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).

TABLE 4-1

Clinical Classification of the Ehlers-Danlos Syndromes, Inheritance Pattern, and Genetic Basis.

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 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.

TABLE 4-2

Selected Hypermobility Assessment Scales.

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 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

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).

TABLE 4-3

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

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.

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

REFERENCES

• Abu A, Frydman M, Marek D, Pras E, Nir U, Reznik-Wolf H, Pras E. Deleterious mutations in the zinc-finger 469 gene cause brittle cornea syndrome. American Journal of Human Genetics. 2008;82(5):1217–1222. https://doi​.org/10.1016/j​.ajhg.2008.04.001 . [PMC free article: PMC2427192] [PubMed: 18452888]
• Agarwal AK, Garg R, Ritch A, Sarkar P. Postural orthostatic tachycardia syndrome. Postgraduate Medical Journal. 2007;83(981):478–480. https://doi​.org/10.1136/pgmj.2006.055046 . [PMC free article: PMC2600095] [PubMed: 17621618]
• Anxiety & Depression Association of America. Chronic pain. 2022. [March 7, 2022]. https://adaa​.org/understanding-anxiety​/related-illnesses​/other-related-conditions/chronic-pain .
• Arendt-Nielsen L, Kaalund S, Bjerring P, Høgsaa B. Insufficient effect of local analgesics in Ehlers Danlos type III patients (connective tissue disorder). Acta Anaesthesiologica Scandinavica. 1990;34(5):358–361. https://doi​.org/10.1111/j​.1399-6576.1990.tb03103.x . [PubMed: 2389651]
• Atzinger CL, Meyer RA, Khoury PR, Gao Z, Tinkle BT. Cross-sectional and longitudinal assessment of aortic root dilation and valvular anomalies in hypermobile and classic Ehlers-Danlos syndrome. Journal of Pediatrics. 2011;158(5):826–830.e821. https://doi​.org/10.1016/j​.jpeds.2010.11.023 . [PubMed: 21193204]
• Aubry-Rozier B, Schwitzguebel A, Valerio F, Tanniger J, Paquier C, Berna C, Hügle T, Benaim C. Are patients with hypermobile Ehlers–Danlos syndrome or hypermobility spectrum disorder so different. Rheumatology International. 2021;41(10):1785–1794. https://doi​.org/10.1007​/s00296-021-04968-3 . [PMC free article: PMC8390400] [PubMed: 34398260]
• Baeza-Velasco C, Espinoza P, Bulbena A, Bulbena-Cabré A, Seneque M, Guillaume S. Hypermobility spectrum disorders/Ehlers–Danlos syndrome and disordered eating behavior. In: Manzato E, Cuzzolaro M, Donini LM, editors. Hidden and Lesser-known Disordered Eating Behaviors in Medical and Psychiatric Conditions. Switzerland: Springer Nature; 2022. https://link​.springer​.com/chapter/10.1007​%2F978-3-030-81174-7_28#citeas .
• Baeza-Velasco C, Gély-Nargeot MC, Bulbena Vilarrasa A, Bravo JF. Joint hypermobility syndrome: Problems that require psychological intervention. Rheumatology International. 2011;31(9):1131–1136. https://doi​.org/10.1007​/s00296-011-1839-5 . [PubMed: 21373784]
• Bascom R, Dhingra R, Francomano CA. Respiratory manifestations in the Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021a;187(4):533–548. https://doi​.org/10.1002/ajmg.c.31953 . [PubMed: 34811894]
• Bascom R, Dhingra R, Francomano CA, Schubart JR. A case–control study of respiratory medication and co-occurring gastrointestinal prescription burden among persons with Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021b;187(4):549–560. https://doi​.org/10.1002/ajmg.c.31947 . [PubMed: 34766427]
