Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. It is characterized by presence of >20% immature mast cells in bone marrow aspirate smears or >10% in peripheral blood. Foresnic Sci Int. Criteria proposed by an expert consensus group include the presence of symptoms in 2 unrelated organs, the evidence of mast cell mediators whether tryptase elevations, or 24 h urine methyl histamine or prostaglandins and the response to the mast cell controller medications. 19. Laboratory tests to support the clinical diagnosis of anaphylaxis. Schwartz LB. Normal mast cells are round and fully granulated with a central nucleus. 2023 TESTING.COM. 1998 Apr 15;91(8):2731-6. If tryptase testing is ordered to see if you experienced a severe allergic reaction, the doctor ordering the test carefully times the sample collection between 15 minutes to 2-3 hours after signs and symptoms of an allergy began. 2 of the 3 B-findings should be present: 1. A commercial test is offered by at least one vendor (Gene by Gene). Anti mediator treatment commonly includes once or twice daily dosing of H1 and H2 antihistamines as well as leukotriene blockers, and cromolyn (30). Anaphylactic shock is a very serious, potentially fatal condition that comes on rapidly. The cost of tryptase testing depends on where the test is administered, the laboratory used, whether other tests are performed at the same time, and whether you have medical insurance. In: Bochner BS, ed. It is not clear the extent to which activated mast cells contribute to this disease, nor whether mast cell activation plays any role in symptoms. The SM component of SM-AHN may be indolent or aggressive. The skin in that area is numbed with medication beforehand. Currently approved mast cell cytoreductive therapies include IFN-alpha and cladribine (31). Most people who have the tryptase blood test will have results that come back as normal. Dizziness, lightheadedness, or cardiac arrhythmia. Anaphylaxis due to acute mast cell mediator release can be triggered by multiple factors and should be promptly address due to the potential for massive cardiovascular collapse and death. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Leuk Res. This means they tested over 20 ng/ml on two separate occasions when they had not recently The presence of osteoporosis in young males should alert the treating physician to the possibility of a diagnosis of mastocytosis. Patients being evaluated for mast cell disorders will have their tryptase level repeated if it is found to be abnormally high. Accessed September 2, 2021. https://www.abim.org/Media/bfijryql/laboratory-reference-ranges.pdf, American Society of Clinical Oncology. If the blood sample is drawn too early or late, results may be misleading. These patients usually have little mast cell bone marrow burden and in some cases present without skin lesions and normal tryptase levels. This website uses cookies to ensure you get the best experience on our website. Doctors may also do tests to learn which treatments could work best. Indolent systemic mastocytosis: This is the most common category of SM. Subvariant designated as telengiectasia macularis eruptiva perstans in former classifications is no longer present in the current classification due to the rarity of the diagnosis and its frequent association with classic MPCM. Akin C, Valent P, Metcalfe DD. Accessed September 22, 2021. https://www.uptodate.com/contents/approach-to-the-patient-with-unexplained-eosinophilia. It is used to examine two specific health situations: whether anaphylaxis shock from an allergic reaction has occurred or if mastocytosis has occurred. Sometimes the tryptase blood test is combined with a histamine test to determine if an allergic reaction has occurred. Adjunctive treatments for the co-existing disease. High grade marrow infiltration with cytopenias (ANC <1000/mL, Hgb <10 g/dl, platelets <100,000/mL), 2. Webtryptase 3 Normal SPEP 7/2018 Normal 2,3 dinor 11b prostaglandin normal leukotriene E4 24 hour urine histamine elevated at 2.871 (nl 0.06-0.131) The simple answer is no, your patients do not have mast cell activation disorder or other described mast cell disorder. If your blood level of tryptase was performed to confirm a severe allergic reaction, a second test will be performed after symptoms resolve to establish a baseline. If I had an allergic reaction, will additional tests be needed to determine what Im allergic to? A bone marrow biopsy to look for systemic disease is generally not indicated in these