Are patients with hypermobile Ehlers–Danlos syndrome or hypermobility spectrum disorder so different?

Aubry-Rozier, Bérengère; Schwitzguebel, Adrien; Valerio, Flore; Tanniger, Joelle; Paquier, Célia; Berna, Chantal; Hügle, Thomas; Benaim, Charles

doi:10.1007/s00296-021-04968-3

Cited by 66Connective tissue disorders researchMusculoskeletal pain and rehabilitationMyofascial pain diagnosis and treatment

Are patients with hypermobile Ehlers–Danlos syndrome or hypermobility spectrum disorder so different?

Open access

Aubry-Rozier, Bérengère, Schwitzguebel, Adrien, Valerio, Flore, Tanniger, Joelle, Paquier, Célia, Berna, Chantal, Hügle, Thomas, Benaim, Charles·2021·Rheumatology International

DOI 10.1007/s00296-021-04968-3PMC PMC8390400

Open this paper in CoChat — free account Open PDF

Abstract

Diagnosing hypermobile Ehlers–Danlos syndrome (hEDS) remains challenging, despite new 2017 criteria. Patients not fulfilling these criteria are considered to have hypermobile spectrum disorder (HSD). Our first aim was to evaluate whether patients hEDS were more severely affected and had higher prevalence of extra-articular manifestations than HSD. Second aim was to compare their outcome after coordinated physical therapy. Patients fulfilling hEDS/HSD criteria were included in this real-life prospective cohort (November 2017/April 2019). They completed a 16-item Clinical Severity Score (CSS-16). We recorded bone involvement, neuropathic pain (DN4) and symptoms of mast cell disorders (MCAS) as extra-articular manifestations. After a standardized initial evaluation (T0), all patients were offered the same coordinated physical therapy, were followed-up at 6 months (T1) and at least 1 year later (T2), and were asked whether or not their condition had subjectively improved at T2. We included 97 patients (61 hEDS, 36 HSD). Median age was 40 (range 18–73); 92.7% were females. Three items from CSS-16 (pain, motricity problems, and bleeding) were significantly more severe with hEDS than HSD. Bone fragility, neuropathic pain and MCAS were equally prevalent. At T2 (20 months [range 18–26]) 54% of patients reported improvement (no difference between groups). On multivariable analysis, only family history of hypermobility predicted (favorable) outcome ( p = 0.01). hEDS and HDS patients showed similar disease severity score except for pain, motricity problems and bleeding, and similar spectrum of extra-articular manifestations. Long-term improvement was observed in > 50% of patients in both groups. These results add weight to a clinical pragmatic proposition to consider hEDS/HSD as a single entity that requires the same treatments.

AI snapshot

Written from the paper’s full text.

TL;DR

In a prospective Swiss cohort of 97 adults with symptomatic generalized hypermobility, patients classified as hEDS and HSD had broadly similar disease severity and extra-articular manifestations, with only pain, motricity problems, and bleeding significantly worse in hEDS. More than half of patients in both groups reported improvement after coordinated physical therapy, supporting the pragmatic view that hEDS/HSD may be considered a single entity requiring the same treatments.

Key findings

Among 97 patients (61 hEDS, 36 HSD; median age 40 years, 92.7% female), total CSS-16 severity was higher in hEDS than HSD (40.0 [31.0–52.0] vs. 31.5 [22.3–35.0], p = 0.04), but only pain, motricity problems, and bleeding were significantly more severe among the 16 items.
Extra-articular manifestations were equally prevalent: bone fragility 23% vs. 28%, DN4-positive neuropathic pain 47% vs. 49%, and suspected MCAS 43% vs. 50% in hEDS vs. HSD, with no significant differences.
At T2 (median 20 months [18–26]), 54% of patients reported improvement, with no significant difference between hEDS and HSD (56% vs. 50%, p = 0.77).
On multivariable analysis, only family history of hypermobility independently predicted favorable outcome (p = 0.01).

Methods

Real-life prospective cohort conducted at a single Swiss reference center (Lausanne University Hospital) between November 2017 and April 2019; adults with symptomatic generalized hypermobility were classified by the 2017 hEDS/HSD criteria.
Patients completed the 16-item Clinical Severity Score (CSS-16), Beighton score, and assessments for bone involvement, neuropathic pain (DN4 > 4/10), and suspected MCAS; all were offered the same coordinated physical therapy and followed at 6 months (T1) and at least 1 year later (T2).
Comparisons used Mann–Whitney U-test, chi-square or Fisher exact tests; factors with p < 0.10 on univariate analysis were entered into multivariable logistic regression (p ≤ 0.05).

Limitations

The authors state this was a monocentric study in a small country, used mostly subjective or detection tools, and that the CSS-16 is not validated for sensitivity/specificity in hEDS/HSD or against other disorders such as fibromyalgia.
The authors state that global evolution was a composite self-report regarding pain, disability, injury, and empowerment, so individual elements could not be analyzed separately, and reasons for loss to follow-up were not assessed, potentially biasing results.
Evident from the text: follow-up data were available for only 59 of 97 patients at T2 (61%), and loss to follow-up was higher in the HSD than hEDS group (56% vs. 30%, p = 0.02), with lost patients at T1 having lower CSS-16 scores.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00296-021-04968-3

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 35 cited sources checked · 0 supported · 0 flagged

Findingown data
On multivariable analysis, only family history of hypermobility was an independent predictor of favorable outcome at T2 (p=0.01).
“On multivariate analysis, only family history of hypermobility was an independent predictor of (favorable) outcome (p = 0.01).”
- Also stated in: § Abstract · plain
  “On multivariable analysis, only family history of hypermobility predicted (favorable) outcome (p = 0.01).”
Quote in the paperNot a substantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
On univariate analyses, family history of hypermobility was associated with better prognosis at T2 (p=0.07).
“On univariate analyses, factors associated with better prognosis at T2 were the initial intensity of pain (p = 0.05), sleep disturbance (p = 0.06), family history of hypermobility (p = 0.07) and DN4 positivity (p = 0.04) (Table 2).”
Quote in the paperNot a substantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
There was no significant difference between hEDS and HSD in improvement at T1 (38% vs 35%, p=1.00).
“The slight percentage difference in improvement favoring the hEDS group was not significant (T1: 38% vs. 35%, p = 1.00; T2: 56% vs. 50%, p = 0.77).”
Quote in the paperSubstantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
hEDS patients had significantly higher total CSS-16 scores than HSD patients (median 40.0 vs 31.5, p=0.04).
“CSS-16 scores were significantly higher for hEDS than HSD patients (40.0[31.0–52.0] vs. 31.5[22.3–35.0], p = 0.04)”
Quote in the paperNot a substantial claim
- Rests on an assumption: The CSS-16 total score is a valid measure of overall clinical severity in hEDS/HSD despite not being validated for sensitivity and specificity.
Findingown data
At T1 (6 months), 36.8% of patients reported improvement.
“In total, 28 (36.8%) patients considered their condition improved at T1 and 32 (54%) at T2 (Fig. 3).”
Quote in the paperNot a substantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.

Findingown data
There was no significant difference between hEDS and HSD in the proportion reporting improvement at T2 (56% vs 50%, p=0.77).
“The slight percentage difference in improvement favoring the hEDS group was not significant (T1: 38% vs. 35%, p = 1.00; T2: 56% vs. 50%, p = 0.77).”
Quote in the paperSubstantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
On univariate analyses, initial pain intensity was associated with better prognosis at T2 (p=0.05).
“On univariate analyses, factors associated with better prognosis at T2 were the initial intensity of pain (p = 0.05), sleep disturbance (p = 0.06), family history of hypermobility (p = 0.07) and DN4 positivity (p = 0.04) (Table 2).”
Quote in the paperNot a substantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
In the HSD group, 22% had another diagnosis that could be confounding with symptoms.
“In the HSD group, 22% had another diagnosis that could be confounding with symptoms (Fabry disease, psoriasic arthritis, multiple sclerosis, Sjögren syndrome).”
Quote in the paperNot a substantial claim
Findingown data
On univariate analyses, sleep disturbance was associated with better prognosis at T2 (p=0.06).
“On univariate analyses, factors associated with better prognosis at T2 were the initial intensity of pain (p = 0.05), sleep disturbance (p = 0.06), family history of hypermobility (p = 0.07) and DN4 positivity (p = 0.04) (Table 2).”
Quote in the paperNot a substantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
At T2 (mean follow-up 20 months), 54% of patients reported improvement.
“In total, 28 (36.8%) patients considered their condition improved at T1 and 32 (54%) at T2 (Fig. 3).”
- Also stated in: § Abstract · plain
  “At T2 (20 months [range 18–26]) 54% of patients reported improvement (no difference between groups).”
Quote in the paperSubstantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
The hEDS and HSD groups did not differ in the presence of bilateral piezogenic papules of the heel (29% vs 22%, p=0.30).
“The groups did not differ in presence of bilateral piezogenic papules of the heel (hEDS and HSD: 29% vs 22%, p = 0.30).”
Quote in the paperNot a substantial claim
Findingown data
On univariate analyses, DN4 positivity was associated with better prognosis at T2 (p=0.04).
“On univariate analyses, factors associated with better prognosis at T2 were the initial intensity of pain (p = 0.05), sleep disturbance (p = 0.06), family history of hypermobility (p = 0.07) and DN4 positivity (p = 0.04) (Table 2).”
Quote in the paperNot a substantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
Among the 16 CSS-16 items, pain, motricity problems, and bleeding were significantly more severe in hEDS than HSD patients.
“among the 16 items, only pain, motor and bleeding problems were significantly more severe in hEDS than HSD patients”
- Also stated in: § Abstract · plain
  “Three items from CSS-16 (pain, motricity problems, and bleeding) were significantly more severe with hEDS than HSD.”
Quote in the paperSubstantial claim
- Rests on an assumption: The CSS-16 total score is a valid measure of overall clinical severity in hEDS/HSD despite not being validated for sensitivity and specificity.
Findingown data
The Beighton score was significantly higher in hEDS than HSD patients (median 7.0 vs 7.0, p=0.03).
“The Beighton score was significantly (Table 1) higher for hEDS than HSD patients (7.0[6.0–9.0] vs. 7.0[4.0–8.0], p = 0.03)”
Quote in the paperNot a substantial claim
Findingown data
The Beighton score did not differ significantly between hEDS and HSD in its categorical form (no/yes: <5/>5).
“but not in its categorical form (no/yes: < 5/ > 5) according to 2017 criterion 1.”
Quote in the paperNot a substantial claim
Findingown data
Spontaneous bleeding problems were significantly more severe in patients with suspected MCAS than in those without (median 2.0 vs 2.0, p<10^-3).
“Spontaneous bleeding problems were significantly more severe in patients with than without suspected MCAS (2.0[2.0–3.0] vs. 2.0[0.3–2.0], p < 10–3).”
Quote in the paperNot a substantial claim
- Rests on an assumption: Suspected MCAS based on coexistence of flush and/or dermographia reflects mast cell activation syndrome.
Findingown data
The neuropathic pain detection score was positive in almost 50% of patients in both groups.
“The neuropathic pain detection score was frequently positive in our cohort, almost 50% in both groups.”
Quote in the paperNot a substantial claim
Findingown data
In approximately 45% of patients, symptoms were compatible with MCAS.
“In approximately 45% of patients, symptoms were compatible with MCAS.”
Quote in the paperNot a substantial claim
Findingown data
The only factor that seemed to influence a favorable evolution was family history of hypermobility.
“The only factor that seemed to influence a favorable evolution was family history of hypermobility.”
Quote in the paperNot a substantial claim
Findingown data
The coordinated physical therapy program resulted in improvement in ≥50% of patients in both hEDS and HSD groups.
“With our program, more than 50% of patients showed improved articular symptoms at the end of follow-up.”
- Also stated in: § Conclusion · plain
  “In addition, improvement was ≥ 50% with a coordinated physical therapy program in both groups.”
Quote in the paperSubstantial claim
- Rests on an assumption: The observed improvement in articular symptoms is attributable to the coordinated physical therapy program rather than to other factors.
Findingown data
In our study, with our severity score, more severely affected patients (more pain or disability) were well detected by the 2017 diagnostic criteria.
“In our study, with our severity score, we confirmed that more severely affected patients (more pain or disability) were well detected by the 2017 diagnostic criteria.”
Quote in the paperSubstantial claim
Findingown data
42% of patients referred to the hypermobility-dedicated consultation met the 2017 diagnostic criteria for hEDS.
“With this dataset, we can confirm that hEDS is not rare [46]: 42% of the patients referred to the hypermobility-dedicated consultation met the 2017 diagnostic criteria.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [46] Demmler JC, Atkinson MD, Reinhold EJ et al (2019) Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case-control comparison. BMJ Open 9:e031365. https://doi.org/10.1136/bmjopen-2019-031365 source
  Not checked in the free run.
Findingown data
hEDS patients had a significantly higher prevalence of severity of spontaneous bleeding than HSD patients.
“However, we found a significantly higher prevalence of severity of spontaneous bleeding in hEDS than HSD patients.”
Quote in the paperSubstantial claim
Findingcitation
Piezogenic papules were no more frequent in hEDS than HSD patients in our cohort.
“As for Mc Gillis et al. [16], piezogenic papules were no more frequent in hEDS than HSD patients in our larger hEDS cohort.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [16] McGillis L, Mittal N, Santa Mina D et al (2020) Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers-Danlos syndrome clinic: a retrospective review. Am J Med Genet A 182:484–492. https://doi.org/10.1002/ajmg.a.61459 source
  Not checked in the free run.
Findingcitation
There was a positive association between spontaneous bleeding and suspected MCAS.
“As suggested by Jesudas et al. [29], we found a positive association between spontaneous bleeding and suspected MCAS.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [29] Jesudas R, Chaudhury A, Laukaitis CM (2019) An update on the new classification of Ehlers-Danlos syndrome and review of the causes of bleeding in this population. Haemophilia 25:558–566. https://doi.org/10.1111/hae.13800 source
  Not checked in the free run.
Findingown data
Long-term improvement was observed in >50% of patients in both groups.
“Long-term improvement was observed in > 50% of patients in both groups.”
Quote in the paperSubstantial claim
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Findingown data
In the cohort, the prevalence of anamnestic bone fragility was 23% for a median age of 40.
“The prevalence of anamnestic bone fragility was high (23% for a median age of 40) in our cohort”
Quote in the paperSubstantial claim
Findingnone given
The 2017 diagnostic criteria could not distinguish patients with more extra-articular manifestations, bone fragility, neuropathic pain, or suspected MCAS.
“The 2017 diagnostic criteria could not distinguish patients with more extra-articular manifestations, bone fragility, neuropathic pain, or suspected MCAS.”
Quote in the paperSubstantial claim
Study design and conductown data
Patients lost to follow-up at T1 had a lower CSS-16 score than those not lost (28.0 vs 34.0, p=0.016).
“However, patients lost to follow-up at T1 had a lower CSS-16 score than those not lost to follow-up (28.0[18.5–34.5] vs. 34.0[27.0–40.5], p = 0.016)”
Quote in the paperNot a substantial claim
Study design and conductown data
The proportion of patients lost to follow-up at T2 was lower in the hEDS than HSD group (30% vs 56%, p=0.02).
“and the proportion of lost patients was lower in the hEDS than HSD group (30% vs. 56%, p = 0.02).”
Quote in the paperNot a substantial claim
Study design and conductown data
The proportion of patients lost to follow-up at T1 was lower in the hEDS than HSD group (13% vs 36%, p=0.01).
“and the proportion of lost patients was lower in the hEDS than HSD group (13% vs. 36%, p = 0.01).”
Quote in the paperNot a substantial claim
Premisecitation
The 2017 diagnostic criteria seemed not to adequately identify the more severely affected patients.
“Unfortunately in recent cohort publications [16, 17], these new criteria seemed to not adequately identify the more severely affected patients”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [16] McGillis L, Mittal N, Santa Mina D et al (2020) Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers-Danlos syndrome clinic: a retrospective review. Am J Med Genet A 182:484–492. https://doi.org/10.1002/ajmg.a.61459 source
  Not checked in the free run.
- cites [17] Copetti M, Morlino S, Colombi M et al (2019) Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients. Rheumatology (Oxford) 58:1722–1730. https://doi.org/10.1093/rheumatology/kez029 source
  Not checked in the free run.
Premisecitation
The 2017 diagnostic criteria did not highlight some extra-articular manifestations of hEDS such as bone involvement, neurologic involvement, sleep disorders, and immune system disorders.
“and did not highlight some extra-articular manifestations of hEDS such as bone involvement [18], neurologic involvement (including small-fiber neuropathy [19]), sleep disorders [20], and immune system disorders such as mast cell disorders [21].”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [18] Eller-Vainicher C, Bassotti A, Imeraj A et al (2016) Bone involvement in adult patients affected with Ehlers-Danlos syndrome. Osteoporos Int 27:2525–2531. https://doi.org/10.1007/s00198-016-3562-2 source
  Not checked in the free run.
- cites [19] Cazzato D, Castori M, Lombardi R et al (2016) Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology 87:155–159. https://doi.org/10.1212/WNL.0000000000002847 source
  Not checked in the free run.
- cites [20] Gaisl T, Giunta C, Bratton DJ et al (2017) Obstructive sleep apnoea and quality of life in Ehlers-Danlos syndrome: a parallel cohort study. Thorax 72:729–735. https://doi.org/10.1136/thoraxjnl-2016-209560 source
  Not checked in the free run.
Interpretationown data
The diagnostic category (hEDS vs. HSD) does not appear to be a prognostic factor for outcomes after physical therapy.
“The diagnostic category (hEDS vs. HSD) does not appear to be a prognostic factor for outcomes after physical therapy.”
Quote in the paperSubstantial claim
Interpretationown data
The results add weight to the proposition to consider hEDS/HSD as a single entity that requires the same treatments.
“Altogether, these results add weight to the proposition to consider hEDS/HSD as a single entity that requires the same treatments.”
Quote in the paperSubstantial claim
Study design and conductreasoning
The sample is representative of the hypermobile and hEDS/HSD patients in the French-speaking part of Switzerland (population 2 million).
“Being the only coordinated center in the French speaking part of Switzerland, our sample is representative of the hypermobile and hEDS/HSD patients in this region with a global population of 2 million.”
Quote in the paperSubstantial claim

May combine two claims. 19
Classified as probably not a substantial claim. 19

May combine two claims.
Findingown data
Fatigue, sleep disturbance, dysautonomia, and gastrointestinal symptoms were severe in >40% of patients.
“Fatigue, sleep disturbance, dysautonomia and gastrointestinal symptoms were severe in > 40% of patients.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
Bone fragility, neuropathic pain (DN4 >4/10), and suspected MCAS were equally prevalent in hEDS and HSD patients.
“The proportion of patients with anamnestic bone fragility was 23% and 28% in the hEDS and HSD groups, DN4 score > 4 was 47% and 49%, and suspected MCAS 43% and 50%, with no significant difference.”
- Also stated in: § Abstract · plain
  “Bone fragility, neuropathic pain and MCAS were equally prevalent.”
Quote in the paperSubstantial claim
- Rests on an assumption: Suspected MCAS based on coexistence of flush and/or dermographia reflects mast cell activation syndrome.
- Rests on an assumption: Anamnestic bone fragility (non-traumatic fractures and low BMD) reflects bone involvement in hEDS/HSD.
May combine two claims.
Findingown data
All included patients reported pain, and most (82%) had a severe score (≥3/4).
“All included patients reported pain, (Table 1) most (82%) with a severe score (≥ 3/4).”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
The 2017 criteria 2A (>5 systemic manifestations), 2B (positive family history), and 2C (musculoskeletal involvement) were more often present in hEDS than HSD patients.
“Criteria 2017 “2” and “3” were by definition more often present in hEDS than HSD patients: the proportion of > 5 systemic manifestations (criterion 2A) was 18% and 0% (p < 10–2), positive family history (2B) 93% and 33% (p < 10–4), and musculoskeletal pain or chronic or recurrent dislocations (2C) 98% and 75% (p < 10–3).”
Quote in the paperSubstantial claim
May combine two claims.
Findingown data
In the cohort, hEDS patients had significantly more pain, disability, and hypermobility than HSD patients.
“In our cohort, hEDS patients presented a more severe phenotype than did HSD patients: significantly more pain, disability and hypermobility.”
Quote in the paperSubstantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingcitation
The proportion of women, mean age, prevalence of pain, and fatigue in the sample are similar to those in prior studies.
“Reassuringly, the proportion of women [16, 17], mean age, prevalence of pain, and fatigue are similar to that in prior studies [16, 17, 40].”
Quote in the paperNot a substantial claim0 of 3 sources checked
- cites [16] McGillis L, Mittal N, Santa Mina D et al (2020) Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers-Danlos syndrome clinic: a retrospective review. Am J Med Genet A 182:484–492. https://doi.org/10.1002/ajmg.a.61459 source
  Not checked in the free run.
- cites [17] Copetti M, Morlino S, Colombi M et al (2019) Severity classes in adults with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients. Rheumatology (Oxford) 58:1722–1730. https://doi.org/10.1093/rheumatology/kez029 source
  Not checked in the free run.
- cites [40] Tinkle BT (2020) Symptomatic joint hypermobility. Best Pract Res Clin Rheumatol 34:101508. https://doi.org/10.1016/j.berh.2020.101508 source
  Not checked in the free run.
May combine two claims.
Findingown data
Among patients lost to follow-up, CSS-16 scores were lower and the proportion of HSD diagnoses was higher than hEDS.
“Among patients lost to follow-up, we found lower CSS-16 scores and a higher proportion of HSD diagnoses than hEDS.”
Quote in the paperNot a substantial claim
May combine two claims.
Findingown data
In the cohort, hEDS and HSD patients showed globally similar severity scores except for pain, motricity problems and spontaneous bleeding, and similar spectrum of extra-articular manifestations.
“Based on a clinical severity scale of 16 items, in our cohort, patients with hEDS fulfilling the 2017 diagnostic criteria and HSD patients showed globally similar severity scores except for pain, motricity problems and spontaneous bleeding, and similar spectrum of extra-articular manifestations.”
Quote in the paperSubstantial claim
- Rests on an assumption: The CSS-16, despite not being validated, is adequate to compare severity between hEDS and HSD patients.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown data
Follow-up data were available for 76 patients at T1 (78%) and 59 at T2 (61%).
“Follow-up data were available for 76 patients at T1 (78%) and 59 at T2 (61%), with a mean follow-up time of 6(6–10) and 20(18–26) months, respectively.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
The CSS-16 pragmatically reflects the authors' clinical evaluation.
“but pragmatically reflects our clinical evaluation.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationown data
These results add weight to a clinical pragmatic proposition to consider hEDS/HSD as a single entity that requires the same treatments.
“These results add weight to a clinical pragmatic proposition to consider hEDS/HSD as a single entity that requires the same treatments.”
Quote in the paperNot a substantial claim
- Rests on an assumption: The CSS-16 total score is a valid measure of overall clinical severity in hEDS/HSD despite not being validated for sensitivity and specificity.
- Rests on an assumption: Self-reported improvement at T2 is a valid measure of mid-term evolution.
Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.
Premisecitation
hEDS and HSD exist on the same physiological continuum, with hEDS being a more marked form.
“very recent studies consider that hEDS and HSD exist on the same physiological continuum (hEDS being a more marked form) [22]”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [22] Atwell K, Michael W, Dubey J et al (2021) Diagnosis and management of hypermobility spectrum disorders in primary care. J Am Board Fam Med 34:838–848. https://doi.org/10.3122/jabfm.2021.04.200374 source
  Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation
hEDS and HSD require the same pattern of multidisciplinary intervention.
“require the same pattern of multidisciplinary intervention [23, 24]”
Quote in the paperSubstantial claim0 of 2 sources checked
- cites [23] Yew KS, Kamps-Schmitt KA, Borge R (2021) Hypermobile ehlers-danlos syndrome and hypermobility spectrum disorders. Am Fam Physician 103:481–492
  Not checked in the free run.
- cites [24] Bennett SE, Walsh N, Moss T, Palmer S (2021) Developing a self-management intervention to manage hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS): an analysis informed by behaviour change theory. Disabil Rehabil. https://doi.org/10.1080/09638288.2021.1933618 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
hEDS and HSD are gathered in the same category for research purposes.
“or are gathered in the same category for research purposes [25, 26].”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [25] Demes JS, McNair B, Taylor MRG (2020) Use of complementary therapies for chronic pain management in patients with reported Ehlers-Danlos syndrome or hypermobility spectrum disorders. Am J Med Genet A 182:2611–2623. https://doi.org/10.1002/ajmg.a.61837 source
  Not checked in the free run.
- cites [26] Vermeulen S, De Mits S, De Ridder R et al (2020) Altered multi-segment ankle and foot kinematics during gait in patients with Hypermobile Ehlers-Danlos Syndrome/Hypermobility spectrum disorder. A case-control study Arthritis Care Res (Hoboken). https://doi.org/10.1002/acr.24526 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
No gene has been identified for hEDS.
“no gene has been identified for hEDS [11, 14].”
Quote in the paperNot a substantial claim0 of 2 sources checked
- cites [11] Malfait F, Francomano C, Byers P et al (2017) The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 175:8–26. https://doi.org/10.1002/ajmg.c.31552 source
  Not checked in the free run.
- cites [14] De Wandele I, Calders P, Peersman W et al (2014) Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: a comparative study with two other EDS types, fibromyalgia, and healthy controls. Semin Arthritis Rheum 44:353–361. https://doi.org/10.1016/j.semarthrit.2014.05.013 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data
Patients lost to follow-up at T2 had a slightly lower but not significantly different CSS-16 score than those not lost (32.5 vs 34.0, p=0.12).
“Patients lost to follow-up at T2 had a slightly lower but not significantly CSS-16 score than those not lost to follow-up (32.5[24.0–35.3] vs. 34.0[27.0–41.0], p = 0.12)”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
The CSS-16 scale has not been validated for sensitivity and specificity for hEDS/HSD.
“The scale has not been validated in terms of sensitivity and specificity for hESD/HSD”
Quote in the paperNot a substantial claim
May combine two claims.
Premisecitation
Neuropathic pain has been described as related to small-fiber neuropathy in HSD/hEDS and to nerve luxation/subluxation related to hypermobility.
“Neuropathic pain has been described as related to small-fiber neuropathy in HSD/hEDS [19] as well as to the well-known nerve luxation/subluxation related to the hypermobility.”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [19] Cazzato D, Castori M, Lombardi R et al (2016) Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology 87:155–159. https://doi.org/10.1212/WNL.0000000000002847 source
  Not checked in the free run.
May combine two claims.
Interpretationcitation
None of the prior studies suggested a difference between hEDS and HSD patients, but a high prevalence of bone involvement seems confirmed.
“None of these prior studies suggested a difference between hEDS and HSD patients, but a high prevalence of bone involvement seems confirmed.”
Quote in the paperSubstantial claim0 of 3 sources checked
- cites [18] Eller-Vainicher C, Bassotti A, Imeraj A et al (2016) Bone involvement in adult patients affected with Ehlers-Danlos syndrome. Osteoporos Int 27:2525–2531. https://doi.org/10.1007/s00198-016-3562-2 source
  Not checked in the free run.
- cites [34] Formenti AM, Doga M, Frara S et al (2019) Skeletal fragility: an emerging complication of Ehlers-Danlos syndrome. Endocrine 63:225–230. https://doi.org/10.1007/s12020-018-1822-y source
  Not checked in the free run.
- cites [35] Banica T, Coussens M, Verroken C et al (2020) Higher fracture prevalence and smaller bone size in patients with hEDS/HSD-a prospective cohort study. Osteoporos Int 31:849–856. https://doi.org/10.1007/s00198-019-05269-z source
  Not checked in the free run.
May combine two claims.
Study design and conductown data
The study did not record evolution reports for pain, disability, injury and empowerment separately, so it could not study whether pain decreased.
“We did not record evolution reports for these elements separately, and therefore could not study whether pain was decreased, for example.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation
The 2017 criteria were proposed to avoid neglecting a potentially severe disorder and to limit overemphasizing a non-pathological variation from the norm.
“The 2017 criteria were proposed to avoid neglecting a potentially severe disorder and to limit overemphasizing a non-pathological variation from the norm [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [15] Tinkle B, Castori M, Berglund B et al (2017) Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet 175:48–69. https://doi.org/10.1002/ajmg.c.31538 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductreasoning
The study was monocentric in a small country, but it is the referral center.
“This was a monocentric study in a small country, yet as described above, it is the referral center, which holds its importance.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S2 (checkable).
Premisecitation
To improve, treat and prevent musculoskeletal manifestations of joint hypermobility, education, active participation and active physical therapy intervention are recommended.
“Generally, to improve, treat and prevent musculoskeletal manifestations of joint hypermobility, the facets of education, active participation and active physical therapy intervention are recommended. [23, 24, 40–43].”
Quote in the paperNot a substantial claim0 of 6 sources checked
- cites [23] Yew KS, Kamps-Schmitt KA, Borge R (2021) Hypermobile ehlers-danlos syndrome and hypermobility spectrum disorders. Am Fam Physician 103:481–492
  Not checked in the free run.
- cites [24] Bennett SE, Walsh N, Moss T, Palmer S (2021) Developing a self-management intervention to manage hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS): an analysis informed by behaviour change theory. Disabil Rehabil. https://doi.org/10.1080/09638288.2021.1933618 source
  Not checked in the free run.
- cites [40] Tinkle BT (2020) Symptomatic joint hypermobility. Best Pract Res Clin Rheumatol 34:101508. https://doi.org/10.1016/j.berh.2020.101508 source
  Not checked in the free run.
- cites [41] Coussens M, Calders P, Lapauw B et al (2021) Does muscle strength change over time in patients with hypermobile ehlers-danlos syndrome/hypermobility spectrum disorder? an eight-year follow-up study. Arthritis Care Res (Hoboken) 73:1041–1048. https://doi.org/10.1002/acr.24220 source
  Not checked in the free run.
- cites [42] Scheper MC, Juul-Kristensen B, Rombaut L et al (2016) Disability in adolescents and adults diagnosed with hypermobility-related disorders: a meta-analysis. Arch Phys Med Rehabil 97:2174–2187. https://doi.org/10.1016/j.apmr.2016.02.015 source
  Not checked in the free run.
- cites [43] Engelbert RHH, Juul-Kristensen B, Pacey V et al (2017) The evidence-based rationale for physical therapy treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome. Am J Med Genet C Semin Med Genet 175:158–167. https://doi.org/10.1002/ajmg.c.31545 source
  Not checked in the free run.
May combine two claims.
Premisecitation
Strong evidence for physical therapy is lacking, yet it is the mainstay of management.
“Strong evidence for physical therapy is lacking [39], yet it is the mainstay of management [8, 40, 41].”
Quote in the paperNot a substantial claim0 of 4 sources checked
- cites [39] Simmonds JV, Herbland A, Hakim A et al (2019) Exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type. Disabil Rehabil 41:445–455. https://doi.org/10.1080/09638288.2017.1398278 source
  Not checked in the free run.
- cites [8] Corrado B, Ciardi G (2018) Hypermobile Ehlers-Danlos syndrome and rehabilitation: taking stock of evidence based medicine: a systematic review of the literature. J Phys Ther Sci 30:843–847. https://doi.org/10.1589/jpts.30.847 source
  Not checked in the free run.
- cites [40] Tinkle BT (2020) Symptomatic joint hypermobility. Best Pract Res Clin Rheumatol 34:101508. https://doi.org/10.1016/j.berh.2020.101508 source
  Not checked in the free run.
- cites [41] Coussens M, Calders P, Lapauw B et al (2021) Does muscle strength change over time in patients with hypermobile ehlers-danlos syndrome/hypermobility spectrum disorder? an eight-year follow-up study. Arthritis Care Res (Hoboken) 73:1041–1048. https://doi.org/10.1002/acr.24220 source
  Not checked in the free run.
May combine two claims.
Study design and conductreasoning
The study was not able to assess the reason for lost to follow-up because it was the patients' decision not to return to clinical care, and it would have been invasive to ask them.
“Unfortunately, we were not able to assess the reason for lost to follow-up because it was the patients’ decision not to return to clinical care, and it would have been invasive to ask them the reason for this.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning
It could be a bias of over-positivity of MCAS symptoms in our cohort.
“Therefore, it could be a bias of over-positivity of MCAS symptoms in our cohort.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given
The scores used were mostly subjective or detection tools.
“The scores used were mostly subjective or detection tools, which are convenient to use in a clinical setting.”
Quote in the paperNot a substantial claim
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationreasoning
The reason for lost to follow-up could be a bias in the results (underestimation or overestimation of effects).
“The reason could be a bias in the results we present (underestimation of effects with more loss of patients with great improvement or over-estimation with more loss of patients with deterioration).”
Quote in the paperNot a substantial claim
Classified as probably not a substantial claim.
Premisecitation
The 2017 criteria of hEDS limits the diagnosis to patients with clear Mendelian transmission or those with extra-articular and systemic manifestation.
“Thus, the 2017 criteria of hEDS limits the diagnosis to patients with clear Mendelian transmission or those with extra-articular and systemic manifestation.”
Quote in the paperSubstantial claim0 of 1 sources checked
- cites [15] Tinkle B, Castori M, Berglund B et al (2017) Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome Type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. Am J Med Genet C Semin Med Genet 175:48–69. https://doi.org/10.1002/ajmg.c.31538 source
  Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.
Interpretationreasoning
A diagnosis is important because the therapeutic approach is different: medication for primary neuropathic pain versus proprioceptive control or surgery for hypermobility-related pain.
“A diagnosis is important because the therapeutic approach is different: medication for primary neuropathic pain versus proprioceptive control or surgery for hypermobility-related pain.”
Quote in the paperNot a substantial claim
May combine two claims.
Interpretationown data
hEDS and HSD patients showed similar disease severity scores except for pain, motricity problems, and bleeding, and a similar spectrum of extra-articular manifestations.
“hEDS and HDS patients showed similar disease severity score except for pain, motricity problems and bleeding, and similar spectrum of extra-articular manifestations.”
Quote in the paperSubstantial claim
- Rests on an assumption: The CSS-16 total score is a valid measure of overall clinical severity in hEDS/HSD despite not being validated for sensitivity and specificity.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation
Chronic pain is an important problem for HSD/hEDS patients.
“Chronic pain is an important problem for HSD/hEDS patients [36].”
Quote in the paperNot a substantial claim0 of 1 sources checked
- cites [36] Syx D, De Wandele I, Rombaut L, Malfait F (2017) Hypermobility, the Ehlers-Danlos syndromes and chronic pain. Clin Exp Rheumatol 35(Suppl 107):116–122
  Not checked in the free run.

32 of 32

The paper relies on this without support.
The CSS-16 total score is a valid measure of overall clinical severity in hEDS/HSD despite not being validated for sensitivity and specificity.
“The scale has not been validated in terms of sensitivity and specificity for hESD/HSD but pragmatically reflects our clinical evaluation.”
The paper relies on this without support.
Self-reported improvement at T2 is a valid measure of mid-term evolution.
“At T1 and T2, patients were asked to consider pain, disability, injury and empowerment together in answering the following question: “Compared to the initial assessment, how do you now consider yourself regarding pain, disability, injury and empowerment?”, with possible answers of improved/not improved.”
The paper relies on this without support.
Suspected MCAS based on coexistence of flush and/or dermographia reflects mast cell activation syndrome.
“Mast cell activation syndrome (MCAS) was clinically suspected if the patient reported the coexistence of flush and/or dermographia.”
The paper relies on this without support.
Anamnestic bone fragility (non-traumatic fractures and low BMD) reflects bone involvement in hEDS/HSD.
“Bone involvement was assessed by a question assessing the prevalence of non-traumatic fractures and personal history of low bone mineral density (BMD).”
The authors state this as an assumption.
The severity of symptoms and a clear diagnosis are motivational factors for attending a tertiary center.
“We can reasonably assume that the severity of symptoms and a clear diagnosis are motivational factors for attending a tertiary center.”
The paper relies on this without support.
The global evolution composite self-report is a valid measure of improvement in pain, disability, injury and empowerment.
“The global evolution is a composite self-report regarding pain, disability, injury and empowerment.”
The paper relies on this without support.
The CSS-16, despite not being validated, is adequate to compare severity between hEDS and HSD patients.
“The CSS-16 is not validated, and its sensitivity and specificity for hEDS or compared to other disorders such as fibromyalgia is not known.”
The paper relies on this without support.
The observed improvement in articular symptoms is attributable to the coordinated physical therapy program rather than to other factors.
“With our program, more than 50% of patients showed improved articular symptoms at the end of follow-up.”

8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Increased risk of bleeding in association with colonoscopy has not been reported in HSD/hEDS.
“Increased risk of bleeding in association with colonoscopy has not been reported but should be assessed in the context of the patient's personal history of bleeding (which may be increased) and the planned procedure, particularly in those with mast cell activation syndrome. 88”
From Hypermobile Ehlers–Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know (2022) · cites this paper as [88]
Laboratory results are usually within normal range in HSD/hEDS.
“Laboratory results are usually within normal range. 88”
From Hypermobile Ehlers–Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know (2022) · cites this paper as [88]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Some hEDS patients are reported not to meet a required criterion
Major
The methods require patients classified as hEDS to meet all three criteria, including criterion 1. Table 1 reports criterion 1 as positive for only 90% of the hEDS group.
Conclusion calls total severity scores similar despite a significant difference
Minor
The conclusion describes the groups as having globally similar severity scores, but Table 1 reports a significantly higher CSS-16 total score for hEDS (40.0 versus 31.5; p = 0.04).

2 of 2

Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4)
Bouhassira, D., Attal, N., Alchaar, H., Boureau, F., Brochet, B., Bruxelle, J., Cunin, G., Fermanian, J., Giniès, P., Grun-Overdyking, A., et al. (2005) · Pain · doi:10.1016/j.pain.2004.12.010 · Cited by 2,730 · see citing works
The 2017 international classification of the Ehlers–Danlos syndromes
Malfait, F., Francomano, C., Byers, P., Belmont, J., Berglund, B., Black, J., Bloom, L., Bowen, J. M., Brady, A. F., Burrows, N. P., et al. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31552 · Cited by 1,936 · cited 6× · see citing works
“Nevertheless, this symptom of spontaneous bleeding was not considered sensitive and specific enough to be included in the 2017 diagnostic criteria [11].”
BackgroundMethodInfluential
Fragility fractures in Europe: burden, management and opportunities
Borgström, F., Karlsson, L. K., Ortsäter, G., Norton, N., Halbout, P., Cooper, C. C., Lorentzon, M., McCloskey, E. V., Harvey, N. C., Javaid, M. K., et al. (2020) · Archives of Osteoporosis · doi:10.1007/s11657-020-0706-y · Cited by 804 · see citing works
Nosology and classification of genetic skeletal disorders: 2015 revision
Bonafe, L., Cormier‐Daire, V., Hall, C., Lachman, R., Mortier, G., Mundlos, S., Nishimura, G., Sangiorgi, L., Savarirayan, R., Sillence, D., et al. (2015) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.37365 · Cited by 569 · see citing works
Hypermobile Ehlers–Danlos syndrome (a.k.a. Ehlers–Danlos syndrome Type III and Ehlers–Danlos syndrome hypermobility type): Clinical description and natural history
Tinkle, B., Castori, M., Berglund, B., Cohen, H., Grahame, R., Kazkaz, H., & Levy, H. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31538 · Cited by 499 · cited 2× · see citing works
“In the absence of molecular support, in 2017, the International EDS Consortium proposed new diagnosis criteria for hEDS [11, 15] that were based on a set of clinical criteria, expertise of the clinicians, and absence of another pathology explaining the symptoms of hEDS.”
Background
Untitled work
(2007) · PubMed · Cited by 356 · see citing works
Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: a national electronic cohort study and case–control comparison
Demmler, J. C., Atkinson, M. D., Reinhold, E. J., Choy, E., Lyons, R. A., & Brophy, S. T. (2019) · BMJ Open · doi:10.1136/bmjopen-2019-031365 · Cited by 271 · cited 1× · see citing works
“With this dataset, we can confirm that hEDS is not rare [46]: 42% of the patients referred to the hypermobility-dedicated consultation met the 2017 diagnostic criteria.”
Method
Haploinsufficiency of TNXB Is Associated with Hypermobility Type of Ehlers-Danlos Syndrome
Zweers, M. C., Bristow, J., Steijlen, P. M., Dean, W. B., Hamel, B. C., Otero, M., Kucharekova, M., Boezeman, J. B., & Schalkwijk, J. (2003) · The American Journal of Human Genetics · doi:10.1086/376564 · Cited by 242 · cited 1× · see citing works
“Despite a probable autosomal dominant inheritance [11] and reports of haploinsufficiency or missense of tenascin X in a few cases [12, 13], no gene has been identified for hEDS [11, 14].”
Background
The effects of gender and pubertal status on generalized joint laxity in young athletes
Quatman, C. E., Ford, K. R., Myer, G. D., Paterno, M. V., & Hewett, T. E. (2008) · Journal of Science and Medicine in Sport · doi:10.1016/j.jsams.2007.05.005 · Cited by 217 · cited 1× · see citing works
“This health condition can be asymptomatic and has a varied prevalence, 2–57% [1, 2].”
Background
The evidence-based rationale for physical therapy treatment of children, adolescents, and adults diagnosed with joint hypermobility syndrome/hypermobile Ehlers Danlos syndrome
Engelbert, R. H. H., Juul‐Kristensen, B., Pacey, V., de Wandele, I., Smeenk, S., Woinarosky, N., Sabo, S., Scheper, M. C., Russek, L., & Simmonds, J. V. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31545 · Cited by 177 · see citing works
Disability in Adolescents and Adults Diagnosed With Hypermobility-Related Disorders: A Meta-Analysis
Scheper, M. C., Juul-Kristensen, B., Rombaut, L., Rameckers, E. A., Verbunt, J., & Engelbert, R. H. (2016) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/j.apmr.2016.02.015 · Cited by 146 · see citing works
Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers‐danlos syndrome hypermobility type compared to other heritable connective tissue disorders
Colombi, M., Dordoni, C., Chiarelli, N., & Ritelli, M. (2015) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31429 · Cited by 127 · see citing works
The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS)
Kucharik, A. H., & Chang, C. (2020) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-019-08755-8 · Cited by 122 · cited 1× · see citing works
“Since this publication, other articles reported a link between hEDS and MCAS [37, 38], and patient EDS association reported this possible association (https:// www.”
Background
Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes
Cazzato, D., Castori, M., Lombardi, R., Caravello, F., Bella, E. D., Petrucci, A., Grammatico, P., Dordoni, C., Colombi, M., & Lauria, G. (2016) · Neurology · doi:10.1212/wnl.0000000000002847 · Cited by 122 · see citing works
Autonomic symptom burden in the hypermobility type of Ehlers–Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls
De Wandele, I., Calders, P., Peersman, W., Rimbaut, S., De Backer, T., Malfait, F., De Paepe, A., & Rombaut, L. (2014) · Seminars in Arthritis and Rheumatism · doi:10.1016/j.semarthrit.2014.05.013 · Cited by 119 · see citing works
Mast cell disorders in Ehlers-Danlos syndrome
Seneviratne, S. L., Maitland, A., & Afrin, L. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31555 · Cited by 107 · cited 1× · see citing works
“Unfortunately in recent cohort publications [16, 17], these new criteria seemed to not adequately identify the more severely affected patients and did not highlight some extraarticular manifestations of hEDS such as bone involvement [18], neurologic involvement (including small-fiber neuropathy [19]), sleep disorders…”
Background
Contemporary approach to joint hypermobility and related disorders
Castori, M., & Hakim, A. (2017) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000541 · Cited by 105 · cited 1× · see citing works
“Yet, some authors doubt that the more severely affected patients are correctly identified [16, 17, 30, 31].”
Background
Living with joint hypermobility syndrome: patient experiences of diagnosis, referral and self-care
Terry, R. H., Palmer, S. T., Rimes, K. A., Clark, C. J., Simmonds, J. V., & Horwood, J. P. (2015) · Family Practice · doi:10.1093/fampra/cmv026 · Cited by 94 · cited 1× · see citing works
“The diagnosis of EDS, especially hypermobile EDS (hEDS), in which extra-articular manifestations can be subtle, is challenging [10].”
Background
Untitled work
(2017) · PubMed · Cited by 90 · see citing works
Multidisciplinary treatment of disability in ehlers–danlos syndrome hypermobility type/hypermobility syndrome: A pilot study using a combination of physical and cognitive‐behavioral therapy on 12 women
Bathen, T., Hångmann, A. B., Hoff, M., Andersen, L. Ø., & Rand‐Hendriksen, S. (2013) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.36060 · Cited by 86 · cited 1× · see citing works
“[45] showed improvement in perceived performance of daily activities, muscle strength and endurance in 12 women via a cognitive behavioral-based intervention including teaching easy exercises to perform at home.”
Background
Broadening the Spectrum of Ehlers Danlos Syndrome in Patients With Congenital Adrenal Hyperplasia
Morissette, R., Chen, W., Perritt, A. F., Dreiling, J. L., Arai, A. E., Sachdev, V., Hannoush, H., Mallappa, A., Xu, Z., McDonnell, N. B., et al. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2015-2232 · Cited by 68 · cited 1× · see citing works
“Despite a probable autosomal dominant inheritance [11] and reports of haploinsufficiency or missense of tenascin X in a few cases [12, 13], no gene has been identified for hEDS [11, 14].”
Background
Exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers–Danlos syndrome – hypermobility type
Simmonds, J. V., Herbland, A., Hakim, A., Ninis, N., Lever, W., Aziz, Q., & Cairns, M. (2019) · Disability and Rehabilitation · doi:10.1080/09638288.2017.1398278 · Cited by 60 · see citing works
Symptomatic joint hypermobility
Tinkle, B. T. (2020) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2020.101508 · Cited by 60 · cited 2× · see citing works
“Strong evidence for physical therapy is lacking [39], yet it is the mainstay of management [8, 40, 41].”
BackgroundResult
Severity classes in adults with hypermobile Ehlers–Danlos syndrome/hypermobility spectrum disorders: a pilot study of 105 Italian patients
Copetti, M., Morlino, S., Colombi, M., Grammatico, P., Fontana, A., & Castori, M. (2019) · Rheumatology · doi:10.1093/rheumatology/kez029 · Cited by 55 · see citing works
Diagnosis and Management of Hypermobility Spectrum Disorders in Primary Care
Atwell, K., Michael, W., Dubey, J., James, S., Martonffy, A., Anderson, S., Rudin, N., & Schrager, S. (2021) · The Journal of the American Board of Family Medicine · doi:10.3122/jabfm.2021.04.200374 · Cited by 52 · cited 1× · see citing works
“In the same vein, very recent studies consider that hEDS and HSD exist on the same physiological continuum (hEDS being a more marked form) [22], require the same pattern of multidisciplinary intervention [23, 24], or are gathered in the same category for research purposes [25, 26].”
Background
Bone involvement in adult patients affected with Ehlers-Danlos syndrome.
Eller-Vainicher, C., Bassotti, A., Imeraj, A., Cairoli, E., Ulivieri, F. M., Cortini, F., Dubini, M., Marinelli, B., Spada, A., & Chiodini, I. (2016) · Osteoporosis International · doi:10.1007/s00198-016-3562-2 · Cited by 51 · see citing works
Painful piezogenic pedal papules in patients with Ehlers-Danlos syndrome
Kahana, M., Feinstein, A., Tabachnic, E., Schewach-Millet, M., & Engelberg, S. (1987) · Journal of the American Academy of Dermatology · doi:10.1016/s0190-9622(87)70192-3 · Cited by 49 · cited 1× · see citing works
“We recorded piezogenic papules separately, added as a diagnostic feature in 2017 [11], based on a small study [32].”
Method
Obstructive sleep apnoea and quality of life in Ehlers-Danlos syndrome: a parallel cohort study
Gaisl, T., Giunta, C., Bratton, D. J., Sutherland, K., Schlatzer, C., Sievi, N., Franzen, D., Cistulli, P. A., Rohrbach, M., & Kohler, M. (2017) · Thorax · doi:10.1136/thoraxjnl-2016-209560 · Cited by 47 · see citing works
An update on the new classification of Ehlers‐Danlos syndrome and review of the causes of bleeding in this population
Jesudas, R., Chaudhury, A., & Laukaitis, C. M. (2019) · Haemophilia · doi:10.1111/hae.13800 · Cited by 43 · cited 2× · see citing works
“However, patients with abnormal hypermobility experience more abnormal bleeding [29].”
Background
Cutis Laxa
Mohamed, M., Voet, M., Gardeitchik, T., & Morava, É. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-7893-1_11 · Cited by 40 · see citing works
Utilization of the 2017 diagnostic criteria for hEDS by the Toronto GoodHope Ehlers–Danlos syndrome clinic: A retrospective review
McGillis, L., Mittal, N., Santa Mina, D., So, J., Soowamber, M., Weinrib, A., Soever, L., Rozenberg, D., Liu, L., Tse, Y., et al. (2020) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61459 · Cited by 35 · cited 6× · see citing works
“Yet, some authors doubt that the more severely affected patients are correctly identified [16, 17, 30, 31].”
BackgroundResultInfluential
Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders.
Yew, K. S., Kamps-Schmitt, K. A., & Borge, R. (2021) · PubMed · Cited by 33 · see citing works
Use of complementary therapies for chronic pain management in patients with reported <scp>Ehlers‐Danlos</scp> syndrome or hypermobility spectrum disorders
Demes, J. S., McNair, B., & Taylor, M. R. G. (2020) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61837 · Cited by 30 · see citing works
The management of osteogenesis imperfecta in adults: state of the art
Lafage‐Proust, M., & Courtois, I. (2019) · Joint Bone Spine · doi:10.1016/j.jbspin.2019.02.001 · Cited by 26 · see citing works
Hypermobile Ehlers-Danlos syndrome and rehabilitation: taking stock of evidence based medicine: a systematic review of the literature
Corrado, B., & Ciardi, G. (2018) · Journal of Physical Therapy Science · doi:10.1589/jpts.30.847 · Cited by 22 · cited 1× · see citing works
“Strong evidence for physical therapy is lacking [39], yet it is the mainstay of management [8, 40, 41].”
Background
Higher fracture prevalence and smaller bone size in patients with hEDS/HSD—a prospective cohort study
Banica, T., Coussens, M., Verroken, C., Calders, P., De Wandele, I., Malfait, F., Zmierczak, H.-G., Goemaere, S., Lapauw, B., & Rombaut, L. (2020) · Osteoporosis International · doi:10.1007/s00198-019-05269-z · Cited by 19 · cited 1× · see citing works
“[35] suggested that bone fragility in hEDS or HSD patients could be linked to lower mechanical strain.”
Background
Skeletal fragility: an emerging complication of Ehlers–Danlos syndrome
Formenti, A. M., Doga, M., Frara, S., Ritelli, M., Colombi, M., Banfi, G., & Giustina, A. (2019) · Endocrine · doi:10.1007/s12020-018-1822-y · Cited by 17 · cited 1× · see citing works
“[34] proposed to screen all patients with hEDS by dual X-ray absorptiometry.”
Background
Developing a self-management intervention to manage hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS): an analysis informed by behaviour change theory
Bennett, S. E., Walsh, N., Moss, T., & Palmer, S. (2022) · Disability and Rehabilitation · doi:10.1080/09638288.2021.1933618 · Cited by 16 · cited 1× · see citing works
“In the same vein, very recent studies consider that hEDS and HSD exist on the same physiological continuum (hEDS being a more marked form) [22], require the same pattern of multidisciplinary intervention [23, 24], or are gathered in the same category for research purposes [25, 26].”
Background
Subjective health complaints and illness perception amongst adults with Joint Hypermobility Syndrome/Ehlers–Danlos Syndrome-HypermobilityType – a cross-sectional study
Hope, L., Juul‐Kristensen, B., Løvaas, H., Løvvik, C., & Mæland, S. (2017) · Disability and Rehabilitation · doi:10.1080/09638288.2017.1390695 · Cited by 16 · cited 1× · see citing works
“[44] showed that all hEDS and HSD patients had higher frequency and severity of subjective health complaints than matched controls.”
Background
Does Muscle Strength Change Over Time in Patients With Hypermobile Ehlers‐Danlos Syndrome/Hypermobility Spectrum Disorder? An Eight‐Year Follow‐Up Study
Coussens, M., Calders, P., Lapauw, B., Celie, B., Banica, T., De Wandele, I., Pacey, V., Malfait, F., & Rombaut, L. (2021) · Arthritis Care & Research · doi:10.1002/acr.24220 · Cited by 11 · see citing works
Altered Multisegment Ankle and Foot Kinematics During Gait in Patients With Hypermobile <scp>Ehlers‐Danlos</scp> Syndrome/Hypermobility Spectrum Disorder: A Case–Control Study
Vermeulen, S., De Mits, S., De Ridder, R., Calders, P., De Schepper, J., Malfait, F., & Rombaut, L. (2022) · Arthritis Care & Research · doi:10.1002/acr.24526 · Cited by 10 · cited 1× · see citing works
“In the same vein, very recent studies consider that hEDS and HSD exist on the same physiological continuum (hEDS being a more marked form) [22], require the same pattern of multidisciplinary intervention [23, 24], or are gathered in the same category for research purposes [25, 26].”
Background
Ehlers-Danlos syndromes: new labels confuse everyone
Williams, A. N. (2019) · BMJ · doi:10.1136/bmj.l6095 · Cited by 6 · see citing works
[Severe Mast Cell Activation Syndrome in a 15-year-old patient with an hypermobile Ehlers-Danlos syndrome].
Daens, S., Grossin, D., Hermanns‐Lê, T., Peeters, D., & Manicourt, D.-H. (2018) · PubMed · Cited by 4 · see citing works
Syndrome d’Ehlers-Danlos (SED) type III (hypermobile): validation d’une échelle clinique somatosensorielle (ECSS-62), à propos de 626 cas
Hamonet, C., Brock, I., Pommeret, S., Pommeret, S., Amoretti, R., Baeza‐Velasco, C., & Metlaine, A. (2017) · Bulletin de l Académie Nationale de Médecine · doi:10.1016/s0001-4079(19)30525-4 · Cited by 3 · see citing works
[News in osteogenesis imperfecta: from research to clinical management].
Aubry‐Rozier, B., Unger, S., Brégou, A., et al. (2015) · PubMed · Cited by 3 · see citing works
Self-citation

Flagged first, then by citations

Research works printed but not linked: 1

de Ferranti SD KE. Physical activity and exercise in patients with congenital heath disease, Literature review current through: Feb 2019. 2019;[cited 2019 Nov 10]. Available from: https://www.uptodate.com/contents/physical-activityand-exercise-in-pat - Search Results. In: PubMed. Accessed 2 Aug 2021

Sorted by citations

Hypermobile Ehlers–Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know
Thwaites, P. A., Gibson, P. R., & Burgell, R. E. (2022) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15927 · Cited by 59 · see citing works
<scp>Ehlers–Danlos</scp> syndromes, hypermobility spectrum disorders, and associated <scp>co‐morbidities</scp>: Reports from <scp>EDS ECHO</scp>
Hakim, A. J., Tinkle, B. T., & Francomano, C. A. (2021) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31954 · Cited by 37 · see citing works
The biopsychosocial impact of hypermobility spectrum disorders in adults: a scoping review
Clark, N., Johnson, M., Rangan, A., Kottam, L., & Swainston, K. (2023) · Rheumatology International · doi:10.1007/s00296-023-05298-2 · Cited by 33 · see citing works
Small fiber neuropathy in hypermobile Ehlers Danlos syndrome/hypermobility spectrum disorder
Fernandez, A., Aubry‐Rozier, B., Vautey, M., Berna, C., & Suter, M. R. (2022) · Journal of Internal Medicine · doi:10.1111/joim.13539 · Cited by 26 · see citing works
Self-citation
Resource utilization and multidisciplinary care needs for patients with Ehlers–Danlos syndrome
Jones, J. T., Black, W. R., Cogan, W., & Callen, E. F. (2022) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.2057 · Cited by 23 · see citing works
Bridging the Diagnostic Gap for Hypermobile Ehlers‐Danlos Syndrome and Hypermobility Spectrum Disorders: Evidence of a Common Extracellular Matrix Fragmentation Pattern in Patient Plasma as a Potential Biomarker
Ritelli, M., Chiarelli, N., Cinquina, V., Bertini, V., Piantoni, S., Caproli, A., Pina, S. E. L. D., Franceschini, F., Zarattini, G., Gandy, W., et al. (2024) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.63857 · Cited by 23 · see citing works
Physical therapy interventions in generalized hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome: a scoping review
Brittain, M. G., Flanagan, S., Foreman, L., & Teran-Wodzinski, P. C. (2023) · Disability and Rehabilitation · doi:10.1080/09638288.2023.2216028 · Cited by 23 · see citing works
“As delineated in the 2017 classification, Generalized Hypermobility Spectrum Disorder (G-HSD) and hypermobile Ehlers-Danlos Syndrome (hEDS) are common connective tissue disorders with overlapping symptoms that may range in severity from asymptomatic to debilitating [7].”
Background
Defining the Chronic Complexities of hEDS and HSD: A Global Survey of Diagnostic Challenges, Life-Long Comorbidities, and Unmet Needs
Daylor, V., Griggs, M., Weintraub, A., Byrd, R. L., Petrucci, T., Huff, M. L., Byerly, K., Fenner, R., Severance, S., Griggs, C., et al. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14165636 · Cited by 29 · see citing works
Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for mucocutaneous bleeding disorders
Sidonio, R. F., Bryant, P., Paola, J. D., Hale, S. A., Heiman, M., Horowitz, G. S., Humphrey, C., Jaffray, J., Joyner, L. C., Kasthuri, R. S., et al. (2023) · Expert Review of Hematology · doi:10.1080/17474086.2023.2171983 · Cited by 20 · see citing works
“Individuals with HSD share many of the clinical findings of EDS including associated bleeding symptoms [62], but do not meet formal EDS diagnostic criteria [61].”
Background
Looking back and beyond the 2017 diagnostic criteria for hypermobile Ehlers‐Danlos syndrome: A retrospective cross‐sectional study from an Italian reference center
Ritelli, M., Chiarelli, N., Cinquina, V., Vezzoli, M., Venturini, M., & Colombi, M. (2023) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.63426 · Cited by 22 · see citing works
“Based on the prevalence of observed signs and symptoms in our cohort, along with cluster analysis and review of relevant literature (Aubry-Rozier et al., 2021; Copetti et al., 2019; Demmler et al., 2019; Gensemer et al., 2021; Kumskova et al., 2023; Malfait et al., 2020; Martinez et al., 2021;…”
BackgroundMethodResult
Clinical characteristics of patients with hypermobile type Ehlers–Danlos syndrome (hEDS) and generalized hypermobility spectrum disorders (G-HSD): an online survey
Teran-Wodzinski, P. C., & Kumar, A. (2023) · Rheumatology International · doi:10.1007/s00296-023-05378-3 · Cited by 20 · see citing works
RNA-Seq of Dermal Fibroblasts from Patients with Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders Supports Their Categorization as a Single Entity with Involvement of Extracellular Matrix Degrading and Proinflammatory Pathomechanisms
Ritelli, M., Chiarelli, N., Cinquina, V., Zoppi, N., Bertini, V., Venturini, M., & Colombi, M. (2022) · Cells · doi:10.3390/cells11244040 · Cited by 19 · see citing works
Improvement in chronic pelvic pain, orthostatic intolerance and interstitial cystitis symptoms after treatment of pelvic vein insufficiency
Smith, S. J., Sichlau, M. J., Smith, B. H., Knight, D. R. T., Chen, B., & Rowe, P. C. (2023) · Phlebology The Journal of Venous Disease · doi:10.1177/02683555231219737 · Cited by 16 · see citing works
Estimates of the excess cost burden of Ehlers-Danlos syndromes: a United States MarketScan® claims database analysis
Schubart, J. R., Schaefer, É., Knight, D. R. T., Mills, S. E., & Francomano, C. A. (2024) · Frontiers in Public Health · doi:10.3389/fpubh.2024.1365712 · Cited by 15 · see citing works
Similarities and differences in self-reported symptoms and comorbidities between hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorders
Darakjian, A. A., Bhutani, M., Fairweather, D., Kocsis, S. C., Fliess, J. J., Khatib, S., Weigel, G. J., McCabe, E. J., Balamurugan, V., Perona, E. E., et al. (2024) · Rheumatology Advances in Practice · doi:10.1093/rap/rkae134 · Cited by 17 · see citing works
“In a study by Aubry-Rozier et al. [14], 97 patients (61 hEDS, 36 HSD) were diagnosed at their specialty clinic with hEDS or HSD and given the 16-item Clinical Severity Score (CSS-16) questionnaire.”
Psychological interventions to improve pain, fatigue, anxiety, depression, and quality of life in children and adults with hypermobility spectrum disorders and Ehlers-Danlos syndrome: a systematic review
Clark, N., Kainth, G. S., Johnson, M., Rangan, A., Kottam, L., & Swainston, K. (2023) · Rheumatology International · doi:10.1007/s00296-023-05503-2 · Cited by 15 · see citing works
Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A scoping review and expert co-creation of evidence-based clinical guidelines
Pezaro, S., Brock, I., Buckley, M., Callaway, S., Demirdas, S., Hakim, A. J., Harris, C. L., Gross, C. H., Karanfil, M., Ray, I. L., et al. (2024) · PLoS ONE · doi:10.1371/journal.pone.0302401 · Cited by 12 · see citing works
Functional neurological signs in hypermobile Ehlers–Danlos syndrome and hypermobile spectrum disorders with suspected neuropathic pain
Fernandez, A., Jaquet, M., Aubry‐Rozier, B., Suter, M. R., Aybek, S., & Berna, C. (2024) · Brain and Behavior · doi:10.1002/brb3.3441 · Cited by 12 · see citing works
“The patient cohort is a subset of previously described population (Aubry-Rozier et al., 2021; Fernandez et al., 2022) who underwent a neurological assessment (between 09-2019and 10-2020;CERVD2019-00093).”
BackgroundSelf-citation
Social media use by patients with hypermobile Ehlers–Danlos syndrome
Halverson, C. M. E., Doyle, T. A., & Vershaw, S. L. (2024) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.2467 · Cited by 10 · see citing works
Nonpelvic comorbid symptoms of 45 patients with pain of pelvic venous origin, before and after treatment
Smith, S. J., Smith, B. H., Sichlau, M. J., Chen, B., Knight, D. R. T., & Rowe, P. C. (2024) · Phlebology The Journal of Venous Disease · doi:10.1177/02683555241273109 · Cited by 10 · see citing works
“23 – 31 Here, symptom prevalence and treatment effects, as measured by reported scores, were reviewed for 21 individual nonpelvic symptoms.”
Assessment of gait mechanics and muscle strength in hypermobile Ehlers Danlos Syndrome
Ball, L. N., Jacobs, M. V., McLouth, C. J., Clasey, J. L., Francomano, C. A., Sheppard, M. B., & Samaan, M. A. (2024) · Clinical Biomechanics · doi:10.1016/j.clinbiomech.2024.106210 · Cited by 10 · see citing works
Autonomic symptom burden, comorbidities and quality of life in women with Hypermobility Spectrum Disorders and hypermobile Ehlers-Danlos syndrome
Collins, M., Liang, E., Fuster, E., & Blitshteyn, S. (2025) · Autonomic Neuroscience · doi:10.1016/j.autneu.2025.103356 · Cited by 10 · see citing works
‘I Have Had to Stop Singing Because I Can't Take the Pain’: Experiences of Voice, Ability, and Loss in Singers With Hypermobility Spectrum Disorders
Jeffery, T., Postăvaru, G.-I., Matei, R., & Meizel, K. (2021) · Journal of Voice · doi:10.1016/j.jvoice.2021.11.017 · Cited by 9 · see citing works
Proteomic discoveries in hypermobile Ehlers–Danlos syndrome reveal insights into disease pathophysiology
Griggs, M., Daylor, V., Petrucci, T., Weintraub, A., Huff, M. L., Willey, S., Byerly, K., Loizzi, B., Morningstar, J. E., Ball, L. E., et al. (2025) · ImmunoHorizons · doi:10.1093/immhor/vlaf044 · Cited by 8 · see citing works
“30,31 Reductions in IL-19, a cytokine associated with Th2-type immune responses and mucosal inflammation, may align with the high prevalence of allergic, dermatologic, and gastrointestinal symptoms observed in individuals with hEDS.”
Defining a core outcome set for hypermobility spectrum disorders and hypermobile Ehlers-Danlos syndrome: A Delphi consensus study
Clark, N., Johnson, M., Rangan, A., Kottam, L., Hogarth, A., Scott, S., & Swainston, K. (2024) · Clinical Rheumatology · doi:10.1007/s10067-024-07172-3 · Cited by 6 · see citing works
“Hypermobility spectrum disorders (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) are inherited connective tissue disorders primarily characterised by joint hypermobility and skin hyperextensibility [1, 2].”
Localized and historical hypermobile spectrum disorders share self-reported symptoms and comorbidities with hEDS and HSD
Fairweather, D., Bruno, K. A., Darakjian, A. A., Wilson, F. C., Fliess, J. J., Murphy, E. F., Kocsis, S. C., Strandes, M. W., Weigel, G. J., Puls, A., et al. (2025) · Frontiers in Medicine · doi:10.3389/fmed.2025.1594796 · Cited by 8 · see citing works
Hypermobility spectrum disorders and active migraine in Israeli adolescents: A nationwide study
Zloof, Y., Simchoni, M., Derazne, E., Tsur, A. M., Tzur, D., Braun, M., Amarilyo, G., Shlaifer, A., Honig, A., & Braun‐Moscovici, Y. (2023) · Headache The Journal of Head and Face Pain · doi:10.1111/head.14526 · Cited by 6 · see citing works
The Underrecognized Conditions of Hypermobile Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders in Women
Robbins, K. (2022) · Nursing for Women s Health · doi:10.1016/j.nwh.2022.03.005 · Cited by 6 · see citing works
Hypermobility spectrum disorders and irritable bowel syndrome: A nationwide study of 1.6 million adolescents
Zloof, Y., Peretz, L., Braun, M., Simchoni, M., Tsur, A. M., Tzur, D., Derazne, E., Ben‐Tov, A., Pinhas‐Hamiel, O., Amarilyo, G., et al. (2023) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.16341 · Cited by 5 · see citing works
An exploration of the journey to diagnosis of Ehlers-Danlos Syndrome (EDS) for women living in Australia
Trudgian, R., & Flood, T. (2024) · PLoS ONE · doi:10.1371/journal.pone.0307574 · Cited by 5 · see citing works
Interdisciplinary pain rehabilitation for patients with Ehlers-Danlos syndrome and hypermobility spectrum disorders
Molander, P., Novo, M., Ringqvist, Å., Hållstam, A., Hesser, H., Löfgren, M., Stålnacke, B., & Gerdle, B. U. C. (2024) · Journal of Rehabilitation Medicine · doi:10.2340/jrm.v56.12431 · Cited by 8 · see citing works
Fear avoidance, fear of falling, and pain disability in hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders
Chuchin, J., & Ornstein, T. J. (2023) · Disability and Rehabilitation · doi:10.1080/09638288.2023.2268520 · Cited by 4 · see citing works
“The literature often combines these hypermobile populations [7,11,12], with recent publications supporting the theory of hEDS and HSD as disorders on the same spectrum of varying symptom severities [7,10].”
Defining the Clinical Complexity of hEDS and HSD: A Global Survey of Diagnostic Challenge, Comorbidities, and Unmet NeedsPreprint
Daylor, V., Griggs, M., Weintraub, A., Byrd, R. L., Petrucci, T., Huff, M., Byerly, K., Fenner, R., Severance, S., Griggs, C., et al. (2025) · medRxiv · doi:10.1101/2025.06.05.25329074 · Cited by 3 · see citing works
Sex differences in self-reported symptoms and comorbidities associated with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A retrospective studyPreprint
Wilson, F. C., Zangerle, D. J., Darakjian, A. A., Bhutani, M., Fliess, J. J., Gehin, J. M., Strandes, M. W., Hamilton, C., Sledge, H. J., Hodge, D. O., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-8310986/v1 · Cited by 2 · see citing works
Tracking changes in autonomic function by coupled analysis of wavelet-based dispersion of heart rate variability and gastrointestinal symptom severity in individuals with hypermobile Ehlers–Danlos syndrome
Mathena, S. A., Allen, R. M., Laukaitis, C. M., & Andrews, J. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2024.1499582 · Cited by 2 · see citing works
Psychometric properties of the Mini-Balance Evaluation Systems Test and physical function measures in patients with Ehlers-Danlos syndrome/hypermobility spectrum disorders
Lee, S., Bourque, J., Noël, L., Hazel, E., Ramsay, E., Bélice, R., & Robbins, S. M. K. (2024) · Disability and Rehabilitation · doi:10.1080/09638288.2024.2361137 · Cited by 2 · see citing works
“Patients who present with similar symptoms but do not meet the exact criteria of heds are instead classified as having hypermobility spectrum disorders (Hsd) [3].”
Ehlers-Danlos Syndromes and Related Disorders: Diagnostic Challenges and the Need for an Interdisciplinary Patient Care in Germany
Kernich, N., Peters, F., Schreml, J., Semler, O., Koch, M., Schönaü, E., Huntgeburth, M., Eysel, P., Krieg, T. M., von Stebut, E., et al. (2024) · Dermatology · doi:10.1159/000542026 · Cited by 2 · see citing works
“Thus, the 2017 hEDS diagnostic criteria make it dif ﬁ cult to differentiate be-tween hEDS and the newly established HSD [19, 21].”
Health care supply in patients with Ehlers-Danlos syndromes and generalized hypermobility spectrum disorder: a German perspective
Rauterberg, J., Hock, M., Kernich, N., Shukri, A., Klapproth, H., Löw, V., Henning, M., & Tantcheva‐Poór, I. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-03937-4 · Cited by 2 · see citing works
Orthopaedic Manifestations in Hypermobile Ehlers-Danlos Syndrome
Eichinger, J. K., Byrd, R. L., Bailey, E., Reis, R. J., Daylor, V., Schiessl, M., Gensemer, C., Friedman, R. J., Patel, S. J., & Norris, R. A. (2025) · Journal of Bone and Joint Surgery · doi:10.2106/jbjs.24.01106 · Cited by 2 · see citing works
The Financial Impact of Ehlers-Danlos Syndromes on Patients in the United States in 2022
Schubart, J. R., Schaefer, É., Mills, S. E., Knight, D. R. T., Shen, C., & Francomano, C. A. (2024) · Mayo Clinic Proceedings Innovations Quality & Outcomes · doi:10.1016/j.mayocpiqo.2024.11.003 · Cited by 2 · see citing works
Introduction: An overview of the Ehlers-Danlos syndromes and hypermobility spectrum disorders
Francomano, C. A., Hakim, A. J., Henderson, L. G. S., & Henderson, F. C. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95082-4.00061-x · Cited by 1 · see citing works
Pain trajectories and exercise-induced pain during 16 weeks of high-load or low-load shoulder exercise in patients with hypermobile shoulders: A secondary analysis of a randomized controlled trial
Liaghat, B., Juul‐Kristensen, B., Christensen, F. H., Nissen, S. E., Skou, S. T., Søgaard, K., Søndergaard, J., & Thorlund, J. B. (2025) · Scandinavian Journal of Pain · doi:10.1515/sjpain-2024-0072 · Cited by 1 · see citing works
Esophageal Dysmotility and Gastroesophageal Reflux Disease Risk in Hypermobile Ehlers-Danlos Syndrome
Butt, M. F., Dervin, H., Hoshino, S., Yazaki, E., Gerard, P., Sweis, R., Sifrim, D. A., Aziz, Q., Zárate-López, N., & Fikree, A. (2026) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2026.04.019 · Cited by 1 · see citing works
Perceptions and experiences of allied health professionals of fabric orthoses for people with joint hypermobility syndromes: a qualitative study
Snowdon, N., & Dadla, S. A. (2023) · International Journal of Therapy and Rehabilitation · doi:10.12968/ijtr.2022.0148 · Cited by 1 · see citing works
A qualitative study exploring participants’ feelings about an online pilates program designed for people with hypermobility disorders
Russek, L. N., Bon, J. D., Simmonds, J. V., Nation, C. S., Higgins, C. V. Z., & Jandrew, T. (2025) · Journal of Bodywork and Movement Therapies · doi:10.1016/j.jbmt.2025.03.002 · Cited by 1 · see citing works
Obstructive sleep apnea and CPAP efficacy in patients with Hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder: a case-control study
Zhang, K. L., Wallon, R., Laukaitis, C. M., & Davies, C. R. (2026) · Sleep And Breathing · doi:10.1007/s11325-026-03763-3
“Both conditions share a range of extra-articular manifestations, and the substantial overlap in features and sequelae suggests hEDS and HSD exist along a continuum rather than as distinct disorders [2].”
E210 施設抑制ミニトマト栽培における総合的害虫管理とその経営的評価(防除法害虫管理 IPM)
杉山, 恵., 片山, 晴., & 西東, 力. (2004) · 日本応用動物昆虫学会大会講演要旨
Symptomatic joint hypermobility is not a barrier to attendance, graduation, or satisfaction for adults participating in a multidisciplinary pain rehabilitation program
Flegge, L. G., Estrella, E., Harris, E. K., Hirsh, A. T., & Bushey, M. A. (2025) · Frontiers in Pain Research · doi:10.3389/fpain.2025.1472160
Proximity extension assay-based serum proteomic profiling identifies shared protein signatures in hypermobile Ehlers–Danlos syndrome and hypermobility spectrum disorders
Cinquina, V., Carini, G., Chiarelli, N., Vezzoli, M., Bertini, V., Venturini, M., Gandy, W., Colombi, M., & Ritelli, M. (2026) · Clinical Proteomics · doi:10.1186/s12014-026-09588-2
“In fact, multiple studies have documented an increased prevalence of immune-mediated disorders like rhinitis, asthma, urticaria, celiac disease, and neuropathies among these patients [7, 40–42].”
Enrichment of an Ehlers-Danlos-like phenotype in women with the FMR1 premutation: a pilot study
Casanova, M., Buchanan, C. B., Hinzman, C., Johnson, L., Okenimkpe, T., Kellum, A., Sheedy, T., Gane, L., Makhoul, E., Hagerman, R. J., et al. (2026) · Journal of Medical Genetics · doi:10.1136/jmg-2025-111346
Diagnostic signs of hypermobility spectrum disorders in adults and children
Trisvetova, E. L. (2024) · Medical news of the North Caucasus · doi:10.14300/mnnc.2024.19018
Outcomes and experiences of patients with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders undergoing surgical interventions: a scoping review
Clark, N., Johnson, M., Adamson, J., Rangan, A., Kottam, L., & Swainston, K. (2026) · Rheumatology International · doi:10.1007/s00296-025-06062-4
Self-Perception of Physical Problems in Patients with Non-Vascular Type of Ehlers–Danlos Syndrome: A Qualitative Study
Palomo-Toucedo, I. C., Reina‐Bueno, M., Munuera-Martínez, P. V., Vázquez-Bautista, M. D. C., Domínguez-Maldonado, G., & León-Larios, F. (2024) · Healthcare · doi:10.3390/healthcare12232392
Functional and structural impairment of small nerve fibers in patients suffering from hypermobile Ehlers Danlos Syndrome/Hypermobility Spectrum Disorder
Fernandez, A., Aubry-Rozier, B., Vautey, M., Berna, C., & Suter, M. (2022) · medRxiv · doi:10.1101/2022.02.17.22271061 · Cited by 1 · see citing works
Self-citation
Relief of benign paroxysmal positional vertigo and temporomandibular disorder using a myofascial induction in genu recurvatum patients: Case reports
Kim, C., Sharkey, J., Slutzky, L. C., & Diaz, G. (2024) · Journal of Bodywork and Movement Therapies · doi:10.1016/j.jbmt.2024.07.041
An examination of the vulvar pain disorders, pain symptoms, and associated vulvovaginal findings experienced among hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder patients: a scoping review
Niedenfuehr, J. M., Cuccaro, P. M., Schick, V., Stevens, D. M., & Markham, C. M. (2026) · Sexual Medicine Reviews · doi:10.1093/sxmrev/qeag066
Optimisation de la prise en charge par l'activité physique des patients atteints d'un syndrome d'Ehlers-Danlos hypermobile
Hakimi, A. (2022) · doi:10.70675/efc16b90za5caz4f84z9a1ez4e24d547c3fc
Prevalence and management of mental health comorbidities in a German cohort of patients with Ehlers-Danlos syndromes and a generalized hypermobility spectrum disorder
Henning, M., Hock, M., Shukri, A., Löw, V., Kernich, N., Rauterberg, J., Klapproth, H., & Tantcheva-Poór, I. (2026) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-026-04242-4
Characteristics of Pain in Patients Diagnosed With Ehlers–Danlos Syndrome and Hypermobility Spectrum Disorders. An Observational Study
Morri, M., Tremosini, M., Forni, C., Moroni, A., Pedrini, E., Cecco, A. D., Gnoli, M., & Sangiorgi, L. (2026) · Pain Research and Management · doi:10.1155/prm/6664142 · Cited by 1 · see citing works
“Aubry-Rozier et al. [14] showed that in the two disease groups, hEDS and HSD, there were signifcant diferences in terms of pain, motor disorders, and bleeding.”
Influential
Hypermobilität und Ehlers-Danlos-Syndrom
Grotz, W., Doll, S., & Gabriel, H. (2024) · CME · doi:10.1007/s11298-024-4007-4
Geschlechtsspezifische operative Therapie in der Orthopädie und Unfallchirurgie
(2024) · doi:10.1055/a-2211-9252
Health-Related Quality of Life in Midlife and Older Women With Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders
Anderson, L. K. (2026) · Nursing for Women s Health · doi:10.1016/j.nwh.2025.09.006
Hypermobile type Ehlers-Danlos syndrome and generalized hypermobile spectrum disorder treatment preferences – a cross-sectional survey of patients
Teran-Wodzinski, P. C., & Kumar, A. (2025) · Rheumatology International · doi:10.1007/s00296-024-05782-3
Understanding the healthcare inequalities within the hypermobility population: Research insights and links to the DHP Annual Conference 2024
Clark, N., & Swainston, K. (2025) · Health Psychology Update · doi:10.53841/bpshpu.2025.34.1.25
Nutritional knowledge, attitudes and dietary behaviours amongst individuals with hypermobility syndromes and associations with co-morbid gastrointestinal symptoms and fatigue: an observational study
Paiba, N., & Harris, M. D. (2023) · European Journal of Integrative Medicine · doi:10.1016/j.eujim.2023.102231
Too high and too loose: dysautonomia and the hypertensive paradox in hypermobility disorders
Johnson, J. W., Mirro, I., & Kontorovich, A. (2026) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000001310

Authors: Aubry-Rozier, B., Schwitzguebel, A., Valerio, F., Tanniger, J., Paquier, C., Berna, C., Hügle, T., & Benaim, C.
Affiliations: HFR Freiburg Kantonsspital (CH)
Centre Hospitalier Universitaire Vaudois (CH)
ORCID: Schwitzguebel, Adrien
Berna, Chantal
Hügle, Thomas
Benaim, Charles
Venue: Rheumatology International
Publisher: Springer Science and Business Media LLC
Published: 2021-08-16
Volume: 41
Issue: 10
Pages: 1785-1794
ISSN: 0172-8172 (ISSN-L)
1437-160X
DOI: 10.1007/s00296-021-04968-3
PMC: PMC8390400
OpenAlex: W3194985992
Cited by: 66
References: 45
Citations by year: 2026: 12 · 2025: 13 · 2024: 20 · 2023: 12 · 2022: 6 · 2021: 2
FWCI: 5.65
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Rheumatology International (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, other-oa)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
SERVAL (Université de Lausanne) (publishedVersion, cc-by)
IRIS (submittedVersion, cc-by)
Funders: Université de Lausanne
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Health Sciences › Medicine › Pharmacology › Musculoskeletal pain and rehabilitation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Myofascial pain diagnosis and treatment
Keywords: hypermobile Ehlers-Danlos syndrome, hypermobility spectrum disorders, disease severity, extra-articular manifestations, neuropathic pain, mast cell activation syndrome, bone fragility, treatment outcomes, clinical severity score
MeSH terms: Adult, Aged, Ehlers-Danlos Syndrome, Female, Humans, Joint Instability, Male, Middle Aged, Prospective Studies, Physical Therapy Modalities, Patient Acuity

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Are patients with hypermobile Ehlers–Danlos syndrome or hypermobility spectrum disorder so different?

Abstract

AI snapshot

TL;DR

Key findings

Methods

Limitations

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks