The complexity of the Ehlers-Danlos syndrome (EDS) and the heterogeneity of its manifestations present ongoing barriers to timely diagnosis and management for affected individuals, especially those with hypermobile EDS (hEDS).1,2 However, recognition of EDS has grown in recent years, and a range of efforts are underway to improve diagnosis and care for this patient population. 

Diagnostic Difficulties in EDS

“EDS encompasses a group of 13 connective tissue disorders, with a 14th type under investigation,” said physical therapist Valerie Rogers, PT, DPT, director of the hypermobility program at the Icahn School of Medicine at Mount Sinai’s Center for Recovery from Complex Chronic Illness in New York, New York. The most common type of EDS is hEDS, which comprises an estimated 90% of EDS cases.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.”

Criteria for diagnosing hEDS were published in 2017, representing a significant achievement in this area.4 However, “We notice that physicians are not recognizing when to apply these criteria,” noted Ina Stephens, MD, professor of pediatrics at the University of Virginia (UVA) School of Medicine in Charlottesville and the interim medical director for the new Ehlers-Danlos Center scheduled to open at UVA in 2026. “EDS patients tend to have symptoms and complications across many different bodily systems and are seen by specialists to address these complaints, but these specialists are often not thinking of a connective tissue disorder,” and thus signs of EDS can be overlooked.

In addition, the diagnostic criteria for hEDS “are considered stringent and may not capture the full spectrum of the disorder, leading to underdiagnosis,” according to Irman Forghani, MD, director of genetics and chief of the Rad Center for Precision Medicine at Mount Sinai Medical Center in Miami Beach, Florida.5 “Diagnosing hEDS still heavily relies on clinical assessment and careful elimination of other potential causes.”

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We need physicians in all specialties to be thinking of connective tissue disorders in their differential and to know their signs and common comorbidities.

In a study published in April 2025 in Genes, Dr Forghani and colleagues cited the critical need for clinicians to exclude alternative diagnoses when considering a diagnosis of hEDS.5 “Our findings underscored the pivotal role of genetic testing in improving diagnostic accuracy and identifying coexisting or alternative heritable disorders,” she said. “Unfortunately, genetic testing remains underutilized due to lack of insurance coverage, as well as limited access in some regions.”

Due to the limited awareness of EDS among many health care providers, patients may be misdiagnosed with conditions such as fibromyalgia, chronic fatigue syndrome, or rheumatoid arthritis, Dr Forghani noted. In many cases, symptoms are attributed to mental illness or attention-seeking.

In a study published by Lee and Chopra in May 2025, a retrospective chart review of 429 patients with hEDS showed that 94.4% had previously been misdiagnosed with psychiatric illnesses. Most of the patients had been told they were “making it up,” that “it was in their head,” or they were seeking attention. Two-thirds of patients had been misdiagnosed with conversion disorder and 4% had received a diagnosis of Munchausen syndrome by proxy or a factitious disorder.6 

“Overall, fragmented health care systems and bureaucratic hurdles slow the diagnostic process, often requiring patients to see many specialists before a diagnosis is made,” Dr Forghani said. “The median time to diagnosis is about 10 years, with patients often seeing more than 10 clinicians and receiving multiple alternative diagnoses before hEDS is confirmed.”7

Consequences of Delayed EDS Diagnosis

As a result of the high rates of missed or delayed diagnosis among individuals with EDS, these “patients are not getting effective treatments, and they feel ‘gaslit’ and ostracized by our medical community in America,” according to Mark E Lavallee, MD, CSCS, a sports medicine and family medicine physician and assistant clinical professor at the Drexel University College of Medicine in Philadelphia, Pennsylvania. Dr Lavallee coauthored the 2017 diagnostic criteria for EDS.4

In many cases, hEDS “presents as part of a triad alongside postural orthostatic tachycardia syndrome and mast cell activation syndrome,” Dr Rogers added.8 “This trio of hypermobility, autonomic dysfunction, and immune dysregulation can be debilitating, and when 1 of the 3 is missed, it often leads to fragmented or ineffective care.” For example, a patient who presents with chronic subluxations may receive only orthopedic care while the systemic and neurologic components of their condition remain unrecognized and unaddressed.

“In some cases, especially when patients have a rare type of EDS such as the vascular type, delayed diagnosis can have fatal results,” Dr Stephens said. “These patients in particular need ongoing screening and precautions in place from an early age for the best outcomes.”

Dr Rogers also pointed to the neurologic phenotypes associated with hEDS as particularly concerning. “Patients may develop upper cervical instabilities, including craniocervical instability and atlantoaxial instability, which can compromise the brainstem and result in significant neurologic symptoms,” she said. “Other associated findings include Chiari malformations, tethered cord syndrome, [cerebrospinal fluid] leaks, and idiopathic intracranial hypertension — each of which may be misdiagnosed or missed altogether without awareness of their connection to hEDS.”

Dr Forghani emphasized that, along with the negative impact on physical health, missed or delayed EDS diagnosis takes a toll on the mental health and economic and social wellbeing of patients. “Chronic pain, social withdrawal, and repeated invalidation by health care providers contribute to high rates of anxiety and depression,” she said.9 “Patients often experience frustration, isolation, and diminished quality of life due to years of uncertainty and disbelief from the medical community.”

Individuals with EDS who are misdiagnosed may also experience increased health care costs10 and lost productivity due to unnecessary testing and treatments. Additionally, delayed access to support services such as physical therapy, occupational therapy, and proper accommodations can lead to further impairment in daily functioning and independence, Dr Forghani continued.

“Ultimately, delayed diagnosis leads to years of unnecessary suffering, mislabeling, and loss of function” for patients with EDS, Dr Rogers stated.

Ongoing Work to Improve EDS Diagnosis and Care

Significant efforts are underway to elucidate the genetic causes of hEDS, identify biomarkers, and ultimately improve diagnosis and treatment for affected individuals.11-13 Meanwhile, physician awareness and education are critical for reducing diagnostic delays and improving treatment in EDS.

“We need physicians in all specialties to be thinking of connective tissue disorders in their differential and to know their signs and common comorbidities,” Dr Stephens advised. “Following that, simple screening for hypermobility should be in every physician’s tool kit.”

While the Beighton Score represents the gold standard for hypermobility assessment,4 Dr Rogers pointed to several limitations of this tool. “Four of its 9 points involve the hands, despite not being the most clinically impactful joints in most patients with this complicated disorder,” she explained. “Additionally, factors like musculoskeletal guarding, chronic pain, or anatomical differences can obscure ligamentous laxity.”

She and her colleagues at the Cohen Center for Recovery from Complex Chronic Illness at Mount Sinai’s Icahn School of Medicine are currently validating a novel assessment tool called the “Iovine Cluster,” which would “offer a more clinically relevant way to assess joint instability across the most commonly affected regions,” she said. This tool “does not aim to replace the Beighton Score outright but rather to supplement it with a functionally oriented tool that reflects real-world instability.”

Among other developments, the Ehlers Danlos Society has launched an initiative called “Road to 2026.” They aim to update the EDS classification criteria and diagnostic guidance for EDS and hypermobility spectrum disorders (HSD) by 2026 to reduce diagnostic delays and improve patient care.13

Research by Chip Norris, Phd, a leading EDS expert, and his colleagues from the Medical University of South Carolina “looks at the root cause of hypermobile type EDS as very different than the other 13 subtypes of EDS, and they have been able to create live mouse models of all 14 subtypes,” Dr Lavallee said. “This holds promise for eventually finding real treatments — if not a cure — for hEDS.”

The Norris Lab has found that rare variants in the Kallikrein gene family are enriched among individuals with hEDS, and the “lab stated that mouse models engineered with these variants display symptoms consistent with hEDS,” Dr Forghani explained. The research describing these observations is currently in preprint.14 “While further studies are needed to confirm these results in larger and more diverse populations, these findings are promising and represent the first genetic and biological evidence linking Kallikrein genes to hEDS.”

These findings complement other emerging research “suggesting that hEDS may involve ongoing degradation of the extracellular matrix, rather than solely being a defect of collagen structure or synthesis,” Dr Rogers noted.12 “These findings suggest hEDS could be driven by dysregulated tissue remodeling pathways, laying the groundwork for future biomarker development.”

Specifically, Colombi and colleagues “identified a unique 52 kDa fragment of fibronectin in the blood of individuals with hEDS and HSD,” Dr Forghani said.12 “This fragment is absent in healthy controls and other EDS subtypes, making it a promising candidate for a blood test to aid diagnosis.”

She also cited the important role of multimodal artificial intelligence approaches, such as the Zebra-Llama large language model,15 in improving EDS diagnosis and care.

“While advancements in the field continue to undergo validation, demonstrate generalizability, and work toward clinical accessibility, the challenges in accurately diagnosing hEDS remain substantial” and the consequences of missed or delayed diagnosis are profound, Dr Forghani stated. “This reality underscores the urgent need for greater clinical awareness, improved diagnostic tools, and the widespread adoption of multidisciplinary care.”