Connecting Ehler’s-Danlos Syndrome and Complex Regional Pain Syndrome 2023

Introduction

The primary objective of this review is to provide a connection between Ehler’s-Danlos syndrome (EDS) and Complex Regional Pain Syndrome (CRPS). Challenges in making a diagnosis in EDS and CRPS include the absence of objective diagnostic tests, unclear or overlapping disease classifications, and/or clinician misconceptions and biases, in addition to limited research about connective tissue disease (CTD) and its overlap with chronic pain syndromes. The purpose in making the connection between EDS and CRPS is to increase the understanding of the pathophysiological mechanisms of both diseases. In addition, the incidence of CRPS can be significantly decreased if the risks of acquiring it are identified and mitigated.

In EDS and CRPS, the absence of objective diagnostic tests along with unclear and overlapping disease classifications, and clinicians’ misconception of both diseases greatly decreases patients’ ability to obtain accurate and timely diagnoses. The incidence of EDS may also be decreased due to patients with mild disease never having the need to seek a medical diagnosis. In addition, patients may fail to obtain accurate diagnoses, fail to receive validation that their symptoms are real and not psychological (eg, conversion disorder), and/or fail to obtain valuable and timely treatment.

Complex regional pain syndrome is an acquired neuropathic pain syndrome occurring in 26.2 per 100,000 people per year. It is rare in children and most often goes into remission in this population. The International Association for the Study of Pain (IASP) developed the Budapest Criteria as a standardized diagnostic tool for CRPS.² Not only can CRPS be severely debilitating and/or lead to temporary or permanent disability, but it can also spread to other extremities.²

Although the pathophysiology of CRPS is largely unknown, it is considered multifactorial and has genetic contributions.¹⁻¹¹ CRPS is classified as type I (without the presence of nerve injury), which is more common, and type II (the presence of nerve injury), which has low remission rates.²

Hooshmand & Phillips, Schwartzman, and others classify CRPS (types I and II) as a systemic disease that can affect any organ or system, and disrupts the normal functioning and physiological processes.¹²˒¹³ Apart from some obvious differences between CRPS and other pain syndromes, the similarities of comorbidities are conspicuous, shown in Table I, and their common features suggest a common pathway.¹⁴ Although the pathophysiology of CRPS is largely unknown, it is considered multifactorial and has genetic contributions.¹⁻¹¹

One possible connection between CRPS and other pain syndromes may be connective tissue disease as the incidence of CRPS is high in patients with EDS.Ascertaining a connection between CTD and CRPS would modify the concept that CRPS is primarily a localized or focal musculoskeletal pain disorder that causes “misfiring nerves” or that represents a nervous system that needs to be “reset.” Rather, CRPS would be viewed as a chronic pain syndrome or systemic disease that affects the autonomic, endocrine, limbic, and immune systems, even though these effects cannot be fully explained.

Ehler’s-Danlos Syndrome is a genetic CTD with the inheritance pattern depending on type (eg, autosomal dominant or autosomal recessive) and may also vary by age, gender, and ethnicity.⁸ There are currently 200 heritable CTDs, including 13 types of EDS.⁵˒⁸ EDS is caused by defects in collagen and other components of the extracellular matrix. These defects lead to joint hyperextensibility and laxity in bodily organs such as skin, ligaments, joints, eyes, bones, blood vessels, and internal organs, and other clinical manifestations including chronic pain.

There are two factors that may contribute to lower incidence of EDS in children. The first is that ossification makes assessment of laxity difficult until at least 6 years of age.⁵ The second is that until the child reaches his or her teens or adulthood and a clear history can be established, some clinicians will not diagnose children with EDS/HSD; or unless “there is clear evidence that a strong family history or genetic family link is involved, it is unlikely that a child will be given a formal HSD or hEDS [hypermobile Ehler’s-Danlos syndrome] diagnosis.”⁵

The 2017 International Consortium classification for EDS incorporates the Beighton score system within the Brighton diagnostic criteria to diagnose the disease, shown in Table II.⁸˒¹¹ The Beighton score system is used as a quick first-line diagnostic screening tool for hypermobility and is one of three criteria in the Brighton diagnostic criteria.

Generalized joint hypermobility (GJH) is considered a prerequisite for the diagnosis of hEDS. GJH may include historical information using the following five-point questionnaire (5PQ) developed by Hakim and Grahame: 1) Can you now (or could you ever) place your hands flat on the floor without bending your knees?; 2) Can you now (or could you ever) bend your thumb to touch your forearm?; 3) As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?; 4) As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?; 5) Do you consider yourself “double-jointed”?⁸˒¹¹ A “yes” answer to two or more questions suggests joint hypermobility with 80% to 85% sensitivity and 80% to 90% specificity.⁸ In addition, if the Beighton score is 1 point below the age and sex-specific cut-off and the 5PQ is “positive” (at least two positive items), then a diagnosis of GJH can also be made.⁸

The Brighton diagnostic criteria includes three criteria for diagnosis of hEDS: Criterion 1 utilizes the Beighton score, and possibly the 5PQ to assess for GJH; Criterion 2 includes Features A-C, where two or more features must be present, to assess systemic manifestations, family history, and/or musculoskeletal complications; and Criterion 3 is exclusion criteria, where all the prerequisites must be met.⁸˒¹¹ Features of connective tissue laxity have been suggested for inclusion in the diagnostic criteria, but currently, only select cutaneous features are included.

Limitations in EDS Diagnostic Criteria

Although familial history of EDS is one criterion (Feature B) out of three in the Brighton diagnostic criteria, there are limitations in utilizing or requiring family history to support a diagnosis. A few limitations related to requiring a positive family history for EDS diagnosis are:

• misdiagnosing EDS for other syndromes
• not identifying hypermobile patients via the Beighton score, and/or not evaluating for EDS in hypermobile patients
• limited clinician knowledge or misconceptions about EDS
• rural settings with limited medical access
• lower education levels
• lower socio-economic status
• history of adoption
• estranged family members
• not sharing medical diagnoses with other family members
• a de-novo gene mutation resulting in disease

In addition to the aforementioned, in some instances and despite meeting Brighton diagnostic criteria, clinicians may refuse to diagnose patients with EDS/HSD unless there is a positive family history. When EDS appears to be new or sporadic, it may be due to incomplete penetrance and/or variable phenotype expression. Clinician should also be aware that it is possible a new genetic mutation or combination of mutations occurred that would enable a new positive diagnosis; a de novo disease-causing mutation, which is when a gene mutation that was not present or transmitted by a parent occurred.

Family history of EDS must be acquired and individually evaluated in each case. However, clinicians currently are only required in the diagnostic criteria to ask whether anyone in the family has EDS, and accept a “yes” or “no” answer. However, it is important for clinicians to follow up a “no” answer by also examining familial details, including familial comorbidities that are associated with CTD, socio-economic and education levels, family dynamics, etc., to ascertain whether a stated negative familial history is truly negative.

Family History

The case study of a negative family history includes the following: grandparents lived in a rural, farm setting with no high school diploma; father was the first person in the family to get a high school diploma; patient was the first in her family to get a graduate degree; family members do not share medical information; parent (father) and patient share similar hypermobility joint features and health complaints; one child of patient (son) and niece also exhibit similar hypermobility joint traits (including heel papules), but have not sought diagnosis due to young age with minimal disability and complaints. In sum, no family members were previously diagnosed with EDS in this case due to rural settings with limited medical access, lower education and socio-economic levels, failure of family members to share health issues, and failure to obtain diagnosis for mild cases.

Patient Scenario

A 51-year-old woman was the first person in her family to be diagnosed with hEDS in 2018 utilizing the Brighton diagnostic criteria, including a 7/9 Beighton score and a positive 5PQ. She reports that hyperextended knees were identified during a scoliosis check in childhood (fifth grade) but it was never documented and no further evaluation/diagnosis of hypermobility was ever made. From age 10 into adulthood, she developed mild to severe health issues that could be attributed to CTD, specifically hEDS; and after bunion surgery in 2012, her orthopedic surgeon stated, “you have a connective tissue disease,” which prompted exploration of that opinion.

In this case, a delay in diagnosis was attributed to having a negative family history for EDS, no vetting into family medical history to ascertain undiagnosed CTD/EDS, the refusal of clinicians to refer to a geneticist, and having no objective diagnostic tests available, including gene testing. This case further substantiates the removal of requiring a positive family history for an EDS diagnosis and identifies multiple barriers in obtaining diagnosis.

Also noteworthy in this case, utilizing the Budapest Criteria, this patient had developed CRPS type II in 2012, which supports the premise that the incidence of CRPS is high in EDS populations.

Gene testing for EDS is in infancy stages and more genes are still being discovered. Because of this, a patient can have a negative gene test and still have EDS. Thus, gene tesing is useful, but not necessarily conclusive. In addition, there are no specific genotype/phenotype correlations to aid in the diagnosis of hEDS, which is the most common type of EDS (80% to 90%).”⁶˒⁸˒¹⁵

Variants in at least 20 genes have been found to be linked to EDS. Of note, some genes associated with EDS appear to be unrelated to collagen; thus it is unclear how variants lead to hypermobility, elastic skin, and other features. More research is needed to develop comprehensive genomic testing to assist in EDS diagnosis, but also to increase understanding of its pathophysiological mechanisms and comorbidities.

As discussed, CRPS and EDS have distinct diagnostic criteria. However, both diseases have more clinical similarities than often realized. They also have similar barriers to diagnosis, including clinician biases and no definitive diagnostic tests. Additionally, both diseases are influenced by age, gender, and ethnicity.

In general, the majority of individuals with either EDS or CRPS are female, diagnosed in adulthood (usually 40 to 50 years of age), experience chronic widespread pain and comorbid conditions, and are required to receive care from multiple specialists.² Both EDS and CRPS can take years or decades to diagnose because of clinicians’ biases or misconceptions of the disease, unfamiliarity with the disease, the variety of symptoms patients present in the clinical setting, and/or because there are no definitive diagnostic tests to confirm the disease.

The literature shows that chronic widespread pain is common in up to 90% of people with EDS, particularly hEDS, and can result in a significant decrease in quality of life and substantial disability.¹⁵ The types of pain that people with EDS and CRPS may exhibit include nociceptive pain, neuropathic pain, and/or central sensitization (CS).¹⁵˒¹⁶ As with EDS, characteristics of CS in CRPS may include the following: allodynia and hyperalgesia; the presence of tremors and/or myoclonus; heightened sensitivity to light, sounds, touch, and odors; poor concentration and poor short-term memory; and/or limbic system dysfunction, among others. Although chronic pain is a commonality in EDS and CRPS, CRPS is different in that it exhibits color, temperature, and skin changes, which are included in the diagnostic criteria.²

A study by Molander et al substantiated that a majority of EDS/HSD patients were female (93.6%) and a majority of EDS patients have concomitant chronic pain conditions (95%).¹⁸ Unfortunately, because EDS and CRPS have very similar clinical characteristics and comorbidities, they are often misdiagnosed for each other and/or patients are often given multiple diagnoses.¹⁹

Stern et al found 8.3% pediatric individuals with EDS (55.6% with hEDS) also had (unspecified) chronic pain syndromes.¹⁹ Hooshmand and Phillips found hEDS patients with CRPS, as well as familial tendencies, supporting the premise of genetic contributions to both EDS and CRPS.²⁰ Chopra and Cooper also discovered CRPS in a pediatric patient with hEDS.¹⁰ Weinstock et al discovered that an adult with CPRS not only had hEDS, but also had a three-generation family history of EDS.²¹ Finally, Weinstock et al stated, “undiagnosed Ehler’s-Danlos syndrome in patients with CRPS could also explain some cases of familial CRPS.”²¹

Although this topical review does not provide an in-depth pathophysiological review of the 13 types of EDS and two types of CRPS, it does identify a compelling connection between the two diseases, presumably due to “fragility of nerve connective tissue.”

This review also does not provide an in-depth discussion of genetic testing for EDS, which has diagnostic limitations, and were discussed; additionally, gene testing is important because it is estimated that 50% of classic EDS (cEDS) patients can have a de novo pathogenic mutation.²²

This topical review also does not discuss how negative family history affects the incidence of EDS diagnosis. However, it does identify clinician limitations and/or biases and other several significant limitations of having family history included in the diagnostic criteria.

It is often challenging for clinicians to identify and treat EDS/hEDS and CRPS, due to questions surrounding the etiology and pathophysiology of the diseases, but also due to multisystem comorbidities, limitations in diagnostic criteria, and the lack of consensus on treatment or guidelines on which treatment can be individualized. Many people with chronic pain have unexplained pain and unexplained comorbidities and see multiple specialists for years or decades before diagnosis. In addition, patients are occasionally misdiagnosed and/or clinicians are skeptical of the diagnosis due to limited experience or awareness of EDS and/or CRPS, which can also result in increased patient suffering.

This article also identified that CRPS and EDS are genetically driven diseases, which often results in multisystem comorbidities that are very similar to each other, and that CTD may be the “missing link.” The development of genomic testing is needed since there are no genotype/phenotype correlations available to diagnose 80% to 90% of EDS patients, which greatly decreases the incidence rate. In addition, the incidence of EDS may also be decreased due to patients with mild disease never seeking a medical diagnosis.

Specific symptoms and progression of EDS are variable, even from parent to child, and cannot be predicted based on diagnostic criteria, family history, or results of genetic testing. It is essential for clinicians to familiarize themselves with diagnostic criteria and/or consider CTD in people with chronic pain, especially those with “unexplained” symptomology or comorbidities. Because of the connection between CTD and chronic pain conditions, evaluating for CTD in patients with chronic widespread pain can rule out CTD and/or obtain a diagnosis enabling early and essential treatment to limit disability and morbidity.

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