I have an elevated serum tryptase and hypermobile Ehlers‑Danlos syndrome; what does this indicate and how should I be evaluated and managed?

Elevated Tryptase (22 ng/mL) with Hypermobile Ehlers-Danlos Syndrome

Your tryptase of 22 ng/mL with hypermobile Ehlers-Danlos syndrome (hEDS) most likely indicates hereditary alpha-tryptasemia (HαT), a genetic condition that frequently co-occurs with connective tissue disorders and causes chronic multisystem symptoms—not systemic mastocytosis or mast cell activation syndrome, which require different diagnostic criteria.

Understanding Your Tryptase Level

Your tryptase of 22 ng/mL sits just above the 20 ng/mL threshold that triggers concern for systemic mastocytosis, but the clinical context matters enormously 1:

• Baseline vs. acute measurement: If this was drawn when you were asymptomatic (not during an acute flare), it represents your baseline tryptase 2, 3
• The hEDS connection: The combination of elevated baseline tryptase with joint hypermobility strongly suggests hereditary alpha-tryptasemia, which affects 4-6% of the general population and is characterized by TPSAB1 gene duplications 1
• HαT typical range: Baseline tryptase in HαT typically ranges from 8-20 ng/mL, though levels up to 25 ng/mL can occur 2, 4

What This Does NOT Mean

This single elevated baseline tryptase does NOT diagnose:

• Systemic mastocytosis – which requires bone marrow biopsy showing ≥15 mast cells in aggregates PLUS either the KIT D816V mutation or aberrant CD25/CD2 expression on mast cells 1
• Mast cell activation syndrome (MCAS) – which requires recurrent episodic symptoms affecting ≥2 organ systems simultaneously, documented acute tryptase rises of ≥20% above baseline plus 2 ng/mL during flares (measured 1-4 hours after symptom onset), and response to mast cell-targeted therapy 5, 3

Critical distinction: Chronic, persistent symptoms between episodes argue AGAINST MCAS and instead suggest functional disorders, dysautonomia (common in hEDS), or HαT 5, 2

Recommended Evaluation Algorithm

Step 1: Confirm True Baseline Elevation

• Repeat tryptase measurement when completely asymptomatic and >24 hours after any symptoms to confirm this is your true baseline 2, 3
• If the repeat value is also 20-25 ng/mL, proceed to Step 2 4

Step 2: Genetic Testing for Hereditary Alpha-Tryptasemia

• Order TPSAB1 gene copy number variation testing via buccal swab (simple cheek swab) 5, 3
• This is the single most likely diagnosis given your hEDS and tryptase level 1
• HαT explains the symptom overlap: cutaneous flushing, pruritus, dysautonomia, functional GI symptoms (IBS-type), chronic pain, and joint hypermobility 1

Step 3: Skin Examination

• Inspect your entire skin surface for urticaria pigmentosa lesions (small red-brown macules/papules that urticate when rubbed—Darier's sign) 2
• Presence of these lesions would shift the diagnosis toward cutaneous or systemic mastocytosis 1, 2

Step 4: Assess for Systemic Mastocytosis Features

You need bone marrow biopsy ONLY if you have:

• Baseline tryptase persistently >20 ng/mL (which you do) AND any of the following 1, 2:
  • Urticaria pigmentosa skin lesions 2
  • Unexplained hepatomegaly or splenomegaly 1
  • Unexplained lymphadenopathy 1
  • Unexplained osteoporosis or pathologic fractures 2
  • Unexplained cytopenias (low blood counts) 1
  • History of severe anaphylaxis to insect stings 2

If you have NONE of these features, bone marrow biopsy is not immediately indicated; HαT testing should be pursued first 1, 2

Step 5: Rule Out MCAS (If You Have Episodic Symptoms)

MCAS requires ALL three criteria 5, 3:

1. Episodic symptoms affecting ≥2 organ systems simultaneously (cardiovascular: hypotension, syncope; dermatologic: urticaria, flushing; respiratory: wheezing; GI: cramping, diarrhea) 5
2. Documented acute tryptase elevation: Draw tryptase 1-4 hours after symptom onset during an episode; diagnostic if it rises ≥20% above your baseline (22 ng/mL) plus ≥2 ng/mL (so ≥28.4 ng/mL during flare) 5, 3
3. Clinical response to mast cell-targeted therapies (H1/H2 antihistamines, cromolyn, leukotriene antagonists) 5, 3

If your symptoms are chronic and persistent (not episodic), MCAS is excluded 5, 2

Practical Management Recommendations

Symptomatic Treatment (Regardless of Final Diagnosis)

• H1 antihistamines: Cetirizine, loratadine, or fexofenadine at standard or up to 4× standard doses for flushing, pruritus, urticaria 2, 3
• H2 antihistamines: Famotidine for GI symptoms (nausea, abdominal pain, diarrhea) 2, 3
• Mast cell stabilizers: Oral cromolyn sodium 200 mg four times daily for GI symptoms 3
• Leukotriene antagonists: Montelukast 10 mg daily if respiratory or cutaneous symptoms persist 3

Trigger Avoidance

• Physical triggers: Extreme heat/cold, vigorous exercise, hot showers, mechanical skin trauma 2
• Medications to avoid or use cautiously: NSAIDs (ibuprofen, naproxen), aspirin, opioids (morphine, codeine), certain antibiotics (vancomycin, fluoroquinolones), radiocontrast dye 2
• Other triggers: Alcohol, emotional stress 2

Emergency Preparedness

• Obtain epinephrine auto-injectors (EpiPen, Auvi-Q) even if you've never had anaphylaxis—patients with elevated baseline tryptase have increased anaphylaxis risk 2
• Wear medical alert identification documenting elevated tryptase and anaphylaxis risk 2
• Educate yourself on anaphylaxis recognition: sudden hypotension, difficulty breathing, throat swelling, widespread urticaria 3

Perioperative Precautions

• Inform anesthesia teams before any surgery about your elevated tryptase 2
• Request premedication with H1 antihistamine, H2 antihistamine, and corticosteroid 12-24 hours before anesthesia 2, 3
• Avoid morphine and meperidine; prefer fentanyl or sufentanil 2

Common Pitfalls to Avoid

• Over-diagnosis of systemic mastocytosis: A tryptase of 22 ng/mL alone does NOT diagnose systemic mastocytosis; bone marrow findings and KIT mutation are required 1, 6
• Misdiagnosing MCAS: Chronic symptoms (not episodic) do not meet MCAS criteria; many hEDS patients have dysautonomia and functional GI disorders that mimic but are not MCAS 5, 2
• Ignoring HαT: This genetic condition is underrecognized and explains the overlap of elevated tryptase, hEDS, dysautonomia, and chronic pain 1
• Unnecessary bone marrow biopsy: If you lack skin lesions, organomegaly, cytopenias, or severe anaphylaxis history, pursue HαT testing before invasive procedures 2, 6

Follow-Up Plan

• Repeat baseline tryptase in 3-6 months to confirm stability 2
• Obtain TPSAB1 genetic testing as first-line investigation 1, 3
• Refer to allergy/immunology specialist experienced in mast cell disorders for comprehensive evaluation 3
• Consider bone marrow biopsy only if red-flag features develop or tryptase rises significantly (>50 ng/mL) 1, 2