In an earlier prospective study most abdominal pain was dyspeptic as it responded to H2 antagonists and the majority of these patients has increased gastric acid secretion. peripheral blood cells in patients with mastocytosis. The most common somatic mutation, Asp816Val (D816V), is located in catalytic domain of KIT and results in augmented mast cell proliferation and survival.8, 9 The D816V mutation is less common in children, especially in those with cutaneous mastocytosis. Other c-kit mutations including V560G, D816Y, D816F, D816H and E839K have been identified in mast cell lines, mast cell leukemia and pediatric mastocytosis.10, 11 Whether these are activating mutations or contribute to ligand independent activation and suppression of Treprostinil sodium apoptosis has not been fully elucidated. A subgroup of patients that present with hypereosinophillic syndrome have the FIP1L1/PDGRFA fusion tyrosine kinase, which can be found in multiple cell lineages including mast cells and eosinophils. This genetic abnormality is associated with increased mast cells in the bone marrow, an elevated tryptase and peripheral eosinophilia, thus highlighting a role for non-KIT dependent pathways in the pathogenesis of mastocytosis.12 Pathologic effects of mast cell mediators Following activation and degranulation, mast cells secrete and generate a host of mediators that contribute to allergic inflammation. The disease manifestations exhibited in mastocytosis are a consequence of increased mast cells present in tissue and the degree of release of mast cell mediators. Table 1 summaries the clinical features associated with mast cell mediators. Mast cell mediator release causes both local tissue and distal inflammation as they are released in to the bloodstream. Clinically, the most significant mediator is histamine. Histamine acts through four different receptors, H1CH4, FNDC3A to mediate vasopermeability, vasodilation, gastrointestinal and bronchial smooth muscle contraction, gastric acid production and pruritus.13 H1 Treprostinil sodium receptors modulate bronchial and GI smooth muscle contraction and may be blocked by antihistamines such as diphenhydramine (Benadryl) and cetirizine (Zyrtec). Stimulation of gastric acid secretion by parietal cells is regulated by H2 receptors and is inhibited by H2 antagonists like ranitidine (Zantac). Mast cells have abundant secretary granule proteases, which make up most of the proteins present in mast Treprostinil sodium cells and the major protease is tryptase. Total tryptase is comprised of mature tryptase stored in granules and released only upon activation and immature (pro) tryptase, which is constitutively secreted by the mast cell. Patients with mastocytosis generally have elevated serum tryptase and histamine.14, 15 Other clinically relevant mediators are prostaglandin D2 and leukotriene C4, which cause similar effects in human lung mast cells. Growth factor and inflammatory cytokines also produced by mast cells include interleukin-3 (IL-3), IL-16 and tissue necrosis factor- (TNF-).16 Table 1 Clinical manifestations and related mast cell mediators SkinPruritusHistamine, PAFFlushingPGD2UrticariaHistamine, PAF, LTC4BlisteringIL-6, tryptase, PGD2, PAFConstitutionalFatigue, weight loss, cachexiaTumor necrosis factor-, IL-1, IL-6.SystemicHypotension and swellingHistamine, PAF, PGD2, LTC4, LTD4, LTE4, endothelinEosinophiliaIL-5Mast cell proliferationSCF, IL-3, IL-6, chymaseFibrosisTransforming growth factor-Inhibition of localized clottingheparinLymphadenopathyIL-16, lymphotaxinGastrointestinalIncreased gastric acidHistamineIntestinal crampingHistamine, PAF, LTC4Skeletal systemOsteoporosisHeparin, tryptaseLungsBronchoconstrictionHistamine, PGD2, PAF, LTC4, LTD4, endothelinMucous and edemaHistamine, PGD2, PAF, LTC4, proteases Open in a separate window PG, prostaglandin; PAF, platelet-activating factor; LT, leukotriene; IL, interleukin; SCF, stem-cell factor. Clinical Features Cutaneous Patterns of Mastocytosis All variants of mastocytosis share clinical features, but skin is the Treprostinil sodium most common organ site of involvement and is often the first sign of the disease. In children, the skin may be the only manifestation of the disease. 17 In 2007, a proposed additional diagnostic category to the WHO nomenclature, termed mastocytosis of the skin (MIS), was introduced.18 MIS proposes to assess disease status based on cutaneous findings, prior to performing a bone marrow biopsy. The diagnosis of MIS is based on the findings of a typical mastocytosis exanthema, comprising the major criterion, and one of 2 minor criteria as determined from a lesional skin biopsy showing Treprostinil sodium either abnormal mast cells in clusters ( 15) or 20 scattered per HPF and/or detection.