Blueprint Differential Diagnosis

Classification

SM is classified as a myeloid neoplasm by the World Health Organization (WHO).^3,a

Systemic Mastocytosis Subtypes^3,7

Systemic mastocytosis

Non-advanced SM

Bone marrow mastocytosis

Indolent SM

Smoldering SM

Advanced SM

Aggressive SM

SM with an associated
hematologic neoplasm

Mast cell leukemia

^a Please note, these are the anticipated changes to the WHO guidelines, 5th edition, volume 11; cited from the beta version (ahead of print) available online.³

Key SM characteristics

Clonal mast cell proliferation driven by the KIT D816V mutation in
~95% of cases^2-6

Abnormal activation of mast cells may lead to potentially debilitating symptoms, including potentially
life-threatening anaphylaxis^1,8-10

Uncontrolled proliferation and activation of mast cells may result in a wide range of potentially severe symptoms^1,8,11,12

Abnormal mast cells⁸

Release of
pro-inflammatory mediators
(eg, tryptase, histamine, IL-6, TNF)⁸

Hallmark Symptoms:

Anaphylaxis with hypotension and syncope^1,10,12

Maculopapular lesions with Darier sign^1,12-14,a

Nausea, vomiting,
and/or diarrhea^1,10,12

Please note, the signs and symptoms discussed
are not comprehensive.

IL-6, interleukin 6; TNF, tumor necrosis factor.
^aSkin lesions in adult patients with SM typically present as maculopapular lesions. A Darier sign might be present, which is defined by the development of a wheal-and-flare reaction of the lesions upon mechanical stroking.¹⁵

References

Clinical presentation

These signs and symptoms represent the clinical spectrum of systemic mastocytosis and are not all-inclusive. Symptoms may vary in individuals, based on the type of systemic mastocytosis and aggressiveness of the disease.^1,3

1 Cardiovascular^1,3,10
anaphylaxis with
hypotension and syncope, palpitations, angioedema

2 Gastrointestinal^1,10,12
nausea, vomiting,
diarrhea, abdominal pain/cramping, heartburn

3 Musculoskeletal^1,3
osteopenia, osteoporosis, fractures, back pain, bone
pain, arthralgias, myalgias

4 Skin^1,3,10,12,13
Darier sign, pruritus, flushing, urticaria, dermatographism

5 Neurocognitive^1,10,16-18
memory/cognitive difficulties, brain fog, lack of focus, dizziness, depression, headache, sleep disturbance, irritability, anxiety, migraines

6 Respiratory^8,19
wheezing, nasal congestion, throat swelling, dyspnea

7 Systemic^1,3,10
anaphylaxis with hypotension and syncope, fatigue, generalized weakness, sweats, chills, weight loss

Symptoms may result from mast cell mediator release in response to specific triggers, which differ for each patient and may include^10,20:

Physical factors^16,17,20,21
Heat, cold, changes
in temperature, pressure,
or friction

Odors^17,20
Perfumes, chemical exposure

Food or beverages^16,17,20,21
Containing or releasing histamine, alcohol

Medications and therapeutic agents^16,17,20,21
Opiates, NSAIDs, antibiotics, anesthetics, vaccinations, and contrast media

Insects^16,17,20,21
Hymenoptera sting or venom

General triggers^16,17,20,21
Environmental allergens, infections, exercise, stress (emotional or physical),
lack of sleep

NSAIDs, nonsteroidal anti-inflammatory drugs.

References

Diagnosis

WHO Criteria for Systemic Mastocytosis

The WHO diagnostic criteria for SM consist of major and minor criteria.^3,a

WHO Systemic Mastocytosis Diagnostic Criteria^3,a

(1 major + ≥1 minor or ≥3 minor)

Major criterion

Multifocal dense infiltrates of MCs (≥15 MCs in aggregates) are detected in sections of bone marrow and/or other extracutaneous organ(s)

Minor criteria (anticipated changes)

Activating KIT point mutation(s) at codon 816 or in other critical regions of KIT^b in bone marrow or
other extracutaneous organ(s)

Baseline serum tryptase concentration >20 ng/mL in the absence of a myeloid-associated hematologic neoplasm.^c In the case of a known HαT, the tryptase level could be adjusted^d

Peripheral blood test may be used to screen for SM^3,22,23

>25% of all MCs are atypical cells (type I or type II) on bone marrow smears or are spindle-shaped in dense and diffuse MC infiltrates in sections of bone marrow or other extracutaneous organ(s)^e

MCs in bone marrow, blood, or another extracutaneous organ(s) aberrantly express 1 or more of the following antigens: CD2, CD25, CD30^f

B- and C-findings

Symptoms related to organ infiltration in SM are classified as B (burden of disease) and C (cytoreduction-required) findings reflecting organ dysfunction and disease aggressiveness, which help to define the subtype of SM.^3,24