children unless there is hepatosplenomegaly, unexplained lymphadenopathy, abnormal CBC with differential or persistently elevated tryptase levels greater than 20 ng/ml. Levels exceeding 20 ng/ml are seen in mastocytosis (26). All 6 patients with HES and elevated tryptase treated with imatinib demonstrated a clinical and hematologic response. Arock M, Akin C, Hermine O, Valent P. Current treatment options in patients with mastocytosis: status in 2015 and future perspectives. The next section in this guide is Stages. A recent new classification of cutaneous mastocytosis in adults and children has been developed to better assess the systemic impact of skin lesions and their potential prognosis (16). Detection of a codon 816 KIT mutation. Elevated serum tryptase is present in perhaps up to 6 percent of the general population. Children with DCM are more prone to systemic mast cell activation symptoms including anaphylaxis, as well as localized symptoms such as flushing, itching and blistering. 8. WebAbstract. Investigational tyrosine kinase inhibitors such as midostaurin have recently yielded promising results in patients with ASM and MCL (32). Notably, the patients with high blood eosinophil counts and low tryptase levels were likely to have more exacerbations than those with low blood eosinophil ALL RIGHTS RESERVED. However, these severe allergic responses are most commonly caused by: Severe allergic reactions must be treated very swiftly to prevent life-threatening complications. Therefore, lesional tissue such as bone marrow or skin have a higher yield of positive results than peripheral blood. UpToDate. Patients with advanced disease categories such as ASM or SM-AHN present with hematologic abnormalities including high or low WBS, anemia, thrombocytopenia and findings indicative of tissue dysfunction. These patients may find that others in their family have similar or related symptoms, as this is a genetic syndrome. The 2023 edition of ICD-10-CM R74.8 became effective on October 1, 2022. These costs are usually covered by insurance when the test is ordered by a doctor. Accessed September 27, 2021.https://www.niaid.nih.gov/research/hereditary-alpha-tryptasemia-faq, National Heart, Lung, and Blood Institute. Presence of mild dysplastic recently described familial hyperalphatryptasemia) may have elevated tryptase levels (27). All rights reserved worldwide. Accessed September 23, 2021. https://www.uptodate.com/contents/food-allergy-in-children-prevalence-natural-history-and-monitoring-for-resolution, Kelso JM. While large studies of multiple different ethnicities need to be done, the estimate is that hereditary alpha tryptasemia may be present in a similar percentage of the general population. The table below provides examples of how initial and repeat tryptase tests may be interpreted: Persistent high tryptase levels in the blood may also be detected in other diseases, including leukemia, chronic kidney failure, chronic liver failure, and other rare blood diseases. PubMed PMID: 21035176; PubMed Central PMCID: PMC3753019. - Clinical significance of serum tryptase, Nam, Young-Hee et al., Journal of Allergy and Clinical For patients with specific venom IgE, immunotherapy is indicated for life and has been shown to be protective for over 80% of these patients (12). Updated July 15, 2021. Hereditary alpha tryptasemia is inherited, meaning affected people have a genetic change that was passed down to them from one of their parents. Patients with HES and elevated serum tryptase were more likely to develop fibroproliferative end organ damage, and 3 of 9 died within 5 years of diagnosis in contrast to 0 of 6 patients with normal serum tryptase levels. CD 25 or CD2 expression is absent, although CD30 is generally found aberrantly on the surface of the mast cells. Tryptase >200 ng.ml or bone marrow infiltration >30%, 2. Patients with ISM have aberrant mast cell collections in their bone marrow, but have no evidence for another hematologic disease or tissue dysfunction. in this case patient will need to be done the platelet count test WebTryptase, Serum Useful For Evaluation of individuals with suspected mast cell activation, which may occur as a result of anaphylaxis or allergen challenge Evaluation of patients Patients with mastoocytosis may have increased risk of systemic reactions during venom immunotherapy. Accessed September 21, 2021. https://medlineplus.gov/ency/article/000844.htm, Akin C. Mast cell disorders: An overview. A medical provider will order