Hypermobile EDS (hEDS)

PREVALENCE: 1 in 3,500 to 1 in 5,000 [26] (but estimated 1:500, see above)

INHERITANCE PATTERN: Autosomal Dominant

SYMPTOMS [27, 28]:

Hypermobile EDS is the most common form of EDS. Measurable and/or observable symptoms [29] include hypermobile (very flexible) joints, frequent dislocations or subluxations of several joints, soft velvety skin, mildly stretchy skin, unexplained stretch marks, abdominal hernias, prolapse of the uterus, colon or pelvic floor (not due to other medical conditions) and atrophic scarring (collapsed, sometimes thin paper-like scars). Other observable symptoms may include blue sclera (whites of the eyes have a blue tint), having a high narrow palate, dental crowding, piezogenic papules on both feet (small, white circular protrusions near the bottom of heels when standing), slow motility, and heart manifestations like an enlarged aortic root or mitral valve prolapse.

However, some of the most debilitating symptoms of hEDS can be non-observable, subjective symptoms. This includes chronic widespread muscle and joint pain, nerve pain [30], severe headaches, migraines or “neck headaches”, fatigue (sometimes severe) [31], insomnia, and depression. Patients with hEDS also tend to have poor proprioception which, by itself, can add multiple injuries. There can also be crossover symptoms from another type of EDS. Many people must also deal with comorbid conditions, such as postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), Chiari I Malformation, immune/autoimmune issues, and many more [32].

hEDS and its criteria are evolving as research advances. Some of the possible mechanisms/causes behind hEDS that have been proposed in the past include mutations on MIA3 [33], which has been published in 2023, alongside research linking folate insufficiency, like the MTHFR genetic mutations, to hEDS [34]. Other earlier findings show a variant of LZST1, alterations in TPSAB1, mutations of Tenascin XB [35].

DIAGNOSTIC CRITERIA [36]:

Hypermobile EDS (hEDS) is the most in-depth and complex type of EDS to diagnose. This is because the symptoms and patient’s history are often extensive, and there are no definite genetic markers to confirm a suspected diagnosis. Prior to 2017, hEDS was diagnosed using the Beighton Score and/or the Brighton criteria. Now, the Beighton Score is just one component of the official criteria that must be satisfied. hEDS does not contain “major criteria” and “minor criteria” like other forms of EDS. Instead, it has a complex set of multifaceted tests that must be met, in their entirety.

There are now three (3) Major Criteria that must all be met to diagnose hEDS. Yet, within each criterion, there are additional features and tests which have their own objectives, symptom checklists, and assessments. It’s also important to note that there are many more symptoms than the ones listed under the diagnostic criteria. While they may constitute the official criteria, these symptoms can be measured objectively. There are many more objective and subjective symptoms than what is listed, so all criteria should be considered in the diagnostic process. Likewise, if a patient does not meet the hEDS criteria but is off by only one symptom or Beighton score, then a doctor must weigh the objective and subjective factors to make this determination.

The criteria for hEDS can be found in the chart and accompanying tables below. (A checklist can be downloaded here.)

hEDS Major Diagnostic Criteria Genetic Markers

ALL three (3) criteria must be met:

  1. Features of Generalized Joint Hypermobility (GJH):
    1. Beighton Score of ≥6 for pre-pubertal children and adolescents
    2. Beighton Score of ≥5 for pubertal men & women up to 50
    3. Beighton Score of ≥4 for men & women >50yo
  2. Fulfillment of at least two of the following featured criteria (features A-C):
    • Feature A – Systemic manifestations of a general connective tissue disorder (a total of five (5) must be present to satisfy Feature A)
      • Unusually soft or velvety skin
      • Mild skin hyperextensibility
      • Unexplained striae such as striae distensae or rubrae at the back, groins, thighs, breasts, and/or abdomen in adolescents, men, or prepubertal women without a history of significant gain or loss of body fat or weight
      • Bilateral piezogenic papules of the heel
      • Recurrent or multiple abdominal hernia(s) (e.g., umbilical, inguinal, crural)
      • Atrophic scarring involving at least two sites and without the formation of truly papyraceous and/or hemosideric scars as seen in classical EDS
      • Pelvic floor, rectal, and/or uterine prolapse in children, men, or nulliparous women without a history of morbid obesity or other known predisposing medical condition
      • Dental crowding and high or narrow palate
      • Arachnodactyly, as defined in one or more of the following: (i) positive wrist sign (Steinberg sign) on both sides; (ii) positive thumb sign (Walker sign) on both sides
      • Arm span-to-height ≥1.05
      • Mitral valve prolapse (MVP) mild or greater based on strict echocardiographic criteria
      • Aortic root dilatation with Z-score > +2
    • Positive family history, with one or more first-degree relatives (biological mother, father, brother, sister) independently meeting the current diagnostic criteria for hEDS
    • Musculoskeletal complications (must have at least one)
      • Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months
      • Chronic, widespread pain for ≥3 months
      • Recurrent joint dislocations or frank joint instability, in the absence of trauma: Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times OR Medical confirmation of joint instability at two or more sites not related to trauma
  3. ALL of the prerequisites must be met:
    • Absence of unusual skin fragility, which should prompt consideration of other types of EDS
    • Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions. In patients with an acquired connective tissue disorder (e.g., lupus, rheumatoid arthritis, etc.), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or instability) cannot be counted towards a diagnosis of hEDS in this situation.
    • Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. Alternative diagnoses and diagnostic categories include but are not limited to, neuromuscular disorders (e.g., myopathic EDS, Bethlem myopathy), other HCTD (e.g., other types of EDS, Loeys–Dietz syndrome, Marfan syndrome), and skeletal dysplasias (e.g., OI). Exclusion of these considerations may be based upon history, physical examination, and/or molecular genetic testing, as indicated.