Tryptase genetics and anaphylaxis

Tryptases secreted by tissue mast cells and basophils can enter the bloodstream. In human subjects tryptases are encoded by several genes and alleles, including alpha, beta, gamma, and delta. Common variations include complete absence of alpha genes. Until recently, alpha tryptase was considered to be the major tryptase secreted at baseline and in mastocytosis. However, lack of alpha tryptase genes has little effect on circulating tryptase levels, which are now thought mainly to consist of inactive pro-beta tryptase secreted constitutively rather than stored in granules with mature tryptases. Pro-beta tryptase levels thus might reflect total body mast cell content. In contrast, mature beta tryptase can increase transiently in severe systemic anaphylaxis and confirm the diagnosis. However, it might fail to increase in food anaphylaxis or might increase nonspecifically in samples acquired after death. Thus pro- and mature beta tryptase measurements are useful but associated with false-negative and false-positive results, which need to be considered in drawing clinical conclusions in cases of suspected anaphylaxis.     

The potential clinical utility of serum alpha-protryptase levels.

BACKGROUND: Because biopsy criteria for diagnosing systemic mastocytosis are not precise, the value of serum alpha-protryptase levels in the work-up of suspected systemic mastocytosis should be considered. OBJECTIVE: A retrospective analysis was performed on subjects with total tryptase serum levels that were high (>/=20 ng/mL), while beta-tryptase serum levels were normal (<1 ng/mL) or modestly elevated (1 to 5 ng/mL). METHODS: Over a 3.5-year period, 52 qualifying specimens were identified from 1369 consecutive samples. The corresponding subjects were divided into those with suspected mastocytosis and those with suspected anaphylaxis. Subjects with suspected mastocytosis were subdivided into 3 subgroups on the basis of biopsy results (positive, negative, or not available). Subjects with suspected anaphylaxis were subdivided into living and deceased subgroups. RESULTS: Among the 15 subjects who underwent biopsy, alpha-protryptase serum levels (the difference between directly-measured levels of serum total tryptase and beta-tryptase), when greater than 75 ng/mL (n = 9), were always associated with a positive biopsy result for systemic mastocytosis; levels from 20 to 75 ng/mL (n = 6) were associated with a positive biopsy result in 50% of subjects. alpha-Protryptase serum levels may be a more sensitive screening test than a bone marrow biopsy for this disorder. Also, elevated alpha-protryptase serum levels in some adult patients return to normal over time, suggesting that mast cell hyperplasia resolved in these patients. Finally, a high alpha-protryptase level may reveal anaphylaxis to be a presenting manifestation of systemic mastocytosis or mast cell hyperplasia. CONCLUSION: Levels of serum alpha-protryptase, relative to those of beta-tryptase, appear to be useful in the diagnostic work-up and follow-up of subjects with suspected systemic mastocytosis.     

Recent advances in mastocytosis research. Summary of the Vienna Mastocytosis Meeting 1998.

The term mastocytosis denotes a heterogenous group of disorders characterized by abnormal growth and accumulation of mast cells in one or more organs. Cutaneous and systemic variants of the disease have been described. Mast cell disorders have also been categorized according to other aspects, such as family history, age, course of disease, or presence of a concomitant myeloid neoplasm. However, so far, generally accepted disease criteria are missing. Recently, a number of diagnostic (disease-related) markers have been identified in mastocytosis research. These include the mast cell enzyme tryptase, CD2, and mast cell growth factor receptor c-kit (CD117). Several gain-of-function-mutations in the kinase domain of c-kit appear to occur in mastocytosis supporting the clonal (neoplastic) nature of the disease. Also, certain point mutations appear to be associated with distinct variants of mastocytosis, i.e. Asp-816-->Val with a subset of sporadic persistent (systemic) mastocytosis (mostly adults), and Gly-839-->Lys with (a subset of) typical pediatric (mostly cutaneous) mastocytosis. Another potential indicator of mast cell neoplasm is the T-/NK-cell-associated marker CD2. This antigen (LFA-2) is abnormally expressed on neoplastic mast cells in cases of systemic mastocytosis or mast cell leukemia, but not found on normal mast cells. The mast cell enzyme tryptase is increasingly used as a serum- and immunohistochemical marker to estimate the actual spread of disease (burden of neoplastic mast cells). The clinical significance of novel mastocytosis markers is currently under investigation. First results indicate that they may be useful to define reliable criteria for the delineation of the disease.     

Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease

BACKGROUND: The serum tryptase level is used as a diagnostic marker in mastocytosis and is considered to reflect the burden of (neoplastic) mast cells (MC). METHODS: In the present study, serum tryptase levels were measured in patients with mastocytosis by fluoroenzyme immunoassay and compared with the extent of infiltration of the bone marrow (BM) by neoplastic MC, determined by tryptase immunohistochemistry. Sixteen patients with cutaneous mastocytosis (CM) and 43 patients with systemic mastocytosis (SM) were examined. RESULTS: In most patients with CM (defined by the absence of dense compact MC infiltrates in tryptase-stained BM sections), normal or near-normal serum tryptase levels (median 10 ng/ml, range 2-23 ng/ml) were measured. By contrast, in the vast majority of patients with SM, elevated serum tryptase levels (median 67 ng/ml) were found. In addition, there was a significant correlation between the grade of infiltration of the BM by neoplastic MC and tryptase levels in patients with SM (r = 0.8). Moreover, enzyme levels differed significantly among the groups of patients with different types of SM. The highest levels (>900 ng/ml) were detected in the patient with MC leukemia, 2 patients with slowly progressing SM and high MC burden (smoldering SM) and 1 patient with indolent SM. In contrast, in all 3 patients with isolated BM mastocytosis (no skin lesions and no signs of multiorgan involvement), serum tryptase levels were <20 ng/ml. CONCLUSIONS: In summary, our data suggest that the measurement of serum tryptase is a reliable noninvasive diagnostic approach to estimate the burden of MC in patients with mastocytosis and to distinguish between categories of disease.     

The potential clinical utility of serum α-protryptase levels

Background: Because biopsy criteria for diagnosing systemic mastocytosis are not precise, the value of serum α-protryptase levels in the work-up of suspected systemic mastocytosis should be considered. Objective: A retrospective analysis was performed on subjects with total tryptase serum levels that were high (≥20 ng/mL), while β-tryptase serum levels were normal (<1 ng/mL) or modestly elevated (1 to 5 ng/mL). Methods: Over a 3.5-year period, 52 qualifying specimens were identified from 1369 consecutive samples. The corresponding subjects were divided into those with suspected mastocytosis and those with suspected anaphylaxis. Subjects with suspected mastocytosis were subdivided into 3 subgroups on the basis of biopsy results (positive, negative, or not available). Subjects with suspected anaphylaxis were subdivided into living and deceased subgroups. Results: Among the 15 subjects who underwent biopsy, α-protryptase serum levels (the difference between directly-measured levels of serum total tryptase and β-tryptase), when greater than 75 ng/mL (n = 9), were always associated with a positive biopsy result for systemic mastocytosis; levels from 20 to 75 ng/mL (n = 6) were associated with a positive biopsy result in 50% of subjects. α-Protryptase serum levels may be a more sensitive screening test than a bone marrow biopsy for this disorder. Also, elevated α-protryptase serum levels in some adult patients return to normal over time, suggesting that mast cell hyperplasia resolved in these patients. Finally, a high α-protryptase level may reveal anaphylaxis to be a presenting manifestation of systemic mastocytosis or mast cell hyperplasia. Conclusion: Levels of serum α-protryptase, relative to those of β-tryptase, appear to be useful in the diagnostic work-up and follow-up of subjects with suspected systemic mastocytosis. (J Allergy Clin Immunol 1999;103:1092-9.)     

Mastocytosis and allergy

PURPOSE OF REVIEW: To illustrate features of allergy in mastocytosis. RECENT FINDINGS: The rates of atopy in patients with mastocytosis have generally been found to be similar to those of the normal population, although the incidence of anaphylaxis is much higher in mastocytosis. Introduction of objective pathologic criteria by the WHO for the diagnosis of mastocytosis has greatly facilitated the workup of patients with suspected mastocytosis, and has led to identification of mast cell disease in a subset of patients with anaphylaxis. There is increasing evidence that an activating c-kit mutation (D816V) exists in a subset of patients with recurrent mast cell activation symptoms who have normal-appearing bone marrow biopsies in routine evaluations without skin lesions. The genetic deficiency of alpha tryptase has not been found to influence serum tryptase levels in patients with mastocytosis. SUMMARY: Pathologic mast cell activation is a key finding in both allergic diseases and mastocytosis, albeit caused by entirely different mechanisms. Mastocytosis should be suspected in patients with recurrent anaphylaxis, who present with syncopal or near-syncopal episodes without associated hives or angioedema.     

