Mast Cell Activation Syndrome (MCAS) in hEDS

See below for Difference Between MCAS and Allergies

Mast cell activation syndrome (MCAS) is increasingly recognized in individuals with hypermobile Ehlers-Danlos syndrome (hEDS), though the relationship between the two remains an area of ongoing research and clinical interest. MCAS involves inappropriate release of chemical mediators from mast cells, leading to a wide range of episodic, multisystem symptoms that can mimic allergic reactions, even when traditional allergy tests are negative. In people with hEDS, this can manifest as skin rashes, gastrointestinal issues, cardiovascular instability, neurological symptoms, and more. The underlying causes are not fully understood, but hypotheses include immune dysregulation, tissue fragility, and mechanical stress due to joint hypermobility. Diagnosis is complicated by overlapping comorbidities, fluctuating symptoms, and limited clinical awareness. Treatment typically involves antihistamines, mast cell stabilizers, and lifestyle adjustments, often guided by trial and error. Despite its challenges, increasing awareness of MCAS in the context of hEDS is helping patients access more comprehensive and effective care.

MCAS Symptoms Common in People with hEDS

MCAS causes episodic, multisystem symptoms due to inappropriate release of mast cell mediators (chemicals released by certain immune cells). In people with hEDS, symptoms may include

• Dermatologic

  • Flushing, itching, hives

  • Dermatographia: skin welts when lightly scratched ("skin writing")Swelling: also called angioedema (rapid skin or tissue swelling)

• Gastrointestinal

  • Abdominal cramps, bloating, diarrhea

  • Food intolerances, especially to histamine-rich foods

• Cardiovascular

  • Lightheadedness, palpitations, low blood pressure

  • Overlaps with POTS symptoms (postural orthostatic tachycardia syndrome: rapid heart rate upon standing)

• Neurological

  • Brain fog (mental cloudiness), fatigue

  • Headaches, anxiety, temperature dysregulation

• Respiratory

  • Congestion, wheezing, throat tightness

• Systemic

  • Medication sensitivities

  • Flare-ups that appear allergic but don’t test positive on allergy tests

Causes of MCAS in People with hEDS

Currently known and proposed mechanisms include

• Connective tissue fragility: Mast cells live in connective tissue. Fragile connective tissue may disrupt mast cell regulation.

• Immune dysregulation: Abnormal mast cell activity that may cause episodic or chronic mediator release and hyperreactivity.

• Mechanical stress: Mast cells can be activated by mechanical stimuli; in hypermobility, tissue microtrauma is hypothesized (but not proven) to contribute to mast cell activation.

• Mediator effects: Mast cell mediators such as histamine and tryptase can affect connective tissue in laboratory models, and it has been hypothesized, but it is not known for certain, whether they significantly worsen joint laxity in hEDS.

Etiology (Cause or origin of a disease) Categories

• Primary (clonal): Rare, often related to mastocytosis (a condition of too many mast cells)

• Secondary (reactive): Triggered by infections, allergens, or physical stimuli

• Idiopathic: No clear cause, common in MCAS

Prevalence in People with hEDS

Exact prevalence is unknown due to inconsistent diagnostic criteria, but current estimates include

• 17%–33% in observational studies of hEDS patients in specialty clinics

• Up to 40–50% report MCAS-like symptoms in patient surveys and support groups

• No population-based studies have definitively quantified prevalence

• Systematic reviews caution that many symptoms attributed to MCAS may overlap with other hEDS comorbidities such as POTS and IBS (irritable bowel syndrome)

While MCAS-like symptoms are common in hEDS, the true prevalence of diagnosable MCAS is uncertain and may be lower than self-reported rates suggest. There is also a possibility that, due to the episodic nature of symptoms, numbers captured in observational studies may be lower than the true population prevalence. The true prevalence is unknown.

Diagnostic Challenges

Because the symptoms of MCAS overlap extensively with other hEDS comorbidities, diagnosing it can be difficult.

• MCAS symptoms overlap with many hEDS comorbidities (e.g., POTS, GI disorders, anxiety)

• Lab markers (e.g., serum tryptase, prostaglandin D2, histamine) must be tested during a flare to be meaningful.

• Some patients benefit from treatment despite normal labs, leading to underdiagnosis or misdiagnosis.

Diagnostic Criteria (AAAAI – American Academy of Allergy, Asthma & Immunology)

1. Typical symptoms in two or more systems

2. Evidence of elevated mast cell mediators

3. Improvement with anti-mast cell treatment

   
   

Real-World Diagnostic Approaches in Clinical Practice

Because of the complex presentation and testing limitations, some physicians—especially those experienced in managing hEDS—use practical, therapeutic trial strategies to help identify likely MCAS when formal diagnostic criteria are hard to meet.