• Bathen T, Hångmann AB, Hoff M, Andersen L, Rand-Hendriksen S. Multidisciplinary treatment of disability in Ehlers-Danlos syndrome hypermobility type/hypermobility syndrome: A pilot study using a combination of physical and cognitive-behavioral therapy on 12 women. American Journal of Medical Genetics. Part A. 2013;161a(12):3005–3011. https://doi​.org/10.1002/ajmg.a.36060 . [PubMed: 23913726]
• Baumann M, Giunta C, Krabichler B, Rüschendorf F, Zoppi N, Colombi M, Bittner RE, Quijano-Roy S, Muntoni F, Cirak S, Schreiber G, Zou Y, Hu Y, Romero NB, Carlier RY, Amberger A, Deutschmann A, Straub V, Rohrbach M, Steinmann B, Rostásy K, Karall D, Bönnemann CG, Zschocke J, Fauth C. Mutations in FKBP14 cause a variant of Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss. American Journal of Human Genetics. 2012;90(2):201–216. https://doi​.org/10.1016/j​.ajhg.2011.12.004 . [PMC free article: PMC3276673] [PubMed: 22265013]
• Beighton P. The Ehlers-Danlos syndrome. Annals of the Rheumatic Diseases. 1970;29(3):332–333. https://doi​.org/10.1136/ard.29.3.332 . [PMC free article: PMC1031273] [PubMed: 5432600]
• Beighton PH, Horan FT. Dominant inheritance in familial generalised articular hypermobility. Journal of Bone and Joint Surgery (British Volume). 1970;52(1):145–147. https://doi​.org/10.1302/0301-620X​.52B1.145 . [PubMed: 5436199]
• Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Annals of the Rheumatic Diseases. 1973;32(5):413–418. https://doi​.org/10.1136/ard.32.5.413 . [PMC free article: PMC1006136] [PubMed: 4751776]
• Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, Hall JG, Hollister DW, Horton W, McKusick VA, Opitz JM, Pope FM, Pyeritz RE, Rimoin DL, Sillence D, Spranger JW, Thompson E, Tsipouras P, Viljoen D, Winship I, Young I. International nosology of heritable disorders of connective tissue, Berlin, 1986. American Journal of Medical Genetics. 1988;29(3):581–594. https://doi​.org/10.1002/ajmg.1320290316 . [PubMed: 3287925]
• Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997. Ehlers-Danlos national foundation (USA) and Ehlers-Danlos support group (UK). American Journal of Medical Genetics. 1998;77(1):31–37. https://doi​.org/10.1002​/(sici)1096-8628(19980428)77​:1<31​::aid-ajmg8>3.0.co;2-o . [PubMed: 9557891]
• Berglund B, Pettersson C, Pigg M, Kristiansson P. Self-reported quality of life, anxiety and depression in individuals with Ehlers-Danlos syndrome (EDS): A questionnaire study. BMC Musculoskeletal Disorders. 2015;16(1):89. https://doi​.org/10.1186​/s12891-015-0549-7 . [PMC free article: PMC4403907] [PubMed: 25880527]
• Blackburn PR, Xu Z, Tumelty KE, Zhao RW, Monis WJ, Harris KG, Gass JM, Cousin MA, Boczek NJ, Mitkov MV, Cappel MA, Francomano CA, Parisi JE, Klee EW, Faqeih E, Alkuraya FS, Layne MD, McDonnell NB, Atwal PS. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. American Journal of Human Genetics. 2018;102(4):696–705. https://doi​.org/10.1016/j​.ajhg.2018.02.018 . [PMC free article: PMC5985336] [PubMed: 29606302]
• Bloom L, Byers P, Francomano C, Tinkle B, Malfait F. The international consortium on the Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):5–7. https://doi​.org/10.1002/ajmg.c.31547 . [PubMed: 28306227]
• Bloom L, Schubart J, Bascom R, Hakim A, Francomano CA. The power of patient-led global collaboration. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):425–428. https://doi​.org/10.1002/ajmg.c.31942 . [PubMed: 34741496]
