The Overview Article: Understanding hEDS

Valerie Iovine Rogers, PT, DPT
 
Ehlers-Danlos Syndrome (EDS) encompasses a group of 13 connective tissue disorders, with a 14th type under investigation. The most common of these is Hypermobile Ehlers-Danlos Syndrome (hEDS), historically referred to as “type 3.” Unlike the other subtypes of EDS, which have confirmed genetic markers and are detectable through genetic testing, hEDS remains a clinical diagnosis without a validated genetic test. 

However, recent research is beginning to reshape our understanding. A 2024 preprint identified a potential connection between hEDS and KLK15; a gene associated with overactivation of the kallikrein-kinin system. This complements another emerging line of research suggesting that hEDS may involve ongoing degradation of the extracellular matrix (ECM), rather than solely being a defect of collagen structure or synthesis. These findings suggest hEDS could be driven by dysregulated tissue remodeling pathways, laying the groundwork for future biomarker development. 

Until genetic or molecular diagnostics are available, clinicians must rely on structured physical assessments and symptom history. Increasingly, hypermobility is being recognized in patients with infection-associated chronic illnesses (IACIs) like Long COVID, often unmasking underlying connective tissue fragility. Whether hypermobility predisposes individuals to IACIs or is exacerbated by them, joint instability is becoming a more visible and relevant clinical factor. 

The Beighton Score remains the gold standard for hypermobility assessment, but it has limitations. Four of its nine points involve the hands, despite not being the most clinically impactful joints in most patients with this complicated disorder. Additionally, factors like musculoskeletal guarding, chronic pain, or anatomical differences (e.g., tibial torsion or limited bony end range) can obscure ligamentous laxity. As such, it's increasingly important to explore and implement alternative assessment tools that reflect instability in meaningful joints, rather than relying solely on passive range in the extremities. 

 
At the Cohen Center for Recovery from Complex Chronic Illness at Mount Sinai’s Icahn School of Medicine, we are currently validating a novel tool called the Iovine Cluster (IC). This tool offers a more clinically relevant way to assess joint instability across the most commonly affected regions. Unlike the binary scoring of the Beighton Score, the Iovine Cluster uses a 0–3 ordinal scale to capture the spectrum of joint instability severity. It includes 42 possible points and incorporates existing validated orthopedic special tests used in physical therapy, allowing for a more nuanced view of articular laxity. 

The Iovine Cluster includes: 

• Two tests for the shoulder (Load & Shift, Sulcus Sign), recognizing it as the most commonly unstable joint. 

• A test for hip instability (Hip Dial Test). 

• Knee evaluation including graded genu recurvatum from the Beighton but adding patellar translation. 

• Foot and ankle tests, assessing ankle inversion range of motion and navicular drop to understand foot/arch instability and its effect on the kinetic chain. 

The Iovine Cluster does not aim to replace the Beighton Score outright but rather to supplement it with a functionally oriented tool that reflects real-world instability. As hypermobility becomes increasingly recognized in diverse patient populations, from pediatric to post-infectious to neurologic cases, it’s crucial that we move beyond outdated scoring systems and toward tools that capture the broader spectrum of presentations. 

 
Hypermobile Ehlers-Danlos Syndrome is a complex, systemic connective tissue disorder that doesn't always follow a linear “mild-to-severe” scale. Instead, patients may exhibit disproportionate involvement in one system over another. Many live with chronic pain, joint subluxations and dislocations, and instability long before receiving an accurate diagnosis. 

hEDS frequently presents as part of a triad alongside Postural Orthostatic Tachycardia Syndrome (POTS) and Mast Cell Activation Syndrome (MCAS). This trio of hypermobility, autonomic dysfunction, and immune dysregulation can be debilitating, and when one of the three is missed, it often leads to fragmented or ineffective care. For example, a patient with diagnosed POTS may still go years without identification of their underlying joint instability or MCAS-related symptoms. Others may present with chronic subluxations and receive only orthopedic care, overlooking the systemic and neurologic components of their condition or care lacks the piece of addressing the stabilization the mast cells as a cause of their vague chronic pain.  

Particularly concerning are the neurologic phenotypes associated with hEDS. Patients may develop upper cervical instabilities, including craniocervical instability (CCI) and atlantoaxial instability (AAI), which can compromise the brainstem and result in significant neurologic symptoms. Other associated findings include Chiari malformations, tethered cord syndrome, CSF leaks, and idiopathic intracranial hypertension; each of which may be misdiagnosed or missed altogether without awareness of their connection to hEDS. 

Ultimately, delayed diagnosis leads to years of unnecessary suffering, mislabeling (e.g., anxiety, somatization), and loss of function. Many patients require assistive devices, intermittent care support, or undergo risky procedures—when earlier identification and conservative stabilization might have prevented decline, or allograft tissue would have been preferable to autografting. 

A crucial but often under-recognized concept in the management of hypermobile patients is regional interdependence; the idea that dysfunction in one region of the body can create compensatory dysfunctions elsewhere. In hypermobility, this concept becomes even more relevant due to the systemic nature of connective tissue laxity and the resulting instability that travels up and down the kinetic chain. We refer to this progression as the RIPPI Cycle: Regional Interdependence and Poor Proprioceptive Input. 

In individuals with connective tissue disorders like hEDS, proprioception is inherently impaired. Mechanoreceptors such as Golgi tendon organs and muscle spindles, which detect tension and changes in muscle length, respectively, rely on the integrity of surrounding connective tissue to function properly. When that tissue is overly lax or damaged, these receptors provide delayed, diminished, or inaccurate feedback. This blunted proprioceptive input interferes with joint position sense, motor planning, and reflexive stabilization; especially during dynamic movements. The result is a body constantly trying to stabilize itself with incomplete information, reinforcing compensatory patterns and leading to further dysfunction. 

One of the most important consequences of this poor proprioception is a lack of awareness of maladaptive movement strategies. Patients may unknowingly rely on hypermobile joints to achieve a range of motion they cannot access through proper segmental control. For instance, if T8 is excessively mobile, the patient may hinge there repeatedly, offloading the segments above and below. Over time, this results in hypomobility or guarding in adjacent areas and a growing dependence on that hypermobile segment. Because they cannot sense this compensatory strategy, they repeat it, deepening the dysfunction. The hypermobility then progresses to pathologic instability, and the body’s ability to move in a coordinated, segmental way continues to deteriorate. 

Let’s walk through a typical cascade of regional interdependence in a hypermobile patient, from the ground up: 

• A collapsed medial arch destabilizes the foundation of the body. This often leads to calcaneal valgus, shifting the subtalar joint into a less optimal position. 

• With altered hindfoot mechanics, the ankle becomes more prone to excess inversion or eversion, increasing fall risk and impairing push-off during gait. 

• This feeds into genu recurvatum, as the knees hyperextend to compensate for the poor foot stability. Chronic hyperextension leads to inhibition of both the quadriceps and hamstrings, disrupting co-contraction and reducing knee control. 

• Loss of muscular support at the knee creates instability and torque at the pelvis, which now must compensate in all three planes—rotationally, anterior-posteriorly, and laterally. 

• This pelvic instability exaggerates preexisting patterns such as functional scoliosis or anterior pelvic tilt. With asymmetry at the pelvis, one side of the thoracic spine elevates or rotates. 

• This misalignment alters scapular orientation, which may predispose the shoulder on the elevated side to downward traction, subluxation, or rotator cuff overuse—especially if that scapula now rests in anterior tilt or winging. 

• As the upper back strains to keep the scapula anchored, the cervical spine loses neutrality. The body adapts by cocking the head to maintain level gaze and visual field equilibrium. 

• This creates excessive mechanical stress at the occiput-C1-C2 complex, especially in those with underlying craniocervical or atlantoaxial instability. Over time, this pattern may exacerbate symptoms like neck pain, dizziness, vision changes, or headaches due to cervical dysfunction or even brainstem compression in severe cases. 

This cascade illustrates why it’s not enough to treat just the symptomatic joint in hypermobile patients. A patient with neck pain might have a structural problem at C1, but they may not stabilize until you correct the foundation of their kinetic chain, from foot to pelvis and beyond. 

Clinicians must shift from a localized to a systems-based approach, recognizing that proprioceptive deficits and instability in one region often originate from, or are sustained by, dysfunction elsewhere. Treating hypermobility means treating global motor control, reinforcing proprioception at every joint, and understanding how instability echoes through the whole body. Without this lens, we risk missing the true driver of dysfunction, and delaying meaningful recovery.