• Diagnosis by Treatment Response

In real-world settings, doctors may prescribe medications typically used to treat MCAS—such as antihistamines, mast cell stabilizers (like cromolyn), or leukotriene inhibitors—and observe whether the patient’s symptoms improve. If there is significant or sustained improvement, especially across multiple symptom systems (e.g., skin, GI, neurologic), it may support a presumptive diagnosis of MCAS.

This method is often used when

• Lab tests like tryptase, histamine, or prostaglandin D2 are normal or unavailable.

• Symptoms are episodic, diffuse, and unexplained by other comorbidities.

• The patient has multiple sensitivities to foods, medications, chemicals, or heat.

• Symptoms overlap with other hEDS conditions such as POTS or IBS, but show clear response to MCAS-targeted treatments.

While not a formal diagnostic method per guidelines, this “diagnosis-by-response” is considered clinically useful and may help avoid years of misdiagnosis or untreated symptoms.

• Symptom Pattern Recognition

In addition to treatment trials, experienced clinicians often recognize MCAS by its distinct multisystem symptom patterns

• Flushing, itching, hives without testable allergens

• Food or drug intolerance with variable triggers

• Cyclical or stress-related flares

• Anaphylaxis-like reactions with negative allergy testing

Because MCAS often presents with overlapping symptoms that don't conform to typical allergy models, some physicians consider a detailed symptom history and flare tracking just as important as lab testing—particularly in hEDS patients, where other causes may already have been ruled out.

Interventions and Treatments

First-line therapies (per AAAAI)

• H1 blockers: Cetirizine, loratadine, diphenhydramine — reduce histamine effects in the skin and respiratory system.

• H2 blockers: Famotidine — reduce histamine activity in the GI tract.

• Leukotriene inhibitors: Montelukast — reduce inflammatory leukotrienes.

• Mast cell stabilizers: Cromolyn sodium, ketotifen — reduce mediator release.

Advanced options

• Low-dose corticosteroids: for severe flares (short term use only)

• Biologics: Omalizumab may help select patients

• Epinephrine autoinjectors: for those with anaphylaxis (life-threatening allergic reaction) risk

Lifestyle modifications

• Avoid known triggers: heat, friction, alcohol, stress, certain foods

• Follow a low-histamine diet

• Use air filters and reduce environmental chemical exposure

• Pace activities and manage stress carefully

Supportive supplements (use with caution)

• Quercetin (plant-based antioxidant)

• Vitamin C

• DAO enzymes: may help break down histamine. Can be purchased over the counter. DAO supplements are often derived from porcine (pig) kidneys or plant extracts. Individuals with allergies to these sources should avoid them

• Some report benefit from low-dose collagen or gelatin, while others do not tolerate them

When to See a Specialist

• Allergist/Immunologist: must be familiar with MCAS—many are not

• Functional or Integrative MD: may consider broader treatment options

• Gastroenterologist: for MCAS-related GI issues

• Cardiologist or POTS specialist: if orthostatic symptoms (dizziness, lightheadedness when standing) are present

• Pharmacist or prescribing provider: to review medication reactions

Controversy and Current Research Status

• The connection between hEDS and MCAS is theoretically plausible but has yet to be proven due to lack of research.

• Some theories suggest that mast cell mediators may degrade connective tissue or worsen autonomic instability.

• No direct genetic or mechanistic link has been established.

• More rigorous studies using standardized MCAS criteria are needed to confirm true prevalence and causation.

Summary

MCAS in hEDS presents with a broad range of symptoms across multiple organ systems, often triggered by mast cell mediators like histamine. Although its exact prevalence and biological mechanisms remain uncertain, patient-reported symptoms are common and often respond to targeted treatments. Diagnosis is difficult due to overlap with other hEDS-related conditions and the need for laboratory tests during symptom flares. First-line treatments include antihistamines, mast cell stabilizers, and trigger avoidance, with more advanced therapies available for complex cases. Supplements and dietary changes may provide additional support for some patients. Because many physicians are unfamiliar with MCAS, especially in the context of hEDS, specialist care and patient advocacy are often essential. Ongoing research is needed to better define this condition and improve outcomes for those affected.

Difference Between MCAS and Allergies

In someone with hypermobile Ehlers-Danlos syndrome (hEDS), both mast cell activation syndrome (MCAS) and allergies can cause similar symptoms—like itching, hives, flushing, stomach upset, and even breathing difficulty—but they are distinct conditions with different causes, triggers, and treatments.

Core Differences

Diagnosis

In hEDS Patients Specifically

Treatment Differences

Summary

• Allergies are your immune system reacting to a specific foreign substance (like pollen or peanuts).

• MCAS is your mast cells releasing chemicals at the wrong time, for unclear reasons—even when there's no true "invader."

Both can look similar, especially in someone with hEDS, but MCAS is usually more widespread, hard to pinpoint, and chronic, while allergies tend to be specific and testable.