allergy tests to determine what substances may be causing a reaction. Recent studies of patients with anaphylaxis and symptoms compatible with mast cell activation and mediator release have lead to the recognition of a non clonal mast cell activation syndrome (MCAS) (17, 18). Accessed September 27, 2021. https://www.nhlbi.nih.gov/health-topics/blood-tests, Payne V, Kam PC. 24. A blood sample may also be taken from a vein in your arm. Akin C, Fumo G, Yavuz AS, Lipsky PE, Neckers L, Metcalfe DD. A test result which shows high levels of tryptase can confirm that an allergic reaction occurred, but it does not tell the doctor what specific substance triggered the allergic reaction. In rare cases, there may be a genetic mutation to blame for these high results. WebThe symptoms vary, as do the organs affected, and can include skin lesions, pain in inner organs, bone pain, diarrhea and vomiting, weight loss, and cardiovascular symptoms. Autoimmune Lymphoproliferative Syndrome (ALPS), Characterizing Food Allergy & Addressing Related Disorders, Prevention, Treatment & Control Strategies, Strategic Partnerships & Research Capacity, Primary Immune Deficiency Diseases (PIDDs), Partnership for Access to Clinical Trials (PACT), Division of Allergy, Immunology, and Transplantation, Division of Microbiology and Infectious Diseases, Dr. Joseph Kinyoun The Indispensable Forgotten Man, Dr. Joseph Kinyoun: Selected Bibliography, Diversity, Equity, Inclusion & Accessibility (DEIA) at NIAID, Intramural Scientist & Clinician Directory, NIAID Appoints Ted Pierson as New Vaccine Research Center Director, Study Shows Most Children Recover from Lyme Disease within Six Months of Treatment, Dizziness and/or difficulty maintaining a normal pulse and blood pressure, GI disturbances including heartburn, IBS, and numerous food and drug reactions and intolerances. Large osteolytic lesions (>2 cm) with pathologic bone fractures. doi: 10.1016/j.jaci.2010.08.035. Jawhar M, Schwaab J, Hausmann D, Clemens J, Naumann N, Henzler T, Horny HP, Sotlar K, Schoenberg SO, Cross NC, Fabarius A, Hofmann WK, Valent P, Metzgeroth G, Reiter A. Splenomegaly, elevated alkaline phosphatase and mutations in the SRSF2/ASXL1/RUNX1 gene panel are strong adverse prognostic markers in patients with systemic mastocytosis. 2004 Apr 15;103(8):3222-5. Mastocytosis (mast cell disease). 16. 6. WebElevated baseline serum tryptase level has been reported to correlate with clonal mast cell disease in patients with insect sting anaphylaxis but may also indicate one of several possible underlying syndromes, including mast cell activation syndrome (MCAS), familial hypertryptasemia, and idiopathic anaphylaxis. In: World Health Organization (WHO) Classification of Tumours. References: - Mast cell tryptase: a review of its physiology and clinical significance. 2. Likewise, some patients without mastocytosis (e.g. Merck Manuals Professional Edition. This provides a test result that is called the total to mature rate. It may also be called the TMR. 2005-2023 American Society of Clinical Oncology (ASCO). Mast cells in aspirate smears are usually <5%. A new expression of mastocytosis has been recognized in the last 10 years in patients presenting with anaphylaxis during hymenoptera stings (9). Sotlar K, Horny HP, Simonitsch I, Krokowski M, Aichberger KJ, Mayerhofer M, Printz D, Fritsch G, Valent P. CD25 indicates the neoplastic phenotype of mast cells: a novel immunohistochemical marker for the diagnosis of systemic mastocytosis (SM) in routinely processed bone marrow biopsy specimens. MPCM is divided into monomorphic and polymorphic and it appears as tan colored to reddish-brown macules and can be slightly raised papules of similar size and shape (monomorphic) and different sizes and shapes (polymorphic). MDS and MPNs are common but occasionally lymphoproliferative disorders can also be seen. WHO criteria to diagnose systemic mastocytosis are as follows (21). This uncommon blood test can help to determine if an allergy or something potentially more systemic and serious has occurred to cause bothersome physical symptoms. Accessed September 22, 2021. https://www.uptodate.com/contents/mast-cell-disorders-an-overview, American Board of Internal Medicine. One of the following C-findings must be present: 1. Presence of hepatomegaly or splenomegaly without hypersplenism or liver dysfunction, 3. Skin biopsy shows high level of infiltration. The purpose of tryptase testing when a severe allergic reaction may have occurred is to confirm that the patients symptoms were caused by an allergy. Greene LW, Asadipooya K, Corradi PF, Akin C. Endocrine manifestations of systemic mastocytosis in bone. Major criterion: Multifocal clusters of mast cells containing >15 mast cells per cluster. Accessed September 27, 2021. https://rarediseases.info.nih.gov/diseases/12980/monoclonal-mast-cell-activation-syndrome, Genetic and Rare Diseases Information Center. Do my tryptase test results show that I may have a mast cell disorder? Tryptase testing on a blood sample takes several hours, so test results are not immediately available after a blood draw. The term Maculopapular cutaneous mastocytosis (MPCM) has been recommended to replace Urticaria Pigmentosa, which is the most common skin presentation in both children and adults. WebDuring mast cellmediated anaphylaxis, total serum tryptase levels (pro + mature) may exceed 11.5 g/l; however, the pathognomonic laboratory finding indicative of mast cell degranulation is the presence of mature tryptase with serum levels exceeding 1 g/l. 7. Updated February 2, 2020. The doctor who ordered your tryptase test can tell you the meaning of your different tryptase levels. They are most numerous in the places where your body meets external environments and objects such as in your skin and the surfaces of your airway and digestive system. Your doctor may call or schedule an appointment to discuss the results with you, or you may access the results through an online portal. Mast cell cytoreductive therapies in these patients are not generally indicated since their mast cell burden is low and the expression of the disease is typically limited to the sting events with few or no mast cell mediators-related symptoms at baseline. 18. Updated August 13, 2021. PubMed PMID: 22041891; PubMed Central PMCID: PMC3224511. We found elevated tryptase levels (more than 15 ng/ml) in 46 out of 103 AML-patients (44.6%) and in 1 out of 57 ALL-patients (1.75%) ( p = <0.0001). Whether current medications can address these symptoms and provide relief that increases the quality of life should be studied in multi center clinical trials. PubMed PMID: 11377686. For this type of blood draw, an elastic band is tied around your upper arm to increase blood in the veins and make them easier to identify. As for mastocytosis, a positive test result must be present with the symptoms of mast cell activation without the presence of an allergy. 29. The urine tests are performed on a 24 hour collection of urine that is started immediately. However, patients with low grade involvement of bone marrow may have tryptase levels less than this threshold. In many medical situations, a second tryptase level is obtained to compare to an abnormal initial test. Aberrant expression of CD25 and/or CD2. Other skeletal findings include patchy or diffuse bone sclerosis and osteolysis (7). Often, an elevated tryptase level after a severe allergic reaction will prompt allergy blood testing to determine what may have provoked the severe reaction. The growth , differentiation and survival of mast cells depends on stem cell factor (SCF) which binds KIT (CD117), a receptor tyrosine kinase expressed on the surface of normal and clonal mast cells. Mastocytosis. If you are being evaluated or monitored for a mast cell disorder or other blood condition, your doctor typically orders a tryptase test, and a blood sample for analysis is drawn in a medical setting. 2010 Dec 23;116(26):5812-7. Atopy, Food and Medication Allergy and Mastocytosis. Right now, the answer is no. J Allergy Clin Immunol. This is the American ICD-10-CM version of R74.8 - other international versions of ICD-10 R74.8 may differ. A recent cross sectional comprehensive survey of over 400 patients with Mastocytosis done under The Mastocytosis Society based in the USA indicated that the symptoms most commonly associated with the disease included anxiety, flushing, itching, fatigue, brain fog, stomach pain, diarrhea, headaches, joint pain, lightheadedness and syncope (8). Allergy blood test. In contrast, IgE mediated food and environmental allergies are not seen in increased frequency in mastocytosis. D816V gain of function mutation is seen in more than 90% of adults and approximately 30% of children in lesional tissue. 