Often seen, rarely recognized: mast cell activation disease – a guide to diagnosis and therapeutic options

Figures & data

Table 1. Symptoms and findings in mast cell (MC) activation disease (73).

System	Potential manifestations of mast cell disease
Constitutional	Fatigue (83%), malaise, asthenia, “chronic fatigue syndrome,” subjective (rarely, objective) hyperthermia (40%) and/or hypothermia (56%), “sense of feeling cold much of the time,” heat and/or cold intolerance (13%), diaphoresis or sweats (47%) (not always nocturnal), flushing, plethora or pallor, increased or decreased appetite, early satiety, weight gain (17%) or loss (16%), pruritus, environmental sensitivities (40%; often odd (16%))
Dermatologic	Rashes (49%) and lesions of many sorts (classic urticaria pigmentosa, “freckles,” telangiectatic/angiomatous lesions, xerosis, warts, tags, folliculitis, ulcers, diffusely migratory but sometimes focally persistent patchy erythema), pruritus (often diffusely migratory, sometimes aquagenic) (63%), flushing (31%), angioedema, striae, dermatographism, excessive hair loss (15%), brittle nails (13%; often also longitudinally ridged), poor healing (23%)
Ophthalmologic	Irritated (often described as “dry”) eyes (53%), increased or decreased lacrimation, suffusion, conjunctivitis, difficulty focusing (30%), lid tremor/tic, solar sensitivity, infectious or sterile inflammation
Otologic	Infectious or sterile otitis externa and/or media, hearing loss or hyperacusis, tinnitus, otosclerosis
Oral/oropharyngeal	Pain (sometimes “burning”), leukoplakia, fibrosis, lichen planus, ulcers, sores (30%), angioedema, dental decay (17%), dysgeusia, throat tickle/discomfort/irritation/pain, post-nasal drip
Lymphatic	Adenopathy (28%), usually sub-pathologic and often waxing/waning in size, sometimes asymptomatic but not uncommonly tender, sometimes focal, sometimes migratory, pathology usually shows a reactive lymphocytosis or sometimes an atypical non-specific lymphoproliferative disorder; left upper quadrant discomfort (likely from release of mediators from splenic MCs with or without detectable splenomegaly)
Pulmonary	Rhinitis, sinusitis (17%), pharyngitis (48%), laryngitis, bronchitis, pneumonitis (often confused with infectious pneumonia), cough (16%), dyspnea (often low-grade, inconstant, “I just can't catch a deep breath” despite normal pulmonary function tests) (53%), wheezing (15%), obstructive sleep apnea, pulmonary hypertension
Cardiovascular	Presyncope (lightheadedness, weakness, dizziness, vertigo) and/or syncope (71%), hypertension and/or hypotension, palpitations and dysrhythmias (47%), chest discomfort or pain (usually non-anginal in character (40%)), coronary and peripheral arterial atherosclerosis/spasm/infarction, aneurysms, hemorrhoids, varicosities, aberrant angiogenesis (hemangiomas, arteriovenous malformations, telangiectasias), migratory edema (often non-dependent and in spite of normal cardiac and renal function) (56%)
Gastrointestinal	Aerophagia, angioedema in any segment of the luminal tract, dysphagia (often proximal (35%), possibly due to pharyngeal angioedema), pain (48%) and inflammation (often migratory) in one or more segments of the luminal tract (from esophagitis to proctitis) and/or one or more solid organs (e.g., hepatitis, pancreatitis), queasiness, nausea ± vomiting (57%), diarrhea (27%) and/or constipation (14%) (often alternating (36%)), malabsorption (more often selective micronutrient malabsorption than general protein-calorie malabsorption), ascites either from portal hypertension and/or peritoneal serositis; gastroesophageal reflux disease (50%; often “treatment-refractory”) and inflammatory/irritable bowel syndrome are common pre-existing diagnoses
Genitourinary	Inflammation (27%; often migratory) in one or more segments of the luminal tracts (ureteritis, cystitis, urethritis, vaginitis, vestibulitis) and/or one or more solid organs (e.g., nephritis, prostatitis), chronic kidney disease, endometriosis, chronic low back pain or flank pain or abdominal pain, hydronephrosis (likely from ureteral angioedema), infertility, erectile dysfunction, decreased libido; in the appropriate setting of multisystem morbidity, miscarriages should prompt consideration of antiphospholipid antibody syndrome potentially due to MCAS
Musculoskeletal	Clinical myositis, often diffusely migratory (fibromyalgia is a common pre-existing diagnosis), subclinical myositis (i.e., asymptomatic elevated creatine kinase not otherwise explained), arthritis (typically migratory), joint laxity/hypermobility, osteoporosis/osteopenia, osteosclerosis, sometimes mixed osteoporosis/osteopenia/osteosclerosis; MCAS-driven musculoskeletal pain (75%) not uncommonly is poorly responsive to non-steroidal anti-inflammatory drugs and narcotics
Neurologic	Headache (especially migraine) (63%), presyncope and/or syncope, peripheral (usually distal) sensory and/or motor neuropathies including paresthesias (58%), tics, tremors (13%; typically resting), chronic inflammatory demyelinating polyneuropathy, seizure disorders (can be “treatment-refractory”)
Psychiatric	Mood disturbances (e.g., anger, depression (13%)), bipolar affective disorder, attention deficit-hyperactivity disorder, post-traumatic stress disorder, other anxiety and panic disorders (16%), psychoses, memory and concentration and word-finding difficulties and other cognitive dysfunction (49%), wide variety of sleep disruptions (including insomnia (35%) and obstructive sleep apnea regardless of weight)
Endocrinologic/metabolic	Abnormal electrolytes (including magnesium) and liver function tests, delayed puberty, dysmenorrhea (11%), endometriosis, osteosclerosis and/or osteoporosis, hypothyroidism, hyperthyroidism, dyslipidemia, hyperferritinemia, selective vitamin and/or other micronutrient deficiencies, weight change, possibly diabetes mellitus
Hematologic/coagulopathic	Polycythemia or anemia, leukocytosis or leukopenia, chronic (usually mild) monocytosis or eosinophilia or basophilia, thrombocytosis or thrombocytopenia, arterial and/or venous thromboembolic disease, aberrant bruising and bleeding (39%); in MCAS the marrow usually does not show increased or even flow-cytometrically aberrant MCs and marrow histology is often interpreted as normal or as unspecified myelodysplastic/myeloproliferative syndrome; standard cytogenetic studies are almost always normal or show culture failure
Immunologic	Types I, II, III, and IV hypersensitivity reactions (e.g., allergy, delayed-type hypersensitivity, etc.), increased risk for malignancy, autoimmunity, impaired healing, increased susceptibility to infection, elevated or decreased levels of one or more isotypes of immunoglobulin; modest monoclonal gammopathy of undetermined significance not uncommon

Most are chronic, low-grade; some are persistent but many are either episodic or waxing/waning. Prevalences of the most common symptoms (≥10% of patients) in an MCAD population (N = 413; LBA, unpublished data) are indicated parenthetically.

Figure 1. Urticaria pigmentosa in a patient with KIT^D816V-positive systemic mastocytosis.

Figure 2. Diagnostic approach to MCAD (from (40)).

Table 2. Criteria proposed to define mast cell activation disease (for references, see text) when all other diagnoses that could better explain the full range and chronicity of the findings in the case have been excluded.

Proposed criteria defining Mast Cell Activation Syndrome (MCAS) (52)	WHO criteria defining Systemic Mastocytosis (SM) (1)
Major criteria	Major criterion
1. Multifocal or disseminated dense infiltrates of MCs in marrow and/or extracutaneous organ(s) (e.g., gastrointestinal or genitourinary tract)	Multifocal dense infiltrates of MCs (i.e., aggregates of >15 MCs) in marrow and/or other extracutaneous organ(s)
2. Constellation of clinical complaints attributable to pathologically increased MC activity (MC mediator release syndrome)
Minor criteria	Minor criteria
1. Abnormal spindle-shaped morphology in >25% of MCs in marrow or other extracutaneous organ(s)	1. Abnormal spindle-shaped morphology in >25% of MCs in marrow or other extracutaneous organ(s)
2. Abnormal MC expression of CD2 and/or CD25 (i.e., co-expression of CD117/CD25 or CD117/CD2)	2. Abnormal marrow MC expression of CD2 and/or CD25 (i.e., co-expression of CD117/CD25 or CD117/CD2)
3. MC genetic changes (e.g., activating KIT codon 816 mutations) shown to increase MC activity	3. Activating KIT mutation at codon 816 in MCs in extracutaneous organ(s)
4. Evidence (typically from body fluids such as whole blood, serum, plasma, or urine) of above-normal levels of MC mediators including: Tryptase Histamine or its metabolites (e.g., N-methylhistamine) Heparin Chromogranin A (note potential confounders of cardiac or renal failure, neuroendocrine tumors, or recent proton pump inhibitor use) Other relatively MC-specific mediators (e.g., eicosanoids including prostaglandin (PG) D2, its metabolite 11-β-PGF2α, or leukotriene E4)	4. Serum total tryptase > 20 ng/ml (does not apply in patients who have associated hematologic non-mast-cell lineage disease)
5. Symptomatic response to inhibitors of MC activation or MC mediator production or action

The diagnosis mast cell activation syndrome is made upon fulfilment of either both major criteria or the second criterion plus at least one minor criterion (modified from (52)). According to the WHO criteria (1), the diagnosis systemic mastocytosis is established if the major criterion and at least one minor criterion or at least three minor criteria are fulfilled.

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