Ehlers-Danlos Syndrome: Its Relationship to POTS, MCAS, CIRS, and Infection

Ehlers-Danlos syndrome has been recognized for many years, but it has received considerably more attention recently—and it is about time.

The Ehlers-Danlos syndromes (EDS) are a group of chronic connective-tissue disorders. Most recognized EDS subtypes have an identified genetic cause. However, the genetic basis of hypermobile Ehlers-Danlos syndrome (hEDS), the most common subtype, has not yet been definitively established.

EDS can cause joints to move beyond their normal range of motion. Commonly affected joints include the fingers, thumbs, elbows, and knees, although the pattern and severity vary considerably among individuals. Some patients have widespread joint hypermobility, while others have only certain joints affected.

Over time, researchers have identified associations between hEDS or hypermobility spectrum disorders and several other conditions, including:

• Chronic musculoskeletal pain

• Postural orthostatic tachycardia syndrome (POTS)

• Mast cell activation syndrome (MCAS)

• Attention-deficit/hyperactivity disorder (ADHD)

• Autism spectrum disorder

• Gastrointestinal dysmotility

• Fatigue and sleep disturbance

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For this discussion, I will focus primarily on hEDS and hypermobility spectrum disorders (HSD) - I will be lumping all hypermobile conditions together. It is important to recognize that not every form of EDS is principally a hypermobility disorder. Certain subtypes, particularly vascular EDS, have distinct clinical features and risks.

People who excel at dance, gymnastics, and yoga often have hypermobile joints. The model's level of flexibility suggests a wingspan longer than her height, as occurs with hypermobility.

Hypermobility and musculoskeletal symptoms

As expected when connective tissue is structurally abnormal, hEDS and HSD are strongly associated with pain and musculoskeletal dysfunction. Patients may experience joint instability, recurrent sprains, subluxations, dislocations, soft-tissue injuries, and early degenerative changes.

Because these manifestations vary by joint and could fill an entire article on their own, I will not explore the individual musculoskeletal complications in detail here.

EDS, hypermobility, and infections

The possible relationship between hypermobility and infection is an emerging area of investigation. It remains unclear whether infections contribute directly to connective-tissue dysfunction, worsen symptoms in genetically susceptible individuals, or simply coexist with hypermobility more frequently than expected.

One published case report described a veterinarian infected with Bartonella henselae and Bartonella koehlerae. She developed progressive rheumatologic symptoms, MRI-confirmed musculoskeletal abnormalities, and acquired joint hypermobility resembling what was then called EDS type III. Following prolonged antimicrobial treatment, her symptoms and joint hypermobility improved substantially.

This case is intriguing, but it remains a single case report and does not establish that Bartonella causes hEDS. It does suggest that certain infections might aggravate connective-tissue symptoms or produce an acquired hypermobility phenotype in some patients. Published Bartonella case report

A small 2024 genetic study of patients with hEDS also reported increased mast-cell hypersensitivity and recurrent infections. However, the study included only 18 affected participants and seven first-degree relatives as controls. Its reported percentages should therefore be considered preliminary and should not be generalized to the entire hEDS population without confirmation in larger studies. 2024 study

Hypermobility, POTS, and MCAS

POTS (Postural Orthostatic Tachycardia Syndrome) and MCAS (Mast Cell Activation Syndrome) are frequently reported among people with hEDS and HSD. However, not everyone with hypermobility develops either condition, and the presence of one does not prove that the others are present.

POTS is a form of autonomic dysfunction characterized by an excessive increase in heart rate upon standing, accompanied by symptoms such as lightheadedness, palpitations, weakness, exercise intolerance, and sometimes fainting.

MCAS involves recurrent episodes of symptoms caused by inappropriate mast-cell mediator release in at least two organ systems and not solely "allergic." Depending on the patient, these may include flushing, itching, hives, swelling, wheezing, diarrhea, abdominal pain, tachycardia, or blood-pressure changes.

A retrospective study found that MCAS was diagnosed more frequently among patients who had both POTS and EDS than among patients who did not have that combination. Other reviews have also described an apparent clinical overlap among these conditions. Nevertheless, diagnostic criteria have varied between studies, and researchers have not yet established a single mechanism that explains the association.

Possible contributors include connective-tissue laxity affecting blood-vessel function, autonomic dysregulation, altered immune signaling, and mast-cell activity. These remain areas of active investigation rather than settled conclusions. Review of mast-cell-related conditions and hypermobility

Overlapping conditions. Hypermobility includes EDS and other hypermobile conditions.

Where CIRS may fit

Chronic inflammatory response syndrome (CIRS) is proposed to occur when a genetically susceptible person develops persistent immune dysregulation following exposure to certain biotoxins, often in association with a water-damaged building.

Within the Shoemaker Protocol® framework, particular HLA-DR/DQ haplotypes are considered markers of susceptibility to an ongoing inflammatory response after biotoxin exposure. HLA molecules help the immune system recognize and present antigens. The proposed problem is not simply that the body cannot “clear toxins,” but that exposure may initiate an immune response that fails to resolve normally in a susceptible individual.

Clinicians who treat CIRS observe that hypermobility, POTS, and mast-cell symptoms frequently coexist in their patients. One proposed explanation is that immune dysregulation, vascular instability, autonomic dysfunction, and connective-tissue vulnerability interact with one another.

At present, however, the relationship between CIRS and hereditary connective-tissue disorders has not been adequately established through large, controlled studies. HLA susceptibility within the CIRS model should not be presented as a proven genetic cause of hypermobile conditions.

The important takeaway

Focusing exclusively on musculoskeletal symptoms in people with hypermobility disorders may result in other associated conditions being overlooked. There is meaningful clinical overlap among hypermobility disorders, POTS, and mast-cell-related symptoms. CIRS and chronic infections may also be relevant in selected patients, although these relationships require considerably more research.

The presence of one condition should prompt clinicians to remain alert for symptoms of the others, but it should not lead to an automatic diagnosis. Each condition requires an appropriate clinical evaluation based on its own diagnostic criteria.

These patients frequently have symptoms involving multiple body systems and may benefit from coordinated care that addresses joint stability, autonomic function, immune and mast-cell symptoms, pain, sleep, nutrition, and any appropriately documented environmental exposures or infections.

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