reviewed. Twenty-three patients were found to have a monoclonal MC disorder of which 19 were diagnosed with SM and 4 with MMAS. In 13/19 SM patients, multifocal MC infiltrates in the bone marrow were found (major criterion), while in 6 the diagnosis was based on the presence of ≥3 minor criteria. Flow cytometric analysis of bone marrow showed CD25 expression of MCs in all patients with SM and MMAS (range: 0.002–0.3% of cells). In bone marrow, the KIT D816V mutation was detected in all SM patients but in only 2 patients with MMAS (range: 0.007–9% mutated cells). Basic tryptase elevation was demonstrated in 16/19 patients with SM but also in 9/19 patients without SM. Our study reveals the heterogeneity of primary MC disorders and the importance of sensitive assays in patients suspected of having SM.

Mast Cell Activation Syndromes

Mast cell activation syndromes(MCAS) are disorders associated with mast cell activation (MCA), and include Primary MCAS, Secondary MCAS and Idiopathic MCAS. MCAS are characterized by clinical symptoms of MCA in cutaneous, gastrointestinal, respiratory, cardiovascular, musculoskeletal and neurological organs. Mast cell (MC) mediators such as tryptase in serum, and/or histamine or prostaglandin urinary metabolites are typically elevated at base line or transiently during episodes of MCA, and there is a total or partial response to mast cell mediators controller medications. In primary MCAS an activating point mutation at codon 816 of KIT on MC is present in most cases of Systemic Mastocytosis (SM) and Monoclonal Mast Cell Activation Syndrome (MMCAS) and is absent in secondary and Idiopathic MCAS. MCAS might be the underlying cause of unexplained symptoms when several organ systems are involved, such as the gastrointestinal tract and the skin. It is especially important to be able to recognize the constellation of clinical features because response to anti-MC mediator medications is often excellent. This update on mast cell disorders (MCD) provides an insight into the classification, clinical presentations, diagnosis, treatment and management. We describe associated conditions, such as Hymenoptera Reactions, Familial Tryptasemia, Postural Orthostatic Tachycardia Syndrome and Ehlers-Danlos Syndrome.

Familial hypertryptasemia with associated mast cell activation syndrome

Familial hypertryptasemia with associated mast cell activation syndrome

Mast cell activation syndromes: definition and classification

Mast cell activation (MCA) occurs in a number of different clinical conditions, including IgE-dependent allergies, other inflammatory reactions, and mastocytosis. MCA-related symptoms may be mild, moderate, severe, or even life-threatening. The severity of MCA depends on a number of different factors, including genetic predisposition, the number and releasability of mast cells involved in the reaction, the type of allergen, presence of specific IgE, and presence of certain comorbidities. In severe reactions, MCA can be documented by a substantial increase in the serum tryptase level above baseline. When symptoms are recurrent, are accompanied by an increase in mast cell-derived mediators in biological fluids, and are responsive to treatment with mast cell-stabilizing or mediator-targeting drugs, the diagnosis of mast cell activation syndrome (MCAS) is appropriate. Based on the underlying condition, these patients can further be classified into i) primary MCAS where KIT-mutated, clonal mast cells are detected, ii) secondary MCAS where an underlying inflammatory disease, often in the form of an IgE-dependent allergy, but no KIT-mutated mast cells, is found, and iii) idiopathic MCAS, where neither an allergy or other underlying disease, nor KIT-mutated mast cells are detectable. It is important to note that in many patients with MCAS, several different factors act together to lead to severe or even life-threatening anaphylaxis. Detailed knowledge about the pathogenesis and complexity of MCAS, and thus establishing the exact final diagnosis, may greatly help in the management and therapy of these patients.

Mastzellaktivierungssyndrome

The description of a monoclonal mast cell activation syndrome in patients with anaphylaxis, who fulfill one or two minor-criteria of mastocytosis, has led to a search for new unrecognized mast cell activation syndromes. New classification of mast cell diseases including well-known diseases is provided in order to be able to better recognize and describe new entities. The term mast cell activation has been defined by verifiable scientific objective and subjective criteria, and known and idiopathic mast cell activation syndromes have been classified. Mast cell activation cannot be defined by symptoms alone, as different diseases and conditions, including those with contribution of different cell types and somatization disorders may lead to similar symptoms. For this reason the preclinical checkpoint mast cell activation was defined to require typical symptoms in combination with demonstration of mast cell mediator release in (an acute) episode(s) as well as with a good response to mast cell mediator-directed therapy. Mast cell activation syndromes were classified in primary (e.g. mastocytosis), secondary (e.g. IgE-mediated allergy) and idiopathic forms. Only through a deeper understanding of mast cell diseases, can new previously unrecognized idiopathic mast cell activation syndrome entities be described and analyzed.