4

Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders

The Ehlers-Danlos syndromes (EDS) are a group of heritable disorders of connective tissue (HDCTs) that share joint hypermobility and skin involvement. Other organ systems are involved to greater or lesser degrees, depending on the type of EDS. Hypermobility spectrum disorders (HSD) are included in this discussion because of their similarities with EDS, especially hypermobile EDS (hEDS), although they do not meet the diagnostic criteria for EDS. This chapter describes the history, diagnosis, and characteristics of EDS/HSD, and reviews their treatment, management, and selected associated physical and mental secondary impairments, many of which can limit activities and restrict participation of affected individuals in work and school. An overview EDS and HSD is provided in Annex Table 4-1 at the end of the chapter. Throughout this chapter, hEDS and HSD are considered together as “hEDS/HSD” because of their clinical similarities. Diagnostic criteria prior to 2017 would not have distinguished between hEDS and HSD, so much of the research on these disorders cited in this report is based on a mix of the two. The term “EDS/HSD” includes HSD with other types of EDS when it encompasses hEDS.

HISTORY OF EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY SPECTRUM DISORDERS

Parapia and Jackson (2008) present a historical review of EDS/HSD. The first report of a patient with joint hypermobility and skin laxity was published in 1892 by Tschernogobow, who presented two patients to the Moscow and Venereology and Dermatology Society (Tschernogobow,

1892). Other cases of joint hypermobility and skin laxity were subsequently reported by Gould and Pyle (1897) and Wile (1883).

In 1901, Ehlers described a patient with joint laxity; unusually stretchy skin; and a history of easy bruising, frequent knee subluxations, and delayed walking (Beighton, 1970). In 1908, Danlos collaborated with Pautier to further explore the physical manifestations of what came to be known as Ehlers-Danlos syndrome (Beighton, 1970).

In the United States, Tobias (1934) reported the first case of EDS/HSD; Ronchese (1936) reported on 24 cases in the literature and 3 whom he had seen personally. McKusick’s first edition of Heritable Disorders of Connective Tissue (1956) chronicled fewer than 100 reports in the literature; this number had risen to 300 by 1966, when the third edition was published. The first suggestion that the condition was inherited as an autosomal-dominant trait was published by Johnson and Falls (1949), who studied a large family with 32 affected members. As described by Parapia and Jackson (2008), Jansen (1955) reviewed all the extant published pedigrees at the time and suggested that a genetic defect of collagen most likely explained the EDS/HSD phenotype; support for this conclusion was later published by Sestak (1962).

By the late 1960s, different forms of EDS/HSD had begun to be recognized (Beighton, 1970; McKusick, 1972). Pinnell and colleagues (1972) described lysyl hydroxylase deficiency in an autosomal-recessive form of EDS presenting with rupture of the ocular globe and scoliosis. This observation represented the first identified molecular causation of a type of EDS. By 1988, nine different types of EDS/HSD had been proposed in an international nosology of HDCTs—the Beighton criteria (Beighton et al., 1988). A simplified classification was later proposed in what was called the Villefranche nosology (Beighton et al., 1998). Almost 20 years would transpire before an updated nosology would be published in 2017, identifying 13 distinct types of EDS, including hEDS (Malfait et al., 2017) (Table 4-1).

By 2017, the molecular cause of 12 of the then 13 types of EDS/HSD had been identified (Table 4-1). In 2018, another gene associated with classical-like EDS (type 2) was identified: bi-allelic alterations in the AEBP1 gene lead to defective collagen assembly and abnormal connective tissue structure (Blackburn et al., 2018). Identification and understanding of the genetic basis of the 13 EDS types, several of which have two or more subtypes, continue to evolve. While joint hypermobility is common to all types of EDS, as well as HSD, other presenting factors may vary among types and individuals. Only one type of EDS (the most common type, hEDS) and HSD remain without a known genetic cause. In an effort to accelerate the search for the hEDS gene(s) and increase the likelihood of finding

TABLE 4-1
Clinical Classification of the Ehlers-Danlos Syndromes, Inheritance Pattern, and Genetic Basis

SOURCE: Malfait et al., 2017, p. 10. © 2017 Wiley Periodicals, Inc.

NOTE: AD, autosomal dominant; AR, autosomal recessive, IP, inheritance pattern; NMD, nonsense-mediated mRNA decay.

them, the International Consortium on the Ehlers-Danlos Syndromes & Hypermobility Spectrum Disorders convened in 2016 to refine the diagnostic criteria for hEDS. These new criteria were significantly more rigorous than the previously defined criteria for what was called the hypermobility type under the Villefranche criteria. Consortium members, led by Castori, recognized that some people who met the Villefranche criteria for the hypermobility type would not meet the new, more restrictive criteria under the 2017 nosology; thus, the concept of “hypermobility spectrum disorders” emerged (Castori et al., 2017). Castori and colleagues (2017) proposed that joint hypermobility exists on a spectrum in the human population. Individuals who meet the established clinical criteria for hEDS receive that diagnosis, while those who do not meet those criteria but manifest symptomatic hypermobility are considered to have HSD. The diagnostic distinction between HSD and hEDS may not be clinically meaningful, however, as both groups may experience the same types of physical and mental impairments and potential functional limitations (Aubry-Rozier et al., 2021).

While the early reports of EDS/HSD focused on the unusual joint and skin findings observed in these patients, clinicians began to recognize the multisystem nature of these disorders, such that they affect virtually every organ system in the body. Secondary impairments include chronic pain (Castori, 2016), gastrointestinal dysmotility (Fikree et al., 2017), chronic fatigue (Hakim et al., 2017a), mental manifestations (Bulbena et al., 2017), dysautonomia (Roma et al., 2018), and cranial and spinal neurologic complications (Henderson et al., 2017). Recent reports suggest that immune dysfunction and mast cell activation are more common in hEDS/HSD than in the general population (Brock et al., 2021). Elevated tryptase levels are present in an estimated 6 percent of the general population. Hereditary alpha tryptasemia (HAT) is associated with an elevated serum tryptase, and persons with HAT may manifest joint hypermobility similar to that seen in other HDCT phenotypes (National Institute of Allergy and Infectious Diseases, 2018). The spectrum of mast cell dysregulation in these disorders is increasingly recognized. Prevalence estimates for these disorders are currently lacking, but this is an area of active investigation (Seneviratne et al., 2017).

Research has shown that individuals who meet the diagnostic criteria for hEDS and HSD have similar extra-articular manifestations and disease severity (Aubry-Rozier et al., 2021), contradicting the initial diagnostic description of HSD as being purely musculoskeletal. Therefore, patients diagnosed with HSD must not be assumed to have a milder condition or problems related only to the musculoskeletal system, as initially presumed when the diagnostic criteria were first established in 2017. These observations have prompted a call for further studies to reassess the 2017 diagnostic criteria and develop evidence-based diagnostic criteria for hEDS and HSD (Tinkle, 2020). Some such studies are currently under way.

