# Sex differences in self-reported symptoms and comorbidities associated with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A retrospective study

## TL;DR

Women with hypermobile Ehlers-Danlos syndrome and related disorders report more symptoms and health issues than men, which may explain why fewer men are diagnosed.

## Contribution

The study identifies sex-specific symptom patterns and biological differences in hEDS/HSD patients, suggesting mast cell activity may underlie sex-based disease severity.

## Key findings

- Females with hEDS/HSD reported significantly more symptoms and comorbidities than males.
- Males more frequently reported ADHD, developmental delays, snoring, and sleep apnea.
- Higher mast cell activity in females correlated with increased IgE levels and fibromyalgia diagnoses.

## Abstract

Although hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are inherited disorders expected to display a 1:1 sex ratio, most studies report a strong female dominance. This study analyzed sex differences in 122 self-reported symptoms and comorbidities in patients diagnosed with hEDS or HSD using the 2017 criteria.

Self-reported data was obtained from November 1, 2019, to April 25, 2025, (n=2,451) from an Intake Questionnaire of adult (≤18 years old) patients diagnosed with hEDS or HSD at the EDS Clinic at Mayo Clinic Florida and analyzed by sex.

We found that 90.6% (n=575) of hEDS patients were female and 9.4% (n=60) were male, with a sex ratio of 9.6:1 female-to-male, while 95.2% (n=1,728) of HSD patients were female and 4.8% (n=88) were male, with a sex ratio of 19.6:1 female-to-male. Females were older than males: hEDS 35 vs. 28 years of age (p<0.001), HSD 34 vs. 31 years of age (p=0.004). Overall, females self-reported more symptoms/comorbidities than males: hEDS 31/122 (25.4%), HSD 59/122 (48.4%). In contrast, only 5/122 (4.1%) symptoms/comorbidities were self-reported more often in males including attention deficit disorder/attention deficit hyperactivity disorder, delay in developmental milestones, snoring, autism spectrum disorder, and obstructive sleep apnea. Females with HSD had more mast cell-related symptoms (i.e., hives p<0.001) which were reflected in higher mast cell scores than males (p<0.001). Patients with higher mast cell scores also had higher serum levels of total IgE (p=0.029). More females with HSD were diagnosed with fibromyalgia (p<0.001) and reported symptoms associated with autonomic dysfunction than males. Aside from abuse, which was higher in females (hEDS p=0.039, HSD p<0.001), few sex differences were reported for psychological symptoms/comorbidities. In support for the idea that elevated mast cell activity in females may lead to extracellular matrix remodeling that promotes hypermobility, females with hEDS/HSD had greater serum collagen-4α1 (p<0.0001) and fibronectin (p=0.015) than males by ELISA.

Females with hEDS and HSD report a higher burden of symptoms/comorbidities than males, providing a possible explanation for fewer males being reported in demographic data. Sex differences in symptoms/comorbidities may reflect sex differences in pathogenic drivers of disease.

Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are inherited conditions that affect the body’s connective tissues, leading to joint hypermobility, chronic pain, and a variety of other symptoms. Although these disorders should occur equally in men and women, most diagnosed patients are women. This study examined possible reasons for that difference by comparing symptoms and health conditions reported by 2,451 adults diagnosed with hEDS or HSD at the Mayo EDS Clinic in Florida between 2019 and 2025. We found that over 90% of hEDS and HSD patients were female, with a female-to-male ratio ranging from 10:1 to 20:1. Women were slightly older than men and reported more symptoms and associated health problems. Men more often reported only a few conditions, including ADHD, developmental delays, snoring, autism, and sleep apnea. Women with HSD reported more mast cell symptoms, a type of immune cell that releases chemicals like histamine and may contribute to tissue remodeling and hypermobility. These higher mast cell symptoms were associated with more allergy symptoms, like hives, and higher IgE levels in the blood. Women with HSD were also more likely to have fibromyalgia and symptoms of autonomic dysfunction (such as dizziness or heart rate changes). Overall, our findings suggest that biological sex differences- possibly through mast cell activation- may drive differences in disease severity and symptom patterns. This may explain why more women are diagnosed and seek treatment for hEDS and HSD, while men may remain underdiagnosed or less affected.