2. Other mutations in genes such as SRSF2, RUNX1, TET2, and ASLX1 can be found mutated in addition to KIT in patients with advanced variants of systemic mastocytosis and are associated with poorer prognosis (3). Diagnostic criteria and classification of mastocytosis: a consensus proposal. Accessed September 21, 2021. https://www.uptodate.com/contents/laboratory-tests-to-support-the-clinical-diagnosis-of-anaphylaxis, Weller PF, Klion AD. Mast cell activation syndrome: Proposed diagnostic criteria. The duplication cannot be easily identified through usual genetic testing including microarrays, or whole exome sequencing. Anaphylaxis. Smoldering systemic mastocytosis: This is a new category denoting patients with high burden of mast cells but no evidence of an overt hematologic disorder or tissue dysfunction. If you notice any lasting pain, bleeding, or signs of infection at the site where the blood was drawn, you should contact your doctor. SM is divided into 5 different subcategories. 13. 1. Imatinib has been approved by FDA to be used for treatment of mastocytosis without or unknown codon 816 KIT mutation. Tryptase should be evaluated in all patients, males and females, presenting with hypotension during hymenoptera stings and at baseline 4-6 weeks later. 2016 Dec;30(12):2342-2350. Minor components of hymenoptera venom may be responsible for the anaphylactic events and may not be included in the skin testing or immunotherapy reagents. Review our cookies information for more details. Patients whose tryptase test results indicate a severe allergic reaction will often have additional testing to determine the substance that triggered the reaction. There are many similarities between patients who have been diagnosed with MCAS and those who have hereditary alpha tryptasemia syndrome. Stem cell transplantation may have a role in selected patients with advanced disease (33). 21. It appears that the more copies one inherits, the higher the blood tryptase level. However, a wide range of symptoms has been reported among individuals with the associated syndrome, many of which can be rather common, so it is difficult to know who has it from symptoms alone. UpToDate. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, Castellani L, Bonetto C, Frattini F, Dama A, Martinelli G, Chilosi M, Senna G, Pizzolo G, Zanotti R. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. Date unknown. Updated July 28, 2020. 4. Splenomegaly with hypersplenism, 4. Because that means that there could bemillions of people carrying multiple copies of the alpha tryptase gene, it should come as no surprise that some people will have more than one explanation for their symptoms. Pathology & Genetics. Anti-mediator treatment Applicable To Abnormal level of acid Mastocytosis. Osteoporosis due to mastocytosis is becoming increasingly acknowledged, can occur in up to 30% of patients with systemic mastocytosis and has been associated with the increase in urinary histamine excretion and the increased presence of serum IL-6. Monoclonal mast cell activation syndrome: This has been introduced as a relatively recent concept to designate patients who present with mast cell activation symptoms (such as recurrent anaphylaxis) but have low level involvement with clonal mast cell disease and do not fully meet the criteria for SM. Well differentiated systemic mastocytosis: This is a rare histopathologic variant originally described in 2004 (28). Horwitz explained that plasma levels of tryptase are usually too low to measure in individuals who dont have mastocytosis or anaphylaxis. Systemic mastocytosis associated with a hematologic neoplasm, 2023 World Allergy Organization. Updated February 23, 2015. Leukemia. Am J Surg Pathol. It occurs in males and females in approximately equal ratios. UpToDate. Tryptase testing may be ordered if a doctor suspects that you have suffered a severe allergic reaction, also called anaphylaxis or anaphylactic shock. When a severe allergic reaction occurs, tryptaste will usually peak within 2 hours of symptom onset. ON THIS PAGE: You will find a list of common tests and procedures that doctors use to find the cause of a medical problem. Mast cells are white blood cells that are part of the bodys immune system and become activated during allergic reactions. Updated June 2017. portal hypertension with ascites), 3. 12. Food allergy in children: Prevalence, natural history, and monitoring for resolution. 3. 