Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are heritable collagen disorders with widespread distribution of fragile connective tissue in the skin, joints, ligaments, and internal organs (1). 255 million people worldwide (3%) are estimated to have hEDS or HSD (2). Unlike the more classical forms of EDS, gene variants unique to hEDS/HSD are unknown except for a recent preprint report of mutations in the kallikrein gene family in patients with hEDS (3). Diagnosis is based on strict, physical criteria developed by the International EDS Consortium (Table 1) (4). Patients diagnosed with hEDS or HSD have been reported to have significantly greater joint pain, musculoskeletal pain, and fatigue than the general population (5). Comorbidities/symptoms of hypermobile patients are often multiorgan, multifaceted, and potentially debilitating (1, 2, 6).

In 2017 a new clinical criterion for the diagnosis of hEDS was published that distinguished hEDS from HSD with a goal of better understanding the similarities and/or differences that exist within the spectrum of disease (4). The criteria for a diagnosis of hEDS briefly includes identification of generalized joint hypermobility (GJH) of specific joints using the Beighton Scale, evidence of a systemic connective tissue disorder, family history and/or musculoskeletal complications, and several exclusions (see Table 1) (4). The Beighton Scale assesses the joint hypermobility of only a few joints such as knees and elbows (4, 7). A Beighton Scale score of ≥ 5/9 after puberty or ≥ 4/9 after age 50 is a positive score (4). Patients are diagnosed with HSD if they do not meet the diagnostic criteria for hEDS, have a positive Beighton Scale score and also have evidence that the joint hypermobility is causing problems and it is not just an asymptomatic feature (feature C of the 2nd EDS criterion) (4, 7). Localized HSD (L-HSD) is diagnosed in patients that do not meet the diagnostic criteria for hEDS, do not have a positive Beighton Score (but their Beighton Score is not zero), and other areas of the body are hypermobile (7). Patients that do not meet the diagnostic criteria for hEDS, have a Beighton Score of zero, and experience hypermobility in other joints are termed historical HSD (H-HSD) (7).

In collaboration with the International Consortium’s working groups and the European Reference Networks, The Ehlers-Danlos Society aims to reassess the 2017 hEDS diagnostic criterion and formally define HSD (8). According to the Ehlers-Danlos Society website, part of their research goals include studying whether symptoms and comorbidities are similar and/or different between hEDS and HSD to determine whether the 2017 diagnostic criteria for hEDS should be revised (9, 10). Since the 2017 diagnostic criterion was established, several studies found either that symptoms and comorbidities between hEDS and HSD were essentially the same (9, 11–14) or that that both similarities and important differences exist (Table 2) (6, 8, 15, 16). A study by Aubry-Rozier et al. (13) examined 61 patients with hEDS and 36 with HSD using the 16-item Clinical Severity Score (CSS-16). They also assessed bone involvement, neuropathic pain (DN4) and symptoms of mast cell disorders (MCAS) as extra-articular manifestations. They found the two diagnoses were similar for most symptoms/comorbidities (Table 2) (13). They concluded from this study that patients with hEDS and HSD should receive the same clinical care. Martinez et al. examined 98 patients with hEDS and 27 with HSD using 7 health questionnaires (Short Form Health Survey (SF-36), Patient Health Questionnaire (PHQ)-15, Tampa Scale for Kinesiophobia (TSK), Fatigue Severity Scale (FSS), Epworth Sleepiness Scale (ESS), Gastro-Questionnaire, Composite Autonomic Symptom Score (COMPASS) 31) (14). They found that although a few differences between hEDS and HSD were observed, that the frequency and severity of most symptoms were indistinguishable between the two diagnoses (Table 2) (14). Ritelli et al. (8) examined 87 patients with hEDS and 126 with HSD for 90 symptoms/comorbidities and found that most occurred more often in patients with hEDS than HSD suggesting that hEDS may be more severe than HSD (Table 2) (8). Ritelli et al. (15) later reported a similar finding examining 9 symptoms/comorbidities in 94 patients with hEDS and 80 with HSD with more hEDS patients identified with these issues (Table 2) (15). Examining 423 patients with hEDS and 1,389 with HSD, we previously reported that most of 115 self-reported symptoms/comorbidities had extensive overlap between the two diagnoses, but that patients diagnosed with HSD reported more symptoms/comorbidities than patients with hEDS, suggesting that symptoms may be worse in patients with HSD (16). It is not clear why differences exist in the findings of different studies. Possible reasons include that most of the studies compared small numbers of patients (under 100/group), from different countries (i.e., races/ethnicities) and different ages (Table 2) (11–15). Importantly, none of these studies (aside from ours) indicated whether the patients diagnosed with HSD were HSD, L-HSD and/or H-HSD.

In previous manuscripts we had included L-HSD and H-HSD as part of our controls (patients attended the EDS Clinic but were not diagnosed with hEDS or HSD) (6, 17, 18). However, we published recently that patients with L-HSD/H-HSD were significantly different than controls that did not have any type of HSD for most of 115 symptoms/comorbidities (16). These findings led us to conduct this study. The goal of this study is to determine whether patients with L-HSD or H-HSD differ in 100 symptoms/comorbidities from controls and/or patients diagnosed with hEDS or HSD. An important issue that needs to be considered in future revisions of the EDS and HSD diagnostic criteria is the question of whether patients with HSD, L-HSD and/or H-HSD should be incorporated more fully into the diagnostic criteria. We found that patients with L-HSD/H-HSD had many symptoms and comorbidities that closely resembled HSD suggesting that revised diagnostic criteria for hEDS and HSD should include L-HSD/H-HSD within a diagnosis of HSD. Additionally, our data indicate that patients with HSD (including L-HSD/H-HSD) have more symptoms/comorbidities than patients with hEDS.

To our knowledge, this is the first study to compare symptoms/comorbidities of L-HSD/H-HSD to controls or to patients diagnosed with hEDS and HSD. In this study, we found that patients with L-HSD/H-HSD had symptoms/comorbidities that closely resembled HSD suggesting that revised diagnostic criteria for hEDS and HSD should include L-HSD/H-HSD in the HSD diagnosis. Most of the symptoms/comorbidities that we examined in this study occurred in all patient groups; however, patients with HSD and L-HSD/H-HSD self-reported more symptoms/comorbidities than those diagnosed with hEDS or controls suggesting that patients with HSD, L-HSD and H-HSD may have more severe disease than patients with hEDS. We found that patients with L-HSD/H-HSD self-reported significantly more symptoms/comorbidities than controls for 62/100 (62%) of issues compared to 58/100 (58%) for HSD and 20/100 (20%) for hEDS. These findings indicate that L-HSD/H-HSD share similar symptoms and comorbidities to HSD and differ from hEDS and controls. Importantly, patients with L-HSD/H-HSD self-reported significantly more symptoms/comorbidities than patients diagnosed with hEDS or HSD for 20/100 (20%) of issues. These symptoms/comorbidities included joint pain, muscle weakness, multiple sensitivities, wheezing/shortness of breath, GERD, pain/cramps in the lower abdomen, constipation, heat and/or cold intolerance, hearing difficulties, ADHD, ASD, snoring, and narcolepsy (Figure 1). Additionally, some symptoms/comorbidities were self-reported exclusively more often in L-HSD/H-HSD patients compared to controls, but not in hEDS or HSD compared to controls, including wheezing, hearing difficulties, narcolepsy, circadian rhythm disorders, and ASD (Figure 1). These findings suggest that patients with L-HSD/H-HSD may have more symptoms/comorbidities than hEDS and HSD patients using current diagnostic definitions. However, it is possible that individuals diagnosed with L-HSD or H-HSD may be less likely to present to a specialty clinic unless they experience significant systemic symptoms (e.g., dysautonomia, GI distress, or neurocognitive issues). This referral or selection bias could contribute to the unexpectedly high symptom burden in this group relative to patients with hEDS or HSD, who may be referred based on more classical joint findings alone. Interestingly, patients with hEDS more closely resembled controls for many symptoms/comorbidities. Controls attended the EDS Clinic because they believed they could have hEDS but did not receive the diagnosis of hEDS, HSD, L-HSD or H-HSD. The controls consistently had fewer symptoms/comorbidities than HSD and L-HSD/H-HSD patients, but we do not know what their appropriate diagnosis is.

Since the development of the 2017 diagnostic criterion, a number of studies have compared hEDS to HSD to determine whether the two diagnoses represent a spectrum or are two distinct conditions. A study by Copetti et al. examined 105 patients diagnosed with hEDS or HSD for 59 characteristics and analyzed data using hierarchical clustering of principal components (11). They found that some patients within both diagnoses were considered more severe regardless of diagnosis and recommended a new severity score. This finding is similar to our previous report that around 70% of the patients seen at the Mayo Clinic Florida EDS Clinic were diagnosed with fibromyalgia, a condition characterized by widespread joint and muscle pain (6). This 70% included patients with L-HSD/H-HSD. We found that patients diagnosed with hEDS or HSD that also had a diagnosis of fibromyalgia (56% of patients) self-reported significantly more symptoms and comorbidities than those without a fibromyalgia diagnosis suggesting more severe disease (6). Copetti et al. (11) did not indicate whether the patients with greater severity in their study also had a diagnosis of fibromyalgia (11). Perhaps future revised hEDS/HSD diagnosis criteria could include an assessment/diagnosis of fibromyalgia.

We recently examined 2,088 patients at the Mayo Clinic Florida EDS Clinic using the 2017 diagnostic criteria comparing 115 self-reported symptoms/comorbidities between hEDS, HSD and controls to determine similarities and differences between the diagnoses (16). We found that all patients experienced some level of these symptoms/comorbidities and they were reported significantly more often in hEDS and HSD compared to controls. Importantly, several symptoms/comorbidities occurred at a high level in both diagnoses including allergies, subluxations, sprains, headache, and migraine (16). However, we found that most symptoms/comorbidities differed between the two diagnoses. Patients diagnosed with HSD self-reported 42 conditions significantly more often compared to hEDS (42/115 or 37%), while only 9 conditions occurred more often in patients with hEDS (9/115 or 8%) (16). One important finding was that the conditions reported more often in hEDS were “structural” like prolapses whereas conditions reported more often in HSD were “functional” like irritable bowel syndrome. These findings indicate that key features of hEDS/HSD like mast cell activation/allergy, subluxations/sprains and headache/migraine are common to both diagnoses, but many other symptoms/comorbidities occur more often in patients with HSD. The structural issues in hEDS patients are not surprising, because the diagnostic criterion selects patients with these issues. What stands out is that this diagnostic “selection” results in patients with fewer systemic symptoms/comorbidities. Our findings of overlap in allergy/mast cell symptoms in hEDS and HSD are congruent with the recent report by Ritelli et al. who discovered plasma biomarkers in both hEDS and HSD, but not in controls, that are the product of extracellular matrix (ECM) degradation (collagen I and fibronectin fragments) (15). Mast cell enzymes are principally responsible for the breakdown of ECM proteins, and so high mast cell activity in hEDS and HSD patients could result in a similar plasma ECM degradation profile. Mast cell hyperactivation that degrades collagen and ECM provides a mechanism for hypermobility and similar symptoms/comorbidities between the diagnoses. Mechanisms to explain the differences between symptoms/comorbidities between the diagnoses are an avid area of research.

In contrast to our findings, several previous studies did not find a significant difference between symptoms and comorbidities between hEDS and HSD (Table 2) (9, 11–14). Ritelli et al. (20) conducted RNA sequencing of skin fibroblast biopsies from 20 patients with hEDS, 20 with HSD and 40 controls using the 2017 criteria, and found that the gene profiles overlapped between hEDS and HSD (Table 2) (20). In contrast, studies by Ritelli et al. have found differences in symptoms/comorbidities between hEDS and HSD with more symptoms in hEDS patients suggesting that they could be more severe than patients with HSD (8, 15). Several explanations for the differences between the studies include age or race differences and/or that Ritelli et al. reported data obtained from the medical record and our studies include self-reported data. Overall, most studies examined a relatively small number of symptoms/comorbidities in a small number of patients (Table 2). Perhaps a larger number of patients is needed before differences between the diagnoses appear. An oral abstract submitted to the Ehlers-Danlos Society 2022 International Scientific Symposium on EDS and HSD reported an initial analysis of the worldwide Ehlers-Danlos Society Registry that examined 8,867 hEDS and 990 HSD patients for 8 symptoms/comorbidities including fatigue, gastrointestinal symptoms, headache, anxiety, depression, dysautonomia, gynae, bladder and mast cell activation disease (9). They did not find any differences in these 8 categories of self-reported symptoms/comorbidities between patients with hEDS or HSD (9). However, the published abstract does not provide information on whether all patients were diagnosed using the 2017 criteria, information on age, race/ethnicity or statistical information. Thus, it is difficult to compare this large number of patients to our findings. We are currently examining whether specific comorbidities obtained from the medical record differ by diagnosis to determine whether self-reported differences match medical record data.

In this study we examined 2,695 patients using the 2017 diagnostic criterion with 60.6% (n = 1,632) diagnosed with HSD, 18.3% (n = 493) hEDS, 10.7% (n = 289) L-HSD or H-HSD, and 10.4% (n = 281) were controls without any of these diagnoses. This study has several advantages including a large number of patients diagnosed using the 2017 criterion, and a relatively large number of controls seen at the EDS Clinic that were not diagnosed with hEDS, HSD or L-HSD/H-HSD. Although the controls were older on average than the other groups, otherwise their demographic data was relatively similar, consisting primarily of non-Hispanic White women (Tables 3, 4). We found that hEDS, HSD and L-HSD/H-HSD patients consistently self-reported more symptoms/comorbidities than controls. Importantly, patients with L-HSD/H-HSD self-reported symptoms/comorbidities at levels that were very similar to HSD but differed from hEDS, as we previously reported (16). One possible explanation for the differences in our findings compared to the initial reports from the Ehlers-Danlos Society Registry is that our population is almost 90% White non-Hispanic and their study included many races/ethnicities. Importantly, our findings indicate that features specific to L-HSD/H-HSD such as hypermobility in other areas of the body, which are not included in the current diagnostic criterion, should be incorporated into future revised diagnostic criteria. Our findings also mirror patient experience, where many patients that do not receive a diagnosis according to the current 2017 diagnostic criterion indicate that they suffer from many of the same symptoms/comorbidities as hEDS and HSD patients, and they are upset that they have not received a diagnosis. Receiving a diagnosis not only confirms that patients’ suffering has a cause/explanation, but it is needed for patients to receive appropriate medical care. Gaining a better understanding of similarities and differences between patients with hEDS, HSD, L-HSD and H-HSD may improve patient care and provide mechanistic insight into the pathogenesis of disease. Research into these mechanisms may lead to improved tailored therapies that reduce the progression of disease.

There are several limitations to the current study. The site of this study is a tertiary care center and findings from patients in this study may not represent other regions of the US or world. Additionally, symptoms/comorbidities were self-reported and not validated through another method. Future studies are needed to examine whether the key findings of this study can be verified when medical records are examined. A strength of this study is that hEDS/HSD patients were diagnosed using the most recent 2017 criterion by physician experts. An additional strength is the large study population that contained an internal control group which was not diagnosed with hEDS, HSD, L-HSD/H-HSD but had the same diagnostic process.

In conclusion, the contribution of this study to the field is that most centers seeing EDS patients do not include L-HSD or H-HSD in a diagnosis of HSD so that these patients may not receive the same level of care as patients diagnosed with hEDS and HSD. Additionally, these patients may not be included in research studies of HSD and we found that these patients self-reported similar, and in some cases higher, levels of symptoms/comorbidities as HSD patients. Thus, our data suggests that the new diagnostic criteria should incorporate these patients into the criteria for HSD so that the patients receive care and research.