Cardiovascular disease and anaphylaxis

PURPOSE OF REVIEW: In severe anaphylaxis, the cardiovascular system is often heavily involved. Preexisting cardiovascular disease may therefore influence the course of anaphylaxis in a negative way. RECENT FINDINGS: Systemic mastocytosis and elevated baseline serum tryptase are associated with severe and fatal anaphylaxis to hymenoptera stings. This is due to an increased number of cardiac mast cells resulting in high concentrations of cardiotoxic mast cell mediators in cardiac tissue during anaphylaxis. Severe anaphylaxis in coronary heart disease, in particular, is explained by an increased load of cardiac mast cells together with coronary stenosis favouring myocardial hypoxia. Contraindications for the use of medications for cardiac disease in patients with anaphylaxis, especially beta-blockers, have been questioned by epidemiologic studies considering the positive effects of these drugs on much more prevalent cardiac diseases. SUMMARY: Preexisting cardiovascular disease, mastocytosis and elevated baseline serum tryptase are risk factors for fatal anaphylactic reactions or lasting morbidity due to myocardial or cerebrovascular infarction induced by anaphylaxis. Life-saving cardiac medications like beta-blockers may increase the severity of anaphylaxis. Since life-threatening cardiovascular diseases are much more frequent than anaphylaxis, the relative risk of either disease with and without these drugs must be analyzed carefully together with the cardiologist.     

How much specific is the association between hymenoptera venom allergy and mastocytosis?

Background:  The preferential association of mastocytosis with hymenoptera sting reactions is well known, but there is no data on the prevalence of clonal mast cell disorders in subjects with severe systemic reactions due to foods or drugs.
Methods:  Patients with food- or drug-induced severe systemic reactions, including anaphylaxis, and increased serum tryptase were studied for the presence of mastocytosis, and compared with a population of patients with hymenoptera allergy. The aetiological role of foods or drugs was assessed according to current recommendations. Systemic reactions were graded in severity according to the procedure described by Mueller. Serum tryptase was considered increased if the level was >11.4 ng/ml. Subjects with increased tryptase had dermatological evaluation and Bone marrow(BM) aspirate-biopsy, which included histology/cytology, flow cytometry and detection of KIT mutations.
Results:  A total of 137 subjects (57 male, mean age 42 years) were studied. Of them, 86 proved positive for drugs and 51 for foods. Overall, out of 137 patients, only nine (6.6%) had a basal tryptase >11.4 ng/ml, and only two (1.5%) were diagnosed with mastocytosis. This was clearly different from patients with hymenoptera allergy, where 13.9% had elevated tryptase and 11.1% had a clonal mast cell disorder.
Conclusion:  The association of clonal mast cell disorders with hymenoptera allergy seems to be more specific than that with food- or drug-induced systemic reactions.     

Cutaneous manifestations in Hymenoptera and Diptera anaphylaxis: relationship with basal serum tryptase

Objectives To compare the clinical presentation of systemic anaphylaxis to Hymenoptera and Diptera with regard to basal serum tryptase (BT) and to evaluate mastocytosis in patients with elevated tryptase.
Patients and Methods The medical records of 140 patients with a history of a systemic reaction to venom were retrospectively reviewed. Symptoms and severity of anaphylaxis and BT were recorded. Most patients with elevated tryptase were screened for mastocytosis: a dermatological examination with a skin biopsy was performed in 19 cases and a bone marrow biopsy in 14 cases.
Results Tryptase was elevated in 23 patients. These patients reported fewer usual skin reactions (urticaria in 26.1% of cases with raised tryptase vs. 76.1% of cases with normal tryptase), more flushing (52.2% vs. 4.3%) and frequently did not present skin reaction (26.1% vs. 9.4%). They presented a more severe reaction (mean grade of severity: 3.48 vs. 2.69). Mastocytosis was diagnosed in seven patients with elevated tryptase: indolent systemic mastocytosis in six cases and cutaneous mastocytosis without systemic involvement in one case. In five cases, mastocytosis was previously undiagnosed. Lesions of cutaneous mastocytosis, diagnosed in five patients, consisted of urticaria pigmentosa in all cases and were often inconspicuous.
Conclusion These results demonstrate particular clinical features of the allergic reaction in patients with elevated BT and the higher frequency of mastocytosis in this population. In patients with a severe anaphylactic reaction without urticaria, but with flushing, tryptase should be assayed and an underlying mastocytosis should be considered.     

