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Since its first description more than a decade ago, our understanding of the clinical impact of hereditary alpha-tryptasemia has continued to evolve. First considered to be a genetic disorder with a subset of patients having a syndromic presentation composed of connective tissue abnormalities, symptoms of autonomic dysfunction, and findings of mast cell activation, we now know that hereditary alpha-tryptasemia is a common genetic trait and modifier of mast cell-mediated reactions. More recent studies have shown some previously held associations with congenital hypermobility and postural orthostatic tachycardia syndrome (POTS) to be lacking, and illuminated previously unappreciated associations with clonal and nonclonal mast cell disorders. With the discovery of heterotetrameric tryptases and demonstration of their unique functional activities, the importance of tryptase gene composition in general has begun to take focus. Hereditary alpha-tryptasemia exists at the end of a spectrum of alpha-tryptase expression and as a natural overexpression model of this protein, brought to the fore the potential of tryptase genotyping as a genetic biomarker for anaphylaxis severity. These data and future studies hold the promise of enhancing our understanding of the role that tryptases play in health and disease.

Background: In patients who require venom immunotherapy (VIT), there is a need to identify underlying mast cell (MC) disorders since these may affect the risk and severity of future sting reactions and the long-term effectiveness of VIT., Methods: 1319 individuals with Hymenoptera venom allergy (HVA) who needed VIT from referral centers in Slovenia, Austria, Croatia, and Poland underwent examination for KIT p.D816V in peripheral blood leukocytes (PBL) using a highly sensitive PCR test and tryptase genotyping by digital droplet PCR. We also included 183 control individuals with large local reactions (LLRs) to Hymenoptera stings and with asymptomatic sensitization to Hymenoptera venoms., Results: 285 of 1319 individuals recommended for VIT (21.6%) were positive for KIT p.D816V in PBL, preferably those who present with severe reaction (33.9% [n = 207 of 610] with Ring-Messmer grade 3-4 vs. 11% [n = 78 of 709] with Grade 1-2; p < .0001), whereas only 1.3% (n = 2 of 152) of controls with LLR and none with asymptomatic sensitization (n = 31) had KIT p.D816V. KIT p.D816V allelic burden was higher in those with severe reaction (median 0.018% [n = 207] in Grade 3-4 vs. 0.001% [n = 78] in Grade 1-2; p < .0001), and the majority had normal baseline serum tryptase levels (69% [n = 196 of 285]). All KIT p.D816V-positive individuals (n = 41) who underwent bone marrow (BM) biopsy were found to have underlying clonal diseases, principally BM mastocytosis. HαT was also associated with severe HVA and symptoms (p < .01), and remarkably, 31.0% (n = 31 of 100) were found to have concomitant KIT p.D816V. Concomitant HαT and KIT p.D816V showed an additive effect, and having both was associated with the highest risk for severe HVA, even higher than having either HαT or KIT p.D816V alone (OR = 3.8; p < .01)., Conclusions: By employing prospective universal tryptase genotyping and examination for KIT p.D816V in PBL in large HVA populations, we have demonstrated a high burden of clonal MC disorders and HαT in patients who require VIT., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Activating mutations in KIT , particularly D816V, have been associated with mastocytosis. Additionally, expression of heterozygous KIT M541L has been primarily reported in patients with pediatric mastocytosis. We thus examined the prevalence of this variant in pediatric and adult patients with mastocytosis ( n = 100) compared to ancestry-matched 1000 genomes controls ( n = 500) and patients with idiopathic anaphylaxis ( n = 23). We then compared clinical symptoms and laboratory data on patients with systemic and cutaneous mastocytosis and bone marrow histopathology on a matched cohort with and without the KIT M541L variant. Overall, the KIT M541L variant was identified in 19 individuals; the majority were diagnosed with systemic mastocytosis (89.4%) with an associated KIT D816V mutation. There were no significant differences in peripheral blood parameters between groups. Patients with mastocytosis carrying the KIT M541L variant did not demonstrate significant differences in symptomatology compared to a matched reference cohort ( n = 13/81) without KIT M541L. In patients with idiopathic anaphylaxis, no significant associations were observed. This study uniquely examines the prevalence and impact of the KIT M541L variant in both adult and pediatric patients with mastocytosis further stratified by disease variant. To our knowledge, this is the first case/control study to show a significant genetic association with mastocytosis at the KIT M541L locus.

Background: Hereditary alpha-tryptasemia (HAT) is a genetic predisposition of autosomal dominant inheritance that leads to a high normal (≥ 8-11.4 μg/L) or pathologically elevated (>11.4 μg/L) basal serum tryptase (BST) concentration. Its prevalence in the United Kingdom and France is reportedly 5%-6%; its prevalence in Germany is unknown. Symptomatic persons with HAT suffer from a complex constellation of symptoms. As described in this review, HAT is an important differential diagnosis in interdisciplinary practice., Methods: This review is based on publications about HAT retrieved by a selective search in PubMed, on relevant presentations at scientific meetings, and on our clinical experience. We also collected our own data on the prevalence and clinical manifestations of HAT., Results: According to the literature, HAT is very common among patients in medical centers with BST values of 8 μg/L or above (64-74%). HAT is most commonly associated with neuropsychiatric symptoms such as exhaustion (85%), depressive episodes (59%), sleep disturbances (69%), and memory impairment (59%-68%), followed by gastrointestinal symptoms such as irritable bowel (30%-60%), nausea (51%), and reflux (49%-77%). Typical mast cell-mediated symptoms, such as flushing (47%), itch (69%), urticaria (37%), and anaphylaxis (14%-28%), are reported as well. Less commonly reported are cardio vascular manifestations, such as hypotonia, dizziness, and tachycardia (34%), and joint hyper - mobility (28%). HAT is more common among patients with systemic mastocytosis (SM; 12%-21%). It is often associated with severe anaphylaxis induced by insect toxins or unknown triggers. The therapeutic options include treatment with antihistamines, mastcell stabilizers, or IgE antibodies., Conclusion: A diagnosis of hereditary alphatryptasemia can be strongly suspected on the basis of thorough history-taking and BST measurement and then confirmed by molecular genetic testing.