• Bogni M, Bassotti A, Leocata G, Barretta F, Brunani A, Bertazzi PA, Riboldi L, Vigna LM. Workers with Ehlers-Danlos syndrome: Indications for health surveillance and suitable job assignment. Medicina del Lavoro. 2015;106(1):23–35. https:​//mattioli1885journals​.com/index.php​/lamedicinadellavoro/article/view/2990 . [PubMed: 25607285]
• Bonadonna P, Bonifacio M, Zanotti R. Mast cell disorders in drug hypersensitivity. Current Pharmaceutical Design. 2016;22(45):6862–6869. https://doi​.org/10.2174​/1381612822666160928121857 . [PubMed: 27779084]
• Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers-Danlos syndrome, classical type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):27–39. https://doi​.org/10.1002/ajmg.c.31548 . [PubMed: 28192633]
• Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer-Seebacher I, Kosho T, Mendoza-Londono R, Pope MF, Rohrbach M, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Zschocke J, Malfait F. The Ehlers-Danlos syndromes, rare types. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):70–115. https://doi​.org/10.1002/ajmg.c.31550 . [PubMed: 28306225]
• Brock I, Prendergast W, Maitland A. Mast cell activation disease and immunoglobulin deficiency in patients with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorder. American Journal of Medical Genetics. Part C: Seminars in Medical Genetics. 2021;187(4):473–481. https://doi​.org/10.1002/ajmg.c.31940 . [PubMed: 34747107]
• Bulbena A, Duro JC, Mateo A, Porta M, Vallejo J. Joint hypermobility syndrome and anxiety disorders. The Lancet. 1988;332(8612):694. https://doi​.org/10.1016​/S0140-6736(88)90514-4 . [PubMed: 2901559]
• Bulbena A, Duró JC, Porta M, Faus S, Vallescar R, Martín-Santos R. Clinical assessment of hypermobility of joints: Assembling criteria. Journal of Rheumatology. 1992;19(1):115–122. [PubMed: 1556672]
• Bulbena A, Mallorquí-Bagué N, Pailhez G, Rosado S, González I, Blanch-Rubió J, Carbonell J. Self-reported screening questionnaire for the assessment of joint hypermobility syndrome (SQ-CH), a collagen condition, in Spanish population. The European Journal of Psychiatry. 2014;28:17–26. https://dx​.doi.org/10​.4321/S0213-61632014000100002 .
• Bulbena A, Pailhez G, Bulbena-Cabré A, Mallorquí-Bagué N, Baeza-Velasco C. Joint hypermobility, anxiety and psychosomatics: Two and a half decades of progress toward a new phenotype. Advances in Psychosomatic Medicine. 2015;34:143–157. https://doi​.org/10.1159/000369113 . [PubMed: 25832520]
• Bulbena A, Baeza-Velasco C, Bulbena-Cabré A, Pailhez G, Critchley H, Chopra P, Mallorquí-Bagué N, Frank C, Porges S. Psychiatric and psychological aspects in the Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):237–245. https://doi​.org/10.1002/ajmg.c.31544 . [PubMed: 28186381]
• Bulbena-Cabré A, Baeza-Velasco C, Rosado-Figuerola S, Bulbena A. Updates on the psychological and psychiatric aspects of the Ehlers-Danlos syndromes and hypermobility spectrum disorders. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):482–490. https://doi​.org/10.1002/ajmg.c.31955 . [PubMed: 34806831]
• Burcharth J, Rosenberg J. Gastrointestinal surgery and related complications in patients with Ehlers-Danlos syndrome: A systematic review. Digestive Surgery. 2012;29(4):349–357. https://dx​.doi.org/10.1159/000343738 . [PubMed: 23095510]