Recent investigations have demonstrated that individuals meeting the diagnostic criteria for hEDS and those diagnosed with HSD have comparable rates of secondary impairments, such as chronic pain, dysautonomia, and gastrointestinal dysmotility. Research also shows that while there are two distinct groups among individuals with hEDS and HSD with respect to the severity of the secondary impairments they experience, the severity groups do not correspond to diagnosis (Copetti et al., 2019).

DIAGNOSIS OF EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY SPECTRUM DISORDERS

Each type of EDS, as well as HSD, has its own set of specific diagnostic criteria (see Annex Table 4-1). Most important in making the diagnosis is the clinician’s awareness that EDS/HSD should be considered. Once a patient has been recognized as having joint hypermobility, the differential

diagnosis should consider the various forms of EDS/HSD. Because the genes underlying the hEDS phenotype are not yet identified, diagnosis of hEDS rests entirely on the clinical criteria. Castori and colleagues (2017) present one widely used diagnostic algorithm for hEDS (see also International Consortium, 2017). These diagnostic criteria incorporate data from the Beighton scoring system used to assess hypermobility (Juul-Kristensen et al., 2017). Table 4-2 lists a number of additional hypermobility scales that can be used to assess hypermobility and diagnose generalized joint hypermobility associated with EDS/HSD.

The clinical diagnostic criteria for 12 other types of EDS are provided on the Ehlers-Danlos Society website,¹ but because of the overlap of symptoms among many types of EDS and HSD, definitive diagnosis includes confirmation through genetic testing of those types for which the responsible genes have been identified. The classical type (cEDS) and vascular type (vEDS) of EDS have their own sets of diagnostic criteria (Byers et al., 2017); diagnostic criteria for the 10 rarer types were published in 2017 (Malfait et al., 2017).

Research consistently describes the challenges and delays involved in establishing a correct diagnosis and receiving proper management for hEDS/HSD (Halverson et al., 2021; Knight, 2015). People with hEDS/HSD commonly report receiving incorrect or incomplete diagnoses, and studies

TABLE 4-2
Selected Hypermobility Assessment Scales

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¹ See https://www.ehlers-danlos.com/eds-types (accessed May 25, 2022).

document an average 11–12 years’ delay in establishing a correct diagnosis (Halverson et al., 2021; Knight, 2015; Terry et al., 2015). Even once diagnosed, individuals often report receiving inappropriate interventions from clinicians who are not knowledgeable about EDS/HSD. Because symptoms of hEDS/HSD are not always visible, affected individuals may experience high levels of distress and isolation as a result of actually or fearing not being believed about their signs and symptoms (Halverson et al., 2021; Knight, 2015; Langhinrichsen-Rohling et al., 2021; Palomo-Toucedo et al., 2020). Psychosocial support is important for patients with these disorders to help them face the challenges associated with the variety of symptoms they experience, as well as the potential effects of those symptoms on daily activities (Miklovic and Sieg, 2022; Palomo-Toucedo et al., 2020).

EDS/HSD are a complex set of disorders in large part because of their manifestations in multiple body systems. Some of the symptoms experienced by affected individuals are not clearly attributable to a single impairment in a specific body system. A well-functioning body depends on the proper functioning of all of its parts together, not just as individual components, operating as a complete system in which all of the parts interact with one another. Accordingly, a malfunction in one part inevitably affects other parts as well. The relationships among body systems are complex and not fully understood by science, a fact that becomes particularly apparent in disorders that, like EDS/HSD, affect tissues throughout the body. Problems in the immune system, for example, such as mast cell activation disease (MCAD), can manifest as symptoms in other body systems, such as gastrointestinal disorders, respiratory difficulties, nonmigraine headaches, and cognitive dysfunction or impairment, sometimes referred to as “brain fog” (Maitland, 2020). Dysfunction of the autonomic nervous system (dysautonomia) also affects the entire body (Maxwell, 2020; Vernino et al., 2021). In EDS/HSD, a variety of factors, including MCAD and dysautonomia, likely contribute to such symptoms as abdominal (gastrointestinal) distress and cognitive impairment (Maxwell, 2020). In addition to cognitive impairment, dysautonomia can manifest as symptoms of anxiety, attention deficit, and insomnia (Maxwell, 2020).

This clinical picture highlights the complex relationship not only among the physical parts of the body and their functioning but also between physical functioning and mental symptoms and functioning (e.g., cognitive function, mood disorders, anxiety). Moreover, individuals with chronic pain have a higher risk of developing symptoms of anxiety or depression, while those with anxiety or depression are more likely to experience chronic or intensified pain (Anxiety & Depression Association of America, 2022; Harvard Health Publishing, 2017).

The historical dichotomy between physical and mental disorders and the medical specialties that address them, combined with the complex

nature of HDCTs and a general lack of knowledge about these disorders among health care providers, undoubtedly contributes to the delayed diagnosis and misdiagnosis often experienced by individuals with EDS/HSD. The problem is bidirectional, with patients caught in the middle. Clinicians trained to address “physical” disorders may inappropriately refer a patient presenting with “unexplained” symptoms to a mental health care provider. Similarly, mental health care providers may not consider the possibility that symptoms commonly associated with a condition such as depression or anxiety may be caused, or exacerbated, by physical disorders.

The question of whether the symptoms commonly associated with a variety of mental disorders (e.g., anxiety disorders, eating disorders, attention-deficit/hyperactivity disorder) are manifestations of a physical disorder (e.g., dysautonomia), a comorbid mental disorder, or a mix of the two is a topic of debate. Two types of literature investigate the relationship between EDS/HSD and various mental disorders: some studies look at the prevalence of specific mental disorders among a population of individuals diagnosed with EDS/HSD, while others look at the prevalence of EDS/HSD or joint hypermobility more generally among a population of individuals diagnosed with a specific mental disorder. For example, the literature contains reports of an increased prevalence of eating disorders among individuals with EDS/HSD (Baeza-Velasco et al., 2022). The researchers posit that oral and gastrointestinal symptoms experienced by some people with EDS/HSD can lead to an aversion to eating, which in turn can develop into an eating disorder. On the other hand, it has been reported that most patients diagnosed with anorexia nervosa also meet the criteria for EDS/HSD (Baeza-Velasco et al., 2022).

The concern is that many individuals with EDS/HSD are inappropriately diagnosed with a psychiatric condition as the sole explanation for their symptoms, while the HDCT goes undiagnosed, and the associated physical impairments go untreated. While science works to establish a better diagnostic process or to define set of concurrent diagnoses, along with more effective standards of care, it is important to acknowledge that clinical assessment of these patients often falls short in investigating and identifying of the underlying causes of their symptoms. It is therefore critical for health care providers to be educated about such disorders as EDS/HSD and the constellation of symptoms with which they present (Miklovic and Sieg, 2022; Mittal et al., 2021). In addition, just as mental health care providers need to be aware of the physical disorders that may accompany symptoms attributable to psychiatric diagnoses, clinicians in primary care and the medical specialties need to be alert to the mental and emotional health of their patients.

Failure to recognize the complex relationships among body systems can lead to inappropriate or incomplete treatment. Treatment of symptoms without identification and treatment of contributing factors is likely to be

successful only partially if at all. For example, appropriate treatment of gastrointestinal symptoms could involve treatment for immune system dysfunction and dysautonomia. Appropriate treatment for pain requires identification and treatment of underlying pathology, as well as interventions to control the pain. Appropriate treatment for symptoms of anxiety could involve treatment of dysautonomia in addition to interventions to address the anxiety. It is clear that individuals with multisystem disorders such as HDCTs require care from multidisciplinary teams to investigate all of the potential causes of their symptoms (both physical and mental) (Miklovic and Sieg, 2022; Mittal et al., 2021).

CHARACTERISTICS OF EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY SPECTRUM DISORDERS

Clinical Picture

The natural history of EDS/HSD is variable. The range and severity of clinical course are best understood in the context of each specific type of EDS and HSD. Nevertheless, as a group, patients with EDS/HSD share general features of joint hypermobility, skin hyperextensibility, and tissue fragility that may affect organ systems, blood vessels, skin, joints, and ligaments (Bloom et al., 2017). It is important to note that specific manifestations may depend on the type of EDS/HSD, with hallmark features, such as vascular rupture (seen in vEDS), being specific to a particular type. Additional features of pain; fatigue; cognitive dysfunction; dysautonomia; and gastrointestinal, respiratory, and immune dysfunction are often underappreciated in EDS/HSD, particularly given their waxing and waning nature in affected individuals. Results of a large survey of patients’ lived experience with hEDS/HSD show the multimorbidity nature of these conditions, with individuals reporting 15–25 symptoms involving different organ systems and having substantial impact on daily functioning (Murray et al., 2013). Schubart and colleagues (2019a) identified three symptom clusters: a pain-dominant cluster, a high symptom burden cluster, and a mental fatigue cluster. The percentage of participants in the pain-dominant subgroup was similar in all EDS/HSD diagnostic subtypes, while the percentage in the high symptom burden subgroup was higher in the cEDS and hEDS/HSD subtypes, and the percentage in the mental fatigue subgroup was higher in the vEDS and “rare/unclassified” EDS subtypes (Schubart et al., 2019a).

EDS/HSD patients often appear healthy but report a constellation of symptoms that may be difficult for clinicians to recognize as being related. Therefore, as described previously, delayed or misdiagnosis is common, and may significantly and negatively impact the clinical course. At the time of diagnosis, patients are likely to have a history of multiple

articular dislocations or subluxations, poor wound healing, easy bruising, and atypical scarring. Such features are often present in childhood but may be considered “normal” for the family or attributed to external factors; in severe cases, child abuse may be suspected. Severe types may also present in relatively young patients with such dramatic manifestations as spontaneous organ rupture or vascular dissection, as is seen in patients with vEDS (Shalhub et al., 2019). Often children show hypersensitivity; difficulties in eating, which may lead to eating disorders; and more fears and anxiety than are found in the general population (Baeza-Velasco et al., 2022; Ezpeleta et al., 2018).

Profound changes in body composition that occur with puberty include, for example, increased musculoskeletal growth and changes in brain development (including cognitive maturation and psychosocial maturation) and in the cardiovascular system. These changes are mediated by hormones that can affect all organ systems. In many individuals with EDS/HSD, particularly those types manifesting hypermobility, puberty is associated with the onset or worsening of secondary impairments, especially in females, and may be a period of disease amplification (Tinkle et al., 2017). These impairments include increased gastrointestinal dysmotility (Dhingra et al., 2021a), respiratory complications (Bascom et al., 2021b), postural tachycardia syndrome (POTS) (Coupal et al., 2019), MCAD (Zierau et al., 2012), increased musculoskeletal pain (Dhingra et al., 2021b; Feldman et al., 2020; Mu et al., 2019), chronic fatigue (Pacey et al., 2015), and neuropsychiatric diagnoses (Kindgren et al., 2021; Tran et al., 2020), among others. Importantly, one study found that in vEDS, mortality was increased 3-fold in males under age 20 as a result of unanticipated vascular events (Pepin et al., 2014).

A recent study assessed the health-related quality of life (HRQoL) and mental health of children and adolescents aged 4–18 with a variety of HDCTs—MFS, LDS, hEDS, and other EDS types—through child- and parent-reported questionnaires (Warnink-Kavelaars, et al., 2022). Parents also reported on the impact of their child’s condition on the family and themselves. Overall, children and adolescents with HDCTs reported “increased pain, decreased physical functioning and general health, a negative mental health state, [and] limitations in school-related and leisure activities and participation with friends and family”; those with hEDS also reported low self-esteem compared with representative general-population samples (Warnink-Kavelaars, et al., 2022, p. 6). With respect to parental and family impact, parents of children with hEDS reported increased distress and limitations on their personal time and family activities relative to the comparison sample. Children and adolescents with hEDS and their parents had the lowest scores on all but a few of the HRQoL subscales. Mu and colleagues (2019) also found that children and adolescents with hEDS/HSD had lower

HRQoL scores compared with healthy controls, and that pain and fatigue were the primary predictors of HRQoL. These findings emphasize the need for psychosocial support among children diagnosed with EDS/HSD and their families.

Epidemiology

Epidemiology addresses the distribution and determinants of health-related states or events in specified populations and the impact of approaches for treating or controlling health problems (Last, 2001, p. 61). This discipline provides a framework for answering many of the questions posed in the committee’s statement of task: the prevalence of HDCTs; the status of diagnosis, treatment, and prognosis for those disorders; their age at onset and gender distribution; laboratory and diagnostic tests for the disorders; their usual clinical course for adults and children; the likelihood, frequency, and duration of changes in the clinical or medical severity of symptoms, such as flare-ups or remissions; the possibility and likelihood of reducing the work-related severity of symptoms; the treatments or circumstances that may lead to vocationally relevant improvement; and secondary impairments that result from either the disorders or their treatments.

Incidence

By definition, all HDCTs are present at birth, as the underlying causative genetic variant exists within an individual’s genome. Some HDCTs are recognized at birth because of their distinct and severe manifestations, whereas the manifestations of many HDCTs evolve over time, with shifting distributions in the population. As discussed previously, delays in diagnosis are well recognized.