Purpose of Review: 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., Recent Findings: 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., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: A close association between hereditary alpha-tryptasemia (HAT) and mast cell (MC) disorders has been previously reported. However, the relationship between HAT and the diagnostic subtypes and clinical features of MC disorders still remains to be established., Objective: To determine the prevalence of HAT in healthy donors (HD) vs patients with different diagnostic subtypes of MC activation syndromes (MCAS) and mastocytosis, and its relationship with the clinical behavior of the disease., Methods: A total of 959 subjects were studied including 346 healthy donors (HD), 464 mastocytosis, and 149 non-clonal MCAS patients. Molecular studies to assess the TPSAB1 genotype were performed, and data on serum baseline tryptase (sBT) and basal MC-mediator release episodes and triggers of anaphylaxis were collected., Results: HAT was detected in 15/346 (4%) HD versus 43/149 (29%) non-clonal MCAS and 84/464 (18%) mastocytosis cases. Among mastocytosis, HAT was more frequently found in patients with MC-restricted KIT D816V (21% vs. 10% among multilineage KIT D816V patients; p = .008). Overall, median sBT was higher in cases presenting with HAT (28.9 vs. 24.5 ng/mL; p = .008), while no significant differences in sBT were observed among HAT + mastocytosis patients depending on the presence of 1 vs. ≥2 extra copies of the α-tryptase gene (44.1 vs. 35.2 ng/mL, p > .05). In turn, anaphylaxis was more frequently observed in HAT + versus HAT - mastocytosis patients (76% vs. 65%; p = .018), while HAT + and HAT - patients who did not refer anaphylaxis as the presenting symptom (n = 308) showed a similar prevalence of subsequent anaphylaxis (35% vs. 36%, respectively)., Conclusion: The frequency of HAT in MC disorders varies according to the diagnostic subtype of the disease. HAT does not imply a higher risk (and severity) of anaphylaxis in mastocytosis patients in whom anaphylaxis is not part of the presenting symptoms of the disease., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Purpose of Review: Mast cell (MC) activation can present with a wide range of symptoms. The mechanisms that cause such activation are varied. One of them is the presence of clonal MCs which is defined, within other possible changes, by the presence of a somatic, activating mutation in the KIT gene. The clinical course and prognosis of patients with this underlying disease may be different from other causes of MC activation (MCA). For this reason, it is important to early diagnose, or at least suspect, which patients with MCA are due to clonal MCs., Recent Findings: The diagnosis of clonality must be made in a comprehensive manner. However, this paper reviews chronologically each of the stages from the patient's first visit to the doctor's office which can be indicative of clonality: clinical presentation of MCA, physical examination, analytical determinations of tryptase, and/or KIT mutational analysis and bone involvement, among others. The different clonality predictive scores proposed are also reviewed and compared. Although the gold standard for the diagnosis of certainty of MC clonality is the performance of a bone marrow (BM) biopsy, there are clinical symptoms, signs, and biological parameters suggestive of clonality, as well as predictive scores, which can guide (or rule out) an early diagnosis and avoid unnecessary BM biopsies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mast cell tumors are a large group of diseases occurring in dogs, cats, mice, as well as in humans. Systemic mastocytosis (SM) is a disease involving the accumulation of mast cells in organs. KIT gene mutations are very often seen in abnormal mast cells. In SM, high KIT/CD117 expression is observed; however, there are usually no KIT gene mutations present. Mastocytoma (MCT)-a form of cutaneous neoplasm-is common in animals but quite rare in humans. KIT/CD117 receptor mutations were studied as the typical changes for human mastocytosis. In 80% of human cases, the KIT gene substitution p.D816H was present. In about 25% of MCTs, metastasis was observed. Changes in the gene expression of certain genes, such as overexpression of the DNAJ3A3 gene, promote metastasis. In contrast, the SNORD93 gene blocks the expression of metastasis genes. The panel of miR-21-5p , miR-379 , and miR-885 has a good efficiency in discriminating healthy and MCT-affected dogs, as well as MCT-affected dogs with and without nodal metastasis. Further studies on the pathobiology of mast cells can lead to clinical improvements, such as better MCT diagnosis and treatment. Our paper reviews studies on the topic of mast cells, which have been carried out over the past few years.

Background: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal., Objective: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT., Methods: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases., Results: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT + patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT - patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01)., Conclusion: Here we confirm the increase incidence of anaphylaxis in HαT + mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative on Mast Cell Disorders have discussed and updated diagnostic criteria and the classification of mastocytosis, based on new insights in the field and data collected in recent years, mostly within ECNM registry projects in which studies on several thousand cases have been performed. Based on this proposal, the World Health Organization has updated its classification of mastocytosis. This article discusses the revised classification of mastocytosis in light of a rapidly moving field and the advent of new diagnostic parameters, new prognostication tools, and new therapies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A KIT activating mutation (usually KIT D816V) is detected in neoplastic cells in greater than 90% of indolent patients with systemic mastocytosis (SM). In more advanced variants of SM, additional genetic defects can be found in several myeloid malignancy-related genes, which can be detected by applying next-generation sequencing. Currently, the techniques recommended to detect the KIT D816V mutation and quantify the mutational burden in peripheral blood, bone marrow, or other organs/tissues are allele specific-quantitative PCR or droplet digital PCR. These techniques are useful for diagnosis, prognostication, follow-up and monitoring of therapeutic efficacy of cytoreductive agents in patients with SM., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To a large extent, the clinical picture of pediatric mastocytosis depends on the age at which it is diagnosed. A neonate with diffuse cutaneous mastocytosis may frequently present in a severe state requiring treatment. Toddlers may require long-term anti-mediator therapy, and this may lead to concerns such as organizing preschool education due to the need for epinephrine injections. A teenager may have to face cutaneous disease persistence or a diagnosis of systemic mastocytosis. Further studies are needed to refine the available treatment options and prognosis for different age groups., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Advanced systemic mastocytosis (SM) is a heterogeneous group of myeloid neoplasms characterized by an uncontrolled expansion of mast cells (MC) in one or more internal organs, SM-induced tissue damage, and poor prognosis. Advanced SM can be categorized into aggressive SM (ASM), MC leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN). In a vast majority of all patients, neoplastic cells display a KIT mutation, mostly D816V and rarely other KIT variants. Additional mutations in other target genes, such as SRSF2 , ASXL1 , or RUNX1 , may also be identified, especially when an AHN is present. During the past 10 years, improved treatment approaches have led to a better quality of life and survival in patients with advanced SM. However, despite the availability of novel potent inhibitors of KIT D816V, not all patients enter remission and others relapse, often with a multi-mutated and sometimes KIT D816V-negative disease exhibiting multi-drug resistance. For these patients, (poly)chemotherapy, antibody-based therapies, and allogeneic hematopoietic stem cell transplantation may be viable treatment alternatives. In this article, we discuss treatment options for patients with drug-resistant advanced SM, including novel KIT-targeting drugs, antibody-based drugs, and stem cell-eradicating therapies.

Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a KIT alteration (NM&#95;000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.

Physiological levels of basal serum tryptase vary among healthy individuals, depending on the numbers of mast cells, basal secretion rate, copy numbers of the TPSAB1 gene encoding alpha tryptase, and renal function. Recently, there has been a growing debate about the normal range of tryptase because individuals with the hereditary alpha tryptasemia (HαT) trait may or may not be symptomatic, and if symptomatic, uncertainty exists as to whether this trait directly causes clinical phenotypes or aggravates certain conditions. In fact, most HαT-positive cases are regarded as asymptomatic concerning mast cell activation. To address this point, experts of the European Competence Network on Mastocytosis (ECNM) and the American Initiative in Mast Cell Diseases met at the 2022 Annual ECNM meeting and discussed the physiological tryptase range. Based on this discussion, our faculty concluded that the normal serum tryptase range should be defined in asymptomatic controls, inclusive of individuals with HαT, and based on 2 SDs covering the 95% confidence interval. By applying this definition in a literature screen, the normal basal tryptase in asymptomatic controls (HαT-positive persons included) ranges between 1 and 15 ng/mL. This definition should avoid overinterpretation, unnecessary referrals, and unnecessary anxiety or anticipatory fear of illness in healthy individuals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Myeloproliferative neoplasms, mastocytosis, myeloid/lymphoid neoplasms with hypereosinophilia and tyrosine kinase gene fusions, and myelodysplastic/myeloproliferative neoplasms are clonal hematopoietic cancers that, with the exception of certain entities, have an indolent course. In addition to their increasingly important role in the diagnosis of these entities, as shown by the recent classification of hematolymphoid tumors in the 5th edition of the World Health Organization and the International Consensus Classification of myeloid neoplasms and acute leukemias, identification of the profile of acquired genetic abnormalities is essential for adapting patient management and early detection of patients at high risk of progression. Alongside molecular abnormalities, cytogenetic abnormalities play an important role in the diagnosis, prognosis and follow-up of these diseases. Here, we review the recent literature on the impact of chromosomal abnormalities in these different entities and provide updated cytogenetic recommendations and guidelines for their management., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

KIT, a type III tyrosine kinase receptor, plays a crucial role in haematopoietic development. The KIT receptor forms a dimer after ligand binding; this activates tyrosine kinase activity leading to downstream signal transduction. The D816V KIT mutation is extensively implicated in haematological malignancies, including mastocytosis and leukaemia. KIT D816V is constitutively active, but the molecular nuances that lead to constitutive tyrosine kinase activity are unclear. For the first time, we present experimental evidence that the KIT D816V mutant does not dimerize like KIT wild type. We further show evidence of decreased stabilization of the tyrosine kinase domain in the KIT D816V mutant, a phenomenon that might contribute to its constitutive activity. Since the mechanism of KIT D816V activation varies from that of the wild type, we explored downstream signal transduction events and found that even though KIT D816V targets similar signalling moieties, the signalling is amplified in the mutant compared to stem cell factor-activated wild type receptor. Uniquely, KIT D816V induces infection-related pathways and the spliceosome pathway, providing alternate options for selective as well as combinatorial therapeutic targeting., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Mastocytosis is a complex heterogenous multisystem disorder that is characterized by pathologic activation or accumulation of neoplastic mast cells (MCs) in one or more organs. This clonal MC expansion is often associated with a somatic gain-of-function mutation (D816V in most of the cases) in the KIT gene, encoding for the MC surface receptor KIT (CD117), a stem cell growth factor receptor. Based on clinical and biochemical criteria, the World Health Organization (WHO) divided mastocytosis into different subclasses. The exact prevalence of mastocytosis remains elusive, but it is estimated that the disease affects approximately 1 in 10,000 persons. The clinical presentation of mastocytosis varies significantly, ranging from asymptomatic patients to a life-threatening disease with multiple organ involvement, potentially leading to cytopenia, malabsorption, hepatosplenomegaly, lymphadenopathy, ascites or osteolytic bone lesions with pathological fractures. Patients with mastocytosis may experience symptoms related to release of MC mediators, such as flushing or diarrhea or even more severe symptoms such as anaphylaxis. Recently, a new genetic trait, hereditary alpha tryptasemia (HaT), was described which involves a copy number variation in the TPSAB1-gene. Its role as standalone multisystem syndrome is heavily debated. There is emerging evidence suggesting there might be a link between HaT and due to the increased prevalence of HaT in patients with SM. The aim of this review is to provide a practical roadmap for diagnosis and management of mastocytosis and its associated entities, since there are still many misconceptions about these topics. Abbreviations: AdvSM: Advanced systemic mastocytosis; ASM: Aggressive systemic mastocytosis; aST: acute serum tryptase; BM: Bone marrow; BMM: Bone marrow mastocytosis; bST: baseline serum tryptase; CM: Cutaneous mastocytosis; DCM: Diffuse cutaneous mastocytosis; HVA: Hymenoptera venom allergy; HaT: Hereditary alpha tryptasemia; ISM: Indolent systemic mastocytosis; MC: Mast cell; MCA: Mast cell activation; MCAS: Mast cell activation syndrome; MCL: Mast cell leukemia; MIS: Mastocytosis in the skin; MMAS: Monoclonal mast cell activation syndrome; MPCM: Maculopapular cutaneous mastocytosis; SM: Systemic mastocytosis; SM-AHN: Systemic mastocytosis with associated hematological neoplasm; SSM: Smouldering systemic mastocytosis; VIT: Venom immunotherapy.

Scombroid poisoning, systemic mastocytosis, and hereditary alpha tryptasemia all present with episodes that resemble allergic reactions. Knowledge regarding systemic mastocytosis and hereditary alpha tryptasemia is quickly evolving. Epidemiology, pathophysiology, and strategies to identify and diagnose are discussed. Evidence-based management in the emergency setting and beyond is also explored and summarized. Key differences are described between these events and allergic reactions., Competing Interests: Disclosure The authors declare that they have no relevant or material financial interests that relate to the research described in this article., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Current diagnostic algorithms for systemic mastocytosis (SM) rely on the detection of KITD816V in blood to trigger subsequent bone marrow (BM) investigations., Methods: Here, we correlated the KITD816V mutational status of paired blood and BM samples from 368 adults diagnosed with mast cell activation syndrome (MCAS) and mastocytosis and determined the potential utility of investigating KITD816V in genomic DNA from blood-purified myeloid cell populations to increase diagnostic sensitivity. In a subset of 69 patients, we further evaluated the kinetics of the KITD816V cell burden during follow-up and its association with disease outcome., Results: Our results showed a high correlation (P < .0001) between the KITD816V mutation burden in blood and BM (74% concordant samples), but with a lower mean of KITD816V-mutated cells in blood (P = .0004) and a high rate of discordant BM + /blood - samples particularly among clonal MCAS (73%) and BM mastocytosis (51%), but also in cutaneous mastocytosis (9%), indolent SM (15%), and well-differentiated variants of indolent SM (7%). Purification of different compartments of blood-derived myeloid cells was done in 28 patients who were BM mast cell (MC) + /blood - for KITD816V, revealing KITD816V-mutated eosinophils (56%), basophils (25%), neutrophils (29%), and/or monocytes (31%) in most (61%) patients. Prognostically, the presence of ≥3.5% KITD816V-mutated cells (P < .0001) and an unstable KITD816V mutation cell burden (P < .0001) in blood and/or BM were both associated with a significantly shortened progression-free survival (PFS)., Conclusions: These results confirm the high specificity but limited sensitivity of KITD816V analysis in whole blood for the diagnostic screening of SM and other primary MCAS, which might be overcome by assessing the mutation in blood-purified myeloid cell populations., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The association between Hymenoptera venom-triggered anaphylaxis (HVA) and clonal mast cell-related disorders (cMCD) has been known for decades. However, recent breakthroughs in peripheral blood screening for KIT p.D816V missense variant have revealed the true extent of this clinical association whilst adding to our understanding of the underlying aetiology. Thus, recent large studies highlighted the presence of KIT p.D816V among 18.2% and 23% of patients with severe Hymenoptera venom-triggered anaphylaxis. A significant proportion of those patients have normal serum basal tryptase (BST) levels, with no cutaneous findings such as urticaria pigmentosa or other systemic findings such as organomegaly that would have suggested the presence of cMCD. These findings of an increased prevalence suggest that the impact of cMCD on anaphylaxis could be clinically underestimated and that the leading question for clinicians could be changed from 'how many patients with cMCD have anaphylaxis?' to 'how many patients with anaphylaxis have cMCD?'. The discovery of hereditary α-tryptasemia (HαT)-a genetic trait caused by an increased copy number of the Tryptase Alpha/Beta 1 (TPSAB1) gene-, first described in 2016, is now known to underlie the majority of cases of elevated BST outside of cMCD and chronic kidney disease. HαT is the first common heritable genetic modifier of anaphylaxis described, and it is associated with increased risk for severe HVA (relative risk = 2.0), idiopathic anaphylaxis, and an increased prevalence of anaphylaxis in patients with cMCD, possibly due to the unique activity profile of α/β -tryptase heterotetramers that may potentiate immediate hypersensitivity reaction severity. Our narrative review aims to highlight recent research to have increased our understanding of cMCD and HαT, through recent lessons learned from studying their association with HVA. Additionally, we examined the studies of mast cell-related disorders in food and drug allergy in an effort to determine whether one should also consider cMCD and/or HαT in cases of severe anaphylaxis triggered by food or drugs., (© 2023 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

The HMC-1.2 human mast cell (huMC) line is often employed in the study of attributes of neoplastic huMCs as found in patients with mastocytosis and their sensitivity to interventional drugs in vitro and in vivo . HMC-1.2 cells express constitutively active KIT, an essential growth factor receptor for huMC survival and function, due to the presence of two oncogenic mutations (D816V and V560G). However, systemic mastocytosis is commonly associated with a single D816V-KIT mutation. The functional consequences of the coexisting KIT mutations in HMC-1.2 cells are unknown. We used CRISPR/Cas9-engineering to reverse the V560G mutation in HMC-1.2 cells, resulting in a subline (HMC-1.3) with a single mono-allelic D816V-KIT variant. Transcriptome analyses predicted reduced activity in pathways involved in survival, cell-to-cell adhesion, and neoplasia in HMC-1.3 compared to HMC-1.2 cells, with differences in expression of molecular components and cell surface markers. Consistently, subcutaneous inoculation of HMC-1.3 into mice produced significantly smaller tumors than HMC-1.2 cells, and in colony assays, HMC-1.3 formed less numerous and smaller colonies than HMC-1.2 cells. However, in liquid culture conditions, the growth of HMC-1.2 and HMC-1.3 cells was comparable. Phosphorylation levels of ERK1/2, AKT and STAT5, representing pathways associated with constitutive oncogenic KIT signaling, were also similar between HMC-1.2 and HMC-1.3 cells. Despite these similarities in liquid culture, survival of HMC-1.3 cells was diminished in response to various pharmacological inhibitors, including tyrosine kinase inhibitors used clinically for treatment of advanced systemic mastocytosis, and JAK2 and BCL2 inhibitors, making HMC-1.3 more susceptible to these drugs than HMC-1.2 cells. Our study thus reveals that the additional V560G-KIT oncogenic variant in HMC-1.2 cells modifies transcriptional programs induced by D816V-KIT, confers a survival advantage, alters sensitivity to interventional drugs, and increases the tumorigenicity, suggesting that engineered huMCs with a single D816V-KIT variant may represent an improved preclinical model for mastocytosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bandara, Falduto, Luker, Bai, Pfeiffer, Lack, Metcalfe and Olivera.)

Background: The Red Española de Mastocitosis (Spanish Network on Mastocytosis) score (REMAs) and the National Institutes of Health idiopathic clonal anaphylaxis score (NICAS) were developed for more efficient screening of mast cell (MC) clonality in MC activation syndromes. In a limited idiopathic anaphylaxis case series, the NICAS showed higher accuracy compared with the REMAs., Objective: To compare the performance of the REMAs against the NICAS in the diagnosis of MC clonality., Methods: We compared the diagnostic value of the REMAs against the NICAS in 182 patients (63% men, median age 56 years) who presented with anaphylaxis triggered by Hymenoptera venom allergy (45%), drugs (15%), food (11%), idiopathic anaphylaxis (20%), and mixed causes (10%). KIT mutation was assessed in parallel in whole blood and bone marrow (BM) and, when negative, in highly purified BM MC. TPSAB1 was genotyped in a subset of 71 patients., Results: We found higher accuracy and rates of correctly classified patients for the REMAs (82% and 84%) compared with the NICAS (75% and 75%; P = .02 and P = .03, respectively), particularly among men (P = .05), patients with systemic mastocytosis (P = .05), those presenting anaphylaxis owing to any cause featuring urticaria (P = .04), cardiovascular symptoms (P = .02), and/or presyncope (P = .02) and those with a blood-negative/BM-positive KIT mutational profile (P = .002), but not hereditary α-tryptasemia-associated genotypes. Combined assessment of the REMAs and KIT D816V in blood yielded an overall improved classification efficiency of 86% versus 84% for REMAs., Conclusions: The combined use of the REMAs and blood detection of KIT D816V is recommended, but more sensitive blood-based molecular assays to detect KIT D816V are needed., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Mastocytosis is a heterogeneous group of neoplasms defined by a numerical increase and accumulation of clonal mast cells (MCs) in various organ systems. The disease may present as cutaneous mastocytosis or systemic mastocytosis (SM). On the basis of histopathological and molecular features, clinical variables, and organ involvement, SM is divided into indolent SM, smoldering SM, SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Each variant is defined by unique diagnostic criteria and a unique spectrum of clinical presentations. A key driver of MC expansion and disease evolution is the oncogenic machinery triggered by mutant forms of KIT . The genetic background, additional somatic mutations, and comorbidities also contribute to the course and prognosis. Patients with SM may also suffer from mediator-related symptoms or even an MC activation syndrome. This article provides an update of concepts on the genetics, etiology, and pathology of mastocytosis, with emphasis on diagnostic criteria and new treatment concepts.

Mast cell disorders include mastocytosis and mast cell activation syndromes. Mastocytosis is a rare clonal disorder of the mast cell, driven by KIT D816V mutation in most cases. Mastocytosis is diagnosed and classified according to World Health Organization criteria. Mast cell activation syndromes encompass a diverse group of disorders and may have clonal or nonclonal etiologies. Hematologists may be consulted to assist in the diagnostic workup and/or management of mast cell disorders. A consult to the hematologist for mast cell disorders may provoke anxiety due to the rare nature of these diseases and the management of nonhematologic mast cell activation symptoms. This article presents recommendations on how to approach the diagnosis and management of patients referred for common clinical scenarios., (Copyright © 2022 by The American Society of Hematology.)

Purpose of Review: To discuss our evolving knowledge about the genetic variations in human tryptase and recent advances in associated clinical phenotypes., Recent Findings: Hereditary alpha-tryptasemia (HAT) is an autosomal dominant genetic trait and a common cause of elevated basal serum tryptase (BST) in Western populations. It is a risk factor for severe anaphylaxis and an established modifier of mast cell mediator-associated symptoms among patients with systemic mastocytosis (SM)., Summary: The unique properties of naturally occurring alpha/beta-tryptase heterotetramers may explain certain elements of phenotypes associated with HAT. Understanding the physiology of tryptases and how this may relate to the clinical features associated with HAT is the first step in identifying optimal medical management and targets for novel therapeutics., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Pathology plays a central role in the diagnosis of systemic mastocytosis (SM), its delineation from other neoplasms and reactive conditions, and in monitoring of SM under therapy. The morphologic hallmark of SM is the accumulation of spindle-shaped, hypogranulated mast cells (MCs) in bone marrow (BM) and other extracutaneous tissues. Four of the 5 World Health Organization-defined diagnostic criteria (ie, compact MC aggregates [=major criterion]; atypical MC morphology; activating KIT point mutations; aberrant expression of CD25 and/or CD2 and/or CD30 in MCs [=minor criteria]) can be addressed by the pathologist. The final classification of SM variants as either BM mastocytosis, indolent SM, smoldering SM, aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), or MC leukemia (MCL) has important prognostic significance and requires the integration of certain morphological, clinical, radiological, and biochemical data, referred to as B- and C-findings. Substantial diagnostic challenges may be posed to the pathologist and clinician especially in the so-called advanced SM variants, that is, ASM, MCL, and SM-AHN. In this article, updated recommendations of the EU-US Cooperative Group regarding standards of pathology in the diagnosis of SM, presented during the year 2020 Working Conference held in September in Vienna, are reported., (Copyright © 2022. Published by Elsevier Inc.)

Mastocytosis comprises rare heterogeneous diseases characterized by an increased accumulation of abnormal mast cells in various organs/tissues. The pathogenesis of mastocytosis is strongly linked to the presence of KIT-activating mutations. In systemic mastocytosis (SM), the most frequent mutation encountered is KIT p.D816V, whose presence constitutes one of the minor diagnostic criteria. Different techniques are used to search and quantify the KIT p.D816V mutant; however, allele-specific quantitative PCR and droplet digital PCR are today the most sensitive. The analysis of the KIT p.D816V allele burden has undeniable interest for diagnostic, prognostic, and therapeutic monitoring. The analysis of non-mast cell hematological compartments in SM is similarly important because KIT p.D816V multilineage involvement is associated with a worse prognosis. In addition, in advanced forms of SM, mutations in genes other than KIT are frequently identified and affect negatively disease outcome and response to therapy. Thus, combined quantitative and sensitive analysis of KIT mutations and next-generation sequencing of other recurrently involved myeloid genes make it possible to better characterize the extent of the affected cellular compartments and additional molecular aberrations, providing a more detailed overview of the complex mutational landscape of SM, in relation with the clinical heterogeneity of the disease. In this article, we report the latest recommendations of the EU-US Cooperative Group presented in September 2020 in Vienna during an international working conference, on the techniques we consider standard to detect and quantify the KIT p.D816V mutant in SM and additional myeloid mutations found in SM subtypes., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The measurement of mast cell tryptase levels in serum has found utility in the diagnosis and management of both clonal mast cell disorders and severe mast cell-dependent systemic reactions in the form of anaphylaxis. A more recent discovery is that a majority of individuals with elevated basal serum tryptase levels have increased germline TPSAB1 gene copy number encoding α-tryptase. This genetic trait is referred to as hereditary α-tryptasemia (HαT) and affects nearly 6% of the general population. In clinical practice, the presence or absence of HαT should thus now be determined when defining what constitutes an abnormal serum tryptase level in the diagnosis of mastocytosis. Further, as rises in serum tryptase levels are used to support the diagnosis of systemic anaphylaxis, variability in baseline serum tryptase levels should be factored into how significant a rise in serum tryptase is required to confirm the diagnosis of a systemic allergic reaction. In practicality, this dictates that symptomatic individuals undergoing evaluation for a mast cell-associated disorder or reaction with a baseline serum tryptase level exceeding 6.5 ng/mL should be considered for tryptase genotyping in order to screen for HαT. This review provides detailed information on how to use the results of such testing in the diagnosis and management of both mastocytosis and anaphylaxis., (Published by Elsevier Inc.)

Mastocytosis is a myeloid neoplasm defined by expansion and focal accumulation of clonal mast cells (MCs) in one or more organs. The disease exhibits a complex pathology and may be complicated by MC activation, bone abnormalities, neurological problems, gastrointestinal symptoms, and/or hematologic progression. The World Health Organization divides mastocytosis into cutaneous forms, systemic mastocytosis (SM) and MC sarcoma. In most patients with SM, somatic mutations in KIT are detected. Patients with indolent SM have a normal to near-normal life expectancy, whereas patients with advanced SM, including aggressive SM and MC leukemia, have a poor prognosis. In those with advanced SM, multiple somatic mutations and an associated hematologic neoplasm may be detected. Mediator-related symptoms can occur in any type of mastocytosis. Symptoms may be mild, severe, or even life-threatening. In patients with severe acute symptoms, an MC activation syndrome may be diagnosed. In these patients, relevant comorbidities include IgE-dependent and IgE-independent allergies. Management of patients with SM is an emerging challenge in daily practice and requires in-depth knowledge and a multidisciplinary and personalized approach with selection of appropriate procedures and interventions. In this article, we review the current knowledge on SM and MC activation syndrome, with emphasis on multidisciplinary aspects in diagnosis and patient-specific management. In addition, we provide a user's guide for application of markers, algorithms, prognostic scores, and treatments for use in daily practice., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Advanced systemic mastocytosis (AdvSM) is characterized by the presence of KIT D816V and other somatic mutations (eg, in SRSF2, ASXL1, and RUNX1) in 95% and 60% to 70% of patients, respectively. The biological and clinical consequences of AdvSM include multilineage involvement (eg, associated hematologic neoplasm) in 60% to 80% of patients, variable infiltration and damage (C-findings) of predominantly bone marrow and visceral organs through affected mast cell (MC) and non-MC lineages, and elevated levels of serum tryptase. Recently, the treatment landscape has substantially changed with the introduction of the multikinase/KIT inhibitor midostaurin and the selective KIT D816V inhibitor avapritinib. In this review, we discuss the evolution of AdvSM response criteria that have been developed to better capture clinical benefit (eg, improved responses and progression-free and overall survival). We propose refined response criteria from European Competence Network on Mastocytosis and American Initiative in Mast Cell Diseases investigators that use a tiered approach to segregate the effects of histopathologic (eg, bone marrow MC burden, tryptase), molecular (eg, KIT D816V variant allele frequency), clinical (eg, C-findings), and symptom response on long-term outcomes. These response criteria require evaluation in future prospective clinical trials of selective KIT inhibitors and other novel agents., (Copyright © 2022. Published by Elsevier Inc.)

Mast cell sarcoma (MCS) is an exceedingly rare form of mastocytosis characterized by invasive malignant mast cell growth and metastatic potential. Diagnosis of MCS is very challenging due to its marked morphologic variations and significant immunophenotypic overlap with other neoplasms. In this study, we undertook an extensive study of 10 cases of MCS from our series, with review of additional 24 cases from the literature, to better clarify the clinicopathologic and molecular features of MCS. From the analyses of our 10 cases, MCS equally involved males and females with a median age of 54.5 years (range 1-63). The bone was the most common site of involvement, as noted in 9/10 of cases. Two patients had prior germ cell tumors (mediastinal germ cell tumor and ovarian dysgerminoma), and concurrent systemic mastocytosis was noted in one of nine patients. Serum tryptase levels were elevated in 6/7 of patients, and 3/9 of patients had mast cell activation symptoms. Morphologically, the tumor cells were typically large and pleomorphic with frequent reactive eosinophils. By immunohistochemical staining, MCS consistently expressed CD43 (8/8), CD117 (10/10), and mast cell tryptase (10/10), as well as CD13 (3/3) and CD33 (10/10), with variable positivity of CD2 (1/9), CD25 (4/9), CD30 (5/8), and CD68 (5/9). Notably, KIT D816V was not detected in nine cases in our study, although two cases had other mutations of KIT gene. Seven out of eight patients received chemotherapy with or without radiotherapy. However, the response was poor, and four out of eight patients died within a median follow-up interval of five months. Taken together, there are no standardized therapeutic regimens available for MCS at this time, and the prognosis is dismal. Therefore, it is critical to further investigate and characterize this rare entity, with the hope of improving diagnostic accuracy and providing more effective, targeted therapies., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Mast cells (MCs) contribute prominently to all allergic diseases, yet are still poorly understood owing to their exclusive residence in tissues. Recently, the use of RNA-sequencing, proteomics, and other technological advances have accelerated the acquisition of new knowledge. This includes an expanded definition of MC heterogeneity and developmental origins, previously unrecognized functions for MCs, discoveries of genetic causes of MC-related disorders, the introduction of new therapies for clonal MC disease, and the identification of new potential target for treatments. This issue of Advances addresses key studies from 2020 to 2021., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Mastocytosis is a rare disease with a low incidence in Asia-Pacific populations. CD30 and CD123 may have potential prognostic and therapeutic value, but the results are inconsistent. Because racial disparities may exist, we aim to evaluate the expressions of CD30 and CD123 in a series of mastocytosis cases in Taiwan. Twelve patients with systemic and 7 with cutaneous forms of mastocytosis were studied. The expressions of CD30 and CD123 were correlated with the clinical features of the patients. Eighty-three percent (10/12) of patients with systemic mastocytosis (SM) had an associated hematological neoplasm. Four of the SM patients had both "B" and "C" findings, and they had a median survival time of 0.9 months. CD30 expression was positive in 50% (6/12) of SM cases and 100% (6/6) of cutaneous mastocytosis cases. CD123 was expressed focally or weakly in only 2 SM-associated hematological neoplasm cases. The distribution of mastocytosis subtypes and the expression of CD30 and CD123 in Taiwan differed from those reported in North America and Europe. However, mastocytosis, especially indolent forms, is easily overlooked as its heterogeneous and nonspecific clinical manifestations. A high index of suspicion and improved diagnostic methods can be helpful., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A male Malayan tiger cub developed well-circumscribed, erythematous, alopecic lesions on the face, torso, and paws when 1-wk-old. Biopsies of a torso lesion and a right front paw lesion at 1-mo-old confirmed cutaneous mast cell tumors (MCTs). MCTs on the paws grew into pendulous masses up to 6.5 cm in diameter by 3-mo-old, but those on the face and torso regressed. Fine-needle aspiration of the spleen at 3-mo-old revealed marked mast cell infiltration. The spleen and the right paw cutaneous MCT were removed; the paw MCT recurred within 7 d. A 12-bp tandem duplication, suggesting a somatic mutation, was identified in exon 8 of c-KIT in DNA extracted from the cutaneous MCT on the right paw and from one over the torso, but not from the spleen. Remaining MCTs on the paws regressed slowly following splenectomy and had completely regressed by 1-y-old. At 7-y-old, there was no recurrence of any mast cell disease. Mast cell disease in this tiger cub is similar to a report in a domestic kitten and to pediatric mastocytosis in humans, which commonly begins in infancy, improves by adolescence, and is associated with somatic c-kit mutations. To our knowledge, mastocytosis has not been reported previously in a juvenile exotic felid.

Activating mutations in c-KIT are associated with the mast cell (MC) clonal disorders cutaneous mastocytosis and systemic mastocytosis and its variants, including aggressive systemic mastocytosis, MC leukemia, and MC sarcoma. Currently, therapies inhibiting KIT signaling are a leading strategy to treat MC proliferative disorders. However, these approaches may have off-target effects, and in some patients, complete remission or improved survival time cannot be achieved. These limitations led us to develop an approach using chemically stable exon skipping oligonucleotides (ESOs) that induce exon skipping of precursor (pre-)mRNA to alter gene splicing and introduce a frameshift into mature KIT mRNA transcripts. The result of this alternate approach results in marked downregulation of KIT expression, diminished KIT signaling, inhibition of MC proliferation, and rapid induction of apoptosis in neoplastic HMC-1.2 MCs. We demonstrate that in vivo administration of KIT targeting ESOs significantly inhibits tumor growth and systemic organ infiltration using both an allograft mastocytosis model and a humanized xenograft MC tumor model. We propose that our innovative approach, which employs well-tolerated, chemically stable oligonucleotides to target KIT expression through unconventional pathways, has potential as a KIT-targeted therapeutic alone, or in combination with agents that target KIT signaling, in the treatment of KIT-associated malignancies., Competing Interests: Declaration of interests G.C. has filed a patent application related to the research reported in this study. G.C. has research support from Hoth Therapeutics for a project not directly related to the research reported in this publication and also serves on their Scientific Advisory Board. The research findings included in this publication were not funded by Hoth Therapeutics, but a technology licensing agreement has been granted to Hoth Therapeutics for this technology after submission and while this study was under review. The terms of this arrangement have been reviewed and approved by North Carolina State University in accordance with its policy on objectivity in research. The remaining authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. All rights reserved.)

Objective: To describe our current understanding of hereditary α-tryptasemia (HαT), how HαT fits into the evolutionary context of tryptases and contemporary framework of mast cell-associated disorders, and to discuss the future clinical and therapeutic landscape for symptomatic individuals with HαT., Data Sources: Primary peer-reviewed literature., Study Selections: Basic, clinical, and translational studies describing tryptase gene composition, generation, secretion, and elevation and the associated clinical impacts of HαT and treatment of such individuals were reviewed., Results: HαT is a common autosomal dominant genetic trait caused by increased TPSAB1 copy number encoding α-tryptase. Approximately 1 in 20 White individuals have HαT, making it by far the most common cause for elevated basal serum tryptase levels. Although many individuals with HαT may not manifest associated symptoms, the prevalence of HαT is increased in patients with clonal and nonclonal mast cell-associated disorders wherein it is linked to more prevalent and/or severe anaphylaxis and increased mast cell mediator-associated symptoms. Increased generation of mature α/β-tryptase heterotetramers, and their unique physiochemical properties, may be responsible for some of these clinical findings., Conclusion: HαT is a common modifier of mast cell-associated disorders and reactions. Nevertheless, whether HαT may be an independent cause of clinical phenotypes with which it has been associated remains unproven. Correct identification of HαT is critical to accurate interpretation of serum tryptase levels in the clinical evaluation of patients. Beyond HαT, we foresee tryptase genotyping as an important parameter in the standard workup of patients with mast cell-associated disorders and development of therapeutic modalities targeting these patients and associated clinical phenotypes., (Published by Elsevier Inc.)

Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with exon 11 mutations., (© 2021 Wiley Periodicals LLC.)

Objective: To aid the clinician in correctly interpreting serum tryptase levels., Data Sources: Primary peer-reviewed literature., Study Selections: Clinical and basic science peer-reviewed studies characterizing the genetic and physiological bases for tryptase generation, secretion, and elevation, including those describing serum tryptase levels in population-based cohort studies., Results: Clinically measured basal serum tryptase (BST) consists of ostensibly inactive alpha- and beta-tryptase precursors. The autosomal dominant genetic trait hereditary alpha-tryptasemia is the most often cause for elevated BST levels, with other acquired causes, such as renal failure and clonal myeloid diseases being far less common. Acute increases in serum tryptase levels resulting from release of mature tryptase from secretory granules is specific to mast cell degranulation but is not detected in all cases of systemic anaphylaxis., Conclusion: Understanding the differences and distinguishing between acute increases in serum tryptase and chronic elevations in BST owing to inherited or acquired conditions is critical in the correct interpretation of this useful clinical biomarker., (Published by Elsevier Inc.)

Background: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms., Objective: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT., Methods: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used., Results: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT., Conclusions: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Mastocytosis is a disorder characterized by the abnormal proliferation and/or accumulation of mast cells in different organs. More than 90% of patients with systemic mastocytosis have a gain-of-function mutation in codon 816 of the KIT receptor on mast cells (MCs). The symptoms of mastocytosis patients are related to the MC-derived mediators that exert local and distant effects. MCs produce angiogenic and lymphangiogenic factors, including vascular endothelial growth factors (VEGFs) and angiopoietins (ANGPTs). Serum concentrations of VEGF-A, VEGF-C, VEGF-D, ANGPT1 and ANGPT2 were determined in 64 mastocytosis patients and 64 healthy controls. Intracellular concentrations and spontaneous release of these mediators were evaluated in the mast cell lines ROSA KIT WT and ROSA KIT D816V and in human lung mast cells (HLMCs). VEGF-A, ANGPT1, ANGPT2 and VEGF-C concentrations were higher in mastocytosis patients compared to controls. The VEGF-A, ANGPT2 and VEGF-C concentrations were correlated with the symptom severity. ANGPT1 concentrations were increased in all patients compared to controls. ANGPT2 levels were correlated with severity of clinical variants and with tryptase levels. VEGF-A, ANGPT1 and VEGF-C did not differ between indolent and advanced mastocytosis. ROSA KIT WT , ROSA KIT D816V and HLMCs contained and spontaneously released VEGFs and ANGPTs. Serum concentrations of VEGFs and ANGPTs are altered in mastocytosis patients.

Mast cells (MCs) are important in intestinal homeostasis and pathogen defense but are also implicated in many of the clinical manifestations in disorders such as irritable bowel syndrome. The utility of specific staining for MCs to quantify and phenotype them in intestinal biopsies in patients with gastrointestinal (GI) symptoms is controversial and is not a widely adopted practice. Whether or not intestinal MCs are increased or have a unique phenotype in individuals with hereditary alpha-tryptasemia (HαT), who have extra copies of the MC tryptase gene TPSAB1 and typically elevated baseline serum tryptase levels >8 ng/mL is not known. We examined the duodenal biopsies of 17 patients with HαT and compared them to 15 patients with mast cell activation syndrome who had baseline serum tryptases <8 ng/mL (MCAS-NT) and 12 GI-controls. We determined that the HαT subjects had increased MCs in the duodenum compared with MCAS-NT and GI-controls (median=30.0; interquartile range [IQR]: 20.0 to 40.0 vs. median=15.0; IQR: 5.00 to 20.0; P=0.013 and median=15.0; IQR: 13.8 to 20.0; P=0.004, respectively). These MCs were significantly found in clusters (<15 MCs) and were located throughout the mucosa and submucosa including the superficial villi compared with MCAS-NT and GI-control patients. Spindle-shaped MCs were observed in all groups including controls. These data demonstrate that HαT is associated with increased small intestinal MCs that may contribute to the prevalent GI manifestations observed among individuals with this genetic trait., Competing Interests: Conflicts of Interest and Source of Funding: Supported in part by a combined grant from the Mastocytosis Society and American Academy of Allergy, Asthma, and Immunology (M.J.H.), the Gatorade Trust through funds distributed by the University of Florida, Department of Medicine (S.C.G.), extramural NIH fund 1R21TR002639-01A1 (M.J.H. and S.C.G.), and the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH (J.J.L.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait characterized by multiple copies of the alpha-tryptase gene at the TPSAB1 locus. Previously described symptomatology involves multiple organ systems and anaphylaxis. The spectrum of mast cell activation symptoms is unknown, as is its association with specific genotypes., Objective: To describe clinical, laboratory, and genetic characteristics of patients referred for the evaluation of mast cell activation-related symptoms and genotype-confirmed HαT., Methods: We retrospectively describe clinical characteristics, baseline tryptase, and tryptase genotype in 101 patients. Patients were referred for mast cell activation-related symptoms and underwent genotyping to confirm diagnosis of HαT., Results: Of 101 patients, 80% were female with average tryptase of 17.2 ng/mL. Tryptase was less than 11.4 ng/mL in 8.9% and greater than 20 ng/mL in 22.3% (range 6.2-51.3 ng/mL). KIT D816V mutation was negative in all subjects tested. 2α:3β was the most common genotype but did not correlate with tryptase levels. Unprovoked anaphylaxis was noted in 57% of the subjects with heterogeneous genotypes. Most common symptoms include gastrointestinal, cutaneous, psychiatric, pulmonary, cardiovascular, and neurologic. A total of 85% of patients were taking H 1 - or H 2 -antihistamines with partial symptom relief. Omalizumab was effective at suppressing anaphylaxis or urticaria in 94% of the patients., Conclusion: HαT encompasses a broad range of baseline tryptase and should be considered in patients with symptoms of mast cell activation and tryptase levels greater than 6.2 ng/mL. Patients may present with complex symptomatology including cutaneous, gastrointestinal, neurologic, and psychiatric symptoms and anaphylaxis, some of which respond to omalizumab., (Copyright © 2021 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait and a common cause of elevated basal serum tryptase in Western populations. It is a risk factor for severe anaphylaxis among individuals with venom allergy and an established modifier of anaphylaxis and mast cell mediator-associated symptoms among patients with systemic mastocytosis. Understanding the physiology of tryptases and how this may relate to the clinical features associated with HαT is the first step in identifying optimal medical management and targets for novel therapeutics., Recent Findings: HαT prevalence is increased in both clonal and non-clonal mast cell-associated disorders where it augments symptoms of immediate hypersensitivity, including anaphylaxis. The unique properties of naturally occurring α/β-tryptase heterotetramers may explain certain elements of phenotypes associated with HαT, though additional mechanisms are being evaluated. This review provides an overview of the clinical and translational studies that have identified HαT as a modifier of mast cell-associated disorders and anaphylaxis and discusses mechanisms that may potentially explain some of these clinical findings.

Background: Mastocytosis is a neoplastic condition characterized by the accumulation of mast cells (MCs) in 1 or more organ. Adults tend to have persistent, systemic mastocytosis, whereas MC infiltration in children is usually limited to the skin and typically regresses after several years. Both adults and children could display mast cell activation symptoms (MCASs) due to MC mediator release. In more than 85% of both adult and pediatric cases, KIT mutations are present, with the KIT D816V mutation being present in most affected adults but in only half the affected children., Objective: To identify the clinical, biological, and molecular factors associated with the regression of cutaneous mastocytosis (CM) in children, and to assess the correlation between MCASs and CM regression., Methods: Patients having suffered from pediatric-onset mastocytosis for at least 8 years were included in a longitudinal cohort study. Clinical data, the baseline serum tryptase level, the KIT sequence, and the progression of MCASs and CM were recorded., Results: CM regressed in 210 of the 272 included patients (77.2%; mean time to regression, 6.10 years). The rare cases of aggressive systemic mastocytosis were symptomatic from the outset. Congenital mastocytosis and the KIT D816V mutation were associated with CM regression (odds ratio, 0.48, P = .031, and 0.173, P = .031, respectively). Aggravation of MCASs over time was correlated with the persistence of skin lesions. However, the MCASs became more intense in 19% of the patients with MCASs at baseline and CM regression, justifying long-term follow-up in this setting., Conclusions: Our results open up new hypotheses with regard to the spontaneous regression of CM in pediatric patients., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)