• Burkitt Wright EMM, Spencer HL, Daly SB, Manson FDC, Zeef LAH, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, Madden C, Dodds A, Chandler KE, Banka S, Au L, Clayton-Smith J, Khan N, Biesecker LG, Wilson M, Rohrbach M, Colombi M, Giunta C, Black GCM. Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. American Journal of Human Genetics. 2011;88(6):767–777. https://doi​.org/10.1016/j​.ajhg.2011.05.007 . [PMC free article: PMC3113239] [PubMed: 21664999]
• Byers PH. Vascular Ehlers-Danlos syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A, editors. GeneReviews® [Internet]. Seattle, WA: University of Washington; 2019. 1993-2022. https://www​.ncbi.nlm​.nih.gov/books/NBK1494/ [PMC free article: PMC1494] [PubMed: 20301667]
• Byers PH, Belmont J, Black J, De Backer J, Frank M, Jeunemaitre X, Johnson D, Pepin M, Robert L, Sanders L, Wheeldon N. Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):40–47. https://doi​.org/10.1002/ajmg.c.31553 . [PubMed: 28306228]
• Carter C, Wilkinson J. Persistent joint laxity and congenital dislocation of the hip. Journal of Bone and Joint Surgery (British Volume). 1964;46:40–45. https://doi​.org/10.1302/0301-620X​.46B1.40 . [PubMed: 14126235]
• Castori M. Ehlers-Danlos syndrome, hypermobility type: An underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN Dermatology. 2012;2012:751768. https://doi​.org/10.5402/2012/751768 . [PMC free article: PMC3512326] [PubMed: 23227356]
• Castori M. Joint hypermobility syndrome (a.k.a. Ehlers-Danlos syndrome, hypermobility type): An updated critique. Italian Journal of Dermatology and Venereology. 2013a;148(1):13–36. [PubMed: 23407074]
• Castori M. Surgical recommendations in Ehlers-Danlos syndrome(s) need patient classification: The example of Ehlers-Danlos syndrome hypermobility type (a.k.a. joint hypermobility syndrome). Digestive Surgery. 2013b;29(6):453–455. https://doi​.org/10.1159/000346068 . [PubMed: 23295898]
• Castori M. Pain in Ehlers-Danlos syndromes: Manifestations, therapeutic strategies and future perspectives. Expert Opinion on Orphan Drugs. 2016;4(11):1145–1158. https://doi​.org/10.1080/21678707​.2016.1238302 .
• Castori M, Morlino S, Celletti C, Celli M, Morrone A, Colombi M, Camerota F, Grammatico P. Management of pain and fatigue in the joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome, hypermobility type): Principles and proposal for a multidisciplinary approach. American Journal of Medical Genetics. Part A. 2012a;158A(8):2055–2070. https://doi​.org/10.1002/ajmg.a.35483 . [PubMed: 22786715]
• Castori M, Morlino S, Dordoni C, Celletti C, Camerota F, Ritelli M, Morrone A, Venturini M, Grammatico P, Colombi M. Gynecologic and obstetric implications of the joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome hypermobility type) in 82 Italian patients. American Journal of Medical Genetics. Part A. 2012b;158A(9):2176–2182. https://doi​.org/10.1002/ajmg.a.35506 . [PubMed: 22847925]
• Castori M, Morlino S, Pascolini G, Blundo C, Grammatico P. Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2015;169C(1):54–75. https://doi​.org/10.1002/ajmg.c.31431 . [PubMed: 25821092]
• Castori M, Tinkle B, Levy H, Grahame R, Malfait F, Hakim A. A framework for the classification of joint hypermobility and related conditions. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):148–157. https://doi​.org/10.1002/ajmg.c.31539 . [PubMed: 28145606]
• Chelimsky G, Chelimsky T. The gastrointestinal symptoms present in patients with postural tachycardia syndrome: A review of the literature and overview of treatment. Autonomic Neuroscience. 2018;215:70–77. https://doi​.org/10.1016/j​.autneu.2018.09.003 . [PubMed: 30245098]
