Is there a relationship between mast cell activation syndrome (MCAS) and Ehlers‑Danlos syndrome (EDS)?

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Last updated: May 28, 2026 • View editorial policy

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Yes, there is a recognized association between MCAS and EDS, though the biological mechanisms remain incompletely understood.

Clinicians should be aware that patients with hypermobile Ehlers-Danlos syndrome (hEDS) have a higher reported incidence of mast cell activation syndrome (MCAS) compared to the general population, with studies showing 23.7-31% of patients with MCAS having concurrent EDS. 1

The Nature of the Relationship

What We Know

The association between these conditions is observed and clinically significant, but the exact pathophysiological link remains under investigation. The 2025 AGA guidelines explicitly state that while theoretical explanations exist for the mechanistic connection, experimental evidence of the biological mechanisms is limited and evolving 1.

Proposed mechanisms include:

  • Altered connective tissue in hEDS (softer, less stiff collagen) may trigger fibroblast dysfunction
  • Mast cells migrate into and proliferate within connective tissue and mucosa
  • Abnormal connective tissue microstructure may affect mast cell behavior and degranulation thresholds
  • Emerging evidence suggests possible autoimmune etiologies linking these conditions 1

Clinical Evidence

In a prospective study of 139 patients with MCAS and refractory GI symptoms, 23.7% had EDS, and 15.1% had both EDS and POTS 1. In a survey of 616 hEDS/HSD patients, 37.5% reported a diagnosis of POTS 1.

Critical Caveat: Not All Patients Need Testing

Universal screening for MCAS in all EDS patients is NOT recommended. Testing should be targeted only to patients presenting with specific clinical manifestations suggesting mast cell activation 1.

When to Suspect MCAS in EDS Patients

Test for MCAS only when patients with hEDS/HSD present with episodic symptoms involving 2 or more organ systems that suggest generalized mast cell activation 1:

  • Cutaneous: urticaria, pruritus, flushing, angioedema (especially eyelids, lips, tongue)
  • Gastrointestinal: crampy abdominal pain, diarrhea, nausea, vomiting
  • Cardiovascular: hypotension, tachycardia, syncope/near-syncope
  • Respiratory: wheezing, shortness of breath, inspiratory stridor
  • Neuropsychiatric: various complaints

Key distinguishing feature: Symptoms should be episodic and acute, not chronic and persistent 2. Chronic symptoms suggest alternative diagnoses.

Diagnostic Approach

Laboratory Testing

If MCAS is suspected based on clinical presentation:

  1. Collect baseline serum tryptase (when asymptomatic)
  2. Collect serum tryptase 1-4 hours following symptom flares
  3. Diagnostic threshold: Increase of ≥20% above baseline PLUS ≥2 ng/mL 1

Important: This increase must be documented on 2 or more occasions to establish MCAS diagnosis 2.

Referral Pathway

If MCAS is supported by clinical and/or laboratory features, refer to an allergy specialist or mast cell disease research center for additional testing (urinary N-methylhistamine, leukotriene E4, 11β-prostaglandin F2α) 1.

Management When Both Conditions Coexist

MCAS-Specific Treatment

When MCAS is suspected or confirmed in EDS patients 1:

Pharmacologic:

  • Histamine receptor antagonists (H1 and H2 blockers)
  • Mast cell stabilizers (cromolyn sodium)

Trigger Avoidance:

  • Certain foods, alcohol
  • Strong smells, temperature changes
  • Mechanical stimuli (friction)
  • Emotional distress
  • Specific allergens (pollen, mold)
  • Medications: opioids, NSAIDs, iodinated contrast 1

Dietary Considerations

Consider elimination diets with appropriate nutritional counseling 1:

  • Low-histamine diet
  • Low fermentable carbohydrates (low FODMAP)
  • Gluten-free or dairy-free
  • Gastroparesis diet (small particle diet)

Critical warning: Dietary interventions must be delivered with nutritional guidance to avoid restrictive eating patterns and nutritional deficiencies.

Controversies in the Literature

There is significant debate about this association. A 2020 systematic review found that current evidence lacks scientific validity, citing poorly defined diagnostic criteria for MCAS and overlapping vague symptoms 3. A 2025 systematic review found no studies meeting strict diagnostic criteria for both conditions 4.

However, the 2025 AGA guidelines (the most recent and authoritative source) acknowledge the observed clinical association and provide specific guidance for evaluation and management, representing expert consensus despite limited mechanistic understanding 1.

Practical Bottom Line

In clinical practice, treat what you can diagnose rigorously. Don't assume MCAS in every EDS patient, but maintain appropriate clinical suspicion when episodic multisystem symptoms are present. Use objective laboratory criteria (tryptase elevation during flares) rather than relying solely on symptom overlap. The relationship exists clinically, even if we don't fully understand why.

References

4
Research

Prevalence of mast cell activation disorders and hereditary alpha tryptasemia among patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: A systematic review.

Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 2025

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This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.