Understanding the Trifecta of MCAS, POTS, and EDS

If you or a loved one have been diagnosed with one of these conditions, chances are you've heard the term “trifecta” or “triad.” The Trifecta refers to the frequent co-occurrence of Mast Cell Activation Syndrome (MCAS), Postural Orthostatic Tachycardia Syndrome (POTS), and Ehlers-Danlos Syndrome (EDS).

Each condition can occur independently, but many people who have one eventually notice symptoms that overlap significantly with the others:

• MCAS involves inappropriate mast cell activation, leading to excessive release of histamine and other inflammatory mediators. Symptoms often include hives, itching, flushing, and gastrointestinal distress.
• POTS is a form of dysautonomia in which standing triggers an abnormal rise in heart rate, often causing dizziness, fainting, palpitations, and fatigue.
• EDS refers to a group of heritable connective tissue disorders marked by joint hypermobility, fragile skin, easy bruising, and a range of systemic symptoms.

While each condition is challenging to manage on its own, the combination—the Trifecta—can be especially complex. Patients often experience chronic pain, fatigue, brain fog, GI issues, heightened sensitivities, and functional limitations that affect every aspect of daily life.

In this article, we’ll explore:

• What each condition actually is
• Why they so often occur together
• How the Trifecta differs from the broader Pentad Super Syndrome
• What diagnosis and treatment typically involve
• Practical strategies you can use right now
• When and how to seek specialized care

This is not a substitute for medical advice, but a roadmap you can take into appointments and use to better understand what your body is trying to tell you.

What Is the EDS Trifecta?

The EDS Trifecta refers to the co-occurrence of:

1. Ehlers-Danlos Syndrome (EDS) or Hypermobility Spectrum Disorders (HSD)
2. Postural Orthostatic Tachycardia Syndrome (POTS)
3. Mast Cell Activation Syndrome (MCAS)

Each of these conditions can exist independently, but they appear together so commonly (especially in women and people assigned female at birth) that it is no longer surprising when someone with one diagnosis is eventually diagnosed with the others.

Clinically, the Trifecta describes a recognizable pattern:

• EDS/HSD affects the scaffolding of the body—connective tissue in joints, skin, blood vessels, and organs.
• POTS affects the wiring of the body—the autonomic nervous system that regulates heart rate and circulation.
• MCAS affects the security system—mast cells that should protect the body but instead become overly reactive.

The result is a multisystem presentation that seldom fits neatly into any single specialty.

The Three Parts of the Trifecta

1. Ehlers-Danlos Syndrome (EDS) & Hypermobility Spectrum Disorders (HSD)

EDS refers to a group of heritable connective tissue disorders. The type most associated with the Trifecta is hypermobile EDS (hEDS) or HSD, which present with:

• Generalized joint hypermobility (often assessed via Beighton scoring)
• Joint instability (sprains, subluxations, dislocations)
• Chronic musculoskeletal pain and fatigue
• Soft or velvety skin, easy bruising, atrophic scars, hernias, prolapse
• Systemic symptoms such as GI complaints, headaches, pelvic floor dysfunction, and autonomic issues

2. Postural Orthostatic Tachycardia Syndrome (POTS)

POTS is a form of dysautonomia defined by:

• A heart rate increase of ≥30 bpm in adults (or ≥40 bpm in adolescents) within 10 minutes of standing
• No significant drop in blood pressure
• Symptoms lasting at least 3–6 months

Common symptoms include:

• Lightheadedness or near-fainting
• Palpitations and chest discomfort
• Exercise intolerance and post-exertional crashes
• Nausea, bloating, or abdominal pain
• Brain fog and cognitive fatigue

In a pediatric registry, 62% of patients with POTS met criteria for hEDS/HSD, highlighting a strong association.

3. Mast Cell Activation Syndrome (MCAS)

Mast cells release histamine, tryptase, prostaglandins, and other mediators. In MCAS, they release them:

• Too often
• In response to inappropriate triggers
• Or in excessive amounts

Common symptom clusters include:

• Skin: flushing, itching, hives, swelling
• GI: cramping, diarrhea, reflux, bloating
• Cardiovascular: palpitations, blood pressure swings
• Respiratory: wheezing, throat tightness
• Neurologic: headaches, brain fog, fatigue, adrenaline surges

MCAS remains an evolving diagnosis, but most frameworks require:

1. Symptoms in two or more organ systems
2. Evidence of abnormal mediator release
3. Clinical improvement with mast-cell–targeted therapy

How the Trifecta Interacts

The Trifecta is not just three conditions coexisting randomly—there are plausible biological connections between them.

Connective Tissue & Circulation (EDS and POTS)

In hEDS/HSD, blood vessels and ligaments may be excessively stretchy, reducing the body’s ability to maintain circulation when standing:

• Blood pools in the legs and abdomen
• Heart rate surges as the body compensates
• Patients feel dizzy, shaky, or faint

This is why POTS is a well-recognized comorbidity of hypermobility disorders.

Mast Cells in Connective Tissue (EDS and MCAS)

Mast cells are embedded in connective tissue. A 2022 review found:

• Higher rates of immune-mediated and allergic conditions in hEDS/HSD
• Symptom overlap between MCAS and hypermobility
• A plausible link between mast-cell mediators and connective tissue fragility

Mast cells and connective tissue are structurally and functionally intertwined.

MCAS and POTS

MCAS can worsen POTS by causing:

• Vasodilation → blood pooling → tachycardia
• Histamine surges → flushing, headaches, palpitations, GI distress

Research highlights:

• In one study, 31% of patients with both POTS and EDS also had MCAS, versus ~2% of those without POTS/EDS.
• In another study, 42% of POTS patients with allergic/GI symptoms showed mast-cell mediator abnormalities.

More research is needed to fully understand these pathways, but the clinical patterns are clear.

A Word of Scientific Caution

While the overlap between EDS, POTS, and MCAS is widely recognized in clinical practice, the scientific evidence tying them together through a single, unified mechanism remains limited. Many studies are small, retrospective, or based on older diagnostic criteria, and the definitions of both MCAS and hEDS continue to evolve.

This dual reality is important to hold:

• Clinically, the overlap is unmistakable and often profoundly disabling, warranting validation, careful assessment, and comprehensive care.
• Scientifically, we still need larger, better-designed studies and more consistent diagnostic frameworks to clarify how—and why—these conditions intersect.

Trifecta vs. Pentad: How They Relate

The Pentad Super Syndrome extends the Trifecta into five domains:

1. Hypermobility / EDS
2. Dysautonomia (including POTS)
3. MCAS
4. Autoimmunity
5. Gastrointestinal dysfunction

How to think about it:

• The Trifecta often describes the earlier phase of illness or is most visible in younger patients.
• The Pentad describes a broader systemic evolution involving autoimmune disease and significant GI dysmotility.
• The Spiky-Leaky Syndrome describes the downstream consequence of chronic mast-cell–driven inflammation, where repeated “spikes” in mediator release lead to progressively “leaky” tissues, vessels, and barriers.

Understanding this distinction helps clinicians:

• Screen earlier for autoimmunity or GI dysfunction
• Adjust treatment intensity as systemic inflammation increases
• Prevent fragmentation of care across too many specialists

What the Trifecta Feels Like

Common symptom clusters include:

Musculoskeletal & Joint Symptoms (EDS/HSD)

• Unstable joints, sprains, subluxations
• Widespread pain, burning sensations
• Neck/back pain, headaches, TMJ issues
• Pelvic floor dysfunction

Autonomic Symptoms (POTS)

• Dizziness, tunnel vision, near-fainting
• Palpitations, breathlessness
• Heat intolerance, sweating changes
• Exercise intolerance and crashes

Mast-Cell Symptoms (MCAS)

• Flushing, hives, swelling
• Sensitivity to foods, medications, or smells
• Adrenaline surges, tremors
• Episodes resembling panic or mild anaphylaxis

GI & Neurologic Overlap

• Bloating, diarrhea, constipation, nausea
• Brain fog, sensory overload
• Migraines, neuropathic pain

Emotional Impact

• Anxiety (both biologically and trauma-driven)
• Depression or grief
• Feeling “too complex” for the medical system

How the Trifecta Is Diagnosed

There is no single test. Diagnosis requires:

1. Detailed History & Physical Examination

Including:

• Symptom timelines across systems
• Family history of hypermobility, aneurysms, allergies, autoimmunity
• Trigger identification
• Functional impact

Physical exam includes:

• Beighton scoring and joint stability
• Skin and connective tissue features
• Cardiovascular and neurologic evaluation

2. Excluding Other Diagnoses

Including:

• Heart disease, arrhythmias
• Endocrine disorders
• Primary GI, dermatologic, or neurologic diseases
• Other connective tissue disorders (Marfan, Loeys–Dietz, vEDS)

3. Targeted Testing

May include:

• Autonomic testing (active stand or tilt-table)
• Screening labs, inflammatory markers, autoimmune workup
• Mast-cell mediator testing (tryptase, histamine, prostaglandins), ideally during flares
• Imaging when red flags are present

Because diagnostic criteria are evolving, clinician experience is essential.

Treatment: Layering Care Across the Trifecta

There is no single medication that fixes everything. Treatment focuses on stabilization, reducing flare severity, and improving functional capacity.

Managing EDS / HSD

• Targeted physical therapy
• Proprioceptive training
• Low-impact strengthening
• Postural retraining
• Activity modification and joint protection
• Multimodal pain management

Managing POTS / Dysautonomia

Non-pharmacologic:

• Increased fluids and salt
• Compression garments
• Head-of-bed elevation
• Recumbent-first exercise programs

Medications:

• Beta-blockers, ivabradine
• Volume expanders or vasoconstrictors
• Subtype-specific therapies when appropriate

Managing MCAS

Trigger management:

• Food, environment, medications, hormonal changes

Medication layering:

• H1 and H2 blockers
• Leukotriene inhibitors
• Cromolyn or other stabilizers
• Omalizumab (Xolair) in select cases

Whole-Person Support

• Sleep optimization
• Nutrition and gut support
• Trauma-informed mental health care
• Work/school accommodations
• Gradual goal-setting and pacing strategies

Actionable Day-to-Day Strategies

Circulation & POTS

• Hydration before getting out of bed
• Slow positional changes
• Compression garments

MCAS & Inflammation

• Consistent antihistamine regimens
• Lower-histamine diet as tolerated
• Keep rescue meds accessible

EDS & Joint Protection

• Avoid end-range stretching
• Use ergonomic supports
• Favor swimming, Pilates, recumbent biking

Nervous System Regulation

• Paced breathing
• Sleep hygiene
• Sensory management tools

Tracking & Advocacy

• Keep a symptom log
• Bring summaries to appointments
• Share educational materials with new providers

Small, consistent changes often outperform dramatic but unsustainable interventions.

How The EDS Clinic Helps

At The EDS Clinic, we see the Trifecta and Pentad every day.

Our team includes clinicians with both professional expertise and lived experience in:

• EDS / HSD
• POTS / dysautonomia
• MCAS / mast-cell disorders
• Complex neuroimmune conditions

We provide virtual care across multiple states, including:

Illinois, Texas, Florida, Alabama, Colorado, California, Indiana, Michigan, Minnesota, Ohio, Washington, with more being added.

With us, you can expect:

• A comprehensive review of symptoms across all systems
• Thoughtful application of diagnostic criteria
• A layered, individualized treatment plan
• Coordination with local specialists
• Ongoing refinement as we learn what your body responds to

You can request an appointment at www.EDS.clinic.

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