book appointment

Hypermobile Ehlers-Danlos Syndrome, Mast Cell Activation Syndrome & Dysautonomia: Understanding the Overlap – A Sydney Neuro & Integrative Health Perspective on Complex Chronic Multisystem Conditions

At Sydney Neuro & Integrative Health, we commonly see patients who have spent years searching for answers to symptoms that appear disconnected, confusing and difficult to explain through conventional models alone.

Many of these individuals present with combinations of:

In many cases, patients have seen multiple practitioners across different specialties, with each symptom often viewed in isolation. However, emerging research and clinical observation increasingly suggest that connective tissue dysfunction, immune dysregulation and autonomic nervous system dysfunction may be deeply interconnected.

One of the most important areas of interest involves the overlap between Hypermobile Ehlers-Danlos Syndrome (hEDS), Mast Cell Activation Syndrome (MCAS) and dysautonomia conditions such as POTS.

What Is Hypermobile Ehlers-Danlos Syndrome (hEDS)?

Hypermobile Ehlers-Danlos Syndrome is a hereditary connective tissue disorder characterised by:

Connective tissue exists throughout the body. It supports joints, stabilises blood vessels, forms fascia, surrounds nerves, lines the gastrointestinal tract and contributes to neurological and vascular integrity.

When connective tissue becomes structurally altered, the effects may extend far beyond the musculoskeletal system alone.

At Sydney Neuro & Integrative Health, many patients with hypermobility also report symptoms involving:

This broader systems-based presentation is one reason increasing attention is being directed toward mast cell involvement.

What Is Mast Cell Activation Syndrome (MCAS)?

Mast cells are specialised immune cells found primarily within connective tissue. They play a major role in immune defence and inflammatory signalling.

When activated appropriately, mast cells release chemical mediators such as:

Under normal conditions, these chemicals help coordinate protective immune responses.

However, in Mast Cell Activation Syndrome (MCAS), mast cells may become excessively reactive or dysregulated, releasing inflammatory mediators inappropriately or excessively.

Symptoms commonly associated with MCAS may include:

Because mast cells reside directly within connective tissue, researchers have increasingly explored whether connective tissue abnormalities may influence mast cell behaviour.

Why Do hEDS, MCAS and Dysautonomia Often Occur Together?

One of the most consistent patterns seen clinically is the overlap between:

At our clinic, this overlap is frequently observed in patients presenting with chronic multisystem symptoms that cannot be explained by a single isolated diagnosis.

Connective Tissue and Mast Cells May Influence Each Other

Mast cells exist within the extracellular matrix and connective tissue framework itself.

In hEDS, connective tissue integrity appears altered. Researchers propose that these structural changes may influence mast cell reactivity, potentially lowering the threshold for activation through:

This area of study is referred to as mechanobiology – how physical properties of tissue influence cellular behaviour.

At the same time, mast cell mediators themselves may further impact connective tissue integrity and vascular stability through chronic inflammatory signalling.

This creates the possibility of a bidirectional feedback loop:

The Nervous System Connection: POTS, Dysautonomia and Neuroimmune Signalling

Many patients with hypermobility and suspected MCAS also demonstrate symptoms of autonomic nervous system dysfunction.

These may include:

Mast cell mediators such as histamine can directly influence:

At the same time, the autonomic nervous system itself regulates aspects of immune activity.

There is constant communication occurring between mast cells, peripheral nerves, autonomic pathways, vascular structures and the gastrointestinal system.

This interconnected relationship may help explain why patients often experience overlapping symptoms across multiple body systems simultaneously.

Gastrointestinal Symptoms and the Gut-Brain Connection

Many individuals with hEDS, dysautonomia and suspected MCAS also report chronic gastrointestinal symptoms including:

Mast cells are highly concentrated within the gastrointestinal tract and play important roles in:

When mast cells become overactive, this may contribute to:

This is one reason why gut health, autonomic regulation and neuroimmune function are often considered together within an integrative clinical framework.

Our Clinical Perspective at Sydney Neuro & Integrative Health

At Sydney Neuro & Integrative Health, we take a systems-based and neurophysiological approach when evaluating patients with complex chronic symptoms.