No relationship between histamine release measured as metabolite excretion in the urine, and serum levels of mast cell specific tryptase in mastocytosis

To test the hypothesis that histamine release in mastocytosis patients generally occurs without activation of the mast cells, histamine turnover, measured as histamine metabolite excretion in the urine, was compared with the serum level of mast cell specific tryptase, which is released only during active discharge of mast cell granular contents. Twenty mastocytosis patients with a wide range of histamine turnover rates were investigated. Slightly increased levels of tryptase were found in seven patients with no obvious relationship to histamine metabolite excretion. In contrast, there seemed to be a connection between the tryptase level and the severity of symptoms. These results strengthen the view that histamine in mastocytosis is predominantly released from the mast cells without any accompanying active release process. This does not exclude the possibility that, in some mastocytosis patients, a limited number of mast cells, or a subpopulation, may be actively secreting histamine together with tryptase.     

Human mast cell tryptase in biology and medicine

The most abundant prestored enzyme of human mast cell secretory granules is the serine-protease tryptase. In humans, there are four tryptase isoforms, but only two of them, namely the alpha and beta tryptases, are known as medically important. Low levels of continuous tryptase production as an immature monomer makes up the major part of the baseline serum tryptase levels, while transient release of mature tetrameric tryptase upon mast cell degranulation accounts for the anaphylactic rise of serum tryptase levels. Serum tryptase determination contributes to the diagnosis or monitoring of mast cell disorders including mast cell activation – induced anaphylaxis, mastocytosis and a number of myeloproliferative conditions with mast cell lineage involvement. Baseline serum tryptase levels are predictive of the severity risk in some allergic conditions.     

Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis

Better methods are needed to assess mast-cell activation in vivo and to distinguish the activation of mast cells from that of basophils. Tryptase, a neutral protease selectively concentrated in the secretory granules of human mast cells (but not basophils), is released by mast cells together with histamine and serves as a marker of mast-cell activation. In 17 patients with systemic mastocytosis, concentrations of tryptase in plasma were linearly related to those of histamine (P less than 0.01). Eleven of the 17 patients had tryptase levels of 4 to 88 ng per milliliter, indicating ongoing mast-cell activation. In each of six patients who experienced corresponding anaphylactic reactions after penicillin, aspirin, or melon ingestion, a wasp sting, exercise, or antilymphocyte globulin injection, tryptase levels in serum ranged from 9 to 75 ng per milliliter, indicating mast-cell activation during each of these events. In contrast, serum tryptase levels were less than 5 ng per milliliter in all patients presenting with myocardial disease (n = 8, 6 with hypotension) or sepsis (n = 6, 3 with hypotension) and in the controls (n = 20). One patient had a myocardial infarction after anaphylaxis in response to a wasp sting and an elevated tryptase level of 25 ng per milliliter. Thus, the plasma or serum tryptase level is a diagnostic correlate of mast-cell-related events.     

Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients

BACKGROUND: Systemic mastocytosis (SM) is a condition typically characterized by an increased number of mast cells in the bone marrow or in skin areas known as urticaria pigmentosa. Patients may present with flushing, itching, gastrointestinal symptoms, arrhythmias, headaches and osteoporosis. Some patients experience systemic symptoms indicative of SM in the absence of a positive bone marrow or skin biopsy, and are known as 'clinical mastocytosis', but are herein referred to as suspected of having systemic mastocytosis. Serum tryptase has been increasingly used as a biochemical marker of mastocytosis, but is not always elevated. OBJECTIVE: To investigate the association of serum levels of two key mast cell mediators, interleukin-6 (IL-6) and tryptase, to each other and with disease severity in patients with mastocytosis. METHODS: Patients responded to an announcement from the Systemic Mastocytosis Society (USA) and submitted frozen serum samples, but the precise diagnosis made by their own health providers was not known until after the assays were completed. There were 9 suspected systemic mastocytosis (SuSM), 3 cutaneous mastocytosis (CM), 11 indolent systemic mastocytosis (ISM), and 3 aggressive systemic mastocytosis (ASM). Five normal volunteers (3 females/2 males) also submitted samples, as did 33 cardiac patients without coronary artery disease. For 2 days prior to and during the collection period, mastocytosis patients were asked to abstain from any over-the-counter or food products containing biogenic amines, as well as drugs prescribed for this condition. Serum levels of IL-6 and tryptase were measured using established assays. RESULTS: Twenty-six patients (14 females/12 males) submitted serum samples. There were 9 cases of SuSM (6 females/3 males) in whom tryptase values were borderline normal; IL-6 values were slightly elevated with one being high. In 3 cases of CM (2 females/1 male), both tryptase and IL-6 were slightly elevated. In patients with ISM (5 females/6 males), only 6/11 had any tryptase elevated significantly as compared to 9/11 with elevated serum IL-6. Three patients with ASM had significant elevations of both IL-6 and tryptase. The most consistent finding was that of IL-6 elevations in 7/7 patients (3 females/4 males) who reported symptoms of osteoporosis and/or bone pain (1 SuSM, 3 ISM, 3 ASM) in the absence of any coexisting condition involving bone pathology. CONCLUSION: Serum IL-6 is elevated in mastocytosis patients and correlates with severity of symptoms and the presence of osteoporosis. High serum IL-6 may not only signify disease progression, but may also participate in the pathophysiology of mastocytosis.     