• Chohan K, Mittal N, McGillis L, Lopez-Hernandez L, Camacho E, Rachinsky M, Mina DS, Reid WD, Ryan CM, Champagne KA, Orchanian-Cheff A, Clarke H, Rozenberg D. A review of respiratory manifestations and their management in Ehlers-Danlos syndromes and hypermobility spectrum disorders. Chronic Respiratory Disease. 2021;18:14799731211025313. https://doi​.org/10.1177​/14799731211025313 . [PMC free article: PMC8312172] [PubMed: 34291699]
• Colige A, Sieron AL, Li SW, Schwarze U, Petty E, Wertelecki W, Wilcox W, Krakow D, Cohn DH, Reardon W, Byers PH, Lapière CM, Prockop DJ, Nusgens BV. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. American Journal of Human Genetics. 1999;65(2):308–317. https://doi​.org/10.1086/302504 . [PMC free article: PMC1377929] [PubMed: 10417273]
• Copetti M, Morlino S, Colombi M, Grammatico P, Fontana A, Castori M. Severity classes in adults with hypermobile Ehlers–Danlos syndrome/hypermobility spectrum disorders: A pilot study of 105 Italian patients. Rheumatology. 2019;58(10):1722–1730. https://doi​.org/10.1093​/rheumatology/kez029 . [PubMed: 30783660]
• Coupal KE, Heeney ND, Hockin BCD, Ronsley R, Armstrong K, Sanatani S, Claydon VE. Pubertal hormonal changes and the autonomic nervous system: Potential role in pediatric orthostatic intolerance. Frontiers in Neuroscience. 2019;13:1197. https://doi​.org/10.3389/fnins.2019.01197 . [PMC free article: PMC6861527] [PubMed: 31798399]
• D’Hondt S, Van Damme T, Malfait F. Vascular phenotypes in nonvascular subtypes of the Ehlers-Danlos syndrome: A systematic review. Genetics in Medicine. 2018;20(6):562–573. https://doi​.org/10.1038/gim.2017.138 . [PMC free article: PMC5993673] [PubMed: 28981071]
• De Baets S, Calders P, Verhoost L, Coussens M, Dewandele I, Malfait F, Vanderstraeten G, Van Hove G, Van de Velde D. Patient perspectives on employment participation in the “hypermobile Ehlers-Danlos syndrome” Disability and Rehabilitation. 2021;43(5):668–677. https://doi​.org/10.1080/09638288​.2019.1636316 . [PubMed: 31287330]
• De Coster PJ, Van den Berghe LI, Martens LC. Generalized joint hypermobility and temporomandibular disorders: Inherited connective tissue disease as a model with maximum expression. Journal of Orofacial Pain. 2005;19(1):47–57. [PubMed: 15779539]
• De Wandele I, Calders P, Peersman W, Rimbaut S, De Backer T, Malfait F, De Paepe A, Rombaut L. Autonomic symptom burden in the hypermobility type of Ehlers–Danlos syndrome: A comparative study with two other EDS types, fibromyalgia, and healthy controls. Seminars in Arthritis and Rheumatism. 2014a;44(3):353–361. https://doi​.org/10.1016/j​.semarthrit.2014.05.013 . [PubMed: 24968706]
• De Wandele I, Rombaut L, Leybaert L, Van de Borne P, De Backer T, Malfait F, De Paepe A, Calders P. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism. 2014b;44(1):93–100. https://doi​.org/10.1016/j​.semarthrit.2013.12.006 . [PubMed: 24507822]
• Delbaere S, Dhooge T, Syx D, Petit F, Goemans N, Destrée A, Vanakker O, De Rycke R, Symoens S, Malfait F. Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers-Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix. Genetics in Medicine. 2020;22(1):112–123. https://doi​.org/10.1038​/s41436-019-0599-6 . [PubMed: 31273343]
• Demmler JC, Atkinson MD, Reinhold EJ, Choy E, Lyons RA, Brophy ST. Diagnosed prevalence of Ehlers-Danlos syndrome and hypermobility spectrum disorder in Wales, UK: A national electronic cohort study and case–control comparison. BMJ Open. 2019;9(11):e031365. https://doi​.org/10.1136​/bmjopen-2019-031365 . [PMC free article: PMC6858200] [PubMed: 31685485]