Rather than viewing connective tissue, the immune system and the nervous system as completely separate entities, we recognise that these systems constantly interact through:

This perspective is particularly important in patients presenting with overlapping symptoms involving:

Our clinical assessments may involve a combination of:

The goal is not simply to label symptoms individually, but to better understand how multiple systems may be interacting within the broader clinical picture.

What Does the Research Currently Show?

Current research demonstrates a strong clinical association between hypermobility disorders, mast cell activation symptoms and autonomic dysfunction.

However, important limitations still exist, including:

While the exact biological mechanisms are still being investigated, the clinical overlap between these conditions is becoming increasingly recognised.

A More Integrated Understanding of Chronic Conditions

For many patients, understanding the relationship between connective tissue, immune regulation and autonomic nervous system function can help make sense of symptoms that previously appeared unrelated.

Rather than operating independently, these systems may function as part of a highly interconnected network where dysfunction in one area can influence many others.

As research continues to evolve, this growing systems-based understanding may provide important insights into conditions such as:

If you are experiencing persistent unexplained symptoms involving dizziness, fatigue, hypermobility, autonomic dysfunction or chronic multisystem health concerns, Sydney Neuro & Integrative Health may be able to help provide a more integrated clinical perspective.

Book your complimentary 10-minute consultation with Dr. Yazbek HERE.

References

  1. Afrin, L. B., Self, S., & Menk, J. (2017). Characterization of mast cell activation syndrome. The American Journal of the Medical Sciences, 353(3), 207–215. https://doi.org/10.1016/j.amjms.2016.12.009
  2. Castori, M., Celletti, C., Camerota, F., Grammatico, P., & Padua, L. (2010). Chronic fatigue syndrome is commonly diagnosed in patients with Ehlers-Danlos syndrome hypermobility type/joint hypermobility syndrome. Clinical and Experimental Rheumatology, 28(4), 597–598.
  3. Fikree, A., Grahame, R., Aktar, R., Farmer, A. D., Hakim, A. J., Morris, J. K., & Aziz, Q. (2017). A prospective evaluation of undiagnosed joint hypermobility syndrome in patients with gastrointestinal symptoms. Clinical Gastroenterology and Hepatology, 15(3), 395–402. https://doi.org/10.1016/j.cgh.2016.10.015
  4. Hakim, A. J., Grahame, R., & Norris, P. (2017). Local and systemic extra-articular manifestations in joint hypermobility syndrome. Rheumatology, 56(12), 2135–2143. https://doi.org/10.1093/rheumatology/kex182
  5. Hamilton, M. J., Hornick, J. L., Akin, C., Castells, M. C., & Greenberger, N. J. (2011). Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1), 147–152. https://doi.org/10.1016/j.jaci.2011.04.037
  6. Kohn, A., Chang, C., & Greenberger, P. A. (2020). The relationship between hypermobile Ehlers-Danlos syndrome and mast cell activation syndrome. Clinical Reviews in Allergy & Immunology, 58(3), 273–297. https://doi.org/10.1007/s12016-019-08755-8
  7. Lyons, J. J., Chovanec, J., O’Connell, M. P., Liu, Y., Selb, J., Zanotti, R., & Metcalfe, D. D. (2021). Heritable risk for severe anaphylaxis associated with increased α-tryptase–encoding germline copy number. Nature Genetics, 53(3), 346–351. https://doi.org/10.1038/s41588-021-00791-8
  8. Molderings, G. J., Brettner, S., Homann, J., & Afrin, L. B. (2011). Mast cell activation disease: A concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology, 4(10), 1–15. https://doi.org/10.1186/1756-8722-4-10
  9. Theoharides, T. C., Valent, P., & Akin, C. (2015). Mast cells, mastocytosis, and related disorders. The New England Journal of Medicine, 373(2), 163–172. https://doi.org/10.1056/NEJMra1409760
  10. Weinstock, L. B., Brook, J. B., Myers, T. L., & Goodman, A. M. (2018). Mast cell activation symptoms are prevalent in postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome. Journal of Clinical Medicine, 7(11), 1–12. https://doi.org/10.3390/jcm7110418
Tagged , , , , , , , , , , ,