B-FINDINGS^a C-FINDINGS^a

HαT, hereditary alpha tryptasemia; ISM, indolent systemic mastocytosis; MC, mast cell; SM-AHN, systemic mastocytosis with an associated hematologic neoplasm; WHO, World Health Organization.
^a Please note, these are the anticipated changes to the WHO guidelines, 5th edition, volume 11; cited from the beta version (ahead of print) available online.³
^b Any type of KIT mutation counts as a minor SM criterion when solid evidence for its transforming behavior is available.³
^c Myeloid neoplasms can lead to increased serum tryptase levels. Therefore, this criterion does not count in cases of SM-AHN.³
^d A possible mode for adjustment has been proposed. The basal tryptase level may be divided by 1 plus the extra copy numbers of the alpha tryptase gene.³
^e In tissue sections, an abnormal MC morphology counts in both a dense infiltrate and a diffuse MC infiltrate. In the bone marrow smear, an atypical morphology of MCs does not count as SM criterion when MCs are located in, or adjacent to, bone marrow particles. Morphologic criteria of atypical MCs have been described.³
^f Expression has to be confirmed by either flow cytometry or immunohistochemistry.³

References

Considerations in the Diagnostic Process

The following diagram is an example of a potential diagnostic workup and is not a specific recommendation or guideline for diagnosing patients with SM.

Recognizing hallmark signs and symptoms^a

Dermatologic
Including: Skin lesions, urticaria, pruritus, flushing^1,3,12,13

Systemic
Including: Recurrent or unexplained anaphylaxis with hypotension and syncope^1,3,10

Gastrointestinal
Including: Diarrhea, bloating, abdominal cramping, nausea, and vomiting^1,3,25

Evaluation of SM

Peripheral blood testing for screening of SM

KIT D816V testing with a
high-sensitivity molecular assay^1,3,8,22

Serum tryptase level^1,3,8,23

Mast cell expression of 1 or more of the following: CD2, CD25, CD30^1,3

Biopsy
Bone marrow biopsy or biopsy of an extracutaneous organ^1,3,8

SM, systemic mastocytosis.
^aPlease note, only select signs and symptoms are shown.

References

Considerations for Systemic Mastocytosis Workup

Click the plus button to reveal answers

Are there MC mediator symptoms?

MC mediator symptoms should raise suspicion of SM; however, a thorough workup is required for definitive diagnosis.^3,10,26

Is there an elevated serum tryptase?

Tryptase >20 ng/mL is considered a minor diagnostic criterion for SM in the WHO guidelines,^a
but basal serum tryptase levels <20 ng/mL might not rule out SM.^1,3,27

Is KIT D816V mutation detected using a high-sensitivity assay?

BM, blood, or other extracutaneous organ(s) may be screened for activating KIT point
mutation(s) at codon 816 or in any other critical regions of KIT. KIT mutation is considered a key
diagnostic component of SM and is a minor criterion in the WHO guidelines.^1,3,22,a

Does biopsy of an extracutaneous organ show multifocal dense infiltrates of MCs?

SM involves proliferation of abnormal MCs, which accumulate in one or more organ systems,
which may include BM, gastrointestinal tract, lymph nodes, spleen, liver, or other organs.
Presence of dense multifocal infiltrates of MCs, defined as ≥15 MCs in aggregates in sections of
BM and/or other extracutaneous organ(s), is a major criterion of SM in the WHO guidelines.^1,3,24,a

Is there any evidence of B- or C-findings?

Evaluation of clinical signs of SM, classified as B- or C-findings, can help define the subtype of SM as they indicate organ involvement and aggressiveness of SM, according to the WHO guidelines.^3,24,a

B (burden of disease) findings:
0 B-finding? Consider BMM
0-1 B-finding? Consider ISM
≥2 B-findings? Consider SSM

C (cytoreduction-required) findings:
0 C-finding? Consider chronic MCL
0-1 C-finding? Consider ASM
Meets criteria for SM and AHN? Consider SM-AHN
≥1 C-finding? Consider acute MCL

AHN, associated hematologic neoplasm; ASM, aggressive systemic mastocytosis; BM, bone marrow; BMM, bone marrow mastocytosis; ISM, indolent systemic mastocytosis; MC, mast cell;
MCL, mast cell leukemia; SM, systemic mastocytosis; SSM, smoldering systemic mastocytosis; WHO, World Health Organization.
^aPlease note, these are the anticipated changes to the WHO guidelines, 5th edition, volume 11; cited from the beta version (ahead of print) available online.³

References:

Pardanani A. Systemic mastocytosis in adults: 2023 update on diagnosis, risk stratification and management. Am J Hematol. 2023;98(7):1097-1116.
Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms. Leukemia. 2022;36(7): 1703-1719.
Verstovek S, Colmenero I, Cozzolino I, et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63
Garcia-Montero AC, Jara-Acevedo M, Alvarez-Twose I, et al. KIT D816V-mutated bone marrow mesenchymal stem cells in indolent systemic mastocytosis are associated with disease progression. Blood. 2016;127(6):761-768.
Kristensen T, Vestergaard H, Bindslev-Jensen C, Møller MB, Broesby-Olsen S. Sensitive KIT D816V mutation analysis of blood as a diagnostic test in mastocytosis. Am J Hematol. 2014;89(5):493-498.
Ungerstedt J, Ljung C, Klimkowska M, Gülen T. Clinical outcomes of adults with systemic mastocytosis: a 15-year multidisciplinary experience. Cancers (Basel). 2022;14(16):3942.
Valent P, Akin C, Gleixner KV, et al. Multidisciplinary challenges in mastocytosis and how to address with personalized medicine approaches. Int J Mol Sci. 2019;20(12):2976.
Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373(2):163-172.
Valent P. Risk factors and management of severe life-threatening anaphylaxis in patients with clonal mast cell disorders. Clin Exp Allergy. 2014;44(7):914-920.
Gilreath JA, Tchertanov L, Deininger MW. Novel approaches to treating advanced systemic mastocytosis. Clin Pharmacol. 2019;11:77-92.
Rossignol J, Polivka L, Maouche-Chrétien L, Frenzel L, Dubreuil P, Hermine O. Recent advances in the understanding and therapeutic management of mastocytosis. F1000Res. 2019;8:F1000 Faculty Rev-1961.
Pyatilova P, Akin C, Alvarez-Twose I, et al. Refined treatment response criteria for indolent systemic mastocytosis proposed by the ECNM-AIM Consortium. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024.
Hartmann K, Escribano L, Grattan C, et al. Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. J Allergy Clin Immunol. 2016;137(1):35-45.
Aberer E, Sperr WR, Bretterklieber A, et al. Clinical impact of skin lesions in mastocytosis: a multicenter study of the European Competence Network on Mastocytosis. J Invest Dermatol. 2021;141(7):1719-1727.
Manjaly Thomas ZR, Hartmann K. Skin disease in mastocytosis. In: Akin C, ed. Mastocytosis. Springer, Cham. 2020:69-91.
Gülen T, Elberink JNGO, Brockow K. Anaphylaxis in mastocytosis. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155.
Jennings SV, Slee VM, Zack RM, et al. Patient perceptions in mast cell disorders. Immunol Allergy Clin North Am. 2018;38(3):505-525.
Scherber RM, Borate U. How we diagnose and treat systemic mastocytosis in adults. Br J Haematol. 2018;180(1):11-23.
Taylor F, Akin C, Lamoureux RE, et al. Development of symptom-focused outcome measures for advanced and indolent systemic mastocytosis: the AdvSM-SAF and ISM-SAF^©. Orphanet J Rare Dis. 2021;16(1):414.
Jennings SV, Slee VM, Hobart JS, et al. International support and advocacy for mast cell disease patients and caregivers. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:267-286.
Castells M, Butterfield J. Mast cell activation syndrome and mastocytosis: initial treatment options and long-term management. J Allergy Clin Immunol Pract. 2019;7(4):1097-1106.
Hoermann G, Sotlar K, Jawhar M, et al. Standards of genetic testing in the diagnosis and prognostication of systemic mastocytosis in 2022: recommendations of the EU-US Cooperative Group.
J Allergy Clin Immunol Pract. 2022;10(8):1953-1963.
Matito A, Morgado JM, Álvarez-Twose I, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. PLoS One. 2013;8(10):e76116.
Vaes M, Benghiat FS, Hermine O. Targeted treatment options in mastocytosis. Front Med (Lausanne). 2017;4:110.
Zanelli M, Pizzi M, Sanguedolce F, et al. Gastrointestinal manifestations in systemic mastocytosis: the need of a multidisciplinary approach. Cancers (Basel). 2021;13(13):3316.
Bibi S, Arock M. KIT and other mutations in mastocytosis. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:267-286.
Akin C, Valent P. Diagnostic criteria and classification of mastocytosis in 2014. Immunol Allergy Clin North Am. 2014;34(2):207-218.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Cutaneous Mastocytosis

Cutaneous mastocytosis (CM) is a form of mastocytosis that affects the skin, with no evidence of systemic mast cell involvement, in primarily pediatric patients.^1-3

Please note: Most patients diagnosed with CM are children, whereas SM is usually diagnosed in adults.^2-4 Adults with skin lesions
may receive a provisional diagnosis of mastocytosis in the skin prior to undergoing complete staging, including bone marrow
analysis, to confirm/exclude CM or SM.^4,5

Common Signs and Symptoms

ISM	CM
DERMATOLOGIC
Darier sign: Elicited upon stroking of lesioned skin^1,2 Darier sign: Elicited upon stroking of lesioned skin^1,2 ^a Please note, the Darier sign depicted here indicates a wheal-and-flare reaction, which was developed upon stroking of the lesion in a patient with CM. The Darier sign is an important clinical feature of mastocytosis skin lesions in patients with CM and SM.^1,2 Patient permissions and image reprint from Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. doi.org/10.1016/j.jaci.2015.08.03. Copyright 2016, have been granted from Elsevier.
Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^1,2,7 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^1,7,8 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199.doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Maculopapular CM, previously known as urticaria pigmentosa, is typically characterized by round brown or red skin lesions^1,2 Polymorphic, larger lesions, may present initially with nodules or plaques, and typically arise on the trunk, head, and extremities; presents in children^1,2 Monomorphic, small round lesions may be present in a small subset of patients, including children^1,2,9 Patient permissions and image reprint from Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. doi.org/10.1016/j. jaci.2015.08.03. Copyright 2016, have been granted from Elsevier.
Not usually observed^1,2	Diffuse CM (DCM), characterized by generalized erythema with a brown or yellow tint and thickened skin. Pronounced dermographism and blisters can be associated with DCM as well^1,2 Patient permissions and image reprint from Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. doi.org/10.1016/j. jaci.2015.08.03. Copyright 2016, have been granted from Elsevier.
Not usually observed^1,2	Mastocytoma, typically presents as 1-3 brown or red nodular lesions and may initially be associated with blisters^1,2 These lesions or blisters can be isolated or multilocalized⁹ Patient permissions and image reprint from Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. doi.org/10.1016/j. jaci.2015.08.03. Copyright 2016, have been granted from Elsevier.
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^7,10,11 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^7,11,12	Not usually observed^1-3
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^7,11-13 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^7,9,14 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^7,15,16	Anaphylaxis is uncommon but may be possible^1,2,17
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^7,12,13,18 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Involvement is most commonly seen in the skin^1,2

Additional Considerations

This section provides some information that may be helpful in further identifying patients with ISM vs CM and is not inclusive of all distinguishing features. Please refer to the formal guidelines for each disorder, if available, for a more comprehensive list.

In pediatric patients, the typical course of CM is usually temporary and often resolves spontaneously around puberty, whereas
ISM in adults is usually chronic.^1,2

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis; SM, systemic mastocytosis.

References:

1. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 2. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 3. Akin C et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:23-34. 4. Valent P et al. Hemasphere. 2021;5(11):e646. 5. Valent P et al. Allergy. 2014;69(10):1267-1274. 6. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 7. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 8. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 9. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63
10. Hamilton MJ. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:115-122. 11. Lim KH et al. Blood. 2009;113(23):5727-5736. 12. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414. 13. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 14. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 15. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 16. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 17. Brockow K et al. Allergy. 2008;63(2):226-232. 18. Pardanani A et al. Leukemia. 2013;27(10):2091-2094.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is a spontaneous appearance of urticaria, defined as wheals (hives), angioedema, or both for >6 weeks
due to known or unknown causes.^1,2

Common Signs and Symptoms

ISM	CSU
DERMATOLOGIC
Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^4-6 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^4,6,7 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^4-6 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Wheals are defined by swelling and erythema of varying size and shape, presenting with itching or burning. Wheals are transient and may resolve within 30 minutes to 24 hours^1,2 Angioedema is characterized by sudden swelling or erythema in the deep layers of the dermis, usually with sensation of tingling, burning, tightness, and pain. Resolution of angioedema is slower than wheals and may take up to 72 hours^1,8 Patient permissions and image reprint from Sussman G et al. Allergy Asthma Clin Immunol. 2015;11(1):7. doi: 10.1186/s13223-015-0072-2 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^6,9,10 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^6,10,11	Some patients can have GI symptoms such as nausea, vomiting, and epigastric abdominal pain¹²
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^6,10,11,13 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^6,14,15 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^6,16,17	Not usually observed^1,2
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^6,11,13,18 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Some additional manifestations such as Kounis syndrome, hypertension, striatum dysfunction, respiratory symptoms, arthritis, arthralgia, or osteoporosis may occur¹²

Additional Considerations

This section provides some information that may be helpful in further identifying patients with ISM vs CSU and is not inclusive of all distinguishing features. Please refer to the formal guidelines for each disorder, if available, for a more comprehensive list.

CSU may occur with daily/almost daily signs and symptoms or as an intermittent/recurrent course. CSU may also recur after
months or years of full remission. ISM is usually chronic.^1,19

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis.

References:

1. Zuberbier T et al. Allergy. 2022;77(3):734-766. 2. Vestergaard C et al. Ther Adv Chronic Dis. 2015;6(6):304-313. 3. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 4. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 5. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 6. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 7. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 8. Sussman G et al. Allergy Asthma Clin Immunol. 2015;11(1):7. 9. Hamilton MJ. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:115-122. 10. Lim KH et al. Blood. 2009;113(23): 5727-5736. 11. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414. 12. Kocaturk E et al. Clin Transl Allergy. 2019;9:48. 13. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 14. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63 15. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 16. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 17. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 18. Pardanani A et al. Leukemia. 2013;27(10):2091-2094. 19. Bibi S et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:207-230.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Mast Cell Activation Syndrome

Mast cell activation syndromes (MCAS) are a clustering of disorders characterized by the accumulation of MCs in tissues and organs,
and/or release of MC mediators, with symptoms related to MC degranulation and mediator release.¹ MCAS can be divided into primary,
secondary, and idiopathic.^2,3 Primary MCAS or monoclonal MCAS (mMCAS) is characterized by lack of cutaneous findings and presence of
KIT D816V mutation or expression of CD25 in MCs.³

Common Signs and Symptoms

ISM	MCAS/mMCAS
DERMATOLOGIC
ISM: Maculopapular lesions in an adult⁴ Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^5-7 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^5,7,8 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^5-7 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Episodic symptoms such as pruritus, urticaria, and flushing may occur^2,9,10
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^7,11,12 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^7,12,13	Patients may present with nausea, vomiting, cramping abdominal pain, and diarrhea^1,3
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^7,12-14 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^7,15,16 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^7,17,18	During episodes of anaphylaxis, cardiovascular, respiratory, dermatologic, and GI organ systems are often affected. Symptoms include urticaria, flushing, pruritus, abdominal cramping, nausea, diarrhea, wheezing, shortness of breath, syncope, and hypotension^1,10
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^7,13,14,19 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Chronic urticaria and angioedema can be a feature of secondary and idiopathic MCAS³ Additional symptoms such as headache, tachycardia, and fatigue may occur^1,9,10

Additional Considerations

This section provides some information that may be helpful in further identifying patients with ISM vs MCAS and is not inclusive of all distinguishing features. Please refer to the formal guidelines for each disorder, if available, for a more comprehensive list.

Basal serum tryptase levels in patients with MCAS/mMCAS are usually normal or mildly increased. If patients with suspected MC disorders
have elevated tryptase levels, evaluation of systemic mastocytosis or hereditary alpha tryptasemia may be warranted.^2,10,20

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis; MC, mast cell.

References:

1. Jackson CW et al. Int J Mol Sci. 2021;22(20):11270. 2. Akin C et al. J Allergy Clin Immunol. 2010;126(6):1099-1104.e4. 3. Akin C. J Allergy Clin Immunol. 2017;140(2):349-355. 4. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 5. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 6. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 7. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 8. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 9. Rossignol J et al. F1000Res. 2019;8:F1000 Faculty Rev-1961. 10. Weiler CR et al. J Allergy Clin Immunol. 2019;144:883. 11. Hamilton MJ. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:115-122. 12. Lim KH et al. Blood. 2009;113(23):5727-5736. 13. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414. 14. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 15. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63 16. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 17. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 18. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 19. Pardanani A et al. Leukemia. 2013;27(10):2091-2094. 20. American Academy of Allergy, Asthma, and Immunology and American College of Allergy, Asthma, and Immunology. Anaphylaxis: a 2023 practice parameter update, 2023. Accessed September 28, 2023. https://college.acaai.org/wp-content/uploads/2023/04/Anaphylaxis-2023-Practice-Parameter-Update-01APR2023.pdf

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Hereditary Alpha Tryptasemia

Hereditary alpha tryptasemia (HαT) is a disorder characterized by an autosomal-dominant genetic trait with extra copies of the
TPSAB1 gene, which encodes α-tryptase.^1-3 HαT is associated with elevated baseline serum tryptase levels (>8 ng/mL).^1-3

Common Signs and Symptoms

ISM	HαT
DERMATOLOGIC
ISM: Maculopapular lesions in an adult⁴ Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^5-7 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^5,7,8 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^5-7 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Typically characterized by recurrent cutaneous symptoms, including flushing and pruritus^1,3 Angioedema and urticaria are commonly reported^9,10
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^7,11,12 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^7,12,13	IBS-like symptoms or symptoms of chronic gastroesophageal reflux are commonly present^1,3
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^7,12-14 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^7,15,16 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^7,17,18	Systemic reaction consistent with IgE-mediated hypersensitivity reaction or systemic venom reaction to stinging insects (Hymenoptera) can occur^3,19
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^7,13,14,20 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Dysautonomia, arthralgia, primary dentition, headache, body pain, connective tissue abnormalities, and joint hypermobility may occur^2,3

Additional Considerations

This section provides some information that may be helpful in further identifying patients with ISM vs HαT and is not inclusive of all distinguishing features. Please refer to the formal guidelines for each disorder, if available, for a more comprehensive list.

Patients with SM may simultaneously have HαT, especially among patients with ISM and BMM. In patients with mastocytosis, presence of
HαT can indicate increased risk and severity for anaphylaxis.^7,21-23

JUMP TO PATIENT PORTRAYALS

BMM, bone marrow mastocytosis; GI, gastrointestinal; IBS, irritable bowel syndrome; IgE, immunoglobulin E; ISM, indolent systemic mastocytosis; MC, mast cell; SM, systemic mastocytosis.

References:

1. Gotlib J et al. J Allergy Clin Immunol. 2021;147(6):2043-2052. 2. Lyons JJ et al. Nat Genet. 2016;48(12):1564-1569. 3. Lyons JJ. Immunol Allergy Clin North Am. 2018;38(3):483-495. 4. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 5. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 6. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 7. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 8. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 9. Lyons JJ, Shwartz, LB. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:35-54. 10. Chollet MB, Akin C. J Allergy Clin Immunol. 2022;149(2):728-735.e2. 11. Hamilton MJ. In: Akin C, ed. Mastocytosis. Springer, Cham. 2020:115-122. 12. Lim KH et al. Blood. 2009;113(23):5727-5736. 13. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414. 14. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 15. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63 16. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 17. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 18. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 19. Jackson CW et al. Int J Mol Sci. 2021;22(20):11270. 20. Pardanani A et al. Leukemia. 2013;27(10):2091-2094 21. Lyons JJ et al. J Allergy Clin Immunol. 2021;147(2):622-632. 22. American Academy of Allergy, Asthma, and Immunology and American College of Allergy, Asthma, and Immunology. Anaphylaxis: a 2023 practice parameter update, 2023. Accessed September 29, 2023. https://college.acaai.org/wp-content/uploads/2023/04/Anaphylaxis-2023-Practice-Parameter-Update-01APR2023.pdf. 23. Sordi B et al. J Allergy Clin Immunol. 2023;151(2):485-493.e11.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Hypereosinophilic Syndrome

Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders characterized by persistently elevated eosinophil count
and eosinophil-mediated organ damage.^1,2

Common Signs and Symptoms

ISM	HES
DERMATOLOGIC
ISM: Maculopapular lesions in an adult³ Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^4-6 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^4,6,7 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^4-6 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Cutaneous manifestations such as urticaria, erythema, angioedema, ulceration, pruritus, or eczema are common^1,2
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^6,8,9 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^6,9,10	Abdominal pain, diarrhea, nausea, and vomiting^1,2 Eosinophilic gastritis, enterocolitis, or colitis may be present²
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^6,9-11 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^6,12,13 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^6,14,15	Weakness, fatigue, and fever may occur^1,2,16
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^6,10,11,17 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Cough, shortness of breath, myalgias, and other cardiac, neurological and respiratory manifestations (eg, rhinitis, asthma, and sinusitis) may occur^1,2,16

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis.

References:

1. Schuster B et al. Allergy. 2020;75(11):3003-3006. 2. Roufosse FE et al. Orphanet J Rare Dis. 2007;2:37. 3. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 4. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 5. Manjaly Thomas ZR, Hartmann K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 6. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 7. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 8. Hamilton MJ. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:115-122. 9. Lim KH et al. Blood. 2009;113(23):5727-5736. 10. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414. 11. Gülen
T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 12. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version
ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63
13. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 14. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 15. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 16. Gotlib J. Am J Hematol. 2017;92(11):1243-1259. 17. Pardanani A et al. Leukemia. 2013;27(10):2091-2094.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a chronic disorder of gut-brain interaction. IBS is characterized by symptoms of recurrent abdominal pain
and disordered defecation.^1-3

Common Signs and Symptoms

ISM	IBS
DERMATOLOGIC
ISM: Maculopapular lesions in an adult⁴ Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^5-7 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^5,7,8 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^5-7 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Not observed^1,3
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^7,9,10 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^7,10,11	Recurrent abdominal pain, change in stool frequency, diarrhea, and/or constipation^1-3 Abdominal bloating and distention are commonly reported symptoms^1-3
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^7,10-12 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^7,13,14 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^7,15,16	Not observed^1,3
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^7,11,12,17 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Patients with IBS commonly also have anxiety and depression³

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis.

References:

1. Lacy BE et al. Am J Gastroenterol. 2021;116(1):17-44. 2. Lacy BE. Int J Gen Med. 2016;9:7-17. 3. Saha L. World J Gastroenterol. 2014;20(22):6759-6773. 4. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199.
5. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 6. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 7. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 8. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 9. Hamilton MJ. In: Akin C, ed. Mastocytosis. Springer, Cham. 2020:115-122. 10. Lim KH et al. Blood. 2009;113(23):5727-5736.
11. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414. 12. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 13. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63 14. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 15. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 16. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 17. Pardanani A et al. Leukemia. 2013;27(10):2091-2094.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is a broad term that includes conditions characterized by chronic inflammation of the GI tract. IBD
includes Crohn disease and ulcerative colitis.¹

Common Signs and Symptoms

ISM	IBD
DERMATOLOGIC
ISM: Maculopapular lesions in an adult² Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^3-5 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^3,5,6 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^3-5 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Psoriasis and mucocutaneous lesions associated with IBD can occur⁷
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^5,8,9 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^5,9,10	Pain in the lower abdomen, swelling, thickening of the bowel wall, diarrhea, and rectal bleeding are frequently reported^1,11
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^5,9,10,12 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^5,13,14 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^5,15,16	Weakness, fatigue, and weight changes may be reported^1,11
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^5,10,12,17 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Nutritional deficiencies, anemia, and thromboembolic disease may occur^11,18

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis.

References:

1. Okobi OE et al. Cureus. 2021;13(8):e16859. 2. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 3. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 4. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 5. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 6. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 7. Antonelli E et al. J Clin Med. 2021;10(2):364. 8. Hamilton MJ. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:115-122. 9. Lim KH et al. Blood. 2009;113(23):5727-5736. 10. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414.
11. Fakhoury M et al. J Inflamm Res. 2014;7:113-120. 12. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 13. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63 14. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 15. Pieri L et al. Am J Hematol. 2016;91(7):692-699.
16. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 17. Pardanani A et al. Leukemia. 2013;27(10):2091-2094. 18. D'Incà R et al. Diagnostics (Basel). 2023;13(18):2931.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Postural Orthostatic Tachycardia Syndrome

Postural orthostatic tachycardia syndrome (POTS) is a chronic multisystem disorder with orthostatic tachycardia as its cardinal feature.^1,2 It
is also characterized by frequent symptoms of orthostatic intolerance that occur with standing, an increase in heart rate ≥30 beats per
minute (or ≥40 beats/min for individuals aged 12-19 years old) when moving from recumbent to standing position, and the absence of
orthostatic hypotension (>20/10 mm Hg drop in blood pressure).^1,2

Common Signs and Symptoms

ISM	POTS
DERMATOLOGIC
ISM: Maculopapular lesions in an adult³ Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^4-6 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^4.6,7 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^4-6 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Some patients may experience episodes of flushing and urticaria¹
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^6,8,9 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^6,9,10	Nausea, bloating, diarrhea, abdominal pain, and vomiting may occur^1,2
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^6,9-11 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^6,12,13 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^6,14,15	Symptoms vary between individuals and can include generalized weakness and fatigue^1,2
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^6,10,11,16 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Some patients with POTS have comorbid conditions or symptoms associated with abnormal mast cell activation such as dyspnea and headache¹ Other common signs and symptoms are related to orthostatic intolerance such as light-headedness, palpitations, tremulousness, and blurred vision^1,2 Sleep disturbances, anxiety, tachycardia, tremor, angina-like chest pain, and migraines may also occur^1,2

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis.

References:

1. Raj SR et al. CMAJ. 2022;194(10):e378-e385. 2. Sheldon RS et al. Heart Rhythm. 2015;12(6):e41-e63. 3. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 4. Hartmann K et al. J Allergy Clin Immunol. 2016;137(1):35-45. 5. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 6. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024. 7. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 8. Hamilton MJ. In: Akin C, ed. Mastocytosis. Springer, Cham. 2020:115-122. 9. Lim KH et al. Blood. 2009;113(23):5727-5736. 10. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414.
11. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 12. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet;
beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63 13. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 14. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 15. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 16. Pardanani A et al. Leukemia. 2013;27(10):2091-2094.

The information presented here outlines general characteristics of each disorder. Presentation of signs and symptoms may vary from patient to patient.

Idiopathic Anaphylaxis

Idiopathic anaphylaxis (IA) is a multisystem disorder, which presents clinically as anaphylaxis of unknown etiology. IA is a diagnosis of
exclusion since its triggers cannot be identified despite a detailed history and careful diagnostic assessment.^1,2

Common Signs and Symptoms

ISM	IA
DERMATOLOGIC
ISM: Maculopapular lesions in an adult³ Monomorphic maculopapular lesions, round, brown or red in color arise predominantly on the thigh and trunk. Lesions may spread or spontaneously disappear, which may or may not indicate disease progression^4-6 Symptoms such as flushing, pruritus, and positive Darier sign may be observed^4,6,7 The Darier sign is an important clinical feature of mastocytosis skin lesions. It is defined by the development of a wheal-and-flare reaction upon mechanical irritation of the lesion^4-6 Patient permissions and image reprint from Mikkelsen et al. Dermatol Reports. 2014;6(1):5199. doi:10.4081/dr.2014.5199 have been granted under the Creative Commons License 4.0 https://creativecommons.org/licenses/by-nc/4.0/legalcode	Acute onset of an illness (minutes to several hours) with simultaneous involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula)^1,8
GASTROINTESTINAL
GI involvement is commonly reported in patients with ISM^6,9,10 Symptoms may include diarrhea, abdominal cramping, bloating, nausea, and vomiting^6,10,11	Severe abdominal symptoms such as diarrhea, repetitive vomiting, nausea, abdominal cramping and pain^1,2,8
SYSTEMIC
Systemic symptoms include fatigue, anaphylaxis, and weight loss^6,10-12 Anaphylaxis may occur; patients typically present with hypotensive syncope and without flushing, urticaria, pruritus, and angioedema^6,13,14 Episodes of anaphylaxis appear more likely to develop in patients with mastocytosis compared to the general population; Hymenoptera stings are a common trigger^6,15,16	Systemic symptoms include episodes of anaphylaxis, which may present as urticaria, angioedema, respiratory compromise, reduced blood pressure or symptoms of end-organ dysfunction, and GI manifestations^1,8,17
OTHER
Additional symptoms such as cognitive impairment, dizziness, headache, osteoporosis, musculoskeletal pain, breathing difficulties, anxiety, or depression may occur^6,11,12,17 Please note that this list is not inclusive of all symptoms patients with ISM may experience	Symptoms of respiratory and/or cardiovascular compromise such as cough, wheeze, dyspnea and tachycardia, light-headedness, and shock^1,8 Reduced blood pressure and associated symptoms of end-organ dysfunction may be present as well⁸

Additional Considerations

This section provides some information that may be helpful in further identifying patients with ISM vs IA and is not inclusive of all distinguishing features. Please refer to the formal guidelines for each disorder, if available, for a more comprehensive list.

Patients with IA may be diagnosed with SM upon further evaluation. Therefore, patients with recurrent, unexplained episodes of anaphylaxis should be screened further for the presence of mastocytosis.^18-20

JUMP TO PATIENT PORTRAYALS

GI, gastrointestinal; ISM, indolent systemic mastocytosis; SM, systemic mastocytosis.

References:

1. Nwaru BI et al. Curr Treat Options Allergy. 2017;4(3):312-319. 2. Sampson HA et al. J Allergy Clin Immunol. 2005;115(3):584-591. 3. Mikkelsen CS et al. Dermatol Reports. 2014;6(1):5199. 4. Hartmann K et al.
J Allergy Clin Immunol. 2016;137(1):35-45. 5. Manjaly Thomas ZR, Hartmann, K. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:69-91. 6. Pyatilova P et al. J Allergy Clin Immunol Pract. 2022;10(8):2015-2024.
7. Hermans MAW et al. Eur J Intern Med. 2016;30:25-30. 8. Cardona V et al. World Allergy Organ J. 2020;13(10):100472. 9. Hamilton MJ. In: Akin E, ed. Mastocytosis. Springer, Cham; 2020:115-122. 10. Lim KH et al.
Blood. 2009;113(23):5727-5736. 11. Taylor F et al. Orphanet J Rare Dis. 2021;16(1):414. 12. Gülen T et al. In: Akin C, ed. Mastocytosis. Springer, Cham; 2020:141-155. 13. Verstovek S et al. Systemic mastocytosis. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet; beta version ahead of print]. International Agency for Research on Cancer; 2023. (WHO classification of tumours series, 5th ed; vol 11). Accessed September 28, 2023. https://tumourclassification.iarc.who.int/chapters/63 14. Alvarez-Twose I et al. J Allergy Clin Immunol. 2010;125(6):1269-1278.e2. 15. Pieri L et al. Am J Hematol. 2016;91(7):692-699. 16. González de Olano D et al. J Allergy Clin Immunol. 2008;121(2):519-526. 17. Pardanani A et al. Leukemia. 2013;27(10):2091-2094. 18. Pardanani A. Am J Hematol. 2023;98(7):1097-1116.
19. Carter MC et al. J Allergy Clin Immunol. 2018;141(1):180-188.e3. 20. American Academy of Allergy, Asthma, and Immunology and American College of Allergy, Asthma, and Immunology. Anaphylaxis: a 2023 practice parameter update, 2023. Accessed September 29, 2023. https://college.acaai.org/wp-content/uploads/2023/04/Anaphylaxis-2023-Practice-Parameter-Update-01APR2023.pdf

Systemic Mastocytosis Overview

Classification

Systemic Mastocytosis Subtypes3,7

Key SM characteristics

Uncontrolled proliferation and activation of mast cells may result in a wide range of potentially severe symptoms1,8,11,12

Clinical presentation

Symptoms may result from mast cell mediator release in response to specific triggers, which differ for each patient and may include10,20:

Diagnosis

WHO Criteria for Systemic Mastocytosis

WHO Systemic Mastocytosis Diagnostic Criteria3,a

Major criterion

Minor criteria (anticipated changes)

B- and C-findings

Considerations in the Diagnostic Process

Evaluation of SM

Considerations for Systemic Mastocytosis Workup

This website is intended solely as an educational resource for healthcare providers practicing in the US.

B-findingsa

High MC Burden

Signs of myelodysplasia and/or myeloproliferationc

C-findings1,2,a

≥1 cytopenia

≥1 cytopenia

Hepatopathy

Hepatopathy

Spleen

Spleen

GI tract

GI tract

Bone

Bone

Medical History

Current Medications

Laboratory Results

Diagnosis

WHO Systemic Mastocytosis Diagnostic Criteria1,a

Major criterion

Minor criteria (anticipated changes)

Medical History

Current Medications

Laboratory Results

Diagnosis

WHO Systemic Mastocytosis Diagnostic Criteria1,a

Major criterion

Minor criteria (anticipated changes)

Medical History

Current Medications

Laboratory Results

Diagnosis

WHO Systemic Mastocytosis Diagnostic Criteria1,a

Major criterion

Minor criteria (anticipated changes)

Cutaneous Mastocytosis

Common Signs and Symptoms

Additional Considerations

Chronic Spontaneous Urticaria

Common Signs and Symptoms

Additional Considerations

Mast Cell Activation Syndrome

Common Signs and Symptoms

Additional Considerations

Hereditary Alpha Tryptasemia

Common Signs and Symptoms

Additional Considerations

Hypereosinophilic Syndrome

Common Signs and Symptoms

Irritable Bowel Syndrome

Common Signs and Symptoms

Inflammatory Bowel Disease

Common Signs and Symptoms

Postural Orthostatic Tachycardia Syndrome

Common Signs and Symptoms

Idiopathic Anaphylaxis

Common Signs and Symptoms

Additional Considerations

Systemic Mastocytosis Subtypes^3,7

Uncontrolled proliferation and activation of mast cells may result in a wide range of potentially severe symptoms^1,8,11,12

Symptoms may result from mast cell mediator release in response to specific triggers, which differ for each patient and may include^10,20:

WHO Systemic Mastocytosis Diagnostic Criteria^3,a

B-findings^a

Signs of myelodysplasia
and/or myeloproliferation^c

C-findings^1,2,a

WHO Systemic Mastocytosis Diagnostic Criteria^1,a

WHO Systemic Mastocytosis Diagnostic Criteria^1,a

WHO Systemic Mastocytosis Diagnostic Criteria^1,a