Systemic mast cell activation syndrome is a mast cell disorder characterized by an unregulated increased activation of mast cells leading to a pathologically enhanced release of mediators. Mutations in tyrosine kinase kit which crucially determines mast cell activity have been suggested as a necessary condition for the development of a clinically symptomatic mast cell disease. At the level of mRNA in mast cell progenitor cells of 20 patients with systemic mast cell activation syndrome and of 20 gender- and age-matched healthy volunteers, the tyrosine kinase kit was investigated for genetic alterations by means of RT-PCR and direct sequencing of the amplificates. In mast cells of 13 out of these 20 patients, multiple predominantly novel potential functionally activating point mutations or complex alterations of the mRNA sequence encoding the tyrosine kinase kit were detected. In contrast, in 19 of the 20 healthy subjects, no functionally relevant alterations of c-kit transcripts were detected. The present findings support the idea that the systemic mast cell activation syndrome is a clonal disease most commonly associated with variable activating mutations in the tyrosine kinase kit.

Supplementary Material to Seidel et al. "Bleeding diathesis in patients with mast cell activation disease" (Thromb Haemost 2011; 106.5) Definition of mast cell activation disease The term mast cell activation disease (MCAD) denotes a collection of disorders characterized by accumulation of pathological mast cells in potentially any or all organs and tissues and/or aberrant release of variable subsets of mast cell mediators (1, 2). A classification has been proposed which differentiates several types and subclasses of MCAD. The traditionally recognized subclass termed systemic mastocytosis (SM) includes disorders characterized by certain pathological immunohistochemical and mutational findings (the WHO criteria; [3]) which are divided into several subtypes. On the other hand, mast cell activation syndrome (MCAS) presents a complex clinical picture of multiple mast cell mediator-induced symptoms, failure to meet the WHO criteria for diagnosis of SM, and exclusion of relevant differential diagnoses (1, 2, 4-7). Mast cell activation disease in general has long been thought to be rare. However, although SM is truly rare, recent findings suggest MCAS is a fairly common disorder ([2], further references therein). Symptoms observed in patients with MCAS are little, if any, different from those seen in patients with SM ([2], further references therein). The clinical manifestation results from episodic release of both preformed and newly-synthesized mast cell mediators either in response to trigger stimuli or spontaneously. The clinical presentation of MCAD is very diverse, since due to both the widespread distribution of mast cells and the great heterogeneity of aberrant mediator expression patterns, symptoms can occur in virtually all organs and tissues. Moreover, symptoms often occur in a temporally staggered fashion, waxing and waning over years to decades. Patients often have a history of chronic and acute mediator

Previous findings suggested an involvement of mast cells in the pathogenesis of irritable bowel syndrome (IBS). The pathophysiological significance of mast cells is defined both by their number in tissue and by their activity. In the present pilot study activity of mast cells in patients with therapy-resistant IBS was investigated for the first time systematically. Twenty patients with therapy-resistant IBS were investigated for the presence of a pathologically increased mast cell mediator release by means of a validated structured interview suitable to identify mast cell mediator-related symptoms and by determing selected surrogate parameters for mast cell activity. Nineteen of the 20 patients presented mast cell mediator-related symptoms. Pathologically increased mast cell activity-related coagulation and fibrinolysis parameters were detected in 11 of 12 patients investigated in that regard. One patient had an elevated level of methylhistamine in urine. The present data provide evidence that in patients with therapy-resistant IBS a pathologically increased systemic mast cell activity may occur with high prevalence. This finding fits to the idea of an assumed contribution of activated mast cells in the pathophysiology of IBS.

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