Identification of alpha‐gal sensitivity in patients with a diagnosis of idiopathic anaphylaxis

IgE antibodies (Ab) specific to galactose‐α‐1,3‐galactose (alpha‐gal) are responsible for a delayed form of anaphylaxis that occurs 3‐6 hours after red meat ingestion. In a unique prospective study of seventy participants referred with a diagnosis of idiopathic anaphylaxis (IA), six (9%) were found to have IgE to alpha‐gal. Upon institution of a diet free of red meat, all patients had no further episodes of anaphylaxis. Two of these individuals had indolent systemic mastocytosis (ISM). Those with ISM had more severe clinical reactions but lower specific IgE to alpha‐gal and higher serum tryptase levels, reflective of the mast cell burden. The identification of alpha‐gal syndrome in patients with IA supports the need for routine screening for this sensitivity as a cause of anaphylaxis, where reactions to alpha‐gal are delayed and thus may be overlooked.     

Is unrecognized anaphylaxis a cause of sudden unexpected death?

Background: Serum tryptase levels reflect mast cell activation and correlate with anaphylactic reactions. Elevated post-mortem serum tryptase levels have been found in witnessed fatal anaphylaxis. Objective: This study was designed to examine whether or not unwitnessed anaphylaxis may be a hitherto unrecognized cause of sudden unexplained death. Methods: Mast cell tryptase was measured by immunoassay in 68 post-mortem sera remaining from a previous study which reported elevated venom-specific IgE antibodies in 22 (23%) of 94 victims of sudden unexpected death. Autopsies were performed in all cases. The cause of death was independently reported by pathologists unfamiliar with the nature of this study. Results: Serum tryptase levels were elevated (> 10ng/mL) in nine of 68 cases. The levels could not be predicted from the clinical circumstances surrounding death. Sera from four individuals contained both elevated tryptase and previously reported elevated venom-specific IgE. Conlusions: We conclude that mast cell activation may accompany up to 13% of sudden unexpected deaths in adults. Measurement of both tryptase and specific IgE antibody levels in post-mortem sera from persons experiencing sudden, unexpected death may identify a small subset of cases due to clinically unrecognized fatal anaphylaxis, including those due to insect stings.     

Systemic mastocytosis presenting with a prominent B lymphocyte proliferation in the bone marrow and extensive fibrosis of the spleen

Systemic mastocytosis is a disease characterized by multifocal mast cell proliferation in the bone marrow or other extracutaneous organs. Because of loosely scattered and hypo-/agranular mast cells, the diagnosis is sometimes very difficult. In the bone marrow, mast cell infiltration may be associated with prominent lymphoid infiltration leading to a misdiagnosis of a low grade non-Hodgkin lymphoma. A 49-year-old woman presented with right arm and leg pain, psychiatric symptoms, and diarrhea for four years. Physical examination and laboratory investigation revealed hepatosplenomegaly, anemia, mild thrombocytosis, mild leucocytosis and lymphocytosis. In the bone marrow biopsy, there was a prominent B lymphocyte proliferation reminiscent of a low grade non-Hodgkin lymphoma/leukemia and there were some spindle cells aggregates in paratrabecular location. The consecutive bone marrow biopsies were similar to the first. The subsequent splenectomy specimen exhibited striking fibrosis. In the lymph node sections, there was marginal zone hyperplasia. Multifocal accumulations of mast cells were strongly positive with mast cell tryptase and CD117 on immunohistochemical staining, though no metachromasia was identified in Giemsa and Toluidine Blue stained aspirates and tissue sections, probably due to hypo-/agranulation of mast cells. The case was presented to emphasize the importance of the antibody to mast cell tryptase in the diagnosis of mastocytosis and to discuss problems of differential diagnosis of systemic mastocytosis.     