Prevalence

As reported in Chapter 2, all types of EDS combined are thought to occur in about 1 in 5,000 people (Pyeritz, 2000; Steinmann et al., 2002). Among all types of EDS, hEDS likely accounts for 80–90 percent of cases (Tinkle et al., 2017). Rarer EDS types include vEDS, with an estimated prevalence of 1/50,000 (Byers, 2019). All other EDS types are extremely rare (Steinmann et al., 2002); musculocontractural EDS and dermatosparaxis EDS, for example, are estimated to have a prevalence of less than 1/1,000,000 (Orphanet, 2022a,b).

Preferred sources of epidemiologic information include large case series and population-based datasets. Current inferences of prevalence are subject to ascertainment and referral bias, and must be viewed with caution.

There is now a genetic test with which to identify many, although not all, of the EDS subtypes (Malfait et al., 2017). An epidemiologic approach to estimating the population prevalence of each EDS subtype with identified pathogenic variants would be to test for this variant in a general-population sample.

As noted in Chapter 2, there currently is no identified gene (pathogenic variant) for hEDS/HSD. Estimates of the prevalence of these disorders therefore derive from screening using standardized tests, such as the Beighton scoring system, and other clinical criteria (Castori et al., 2017). Mulvey and colleagues (2013) estimate a general-population prevalence of joint hypermobility of 18 percent, determined using a validated self-administered screening tool (Hakim and Grahame, 2003), with chronic widespread pain being present in a subset of these cases, perhaps indicating that the true prevalence of hEDS/HSD is much higher than 1/5,000.

A recent estimate of the prevalence of EDS/HSD derives from a national electronic cohort study and nested case control study conducted in Wales, United Kingdom. To derive this estimate, the researchers identified persons who were assigned a coded diagnosis of EDS/HSD or joint hypermobility syndrome (an older diagnostic term that includes both HSD and hEDS) between 1990 and 2017, finding a point prevalence of 10 cases in a practice of 5,000 patients (Demmler et al., 2019). Outpatient records were classified according to the READ 2 criteria and inpatient records according to the International Classification of Diseases, 10th edition (ICD-10).

Age and Gender Effects

hEDS/HSD are recognized in equal proportions in boys and girls. Increased joint hypermobility is seen in pubertal females (Quatman et al., 2008). Clinicians have observed the emergence of a female predominance in symptomatic EDS in the peripubertal period. The above-cited national cohort study of individuals with EDS/HSD in Wales, United Kingdom, showed a gender difference of 8.5 years in the mean age at diagnosis: the highest proportion of males was first identified at ages 5–9, while the highest proportion of females was diagnosed at ages 15–19 (Demmler et al., 2019). Overall, among 6,021 identified individuals, 30 percent were male and 70 percent female. This finding is supported by large case control studies of U.S. private insurers showing increased prescription drug claims for females beginning peripubertally (Bascom et al., 2021b; Dhingra et al., 2021a). Of note, a community-based survey conducted by Mulvey and colleagues (2013) found a progressive decline in the prevalence of joint hypermobility throughout adulthood (Mulvey et al., 2013).

Manifestations

The 2017 report of the International Consortium on Ehlers-Danlos Syndromes & Hypermobility Spectrum Disorders provides a detailed review of clinical findings for EDS/HSD, organized by organ system and derived from clinical experience, case series, and some large population samples (Bloom et al., 2017; Hakim et al., 2021). Annex Tables 5-3–5-12 list many of the physical and mental impairments associated with EDS/HSD. Studies cited below provide epidemiologic evidence for specific organ system manifestations associated with these disorders. This research shows greater prevalence of symptoms and diagnoses involving diverse organ systems among persons with EDS/HSD than was previously thought. These findings provide growing evidence that EDS/HSD should be viewed as a disorder not only with musculoskeletal manifestations but also with diverse, multi–organ system manifestations, including orthostatic intolerance (De Wandele et al., 2014a,b; 2014b; Hakim et al., 2017b; Roma et al., 2018; Rowe et al., 1999; Rowe, 2022), gastrointestinal symptoms, neurologic manifestations, respiratory manifestations (Bascom et al., 2021a,b; Chohan et al., 2021), and psychiatric manifestations (Bulbena et al., 2017). Notably, the pathophysiologic relationship between EDS/HSD and many of these manifestations and comorbid conditions is unclear, and the evidence linking them is primarily associative; many are also common in chronic conditions that are not characterized by connective tissue dysfunction. Further research is needed to understand the pathogenetic sequence for these manifestations and the implications for primary/secondary/tertiary prevention and disease state management.

Multisystem manifestations are often significant, but may vary both among individuals and throughout an affected individual’s lifetime. Not only do the physical and mental secondary impairments experienced by individuals with EDS/HSD differ from person to person, but the presence and severity of the impairments also may fluctuate (wax and wane) over time. A growing body of literature suggests that comorbid conditions, such as orthostatic intolerance and immune dysregulation, collectively contribute to disease severity and thus to an individual’s experience and associated disability (Copetti et al., 2019; Kalisch et al., 2020; Krahe et al., 2018). Individuals with versus those without hEDS/HSD also develop migraines earlier, have more days with migraines per month, and experience more accompanying symptoms (Puledda et al., 2015).

Patients will likely experience musculoskeletal and other disease manifestations throughout life. Joint hypermobility contributes to articular instability, with subluxation or dislocation leading to pain and premature degenerative arthritis over time. Hand and wrist pain can compromise fine motor skills, making it difficult to perform such activities as keyboarding

and other fine motor tasks that may be required for work or school. Pes planus (flat feet, usually associated with ankle pronation) is common in all forms of EDS/HSD and may further contribute to joint instability and pain; moderate to severe pes planus has been associated with knee and intermittent lower back pain (Kosashvili et al., 2008). Clinically significant and progressive scoliosis may develop, particularly in the kyphoscoliotic, classical, and arthrochalasia types of EDS as well as hEDS/HSD (Yonko et al., 2021). In addition, EDS/HSD patients are at increased risk of craniocervical and other spinal instability and such central nervous system pathologies as Chiari 1 malformation, intracranial hypertension, tethered cord syndrome, and syringomyelia (Henderson et al., 2017; Klinge et al., 2021, 2022). Myopia is common but nonspecific, and there is an increased risk for retinal detachment, glaucoma, strabismus, cataract, amblyopia, cornea scarring or rupture, and blindness (Louie et al., 2020). EDS/HSD is also associated with immune dysfunction, including MCAD, as well as primary immune deficiencies, which in turn can contribute to immune-mediated pathology in one or multiple organ systems (Brock et al., 2021; Sordet et al., 2005). Acute catastrophic events experienced during the course of disease are most likely to be seen in patients with vEDS, cEDS, or kyphoscoliotic EDS (kEDS) (Bowen et al., 2017; Brady et al., 2017; Byers et al., 2017). Such events include stroke, arterial dissection, spontaneous cerebrospinal fluid leak, ruptured aneurysm, spontaneous rupture of bladder, diverticulum, incarcerated hernia, intestinal intussusception, gastric perforation, and peripartum uterine rupture (Castori et al., 2015; Gilliam et al., 2020).

Gastrointestinal problems can be pronounced and contribute to high levels of health impairment and functional limitations in patients with hEDS/HSD. Individuals who experience frequent episodes of gastroinstestinal distress require access to a restroom whenever necessary at work or school. These problems are amplified by the presence of POTS or MCAD (Chelimsky and Chelimsky, 2018; Hsieh, 2018; Inayet et al., 2018; Lam et al., 2021; Mehr et al., 2018; Tai et al., 2020; Wilder-Smith et al., 2019). Genitourinary conditions are also common and can affect activities and participation (Nee et al., 2019). For example, urinary incontinence can make it difficult to stand for extended periods of time without leakage. A study of gynecologic symptoms in hEDS/HSD indicated high frequencies of menorrhagia, dysmenorrhea, and dyspareunia (Hugon-Rodin et al., 2016). Urogynecological problems are amplified by comorbid POTS and MCAD, and hEDS/HSD symptoms may increase before and during menses (Patel and Khullar, 2021; Peggs et al., 2012). Adolescents with EDS/HSD may also experience severe gynecological symptoms (Hernandez and Dietrich, 2020).

Since the first clinical report in 1988, several psychopathological conditions, especially anxiety and depression, have been reported consistently in individuals with EDS/HSD (Baeza-Velasco et al., 2011; Bathen et al.,

2013; Berglund et al., 2015; Bulbena et al., 2017; Bulbena et al., 1988; Bulbena et al., 2015). Chronic pain is also common among individuals with EDS/HSD (Voermans et al., 2010a), with studies finding a prevalence of between 43 percent (Kalisch et al., 2020) and 99 percent (Murray et al., 2013). Individuals with EDS/HSD commonly experience severe fatigue as well (Voermans et al., 2010b). Depression is common among individuals with other chronic conditions, including pain, and dysautonomias can cause symptoms commonly associated with anxiety.

As noted, EDS/HSD may manifest in several organ systems, and these manifestations can result in impaired quality of life (Berglund et al., 2015) and employment difficulties. A survey of 455 persons with hEDS/HSD showed that 55 percent were currently employed, and 24 percent were working only part-time as a result of their disorder (Murray et al., 2013), while 12 percent (54 of 466 respondents) indicated they were not working because of hEDS/HSD-associated limitations. Among those who were working, half had to change roles or take on less responsibility because of their diagnosis. Of the 119 student respondents, 18 percent were unable to attend school full-time, and 32 percent reported not being enrolled in school at all because of their EDS/HSD diagnosis.

The most common manifestations of EDS/HSD that impact quality of life are chronic pain (joint and limb), chronic fatigue, and hypermobility (Murray et al., 2013). Other organ systems that may be affected by EDS/HSD include the gastrointestinal, nervous, ocular, respiratory, and urogenital systems. All of these manifestations, along with anxiety, depression, and fibromyalgia, can affect an individual’s participation in work, school, and other activities (Murray et al., 2013). In particular, hEDS/HSD appear to be associated with greater pain and work impairment (De Baets et al., 2021), whereas cEDS has a greater effect on activities of daily living; both types of EDS/HSD were found to result in greater perceived disability than is evident in the general population (Bogni et al., 2015). hEDS/HSD are also associated with mobility disability, which was found to be more prevalent among individuals who are older, have more fatigue, and have a higher body mass index (Kalisch et al., 2020). Mobility issues can be an impediment to working for individuals with hEDS/HSD who need a wheelchair or have difficulty accessing public transportation, and some pain medications used for EDS/HSD have sedative side effects that preclude driving. Obstructive sleep apnea occurs among those with EDS/HSD more frequently than in the general population and is associated with greater fatigue, particularly during the day, and poorer quality of life (Gaisl et al., 2017); daytime sleepiness can affect an individual’s ability to work regular hours. POTS, a frequent manifestation of EDS/HSD, is associated with a variety of persistent symptoms, such as cognitive impairments (e.g., in attention and recall), fatigue, low energy, headaches, and sleep disturbances, and can have substantial

effects on various aspects of quality of life (Mathias et al., 2021; Vernino et al., 2021), including employment and household tasks. Individuals with EDS/HSD report that their pain and fatigue can make working difficult, requiring reduced hours or different jobs, and in some cases leading them to leave a job or be terminated (Palomo-Toucedo et al., 2020).

TREATMENT AND MANAGEMENT

There is no cure for EDS/HSD, and management strategies rely on preventing and mitigating symptoms and treating associated physical and mental secondary impairments; these interventions are important for managing functional limitations and reducing HDCT-related disability. This section addresses the management of EDS/HSD; Chapter 5 addresses the relationship among secondary impairments associated with these disorders, their potential effects on function, and considerations relevant to Social Security Administration disability determinations.

Given the paucity of clinical trials or large-scale studies of specific therapeutic options for EDS/HSD, experts caring for patients with these disorders have developed management algorithms. The International Consortium on the Ehlers-Danlos Syndromes & Hypermobility Spectrum Disorders is the leading authority on EDS/HSD diagnosis, classification, and management, and as noted earlier, in 2017 published clinical practice guidance (Bloom et al., 2017; Malfait et al., 2017). More recent clinical guidance was published in the December 2021 issue of the American Journal of Medical Genetics (Hakim et al., 2021).

The treatment burden for EDS/HSD includes high numbers of clinician encounters to manage multisystem manifestations. Demmler and colleagues (2019) found that adults with EDS/HSD had significantly more diagnoses in 16 of 20 Read Code disease categories compared with controls, as well as more prescriptions for 15/17 Read Codes. A large proportion of persons with EDS/HSD require medications chronically, with a subset meeting criteria for polypharmacy—a substantial medication burden. Numbers of surgical procedures can be very high as well, as are the need for and use of allied health professional services. Durable medical equipment, including braces and mobility assistive devices, also may be required.

Education is particularly important for optimal EDS/HSD management, not only for patients and families but also for members of their health care team so they can appropriately identify and manage disease manifestations and coordinate multidisciplinary care (Miklovic and Sieg, 2021; Mittal et al., 2021). Patients and providers should understand how to recognize EDS/HSD-related disease manifestations and what monitoring practices may be beneficial in assessing the development of complications seen generally in EDS/HSD or specific to a certain EDS type. In addition, multidisciplinary

care teams should include a clinical geneticist to provide guidance on the implications of EDS/HSD for family members and the risk of recurrence within the family. Patients should be counseled on strategies for preventing or mitigating symptoms, as well as the risks associated with certain activities that may result in physical trauma, such as physically demanding activities or pregnancy and childbirth. Moreover, their hypersensitivity may cause individuals with EDS/HSD to have poor tolerance for pharmacologic treatments, a possibility clinicians need to consider when prescribing such drugs as corticoids, antidepressants, and some antibiotics. Given the lack of clinical experience with EDS/HSD in most clinical settings, it is important for those with expertise in EDS/HSD to educate other members of the patient’s care team regarding the disorders and develop monitoring and treatment plans collaboratively. Anyone newly diagnosed with vEDS or some other rare EDS type that is considered to pose a high risk of significant cardiovascular involvement should be referred to a clinical center with experience and expertise in EDS management (Byers et al., 2017).