• Dhingra R, Bascom R, Thompson E, Francomano CA, Schubart JR. Gastrointestinal medication burden among persons with the Ehlers-Danlos syndromes. Neurogastroenterology and Motility. 2021a;33(7):e14077. https://doi​.org/10.1111/nmo.14077 . [PubMed: 33393191]
• Dhingra R, Hakim A, Bascom R, Francomano CA, Schubart JR. Arthritis Care & Research. 2021b. Prescription claims for immunomodulator and anti-inflammatory drugs among persons with Ehlers-Danlos syndromes. https://doi​.org/10.1002/acr.24819 . [PubMed: 34788905]
• Drugs.com. What drugs should you avoid with Ehlers-Danlos syndrome? Medically reviewed by Sally Chao, MD. 2021. [February 14, 2022]. https://www​.drugs.com​/medical-answers/drugs-avoid-ehlersdanlos-syndrome-3559403/
• Dündar M, Müller T, Zhang Q, Pan J, Steinmann B, Vodopiutz J, Gruber R, Sonoda T, Krabichler B, Utermann G, Baenziger JU, Zhang L, Janecke AR. Loss of dermatan-4-sulfotransferase 1 function results in adducted thumb-clubfoot syndrome. American Journal of Human Genetics. 2009;85(6):873–882. https://doi​.org/10.1016/j​.ajhg.2009.11.010 . [PMC free article: PMC2790573] [PubMed: 20004762]
• Eagleton M. Arterial complications of vascular Ehlers-Danlos syndrome. Journal of VascularSurgery. 2016;64(6):1869–1880. https://doi​.org/10.1016/j​.jvs.2016.06.120 . [PubMed: 27687326]
• Ezpeleta L, Navarro JB, Osa N, Penelo E, Bulbena A. Joint hypermobility classes in 9-year-old children from the general population and anxiety symptoms. Journal of Developmental and Behavioral Pediatrics. 2018;39(6):481–488. https://doi​.org/10.1097/dbp​.0000000000000577 . [PubMed: 29847358]
• Feldman ECH, Hivick DP, Slepian PM, Tran ST, Chopra P, Greenley RN. Pain symptomatology and management in pediatric Ehlers-Danlos syndrome: A review. Children (Basel). 2020;7(9):146. https://doi​.org/10.3390/children7090146 . [PMC free article: PMC7552757] [PubMed: 32967103]
• Fikree A, Chelimsky G, Collins H, Kovacic K, Aziz Q. Gastrointestinal involvement in the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):181–187. https://doi​.org/10.1002/ajmg.c.31546 . [PubMed: 28186368]
• Gaisl T, Giunta C, Bratton DJ, Sutherland K, Schlatzer C, Sievi N, Franzen D, Cistulli PA, Rohrbach M, Kohler M. Obstructive sleep apnoea and quality of life in Ehlers-Danlos syndrome: A parallel cohort study. Thorax. 2017;72(8):729–735. https://doi​.org/10.1136​/thoraxjnl-2016-209560 . [PubMed: 28073822]
• Gilliam E, Hoffman JD, Yeh G. Urogenital and pelvic complications in the Ehlers-Danlos syndromes and associated hypermobility spectrum disorders: A scoping review. Clinical Genetics. 2020;97(1):168–178. https://doi​.org/10.1111/cge.13624 . [PMC free article: PMC6917879] [PubMed: 31420870]
• Giunta C, Elçioglu NH, Albrecht B, Eich G, Chambaz C, Janecke AR, Yeowell H, Weis M, Eyre DR, Kraenzlin M, Steinmann B. Spondylocheiro dysplastic form of the Ehlers-Danlos syndrome—An autosomal-recessive entity caused by mutations in the zinc transporter gene SLC39A13. American Journal of Human Genetics. 2008;82(6):1290–1305. https://doi​.org/10.1016/j​.ajhg.2008.05.001 . [PMC free article: PMC2427271] [PubMed: 18513683]
• Gould GM, Pyle WL. Anomalies and curiosities of medicine. Philadelphia: W.B. Saunders; 1897. https://collections​.nlm​.nih.gov/catalog/nlm​:nlmuid-57221200R-bk .
• Guier C, Shi G, Ledford C, