Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects

Molderings, Gerhard J.; Meis, Kirsten; Kolck, Ulrich W.; Homann, Jürgen; Frieling, Thomas

doi:10.1007/s00251-010-0474-8

Cited by 49 publications

(42 citation statements)

References 31 publications

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“…This finding supports our previous suggestion that the clinical presentation of MCAD, i.e. subtype, severity and therapy responsiveness, is not determined by one KIT mutation alone but by multiple co-occuring mutations in KIT and/or other relevant genes [3], [22]. In fact, there is accumulating evidence for the presence of disease-relevant multiple co-occurring mutations in KIT [12], [17], [22], [25], [26] as well as of a combination of KIT mutations with mutations in other genes (e.g., JAK2, TET2, DNMT3A, ASXL1, CBL, U2AF1, SRSF2, MS4A2; [11], [27]–[31]).…”

Section: Discussionsupporting

confidence: 91%

“…We found increased heparin levels in blood indicating a pathological increase in mast cell activity in approximately 50% of MCAD patients and and in 17% of the control subjects ([21] and references therein; unpublished data). (2) In our comparative analysis of KIT mutations in mast cells from patients with MCAD and control subjects we detected potentially functionally activating genetic alterations in 13 of 20 patients (65%) and in 3 of 20 control subjects (15%) [22]. In both studies those control subjects exhibiting an increased mast cell activity and KIT mutations, respectively, possibly represent individuals affected with MCAD at a subclinical stage.…”

Section: Discussionmentioning

confidence: 75%

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Familial Occurrence of Systemic Mast Cell Activation Disease

et al. 2013

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Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT) among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001). In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members. In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD), mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity. Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis) should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 75%

Familial Occurrence of Systemic Mast Cell Activation Disease

et al. 2013

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“…Second, only a handful of the more than 60 releasable mast cell mediators can be detected by routine commercial techniques. We take care of patients presenting with an intense mast cell mediator release syndrome and functionally activating nonD816V mutations in mast cells 6 but lacking increased examinable mediators. Third, if liberation of mediators from mast cells is a result of a selective/differential/piecemeal release process, 7 only a few mediators that may not be detectable by current techniques may be released, inducing the apparent mediator release syndrome in part by the amplification cascade of basophil, eosinophil, and general leukocyte activation.…”

Section: To the Editormentioning

confidence: 99%

“…[3][4][5][6] The discrepancy might be a result of the difference in pathological states of patients at the time of sampling (eg, different inflammatory profiles, medications, atopy, infection, and many other factors), reflecting great heterogeneity of NPs in different environments. Despite this, the low positive production of IL-5 is still in question because NP is also shown to be a T H 2-associated inflammation in adult Chinese patients.…”

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confidence: 99%

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Akin

Valent

Metcalfe

2011

Journal of Allergy and Clinical Immunology

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“…3 In mastocytosis, mast cell aggregates may be distributed in a patchy fashion, and a single bone marrow biopsy may fail to show findings of SM in about one-sixth of cases. 4 Secondary MCASs are due to conditions that produce the symptoms and signs of mast cell activation and include allergic disorders, physical urticarias, and chronic autoimmune urticaria.…”

Section: O N O T C O P Ymentioning

confidence: 99%

A 60-year-old woman with recurrent episodes of flushing, urticaria, and angioedema

Patel

Baldwin

2015

allergy asthma proc

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Recurrent episodes of flushing, urticaria, and angioedema raise suspicion for many conditions with a wide differential diagnosis. The diagnostic approach involves consideration of allergic, cardiovascular, gastrointestinal, endocrine, infectious, neurologic, dermatologic, and drug-related A 60 year-old woman with recurrent episodes of flushing, urticaria, and angioedema presented to the allergy clinic for follow-up after an emergency department (ED) visit for "total body flushing" about an hour after eating wheat crackers, cheddar cheese, and decaffeinated tea. She had previously presented to a local ED with "flushing" involving her arms, legs, torso, neck, and face. She denied gastrointestinal symptoms at that time, but she reported previous similar episodes that were associated with abdominal discomfort and diarrhea. In the ED, she was treated with epinephrine, diphenhydramine, and steroids with resolution of her symptoms.Her medical history included asthma, fibromyalgia, osteoarthritis, migraine headaches, hypothyroidism, and hyperlipidemia. Her medications included albuterol as needed, sumatriptan, fexofenadine, levothyroxine, and fluoxetine. Her allergy history included hives when exposed to tetracycline, gastrointestinal upset, and a syncopal episode when exposed to smells of eggs and popcorn and local swelling to stinging insects. PHYSICAL EXAMINATIONShe was a comfortable-appearing woman. Her vital signs were temperature 36.7°C, heart rate 68 beats per minute, blood pressure 120/72 mm Hg, and respiratory rate 16 breaths per minute. Head, eyes, ears, nose, and throat exam was unremarkable. Lungs were clear to auscultation bilaterally. Cardiac exam revealed a regular rate with no murmurs. Skin exam revealed no flushing, urticaria, angioedema, eczema rashes, dermatographism, or urticaria pigmentosa lesions. The remainder of the physical examination was unremarkable.

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Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects

Cited by 49 publications

References 31 publications

Familial Occurrence of Systemic Mast Cell Activation Disease

Familial Occurrence of Systemic Mast Cell Activation Disease

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A 60-year-old woman with recurrent episodes of flushing, urticaria, and angioedema

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