Expression of alpha-tryptase and beta-tryptase by human basophils

BACKGROUND: Alpha and beta-tryptase levels in serum are clinical tools for the evaluation of systemic anaphylaxis and systemic mastocytosis. Basophils and mast cells are known to produce these proteins. OBJECTIVE: The current study examines the effect of the alpha,beta-tryptase genotype on basophil tryptase levels and the type of tryptase stored in these cells. METHODS: Tryptase extracted from purified peripheral blood basophils from 20 subjects was examined by using ELISAs measuring mature and total tryptase and by using an enzymatic assay with tosyl-Gly-Pro-Lys-p-nitroanilide. Tryptase genotypes (4:0, 3:1, and 2:2 beta/alpha ratios) were assessed by using a hot-stop PCR technique with alpha,beta-tryptase-specific primers. Total alpha,beta-tryptase mRNA was measured by means of competitive RT-PCR, and ratios of alpha to beta-tryptase mRNA were measured by means of hot-stop RT-PCR. RESULTS: Tryptase in all but one of the basophil preparations was mature and enzymatically active. Tryptase quantities in basophils were less than 1% of those in tissue mast cells. Tryptase genotypes (beta/alpha) among the 20 donors were 4:0 in 7, 3:1 in 7, and 2:2 in 6. Tryptase protein and mRNA levels per basophil were not affected by the tryptase genotype. CONCLUSION: Basophils from healthy subjects contain modest amounts of mature and enzymatically active tryptase unaffected by the tryptase genotype.     

Mastocytosis and Hymenoptera venom allergy

PURPOSE OF REVIEW: Mastocytosis is a rare disease characterized by increased mast cells in skin and/or internal organs. We evaluate the impact of mastocytosis on diagnosis and treatment of Hymenoptera venom allergy. RECENT FINDINGS: Patients with Hymenoptera venom allergy who suffer from mastocytosis develop life-threatening sting reactions more often than those who do not. When patients with Hymenoptera venom allergy were systematically examined for mastocytosis, it was found to be represented to an abnormally high extent. Most patients with mastocytosis tolerate venom immunotherapy with no or only minor systemic symptoms. Venom immunotherapy was found to be marginally less effective in patients with mastocytosis than in those without evidence of mast cell disease (defined as absent cutaneous mastocytosis combined with a serum tryptase concentration of <11.4 microg/l). Several deaths from sting reactions were reported in patients with mastocytosis after venom immunotherapy was stopped. These patients should have venom immunotherapy for the rest of their lives. SUMMARY: Patients suffering from mastocytosis and Hymenoptera venom allergy are at risk from a particularly severe sting anaphylaxis. They need optimal diagnosis and treatment. In patients presenting with Hymenoptera venom allergy, screening tests by measurement of serum tryptase concentration, and a careful skin examination, are highly recommended.     

Mastocytosis and related disorders

Mastocytosis represents a heterogeneous group of disorders characterized by an abnormal accumulation of mast cells in one or more organ systems. Mastocytosis is further divided into different subtypes according to the sites of involvement, laboratory findings, and degree of organ impairment. Cutaneous mastocytosis is diagnosed in the presence of skin involvement and absence of extracutaneous disease, and is most commonly seen in the pediatric population. Systemic mastocytosis, the disease form most commonly seen in adults, is characterized by the presence of multifocal, compact (dense) mast cell aggregates in the bone marrow or other extracutaneous organs. The mast cells may display atypical, often spindle-shape morphology and/or aberrant CD2 and/or CD25 expression. Elevation of serum tryptase and/or presence of KIT D816V mutation are other common findings. Systemic mastocytosis is further divided into different subtypes based on a combination of clinical features and laboratory findings. Recent studies have indicated that CD30 is frequently expressed in aggressive systemic mastocytosis and mast cell leukemia but infrequently in indolent systemic mastocytosis, and may be a useful marker for distinguishing these subtypes of systemic mastocytosis from one another. A group of related myeloid disorders, collectively termed myelomastocytic overlap syndromes, may pose diagnostic difficulty because of their significant clinical and pathologic overlap with systemic mastocytosis, and these will also be discussed in this review.