Once a diagnosis of EDS/HSD has been made, patients should be counseled regarding potential disease-associated manifestations that necessitate immediate care. Acute, sometimes atraumatic dislocations are common. In certain types of EDS, urgent conditions may be signaled by the sudden onset of severe pain, including chest pain, or bleeding that can occur with vascular or organ (spleen, liver, colon, gravid uterus) rupture. Acute ruptures are most commonly seen in vEDS or kEDS, and more rarely in other types of EDS (D’Hondt et al., 2018; Lum et al., 2011). Any acute reduction in vision or increase in ocular discomfort requires emergency ophthalmic evaluation. Rapidly progressing neurologic signs may indicate central nervous system involvement requiring urgent management (Henderson et al., 2017, 2019). Finally, the sudden onset of shortness of breath may indicate spontaneous pneumothorax, for which immediate evaluation and treatment are required.

Monitoring for the presence of certain disease manifestations can be helpful in preventing the above emergencies by identifying early signs of pathology in asymptomatic patients. Specifically, all adult and pediatric EDS patients should undergo baseline cardiovascular evaluation. Cardiovascular assessment should include echocardiography to determine the presence and degree of cardiovascular involvement, such as valvular disease or aortic dilation (Atzinger et al., 2011). Patients with normal baseline studies and an EDS type considered low-risk for cardiovascular involvement may require fewer repeat evaluations, although no standardized interval for repeat testing has been established. Patients with abnormal findings or those with an EDS type considered high-risk for cardiovascular involvement (such as vEDS or kEDS) should be managed by a cardiovascular specialist to provide frequent monitoring and initiate specific interventions (e.g., pharmacologic,

surgical) as needed. In addition, patients with many of the rarer forms of EDS have cardiovascular involvement with functional consequences necessitating lifelong specialist management (Brady et al., 2017).

Given the risk of retinal detachment, lens luxation, and cornea breakdown, all EDS patients should undergo baseline ophthalmologic evaluation that is repeated at regular intervals to assess for evidence of corneal, lenticular, scleral, or retinal involvement. Although patients with kEDS are at the greatest risk for disease-related manifestations involving the eye, including retinal detachment, scleral fragility, globe rupture, and glaucoma, patients with other EDS types may be affected by these conditions and benefit from regular evaluation as well.

Several management considerations apply broadly to EDS/HSD, and strategies for mitigating certain symptoms can be used in patients with any EDS/HSD type. Evidence suggests that similar management strategies can be used for patients with hEDS and HSD (Aubry-Rozier et al., 2021). Joint hypermobility is a common feature in both, and preventive measures to minimize recurrent dislocations and/or the early onset of osteoarthritis are advised for individuals with either disorder. Preservation of joint function may be supported if the patient limits certain high-risk activities, such as contact sports or gymnastics, while engaging in joint-sparing, appropriate muscle-strengthening activities, such as water exercises or Pilates (Bowen et al., 2017). Joint management should include consultation with physical and occupational therapists, as well as evaluation by an orthotist. Although robust data are lacking, one study found that the majority of EDS/HSD patients enrolled in a physical therapy program reported benefit (Rombaut et al., 2011). For patients experiencing musculoskeletal pain related to joint hypermobility, pharmacologic treatment can be helpful but should be monitored by a clinician experienced in EDS/HSD management. Over-the-counter and prescription pain medications, as well as supplements, are more likely to cause adverse reactions in this population than in the general population (Agarwal et al., 2007; Bonadonna et al., 2016; Drugs.com, 2021; Song et al., 2020; Tahir et al., 2020; Vernino et al., 2021).

Spinal disease is a common feature of many forms of EDS/HSD. Scoliosis may be diagnosed in both children and adults, and clinically significant scoliosis may necessitate bracing or surgical intervention, especially in patients with kEDS but also in those with the cEDS, hEDS/HSD, and arthrochalasia EDS types. Experts in spine care should be involved in the care of EDS/HSD patients experiencing neck pain; headaches; migraines; or signs and symptoms suggestive of Chiari I malformation, intracranial hypertension, craniocervical or atlantoaxial instability, tethered cord, syringomyelia, dystonias, or Tarlov cysts (Henderson et al., 2017). Evaluation should include advanced imaging, such as magnetic resonance imaging.

Additional manifestations of EDS/HSD vary but may warrant specialty referral and assessment. Patients with gastrointestinal complaints should undergo a complete evaluation, including evaluation for extraluminal conditions. Upper endoscopy and colonoscopy should be approached with caution in individuals with EDS/HSD because of their underlying tissue fragility and increased risk of mucosal bleeding and complications from sedation (Kilaru et al., 2019). Immunologic involvement, particularly in patients with recurrent infections or those with symptoms of mast cell activation, requires consultation with a provider with expertise in allergy and immunology. Dysautonomia may be present, particularly in patients with hEDS/HSD. It may cause orthostatic intolerance, as well as tachycardia and/or palpitations, and contribute to a number of secondary neurological manifestations, such as fatigue, dizziness, syncope, and memory and concentration problems (Tinkle et al., 2017). Patients experiencing these complications, as well as those affected by recurrent headache, a common feature in patients with hEDS/HSD, should receive a neurologic evaluation. Patients with respiratory symptoms should receive a baseline assessment—spirometry with flow-volume loops and assessment of bronchodilator responsiveness.

Psychological assessment is important to screen for the presence of anxiety, phobic features, and depression since they frequently go unnoticed, and can interfere with daily life functions and even adherence to treatments. Individuals with EDS/HSD often have been classified as “somatizers” by clinicians unfamiliar with the disorders (Bulbena-Cabré et al., 2021). However, research on the biological and clinical basis of EDS/HSD is improving understanding of their physiology and psychopathology. The literature confirms that psychological processes, such as fear, emotional distress, or negative emotions, in EDS/HSD have a significant impact on patients’ outcomes (Bulbena-Cabré et al., 2021) and can interfere with daily activities and participation in work or school (see Chapter 5). ESD/HSD have common systemic associations with anxiety disorders, as well as significant correlations with neurodevelopmental, eating, mood, and sleep disorders (Bulbena-Cabré et al., 2021). All of these psychological issues need to be addressed in the assessment and management of individuals with EDS/HSD. It is important to reiterate that the relationships (associative or causal) among the different manifestations of EDS/HSD, as well as the relationships of those manifestations to the underlying disorder, are not fully understood. The presence and treatment of comorbid psychological disorders should not preclude the assessment and treatment of physical conditions that may underlie or contribute to symptoms associated with the psychological disorders.

Management of EDS/HSD patients should also include special consideration of specific transient states, such as the perioperative or peripartum

periods. Patients undergoing surgical interventions are more likely than the general population to experience adverse events associated with both soft-tissue fragility and anesthesia reactions/intolerance. Determining the presence and severity of patient-specific and EDS/HSD type–specific manifestations, such as bleeding, poor wound healing, cardiovascular involvement, or increased risk of joint subluxation or dislocation and cervical spine injury, is crucial during preoperative consultation. Tissue fragility associated with HDCTs motivated a recent assessment of surgical risk associated with EDS/HSD (and Marfan syndrome) as compared with controls in a national database (Jayarajan et al., 2020). The overall complication rate for all inpatient vascular surgery procedures was statistically greater for EDS/HSD patients (52.2 percent) than for controls (44.6 percent) (p < 0.0001). Patients with EDS/HSD showed an increased risk of postoperative hemorrhage (39 percent versus 22 percent for controls), but not of respiratory failure (8.7 percent versus 10.7 percent for controls).

Anecdotal reports beginning in 1990 (Arendt-Nielsen et al., 1990) and corroborated in 2005 (Hakim et al., 2005) indicate insufficient effect of local analgesics among persons with hEDS/HSD. Accordingly, preprocedure screening with a simple questionnaire (Hakim and Grahame, 2003) has been recommended to detect hypermobility and alert proceduralists intending to use local anesthetics for pain control in these patients. In 2017, the Patient-Centered Outcomes Research Institute–funded EDS Comorbidity Coalition conducted a research prioritization exercise; among 80 research ideas proposed, one of the 3 highest priorities was the issue of local anesthetic resistance (Bloom et al., 2021; Hakim et al., 2005). To assess the prevalence of this problem, Schubart and colleagues (2019b) conducted an online survey, finding that 88 percent of people with versus 33 percent of those without EDS/HSD reported inadequate response to local anesthesias. Postoperative pain management also is often inadequate in EDS/HSD patients, and the pain they experience may seem out of proportion. Clinicians need to understand that nociception is altered in these patients, and they may require more pain medication and different combinations of medications. A recent study of hEDS/HSD patients undergoing craneo-cervical fixation surgery found that opioid-free anesthesia in addition to postoperative administration of lidocaine, ketamine, and dexmedetomidine significantly reduced postoperative pain and the need of methadone rescues compared with opioid-based anesthesia and postsurgical management (Ramírez-Paesano et al., 2021).

The examples given above, supported by the committee members’ experience, indicate that persons with EDS/HSD have particular risks associated with procedures. A number of preoperative and preprocedural screening tools can be used to identify, quantify, communicate, and manage these risks (Moonesinghe et al., 2013). There remains, however, a need to

better understand and quantify procedural and surgical risks in EDS/HSD, as well as the other HDCTs. Needed as well are simple screening tools that can be used by anesthesiologists and proceduralists, particularly given the likelihood that a substantial proportion of persons with EDS/HSD are undiagnosed, but the lack of diagnosis does not remove the risk.

Use of desmopressin, a synthetic form of vasopressin, may be helpful in achieving hemostasis during and after invasive procedures (Castori, 2012). Patients with easy bruising and those demonstrating skin fragility, a notable feature in cEDS and vEDS, may benefit from daily ascorbic acid (Bowen et al., 2017). Surgical incisions (or wounds following trauma) should be closed without tension, deep stitches should be applied generously and closely, and cutaneous stitches should be left in place twice as long as in non-EDS patients; additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar (Castori, 2012, 2013b). Mast cells play a role in wound healing (Komi et al., 2020) and tolerance of adhesives; notably, their activation can be common and poorly controlled after such stressors as surgery. In addition, it may be advisable to counsel patients that, regardless of the best surgical interventions, they may have an elevated risk of postoperative complications (Guier et al., 2020; Kulas Søborg et al., 2017; Louie et al., 2020; Yonko et al., 2021) and decreased likelihood of surgical success (Rombaut et al., 2011; Yonko et al., 2021). In addition to those risks, moreover, surgical intervention and anesthesia may provoke POTS and MCAD. To limit surgical morbidity, all conservative (i.e., nonsurgical) measures should be exhausted before surgery for individuals with EDS/HSD is contemplated (see Table 4-3).

Patients contemplating pregnancy should be counseled about the risk of obstetrical complications (Byers, 2019; Byers et al., 2017; Eagleton, 2016; Karthikeyan and Venkat-Raman, 2018; Pepin et al., 2000; Pezaro et al., 2018). Preterm labor or premature rupture of membranes may occur in pregnant patients with EDS/HSD (Byers, 2019; Pezaro et al., 2018). Delivery may be precipitous and complicated by postpartum hemorrhage, extensive laceration, or extension of episiotomy incisions, or contribute to genitourinary complications, such as pelvic organ prolapse (Karthikeyan and Venkat-Raman, 2018; Pezaro et al., 2018). Similar to individuals with Loeys-Dietz syndrome, women with vEDS are at increased risk for uterine rupture and peripartum hemorrhage (Byers, 2019; Eagleton, 2016; Meester et al., 2017).

As discussed in Chapter 5, chronic pain and fatigue each have different, multifactorial causes. Management of each of these symptoms requires identification of and interventions to address the root cause. For example, management of fatigue caused by dysautonomia, MCAD, or sleep apnea requires treatment of that cause. Once the cause has been managed, relaxation techniques and mindfulness-based exercises can be helpful.

TABLE 4-3
Surgical and Anesthetic Recommendations for Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Hypermobility Type (JHS/EDS-HT)

SOURCE: Castori, 2013b. Copyright © 2013 Karger Publishers, Basel, Switzerland.

Psychosocial support and education are cornerstones of EDS/HSD management. The Ehlers-Danlos Society provides an abundance of information for both providers and patients, including community resources and support groups (www.ehlers-danlos.com).

PROGNOSIS

The prognosis and clinical course of EDS/HSD depend on individual patient factors (e.g., personal factors in the International Classification of Functioning, Disability and Health [ICF] model of disability described in Chapter 1), which vary greatly among affected individuals and are often related to the severity of disease-related physical and mental impairments, as well as the EDS/HSD type. As discussed previously, HDCTs are lifelong disorders. Recent longitudinal data from a well-characterized cohort of individuals with different types of EDS, assessed with repeated administration of standardized instruments (Schubart et al., 2022), support the

clinical impression of heterogeneity in clinical course. For many, EDS/HSD symptoms and disease burdens are chronic. Some persons with EDS/HSD experience a marked worsening over time, while a few see a decrease in the intensity and severity of manifestations. Overall, large cross-sectional case control studies of national prescription claims databases as a proxy for disease indicate an increase in multiple prescribed medications over the life course in persons with EDS/HSD compared with controls (Bascom et al., 2021b; Dhingra et al., 2021b).

It is important to note that patients with vEDS have a decreased life expectancy, with a median survival age of 46 for males and 54 for females (Pepin et al., 2014). The gender difference, which closes by age 40, appears attributable to a greater proportion of deaths among males, especially in the second decade of life: one study found that 18 percent of deaths among males compared with 7 percent of females occurred by age 20 (Pepin et al., 2014). Appropriate surveillance and management of at-risk individuals can be expected to improve life expectancy (NORD, 2017). Although patients with the most common forms of EDS/HSD do not have decreased life expectancy, the disorders may profoundly impact their quality of life. Longitudinal studies of individuals with different types of EDS/HSD would increase understanding of the clinical course of the disorders; their effects on functioning; and potentially the impact of interventions, including reasonable accommodations, on participation in work and school.

EMERGING TREATMENTS

Emerging treatments or interventions for EDS/HSD are limited; clinical trials evaluating the efficacy of various treatments, aimed not only at the underlying disease but also at the specific disease-associated manifestations, are generally lacking. Several ongoing clinical trials have been registered in ClinicalTrials.gov (NLM, 2022). As of early February 2022, the database included a total of 46 active clinical trials for EDS, almost all of them in the United States and Europe (mainly France). Some trials target specific subtypes of EDS. Several trials have been completed; their results have not yet been published, but it is reasonable to expect this to occur in the next couple of years. Participants are actively being recruited for still other trials. All of these trials have been designed to address basic mechanisms of disease, secondary impairments, and/or the efficacy of various interventions with respect to function. A wide variety of interventions are being tested, including drugs, rehabilitation strategies, behavioral interventions, and assistive devices, among others.

FINDINGS AND CONCLUSIONS

Findings

4-1. The Ehlers-Danlos syndromes (EDS) are a group of multisystem, heritable disorders of connective tissue (HDCTs) that share common elements of joint hypermobility and skin and soft tissue involvement. Hypermobility spectrum disorders (HSD) are also multisystem connective tissue disorders that are clinically similar to hypermobile EDS (hEDS) with respect to their manifestations and management.

4-2. Many factors, including underdiagnosis, lead to an underestimate of the prevalence of EDS/HSD.

4-3. EDS/HSD can manifest in physical and mental secondary impairments in any organ system and often in multiple organ systems in a given individual.

4-4. The type and severity of physical and mental manifestations associated with EDS/HSD often vary both among individuals and throughout an affected individual’s lifetime. Epidemiologic evidence supports multi–organ system manifestations, high treatment burden, and high disease burden.

4-5. The pathophysiologic relationships between EDS/HSD and many of their manifestations and comorbid conditions are unclear, and the evidence linking them is primarily associative.

4-6. Diagnosis of EDS/HSD is based on established clinical criteria, and most, though not all, types can be confirmed through genetic testing.

4-7. Diagnosis of hEDS and HSD is based solely on clinical criteria, since neither has a known genetic test. Understanding of and diagnostic criteria for hEDS and HSD continue to evolve.

4-8. There are currently no curative treatments for EDS or HSD. Management of the disorders involves early diagnosis and recognition; monitoring; and treatment of the manifestations in multiple organ systems, including treatment of associated physical and mental secondary impairments present at the time of identification and preventive measures to lessen or prevent problems that may develop over time.

4-9. The prognosis and clinical course of EDS/HSD depend on individual patient factors, which vary greatly among affected individuals and are often related to the severity of disease-associated physical and mental impairments, as well as the EDS/HSD type.

4-10. Individuals with vascular EDS (vEDS) have a decreased life expectancy, with a median survival age of 46 for males and 54 for females.

4-11. Diagnosis and management of EDS and HSD involve specialists across multiple physical and mental health disciplines.

4-12. Delayed diagnosis may result in a lack of or inappropriate management that may exacerbate physical and mental manifestations of EDS/HSD. Unanticipated risks and harms may attend routine procedures and therapies that carry EDS/HSD-specific risks, such as tissue fragility and physiologic reactivity resulting from autonomic and immune dysregulation.

4-13. EDS/HSD can affect individuals’ everyday physical and mental functioning, particularly as a result of limitations associated with pain, fatigue, and anxiety.

4-14. Secondary impairments in any of the body systems can be severe and affect the functioning of individuals with EDS/HSD.

4-15. Physical and mental secondary impairments associated with EDS/HSD often manifest or worsen during puberty, especially in females. Males with vEDS are at higher risk for complications during puberty.

4-16. Pregnancy can be a high-risk condition in some individuals with EDS; women with vEDS have an increased risk of uterine rupture or peripartum hemorrhage.

4-17. Following trauma or surgery, individuals with versus those without EDS/HSD often have a worse trajectory in terms of both length of recovery and frequency of complications.

Conclusions

4-1. EDS and HSD have multiple clinical manifestations that, individually or in combination, can cause functional limitations of varying severity. Some manifestations may become apparent only with age, and the types and severity of manifestations may vary throughout an affected individual’s lifetime.

4-2. Development of a screening tool to identify EDS/HSD could provide timely diagnosis of the disorders and help mitigate the negative effects of delayed diagnosis and EDS/HSD-specific risks that may attend routine procedures and therapies.

4-3. Management of EDS/HSD requires a multidisciplinary approach and involves early diagnosis of the multisystem findings, treatment of associated physical and mental secondary impairments, and measures to reduce or prevent problems that may present over time.

4-4. More research is needed on the pathophysiological mechanisms of EDS/HSD and their comorbid conditions and the implications for appropriate management and outcomes of the many secondary impairments associated with EDS/HSD.

4-5. Longitudinal studies of individuals with different types of EDS/HSD would increase understanding of the clinical course of the disorders; their effects on physical and mental functioning; and potentially the impact of interventions, including reasonable accommodations, on participation in work and school.

4-6. Health care providers need to be aware of the EDS/HSD-specific risks that may attend routine procedures and therapies.

REFERENCES

ANNEX TABLE 4-1
Overview of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders

NOTE: HDCT = heritable disorder of connective tissue and disability.

SOURCES: Bertoli-Avella et al., 2015; Callewaert, 2019; Doyle et al., 2012; Frischmeyer-Guerrerio et al., 2013; Greally, 2020; Gupta et al., 2002; Lindsay et al., 2012; Loeys and Dietz, 2018; Loeys et al., 2005, 2010; Matyas et al., 2014; Regalado et al., 2011; Rienhoff et al., 2013; Tan et al., 2013; Van Hemelrijk et al., 2010.