Introduction
Mast cell activation syndrome (MCAS) is a heterogeneous clinical condition characterized by recurrent episodes of mast cell mediator release leading to multisystem involvement. Over the past decade, MCAS has gained increasing recognition in clinical immunology practice; however, its diagnostic boundaries and classification have evolved considerably. The first comprehensive diagnostic framework, published in 2010, proposed that MCAS should be defined by the presence of episodic symptoms involving at least two organ systems, a significant event-related increase in serum tryptase according to the “20% + 2 ng/ml” formula, and a documented clinical response to mast cell–targeted therapy [1]. This approach was subsequently supported and refined by international consensus reports published in 2013 [2] and later expanded in 2020 [3], with further clinical characterization of MCAS phenotypes in real-life cohorts [4–6].
Despite these advances, the diagnosis of MCAS remains challenging in daily clinical practice. One major difficulty is the heterogeneous and often fluctuating nature of clinical manifestations, combined with the difficulty of documenting event-related increases in mast cell mediators during acute episodes and the practical challenges of capturing these episodes in real time [1, 3]. In real-life settings, patients may present with evolving symptom patterns over time, and diagnostic criteria may only be fulfilled after prolonged follow-up rather than at initial evaluation. Furthermore, significant overlap exists between MCAS and other mast cell-related or inflammatory disorders, including systemic mastocytosis, recurrent anaphylaxis, chronic spontaneous urticaria, allergic airway diseases, and functional gastrointestinal disorders, which may complicate diagnostic decision-making and delay appropriate management [1–4]. More recently, a comprehensive update by the Collegium Internationale Allergologicum (CIA) published in 2022 provided a refined and widely accepted classification and diagnostic framework for mast cell activation syndromes [5]. According to this consensus, MCAS should be diagnosed in patients with recurrent, severe, and systemic mast cell activation events, typically resembling anaphylaxis, accompanied by a substantial event-related increase in mast cell-derived mediators, most commonly serum tryptase, and a documented response to mast cell-directed therapy [5]. Importantly, the authors also emphasised that mast cell activation exists along a clinical spectrum and that patients who do not strictly fulfil all MCAS criteria may still present with mast cell activation disorders, particularly in real-life clinical practice, underscoring the importance of longitudinal assessment and careful phenotypic characterization [5].
In this context, real-life cohort studies play a crucial role in improving the understanding of mast cell activation disorders, their clinical phenotypes, associated comorbidities, laboratory features, and treatment responses.
Aim
In the present study, we aimed to describe the demographic characteristics, clinical manifestations, laboratory findings, and therapeutic outcomes of patients evaluated for non-clonal mast cell activation syndromes in a real-life tertiary care setting. By doing so, we sought to contribute one of the few detailed case series from Türkiye addressing the diagnostic challenges and management strategies associated with mast cell activation disorders.
Material and methods
Study design and setting
This study was designed as a retrospective observational cohort conducted at the Department of Allergy and Immunology, University of Health Sciences, Süreyyapaşa Training and Research Hospital, Istanbul, Türkiye. Medical records of adult patients evaluated in our clinic between in 2015-2025 for symptoms suggestive of mast cell activation were reviewed.
Patient selection
Patients were included if they fulfilled the non-clonal mast cell activation syndromes criteria according to the consensus [1, 2, 3, 4]. Accordingly, eligibility required:
Recurrent, acute, and clinically severe symptoms involving ≥ 2 organ systems, typically resembling anaphylaxis, including cutaneous, gastrointestinal, cardiovascular, and/or respiratory manifestations.
Objective evidence of mast cell activation, documented by event-related serum tryptase elevation according to the “20% + 2 ng/ml” formula during longitudinal follow-up.
Clinical improvement with mast cell–directed therapy.
No evidence of IgE- or non–IgE–mediated hypersensitivity temporally associated with mast cell activation episodes.
Exclusion criteria included age < 18 years, incomplete medical records, presence of clonal mast cell disorders, or alternative diagnoses explaining symptoms.
Data collection
Because the study was retrospective, all information was extracted from electronic hospital records. The following variables were collected:
Demographic characteristics: age, sex, age at symptom onset, follow-up duration.
Atopy assessment: Atopy was defined as the presence of a positive skin prick test and/or serum specific IgE to aeroallergens in conjunction with compatible clinical history (e.g., allergic rhinitis or asthma).
Clinical manifestations: flushing, pruritus, urticaria, angioedema, abdominal pain, nausea, vomiting, diarrhoea, dyspnoea, wheezing, hypotensive episodes, syncope, headache, etc.
Laboratory findings: baseline serum tryptase, event-related serum tryptase measured during acute episodes and documented during longitudinal follow-up, hematologic evaluation, and KIT mutation testing.
Imaging or additional diagnostic evaluations.
Treatments: H1/H2 antihistamines, leukotriene antagonists, mast cell stabilizers, omalizumab, systemic therapies.
Response to treatment: improvement documented in follow-up visits.
Results
Demographic characteristics
A total of 21 patients diagnosed with non-clonal mast cell activation syndromes were included in the study. The cohort was predominantly female (n = 18, 85.7%), with only 3 (14.3%) male patients. The mean age was 50.1 years (median: 50; range: 23–69 years) (Table 1).
Clinical characteristics
Patients exhibited a multisystemic but heterogeneous clinical profile, with early symptom onset (median: 30 years) and a prolonged disease course. The median follow-up duration was 24 months (range: 7–60 months), allowing real-life longitudinal assessment of symptom variability and treatment response. All patients experienced recurrent acute systemic flares characterized by sudden onset of multisystem involvement. These episodes were clinically severe and included hypotension or presyncope/syncope, respiratory compromise, and gastrointestinal symptoms, resembling anaphylaxis. Due to the severity of these episodes, epinephrine auto-injectors were prescribed to all patients.
Six (28.5%) patients had atopy, defined as the presence of a positive skin prick test and/or serum specific IgE to aeroallergens, accompanied by clinical manifestations such as allergic rhinitis or asthma. Fifteen (71.4%) patients had concomitant comorbid conditions, including chronic spontaneous urticaria, allergic rhinitis, and asthma.
Cutaneous manifestations were present in all patients (100%), making them the most consistent and dominant clinical component. Flushing, pruritus, urticaria, and angioedema occurred in episodic patterns. Gastrointestinal involvement was documented in 42.9% of patients (9/21), most commonly presenting with abdominal pain, nausea, vomiting, or diarrhoea. Cardiovascular symptoms were present in 61.9% of patients (13/21), including hypotensive episodes or presyncope/syncope. Respiratory symptoms were observed in 76.2% of the cohort (16/21) (Table 2).
Table 2
Clinical manifestations of non-clonal mast cell activation syndromes (n = 21)
Comorbid conditions were frequent in this cohort. Chronic spontaneous urticaria (CSU) was the most common comorbidity, present in 14 of 21 patients (66.7%). Allergic rhinitis was identified in 11 (52.4%) patients, and asthma in 5 (23.8%) patients. According to current consensus classifications, the presence of these concomitant conditions is consistent with a secondary MCAS phenotype rather than idiopathic disease.
In terms of triggering factors, medications were identified as triggers in 12 patients, including at least two different drug groups in 9 of them. Food-related reactions were reported in 9 patients, venom exposure in 1 patient, insect stings in 4 patients, temperature changes in 2 patients, and stress was noted as a precipitating factor in 7 patients, contributing to episodic attacks.
Laboratory findings and diagnostic work-up
Baseline laboratory assessments revealed a heterogeneous but characteristic pattern compatible with non-clonal mast cell activation syndromes. Serum tryptase levels were available for all patients. The median baseline tryptase was 13.4 ng/ml (range: 2–30 ng/ml). Only 3 (14.3%) patients demonstrated serum tryptase elevations ≥ 20 ng/ml, fulfilling one of the minor criteria defined for systemic mastocytosis; however, none met the major criterion or accumulated sufficient minor criteria to establish a diagnosis of clonal mast cell disease. All patients eventually exhibited a “20% + 2 ng/ml” event-related tryptase increase during follow-up.
KIT D816V mutation analysis performed on peripheral blood samples was negative in all patients. Bone marrow biopsy was performed in 6 (28.6%) patients due to elevated baseline serum tryptase levels, severe systemic reactions, or clinical suspicion of systemic mastocytosis, in order to evaluate for possible clonal mast cell disease.
Hematologic parameters, including eosinophil count and percentage, were within normal limits in the majority of the cohort. Mild eosinophilia was detected in 4 (19.0%) patients, but without evidence of hypereosinophilic syndromes or secondary allergic triggers. Liver function tests, including AST, ALT, ALP, and LDH, were largely unremarkable except for mild LDH elevations in selected cases, interpreted as nonspecific findings rather than indicators of infiltrative disease.
Autoimmune screening was performed in 8 (38.1%) patients. Among these patients, ANA positivity was observed in 5 cases, ANCA positivity in 2 cases, and ENA panel positivity in 1 case.
Overall, laboratory evaluation supported a non-clonal mast cell activation pattern. The absence of clonal markers was supported by negative KIT D816V mutation analysis in peripheral blood samples in all patients. In the 6 patients who underwent bone marrow biopsy, mast cell immunophenotype was assessed using flow cytometry, and no aberrant expression of CD25 or CD2 was detected.
All patients (100%) received H1 and/or H2 antihistamines as baseline therapy. Leukotriene receptor antagonists were prescribed to 11 (52.4%) patients. Omalizumab therapy was administered to 11 (52.4%) patients. Cromolyn sodium was used in 3 (14.3%) patients. Systemic corticosteroids were used intermittently for acute exacerbations and were not administered as long-term maintenance therapy. Adrenaline auto-injectors were prescribed to all patients (100%) (Table 3).
Table 3
Treatment modalities in patients with non-clonal mast cell activation syndromes (n = 21)
Discussion
In this real-life cohort, we evaluated the clinical characteristics, laboratory findings, and treatment patterns of patients with non-clonal mast cell activation syndromes. Our results demonstrate that patients predominantly presented with recurrent, severe, and systemic episodes involving typical organ systems, including cutaneous, gastrointestinal, cardiovascular, and respiratory manifestations, consistent with current diagnostic criteria. Extensive diagnostic work-up, including peripheral blood KIT analysis in all patients and bone marrow evaluation in selected cases, did not reveal evidence of clonal mast cell disease.
A substantial proportion of patients in our cohort had concomitant comorbid conditions, including chronic spontaneous urticaria, allergic rhinitis, and asthma. According to current consensus classifications, the presence of these concomitant conditions is more consistent with a secondary MCAS phenotype rather than idiopathic disease, highlighting the importance of careful phenotypic classification in real-life clinical practice [5].
In our cohort, the majority of patients were female, which aligns with previous reports indicating a female predominance in non-clonal mast cell activation syndromes cases [6].
The frequency of atopy and atopic diseases in patients with mast cell disorders appears to be similar to that observed in the general population. In systemic mastocytosis, a prevalence of approximately 30% has also been reported. In our cohort, the rate of atopy was comparable, observed in 28.5% of patients [7–9].
Multisystem involvement, particularly cutaneous manifestations, was frequent in our patients. As defined in the consensus reports, the diagnosis of MCAS requires the involvement of at least two organ systems. Accurate characterization of the affected systems and symptom patterns is critical not only for diagnosis but also for excluding differential diagnoses such as idiopathic anaphylaxis, clonal mast cell disorders, and mastocytosis [10].
All our patients exhibited episodic symptoms, a hallmark of mast cell activation disorders [11, 12]. Among mast cell mediators, serum tryptase remains the most accessible and widely used biomarker for mast cell activation [13, 14]. Although diagnostic tryptase elevation was not detectable at initial evaluation in all patients, following prolonged longitudinal follow-up with repeated measurements during symptomatic episodes, all patients eventually demonstrated a diagnostic increase in serum tryptase. Therefore, in patients with a compatible multisystemic clinical phenotype involving at least two organ systems, the absence of an initial demonstrable tryptase elevation should not preclude continued follow-up with a working diagnosis of suspected MCAS. Importantly, our findings reflect real-life clinical practice, where patients often present with evolving symptom patterns and may fulfil diagnostic criteria only after prolonged longitudinal follow-up.
The cornerstone of treatment in MCAS is the suppression of mast cell mediator release during episodes. Therefore, antihistamines remain the first-line therapy for both diagnostic confirmation and long-term symptom control [15]. In cases with inadequate control, stepwise escalation of therapy is recommended according to the patient’s clinical phenotype [16].
Data on omalizumab use in MCAS are still limited; however, several reports have demonstrated significant improvement in symptom scores following treatment [17]. A 2025 PubMed systematic review identified 21 non-clonal mast cell activation syndromes patients treated with omalizumab, with most showing clinical improvement [18]. In our series, 11 patients received omalizumab due to persistent episodic symptoms despite antihistamine therapy, and all demonstrated clinical response. Omalizumab appears to act as an effective mast cell–stabilizing agent in this setting [17].
As recommended by international guidelines, all patients with a history of systemic reactions should carry adrenaline auto-injectors [19]. Consistent with these recommendations, all our patients were prescribed and trained in the use of auto-injectors.
Monoclonal mast cell activation syndrome should be considered in the differential diagnosis of this patient group. Peripheral blood C-KIT D816V mutation analysis should be performed in all suspected cases, and bone marrow aspiration and biopsy should be carried out when clinical suspicion remains high [20]. In our cohort, C-KIT mutation testing was performed in all patients, and bone marrow aspiration biopsy was conducted in those with high clinical suspicion.
Non-clonal mast cell activation syndromes represent a real-life diagnostic and therapeutic challenge. Our data suggest that omalizumab, as an add-on therapy, provides meaningful clinical improvement even in patients without measurable tryptase elevation, supporting a phenotype-based management approach.
In our cohort, bone marrow evaluation was performed in 6 patients, allowing confident exclusion of clonal mast cell disease in these cases. Therefore, these patients were classified as consistent with idiopathic (non-clonal) MCAS. In the remaining patients, the presence of concomitant atopic or inflammatory comorbidities suggests a secondary MCAS phenotype. However, definitive classification could not be established in all cases due to the absence of bone marrow assessment in the entire cohort.
This study has several limitations that should be acknowledged. First, due to the retrospective design and the real-life clinical setting, comprehensive genetic evaluation for hereditary α-tryptasemia (HαT) could not be performed. Given the growing recognition of HαT as a relevant predisposing factor in patients with mast cell activation syndromes, the lack of systematic HαT testing may have limited precise subclassification of some patients within the MCAS spectrum. Future prospective studies incorporating genetic testing for HαT may help to further refine phenotypic classification and improve diagnostic accuracy.