2016 Jan;137(1):35-45. CD25 can be detected by immunohistochemistry in bone marrow biopsy sections or flow cytometry (23, 24). There is a typical history of flushing when the lesion is rubbed or disturbed. Updated August 23, 2018. Hepatomegaly with liver dysfunction (e.g. Lyons JJ, Yu X, Hughes JD, Le QT, Jamil A, Bai Y, Ho N, Zhao M, Liu Y, O'Connell MP, Trivedi NN, Nelson C, DiMaggio T, Jones N, Matthews H, Lewis KL, Oler AJ, Carlson RJ, Arkwright PD, Hong C, Agama S, Wilson TM, Tucker S, Zhang Y, McElwee JJ, Pao M, Glover SC, Rothenberg ME, Hohman RJ, Stone KD, Caughey GH, Heller T, Metcalfe DD, Biesecker LG, Schwartz LB, Milner JD. Cutaneous mastocytosis. Although the expression of anaphylaxis is increased in patients with mastocytosis due to specific and non specific triggers, hymenoptera venoms remain the most common offender. Current classification of mastocytosis is shown in Table 1 (21). Hartmann K, Escribano L, Grattan C, Brockow K, Carter MC, Alvarez-Twose I, Matito A, Broesby-Olsen S, Siebenhaar F, Lange M, Niedoszytko M, Castells M, Oude Elberink JN, Bonadonna P, Zanotti R, Hornick JL, Torrelo A, Grabbe J, Rabenhorst A, Nedoszytko B, Butterfield JH, Gotlib J, Reiter A, Radia D, Hermine O, Sotlar K, George TI, Kristensen TK, Kluin-Nelemans HC, Yavuz S, Hgglund H, Sperr WR, Schwartz LB, Triggiani M, Maurer M, Nilsson G, Horny HP, Arock M, Orfao A, Metcalfe DD, Akin C, Valent P. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology. Comprehensive information for people with cancer, families, and caregivers, from the American Society of Clinical Oncology (ASCO), the voice of the world's oncology professionals. Int Arch Allergy Immunol. Tryptase is a protein that can circulate in your bloodstream. We do not know yet the association, but this is an area of active research. By contrast, in children, the situation is different. About 80-90% of SM patients have a baseline tryptase over 20 ng/ml. Tryptase testing requires a blood sample. 2015 Jun;94(6):474-90. Were you able to determine my normal, or baseline, level of tryptase? The most common activating mutation in codon 816 located in exon 17 of KIT is a valine substitution for aspartate (D816V) and is found in over 90% of patients with systemic mastocyosis and in the skin biopsies of over 30% children with cutaneous mastocytosis (2). Whether follow-up testing is necessary depends on the reason for tryptase testing and the test result. Many test results for the tryptase blood test are communicated as normal or abnormal or high. Some medical providers, however, may provide the actual numbers of the test instead. Risk of progression to an advanced variant is less than 5%. Confusion, itching, difficulty breathing or a loss of consciousness. Tryptases are the most abundant proteases in the human mast cell, comprising up to 20 percent of the total cell protein [6-8]. Results that are 11-19 typically require follow-up testing to determine what may be happening. N Engl J Med. Patients with WDSM may fall into any subvariant of SM. A small sample of blood is then withdrawn using a needle attached to a collection tube. Lab Interpretation: High tryptase in adults. Most patients with adult onset skin lesions will have systemic mastocytosis. A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib. WebNormal serum levels of mature tryptase are less than 1 ng ml 1 (normally undetectable). Additional tests to evaluate for other abnormalities and problems with vital organs caused by mast cells may include: After your tryptase test results are available, it may be helpful to ask your doctor some of the following questions. Leuk Res. Date unknown. 2014 May-Jun;2(3):266-70. WebThe basal serum tryptase level in healthy individuals results from the constant release of the enzyme from mature tissue MCs [41]. Cutaneous mastocytosis is almost exclusively seen in children with early onset skin lesions. WebBlood tests show Tryptase low, IgE normal, all blood parameteres normal except RBC high, MCV low ,MCH low ,hb normal. 2006 Aug;26(3):465-85. Accessed September 21, 2021. https://emedicine.medscape.com/article/2093911-overview, MedlinePlus: National Library of Medicine. SCF is expressed on fibroblasts, melanocytes and others cells of the connective tissue and mucosal membranes, which have similar homing patterns as mast cells. Your health care team may ask you to schedule a blood draw at a time when you dont have any symptoms of allergy or mast cell activation. Again, it must be stressed that there is great variability from person to person in terms of what symptoms the duplications or triplications do or do not cause. 2014 Jan-Feb;2(1):70-6. Gonzlez de Olano D, de la Hoz Caballer B, Nez Lpez R, Snchez Muoz L, Cuevas Agustn M, Diguez MC, Alvarez Twose I, Castells MC, Escribano Mora L. Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA).