Hypermobile Ehlers-Danlos Syndrome <-> Myalgic Encephalomyelitis Chronic Fatigue Syndrome

name: com_Hypermobile_Ehlers-Danlos_Syndrome__Myalgic_Encephalomyelitis_Chronic_Fatigue_Syndrome
creation_date: '2026-11-02T13:25:53Z'
curation_status: CANDIDATE
notes: >-
  A clinical overlap between hypermobile Ehlers-Danlos syndrome (hEDS) and
  myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is widely
  described, and chronic fatigue is a major feature of hEDS. Most of the
  quantitative evidence, however, measures generalized joint hypermobility by
  Beighton score, not clinically diagnosed hEDS. Beighton-defined
  hypermobility is common in the general population and is a much broader
  phenotype than hEDS, and in a chronic-fatigue clinic the Beighton score
  agreed poorly with clinical assessment of joint laxity (kappa about 0.4;
  PMID:34957987).
  With that caveat, two case-control studies found joint hypermobility more
  often in CFS than in controls (20.6% against 4.3% in adults; 60% against 24%
  in children, OR 3.5), and a meta-analysis of functional somatic syndromes
  including CFS found an overall OR of 3.27 while rating most studies fair to
  poor. A Dutch adolescent study found no difference in Beighton score or
  collagen biochemistry between CFS and controls, though CFS patients had
  more extensible skin. In a registry of 815 people with ME/CFS, the 15.5%
  who were hypermobile were more likely to report EDS and POTS and had worse
  quality of life. A US pediatric cohort, by contrast, found no difference in
  ME/CFS presentation by hypermobility status. The only direct hEDS-ME/CFS
  data are a case series of 12 adolescents with CFS and EDS (6 hypermobile
  type), all with orthostatic intolerance. Directionality is UNKNOWN. No
  ICEES KG signal is possible, because hEDS (MONDO:0007523) is not a node in
  the ICEES KG 8-20-2024 snapshot.

disease_a:
  slug: Hypermobile_Ehlers-Danlos_Syndrome
  preferred_term: Ehlers-Danlos syndrome, hypermobility type
  term:
    id: MONDO:0007523
    label: Ehlers-Danlos syndrome, hypermobility type

disease_b:
  slug: Myalgic_Encephalomyelitis_Chronic_Fatigue_Syndrome
  preferred_term: myalgic encephalomyelitis/chronic fatigue syndrome
  term:
    id: MONDO:0005404
    label: myalgic encephalomeyelitis/chronic fatigue syndrome

directionality: UNKNOWN

hypotheses:
- description: >-
    Hypothesis: laxity of connective tissue in the walls of dependent veins
    lets them distend excessively under ordinary hydrostatic pressure, so
    blood pools on standing. The resulting orthostatic intolerance (postural
    tachycardia or neurally mediated hypotension) contributes to the fatigue
    and exercise intolerance that lead to an ME/CFS diagnosis. This was
    proposed from a small case series. It has not been tested experimentally,
    and it would explain only the subset of ME/CFS with a connective-tissue
    phenotype and orthostatic intolerance.
  evidence:
  - reference: PMID:10518084
    reference_title: Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twelve patients (11 female), median age 15.5 years, met diagnostic criteria for CFS and EDS, and all had either postural tachycardia or neurally mediated hypotension in response to orthostatic stress. Six had classical-type EDS and 6 had hypermobile-type EDS."
    explanation: >-
      A case series in which every adolescent with both CFS and EDS (half of
      them hypermobile type) had orthostatic intolerance, the observation the
      venous-pooling hypothesis was proposed to explain.
  - reference: PMID:10518084
    reference_title: Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome.
    supports: SUPPORT
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose that the occurrence of these syndromes together can be attributed to the abnormal connective tissue in dependent blood vessels of those with EDS, which permits veins to distend excessively in response to ordinary hydrostatic pressures."
    explanation: >-
      The authors' proposed mechanism, stated as a proposal rather than
      demonstrated, linking EDS connective tissue to venous pooling.
  pathophysiology:
  - name: Venous wall laxity and orthostatic venous pooling
    description: >-
      Proposed (not experimentally confirmed) mechanism: abnormal connective
      tissue in dependent veins allows excessive distension and pooling on
      standing, reducing venous return and producing orthostatic intolerance.
    notes: >-
      No biological process is bound. The cited proposal (PMID:10518084) is
      passive distension of a connective-tissue-abnormal vein wall, not reduced
      smooth-muscle constriction, so GO:0042310 vasoconstriction (DECREASED)
      would assert a mechanism the source does not make. OLS searches of GO for
      "vein distension" and "blood vessel wall compliance" returned no terms;
      "vein" returned only vein smooth muscle contraction and its regulation
      (GO:0014826, GO:0062086-GO:0062088), which are active smooth-muscle
      processes, plus morphogenesis and insect wing-vein terms.

association_signals:
- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005404
  population: >-
    Adults with CFS and age- and sex-matched healthy volunteers, screened for
    generalized joint hypermobility (Beighton score); about 68 per group.
  mapping_notes: >-
    Measures generalized joint hypermobility, not clinically diagnosed hEDS,
    so it bears on the hEDS claim only indirectly.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: PREVALENCE
      metric_value: 20.6
      notes: Generalized joint hypermobility in CFS, against 4.3% in controls.
    evidence:
    - reference: PMID:16396727
      reference_title: Generalized joint hypermobility is more common in chronic fatigue syndrome than in healthy control subjects.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Compared with the healthy volunteers (4.3%, 3/68), significantly more patients with CFS (20.6%, 14/69) fulfilled the criteria for generalized joint hypermobility (Fisher exact test, P < .004)."
      explanation: >-
        Generalized joint hypermobility was about five times as common in
        adults with CFS as in matched controls.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005404
  population: >-
    58 consecutive children with incident CFS and 58 gender-matched controls
    from a dermatology clinic, compared by Beighton score.
  mapping_notes: >-
    Measures joint hypermobility (Beighton score of 4 or more), not
    clinically diagnosed hEDS.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: OR
      metric_value: 3.5
      metric_ci_lower: 1.6
      metric_ci_upper: 7.5
      notes: Odds of joint hypermobility in all CFS patients against controls.
    evidence:
    - reference: PMID:12219066
      reference_title: Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The odds ratio for hypermobility in all patients with CFS versus healthy controls was 3.5 (P <.001; 95% CI, 1.6-7.5)."
      explanation: >-
        Pediatric case-control study showing higher odds of joint
        hypermobility in CFS.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005404
  population: >-
    Systematic review and meta-analysis of controlled studies of joint
    hypermobility in functional somatic syndromes (5 fibromyalgia, 3 CFS, 3
    functional gastrointestinal disorder studies).
  mapping_notes: >-
    The pooled odds ratio combines three syndromes, not CFS alone, and
    measures joint hypermobility rather than hEDS.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: OR
      metric_value: 3.27
      metric_ci_lower: 1.83
      metric_ci_upper: 5.84
      notes: Pooled odds of joint hypermobility across functional somatic syndromes.
    evidence:
    - reference: PMID:34237584
      reference_title: "Functional somatic syndromes and joint hypermobility: A systematic review and meta-analysis."
      supports: SUPPORT
      directness: INDIRECT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "There is some evidence for an association between FSS and JH, but this is limited by the generally poor quality of studies and the narrow range of FSS studied."
      explanation: >-
        The meta-analysis supports an association but rates the underlying
        studies as generally poor quality.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005404
  population: >-
    32 adolescents with CFS (CDC criteria) at a Dutch tertiary hospital and
    167 healthy adolescents, compared on joint mobility, skin extensibility,
    arterial properties and collagen biochemistry.
  mapping_notes: >-
    Recorded as REFUTE for joint hypermobility, the main measure most other
    studies rely on. The same study found more extensible skin in CFS, so its
    result is mixed rather than wholly negative.
  directionality: UNKNOWN
  evidence:
  - reference: PMID:15805343
    reference_title: "Is chronic fatigue syndrome a connective tissue disorder? A cross-sectional study in adolescents."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Joint mobility, Beighton score, and collagen biochemistry, all indicators of connective tissue abnormality, were equal for both groups."
    explanation: >-
      No excess joint hypermobility or abnormal collagen metabolism in
      adolescents with CFS compared with healthy controls.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005404
  population: >-
    815 participants of the You + ME Registry with ME/CFS, classified as
    hypermobile or not by self-assessed Beighton score.
  mapping_notes: >-
    Self-reported data; EDS diagnosis is self-reported and not confirmed as
    hEDS.
  directionality: UNKNOWN
  statistics:
    metrics:
    - metric_type: PREVALENCE
      metric_value: 15.5
      notes: Self-assessed joint hypermobility among ME/CFS registry participants (126/815).
    evidence:
    - reference: PMID:38545281
      reference_title: "Do people with ME/CFS and joint hypermobility represent a disease subgroup? An analysis using registry data."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "JH+ participants were more likely to be female, report Ehlers-Danlos Syndrome (EDS), Postural Orthostatic Tachycardia Syndrome (POTS), and a family history of EDS."
      explanation: >-
        Within ME/CFS, hypermobile participants more often reported EDS and
        POTS, suggesting a hypermobile, dysautonomic subgroup.

- source: LITERATURE
  method: LITERATURE_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005404
  population: >-
    55 young people meeting Fukuda criteria for ME/CFS in a US observational
    cohort, compared by Beighton score of 4 or more.
  mapping_notes: >-
    Recorded as REFUTE for the claim that hypermobile ME/CFS is a distinct
    clinical subgroup, which conflicts with the registry result above. It
    does not address whether hypermobility is more common in ME/CFS.
  directionality: UNKNOWN
  evidence:
  - reference: PMID:34537220
    reference_title: The Presentation of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Is Not Influenced by the Presence or Absence of Joint Hypermobility.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no significant difference between the groups in measures of health-related quality of life using a Beighton score cutoff of 4 or a cutoff of 5 to define joint hypermobility."
    explanation: >-
      In this pediatric cohort, hypermobile and non-hypermobile ME/CFS
      patients did not differ in onset, symptoms, comorbidities or quality of
      life.

- source: ICEES
  method: EHR_COHORT_ASSOCIATION
  signal_disorder_a_id: MONDO:0007523
  signal_disorder_b_id: MONDO:0005404
  population: ICEES KG snapshot 8-20-2024 (RENCI/UNC).
  mapping_notes: >-
    No ICEES signal exists for this pair. hEDS (MONDO:0007523) is not a node
    in the 8-20-2024 snapshot, as confirmed when the hEDS-POTS and hEDS-MCAS
    comorbidity entries were curated.
  directionality: UNKNOWN