The Triad: hEDS, POTS, and MCAS

If you've been diagnosed with hypermobile Ehlers-Danlos syndrome and your symptoms are bigger than your joints — dizziness, hives, GI chaos, fatigue, brain fog — there's a name for what's likely happening. Three names, actually, that increasingly belong together.

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The three conditions

hEDS — Hypermobile Ehlers-Danlos Syndrome

A heritable connective tissue disorder affecting collagen — the protein scaffolding for skin, joints, blood vessels, and organs. In hEDS, that scaffolding is more elastic and less reliable than it should be.

Common findings: joint hypermobility with frequent subluxations or dislocations, soft or stretchy skin, easy bruising, slow wound healing, chronic musculoskeletal pain, and a constellation of "extra" symptoms that don't seem connective-tissue at all.

POTS — Postural Orthostatic Tachycardia Syndrome

A form of autonomic dysfunction. Defined by a heart rate increase of ≥30 bpm (≥40 in adolescents) within 10 minutes of standing, without a significant drop in blood pressure, plus symptoms.

Common findings: lightheadedness or near-syncope on standing, palpitations, exercise intolerance, brain fog, fatigue, heat intolerance, GI symptoms, and a sense that gravity itself is a workout.

MCAS — Mast Cell Activation Syndrome

Inappropriate release of histamine and other mast cell mediators across multiple organ systems. Covered in detail in my MCAS primer.

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Why they cluster

The exact mechanism is still being worked out, but several threads are visible:

• Vascular fragility from connective tissue laxity contributes to poor venous return → orthostatic symptoms.
• Mast cells live in connective tissue. Altered collagen structure may change their stability.
• Autonomic dysregulation and mast cell activation feed each other — adrenergic surges can degranulate mast cells, and mast cell mediators can destabilize autonomic tone.

Whatever the precise mechanism, the clinical overlap is real. Roughly 30–60% of hEDS patients also meet criteria for POTS, MCAS, or both, depending on the cohort and the diagnostic threshold.

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What this means clinically

If you have one of these three diagnoses, screening for the other two is reasonable — not maximalist medicine. Symptoms that don't fit your "main" diagnosis often fit one of the others.

A reasonable workup adds:

• For suspected POTS: active stand test or tilt-table, basic autonomic history, plasma volume considerations, sometimes a 24-hour Holter.
• For suspected MCAS: baseline and flare tryptase, 24-hour urine n-methylhistamine and prostaglandin D2, trial of H1/H2 blockade.
• For suspected hEDS: Beighton score, family history, skin findings, and the 2017 international diagnostic criteria.

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What treatment looks like when all three are present

There is no single fix. The pattern of care that works:

• Volume and salt — many POTS patients need 2–3 L of fluid and 8–10 g of sodium daily.
• Compression — abdominal binders or 20–30 mmHg compression to the waist.
• Graded exercise — recumbent first (rower, recumbent bike, swimming), then upright as tolerated.
• Mast cell stabilization — H1 + H2 antihistamines daily, plus a stabilizer like cromolyn, quercetin, or ketotifen.
• Joint protection — appropriate strengthening, avoidance of end-range stretching, attention to subluxation patterns.
• Sleep, stress regulation, pacing — not optional. The autonomic system needs the input.

Pharmacologic add-ons depending on the dominant phenotype: beta blockers, ivabradine, midodrine, fludrocortisone, low-dose naltrexone.

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What to ask for

If you have one of these and suspect another, the right ask isn't "I think I have all three." It's:

"I'd like to be evaluated for the conditions known to co-occur with [your diagnosis] — specifically POTS and MCAS. Here are the symptoms that prompted the question."

That gets a real workup. And a real workup gets you to a treatment plan that addresses the system, not just the slice.