Summary of: Association of POTS, HSD, and MCAS in Young Patients; prevalence, overlap and response to therapy depends on the definition

Rebekah Beattie
6 hours ago
3 min read

Original article by: Lilian Yao, Kavya Subramaniam, Katherine M. Raja, Abi Arunachalam, Aubrey Tran, Tripti Pandey, Sahana Ravishankar, Sahan Suggala, Caitlyn Hendrickson, and Andrew J. Maxwell.

Summary by: Rebekah Beattie, Clinical Evidence and Dissemination Lead for the HMSA.

Original article is available at: https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1513199/full

Introduction

Clinicians are increasingly recognising that certain conditions - such as postural orthostatic tachycardia syndrome (POTS), joint hypermobility disorders, and mast cell activation syndrome (MCAS) - frequently co-occur. However, the diagnostic criteria applied to each of these conditions significantly influence their reported prevalence. When more strict definitions are used, many patients who might benefit from treatment may be excluded from diagnosis.

The diagnosis of MCAS is particularly complex. While some practitioners require specific laboratory evidence, such as elevated tryptase levels (a marker of allergic or mast cell activity), others support a more clinically driven approach based on symptom presentation and response to treatment. A similar challenge exists with hypermobility diagnoses: some clinicians adhere strictly to criteria for hypermobile Ehlers-Danlos syndrome (hEDS), whereas others consider individuals with partial or near-qualifying features as clinically relevant.

This study examines the extent to which these conditions overlap in a cohort of young individuals diagnosed with POTS and evaluates whether those not meeting the most strict criteria still benefit from targeted treatment. The findings suggest that broadening the diagnostic criteria may facilitate timely treatment and improved outcomes.

Table 1 lists various conditions that support a diagnosis of more serious hypermobility issues, such as bowel issues, sleep problems, and specific syndromes like Chiari malformation.

A white table listing medical conditions such as Chiari malformation and scoliosis. Note states minor criteria aren't standalone for diagnoses.

Methods

Researchers looked back at the medical records of 100 young people (aged 8-25) who were diagnosed with POTS. They sorted them into groups based on how strict the definitions were for hypermobility and MCAS.

Hypermobility Categories (Table 2):

• Strict: Fully meets the 2017 hEDS criteria.

• Conservative: Almost meets hEDS criteria or meets updated paediatric criteria + 1 additional condition from Table 1.

• Loose: Diagnosed with Hypermobility Spectrum Disorder (HSD) but with + 1 additional condition from Table No Evidence: Doesn’t meet any definition.

MCAS Categories:

• Strict: Meets tight lab-based Consensus-1 standards.

• Conservative: Has some positive lab results (Consensus-2).

• Loose: Has symptoms and gets better with treatment, even if lab tests are normal.

• No Evidence: No evidence of MCAS.

Table 2 defines the four hypermobility categories, from strict hEDS to no signs of disease.

Criteria list for hypermobility syndromes with references to 2017 standards and Table 1, divided into four categories: No evidence, Loose, Conservative, Strict.

Results

Out of the 100 young people with POTS

• Only 2 met the strictest definition for MCAS (based on tryptase lab results).

• But when using the broader conservative definition, 41 patients met criteria for MCAS.

• Using the loosest definition, 87 patients were considered to have MCAS.

Most patients also had some form of hypermobility:

• 13 met the strict hEDS criteria.

• 31 met “near-hEDS” (conservative).

• 34 had signs of HSD (loose).

Laboratory Testing Limitations:

Among tested markers for MCAS:

Plasma histamine (a chemical released during allergic reactions) was the most frequently elevated biomarker.

Chromogranin A (a protein that can reflect certain types of cell activity, including in the gut and nervous system) was the next most common.

Tryptase, the gold-standard for strict MCAS diagnosis, was rarely elevated, supporting the argument that it may not be a reliable sole marker for MCAS.

The degree of diagnostic overlap between POTS, MCAS, and hypermobility varied significantly depending on which diagnostic criteria was applied:

• Using strict criteria, only 1 patient had all three conditions.

• Using conservative criteria, the number of patients with the full triad increased to 13.

• Using loose criteria, even more overlap was found - 34 patient had all three conditions.

Treatment Response

Of the 90 patients assessed, 74 (82%) improved with MCAS-directed therapies. Importantly, patients without positive lab results still showed clinical improvements following treatment.

Discussion

This study shows that a lot of young people with POTS also have signs of hypermobility and MCAS. But if doctors use only the strictest criteria, they will miss many patients who could benefit from treatment. The researchers argue that it makes sense to use broader criteria - especially since treatments for MCAS are generally safe and can make a big difference.

They also propose a possible link between these conditions: abnormal mast cells might release chemicals that weaken connective tissue (causing hypermobility) or irritate nerves (leading to disrupted activity which can cause dysautonomia). Treating mast cell problems could potentially help with all three issues.

They conclude that using a flexible approach to diagnosis, especially in young people, helps more patients get the treatment they need. Even though it’s not perfect, the benefits of treating those who respond outweigh the risks of overtreating.