*Note- this is a complex topic, we are doing our best to write an article with citations to ensure accuracy, but bear with us.

Mast cell disorders are a group of conditions marked by abnormal mast cell activity or accumulation. Mast cells are critical immune cells that play a role in allergy, inflammation, tissue repair, and host defense. When these cells malfunction, the result can range from mild allergic symptoms to life-altering systemic illness.

We're exploring how mast cells work, the difference between Mast Cell Activation Syndrome (MCAS) and mastocytosis, challenges with diagnostic testing, and emerging research on the possible connection between mast cell dysfunction and hypermobile Ehlers-Danlos Syndrome (hEDS).

What Is a Mast Cell and What Does It Do?

Mast cells originate from the bone marrow and migrate into tissues, where they mature. They reside mainly at the interfaces between the external environment and the internal body—such as the skin, lungs, gastrointestinal tract, and blood vessels.

Upon stimulation (by allergens, pathogens, physical triggers, or stress), mast cells degranulate, releasing potent chemical mediators, including:

• Histamine – triggers itching, hives, and swelling
• Tryptase and chymase – proteolytic enzymes that can break down tissue
• Prostaglandins and leukotrienes – inflammatory lipid molecules
• Cytokines and chemokines – signal other immune cells to join the response

Mast cells are essential for protection, but their dysregulation can lead to widespread dysfunction and damage.

Sources:
https://www.ncbi.nlm.nih.gov/books/NBK499904/
https://www.frontiersin.org/articles/10.3389/fimmu.2015.00620/full

MCAS vs. Mastocytosis: What’s the Difference?

Mastocytosis is a clonal disorder where there are too many mast cells in the body, typically caused by a mutation in the KIT gene, most commonly D816V. These mast cells proliferate abnormally and infiltrate organs such as skin, bone marrow, liver, spleen, and gastrointestinal tract.

Subtypes include:

• Cutaneous Mastocytosis – affects the skin only
• Systemic Mastocytosis – involves internal organs and may present with fatigue, flushing, abdominal pain, and anaphylaxis

Source:
https://www.allergy.org.au/patients/allergy-testing/mastocytosis

Mast Cell Activation Syndrome (MCAS)
MCAS occurs when mast cells release their mediators inappropriately, even though their number is normal. This release may be triggered by stress, food, environmental allergens, infections, or may be idiopathic.

MCAS is classified as:

• Primary MCAS – linked to clonal mast cells or KIT mutation (overlaps with mastocytosis)
• Secondary MCAS – due to an external trigger like allergy or infection
• Idiopathic MCAS – no known trigger or mutation is found

Patients often experience:

• Gastrointestinal symptoms (nausea, diarrhea, abdominal pain)
• Cardiovascular symptoms (dizziness, low blood pressure)
• Neurologic symptoms (brain fog, migraines)
• Dermatologic symptoms (rashes, flushing, hives)

Source:
https://en.wikipedia.org/wiki/Mast_cell_activation_syndrome
https://www.verywellhealth.com/mast-cell-activation-overview-4583920

Diagnostic Testing for Mast Cells Disorders

Mast cell disorders are complex, multi-systemic conditions that often overlap with other chronic illnesses. Diagnosing MCAS and distinguishing it from mastocytosis requires vigilance, timing, and symptom tracking. Diagnosing mast cell disorders is complex and requires a combination of lab testing, clinical symptoms, and timing. Many patients are often disappointed in lab results that are actually not properly handled returning "normal" results. 

Common Diagnostic Tools

• Serum tryptase: Elevated baseline (>20 ng/mL) is a marker for mastocytosis. In MCAS, a rise of 20% above baseline + 2 ng/mL during an event may support diagnosis.
• 24-hour urine testing: Looks for elevated levels of mast cell mediators such as histamine metabolites, prostaglandin D2, and leukotriene E4.
• Bone marrow biopsy: Used to confirm systemic mastocytosis, identify mast cell infiltration and KIT mutations.

Challenges in Diagnosis

• Mast cell disorders are complex, multi-systemic conditions that often overlap with other chronic illnesses. 

• Timing is critical: Samples need to be taken during or soon after an episode for accurate mediator detection.
• Symptom variability: MCAS presents differently in each person and can mimic other disorders like IBS, anxiety, and POTS.
• Limited awareness: Many providers are not familiar with MCAS, leading to underdiagnosis or misdiagnosis.

Source:
https://www.allergy.org.au/hp/papers/testing-for-mast-cell-activation-disorders-and-syndrome
https://www.wjgnet.com/2218-6204/full/v3/i1/1.htm

Mast Cells and Connective Tissue Breakdown
Mast cells release enzymes such as tryptase and chymase, which degrade collagen, elastin, and other structural proteins in connective tissue. In normal situations, this is part of tissue remodeling and wound healing. But in excess, these enzymes may contribute to:

• Tissue fragility
• Joint hypermobility
• Abnormal wound healing
• Bone weakening and osteoporosis

Sources:
https://pubmed.ncbi.nlm.nih.gov/2222442/
https://journals.aai.org/jimmunol/article/169/2/1014/71028/Mast-Cell-Chymase-Modifies-Cell-Matrix

The Emerging Connection Between Mast Cells and hEDS
Recent research suggests that mast cell dysfunction may be more than just a comorbidity—it might play a causative role in some presentations of hypermobile Ehlers-Danlos Syndrome (hEDS).

Key Observations and Hypotheses

• Symptom overlap: Many hEDS patients experience MCAS-like symptoms (gastrointestinal distress, chronic pain, allergic reactions, POTS).
• Tissue degradation: Mast cell mediators may directly damage connective tissues, contributing to joint instability and tissue fragility.
• Shared genetic susceptibilities: Some studies propose a common genetic underpinning between hEDS and mast cell disorders.
• A recent 2024 study identified immunogenetic variants that may increase both susceptibility to infections and hypersensitivity reactions in hEDS patients, pointing toward mast cell dysregulation as a potential upstream factor.

Sources:
https://pubmed.ncbi.nlm.nih.gov/39451569/
https://pmc.ncbi.nlm.nih.gov/articles/PMC9022617/
https://drtaniadempsey.com/ehlers-danlos-syndrome-hypermobility-and-mast-cell-activation-syndrome-the-connection/

Today In Research

New research into mast cell activity and connective tissue breakdown is beginning to reshape how we understand hypermobility syndromes like hEDS. This is happening now at the MUSC Norris lab under the new leadership of the MUSC EDS Institute by Dr. Anne Maitland, world-renowned expert in mast cell disorders. There they are committed to evolving science may lead to more targeted treatments in the future, especially as researchers explore the role mast cells play in connective tissue integrity and systemic inflammation.

Additional Reading:

NIH – Mast Cells in Health and Disease

Frontiers in Immunology – Mast Cells in Allergy and Beyond

PubMed – Mast Cells and Collagen Breakdown

PMC – Mast Cell Activation in hEDS

PubMed – Mast Cell Hypersensitivity Genetics in hEDS

Nonprofits

The Mast Cell Society - https://tmsforacure.org/