What is Mast (Mastocytosis) cell activation syndrome?

What is Mast Cell Activation Syndrome (MCAS)?

Mast Cell Activation Syndrome (MCAS) is a primary clinical condition characterized by spontaneous, recurrent episodes of systemic anaphylaxis affecting at least 2 organ systems concurrently, caused by inappropriate release of mast cell mediators, with documented elevation of these mediators during symptomatic episodes and improvement with targeted antimediator therapy. 1

Core Diagnostic Criteria

MCAS requires all three of the following elements to be present 1:

• Recurrent symptoms consistent with mast cell activation involving two or more organs simultaneously (such as skin flushing with gastrointestinal cramping, or cardiovascular symptoms with respiratory complaints) 1

• Documented elevation of validated mast cell mediators during symptomatic episodes, including:

  • Serum tryptase (acute level showing ≥20% increase above baseline plus 2 ng/mL) 1
  • Urinary histamine metabolites (N-methylhistamine) 1
  • Prostaglandin D2 metabolites (11β-PGF2α) 1
  • Leukotriene metabolites (LTE4) 1

• Clinical response to medications targeting mast cells or their mediators (H1/H2 antihistamines, leukotriene receptor antagonists, mast cell stabilizers, or COX inhibitors) 1

Critical Distinction from Systemic Mastocytosis

MCAS is fundamentally different from systemic mastocytosis—MCAS patients do NOT meet WHO criteria for mastocytosis. 1 Specifically, MCAS patients lack:

• Multifocal dense infiltrates of ≥15 mast cells in bone marrow aggregates 1
• KIT D816V or other activating KIT mutations 1
• Aberrant CD25 expression on mast cells 1
• Persistently elevated baseline serum tryptase >20 ng/mL (though some elevation may occur) 1
• Skin lesions typical of mastocytosis (urticaria pigmentosa) 2

Clinical Presentation Across Organ Systems

Cutaneous Manifestations

• Flushing, pruritus, urticaria, and angioedema 2, 3

Gastrointestinal Symptoms

• Abdominal cramping, diarrhea, nausea, vomiting, and malabsorption 2, 4
• Often misdiagnosed as irritable bowel syndrome or functional dyspepsia 4, 5

Cardiovascular Symptoms

• Hypotension, tachycardia, presyncope or syncope 2
• Anaphylaxis requiring immediate epinephrine administration 1

Neuropsychiatric Symptoms

• "Brain fog," poor concentration, fatigue, and crash sleepiness 6
• Headaches and cognitive dysfunction 3

Respiratory Symptoms

• Wheezing, dyspnea, and throat tightness 2

Subtypes of MCAS

Primary MCAS is classified based on genetic or clonal findings 1:

• Primary MCAS with somatic mutation: Clonal MCAS with KIT mutations but not meeting full mastocytosis criteria 1
• Primary MCAS with germline mutation: Hereditary alpha-tryptasemia (increased TPSAB1 gene copy numbers encoding α-tryptase) 1
• Idiopathic MCAS: No identifiable mutation, trigger, or genetic trait 1

Secondary MCAS involves normal mast cells activated by external triggers (IgE-mediated allergies, drugs, infections) and must be excluded before diagnosing primary MCAS 1

Diagnostic Algorithm

Step 1: Evaluate for Systemic Mastocytosis First

• Bone marrow biopsy with immunophenotyping 2
• KIT D816V mutation testing (peripheral blood or bone marrow) 2
• Baseline serum tryptase level 2
• Flow cytometry for aberrant CD25/CD2 expression on mast cells 2

Step 2: If WHO Criteria NOT Met, Assess for MCAS

• Measure acute tryptase during symptomatic episodes (within 1-4 hours of symptom onset) 3
• Collect 24-hour urine for mast cell mediator metabolites (N-methylhistamine, 11β-PGF2α, LTE4) 1
• Document symptoms affecting ≥2 organ systems concurrently 1

Step 3: Exclude Secondary Causes

• Rule out IgE-mediated allergies through specific IgE testing 1
• Evaluate for drug reactions, infections, chronic inflammatory disorders 1
• Consider other neoplastic or autoimmune conditions 1

Step 4: Consider Hereditary Alpha-Tryptasemia

• If baseline tryptase is elevated (but <20 ng/mL) without meeting mastocytosis criteria, test for TPSAB1 gene duplications/triplications 1
• This condition affects 4-6% of the general population and causes multisystem symptoms including dysautonomia, joint hypermobility, and chronic pain 1

Management Approach

First-Line Therapy

• Non-sedating H1 antihistamines (can increase to 2-4 times FDA-approved doses for refractory symptoms) 6
• H2 antihistamines added within 1-2 weeks if symptoms persist (combined H1/H2 therapy more effective than monotherapy) 6

Second-Line: Mast Cell Stabilizers

• Oral cromolyn sodium for persistent symptoms, especially neurologic and gastrointestinal manifestations (introduce progressively to minimize side effects) 6

Additional Targeted Therapy Based on Mediator Elevation

• Leukotriene receptor antagonists if urinary LTE4 elevated 1
• Aspirin or COX inhibitors if prostaglandin metabolites elevated 1

Critical Pitfall to Avoid

Do NOT use sedating antihistamines as first-line when sleepiness or fatigue is a primary complaint—they will worsen symptoms. 6 Always start with non-sedating second-generation H1 antihistamines.

Prognosis and Associated Conditions

• MCAS patients have normal life expectancy when appropriately managed 1
• Some patients with clonal MCAS may progress to indolent systemic mastocytosis, though this is uncommon 1
• Evaluate for associated conditions: autonomic dysfunction, small fiber neuropathy, connective tissue disorders (especially with hereditary alpha-tryptasemia), and psychiatric comorbidities 1, 5
• Patients often experience significant diagnostic delays and are frequently mislabeled with functional disorders before correct diagnosis 4, 5

When to Refer

Referral to specialized centers with expertise in mastocytosis is strongly recommended for:

• Complex or borderline cases 2
• Patients not responding to first-line therapy 2
• Confirmation of diagnosis when criteria are unclear 2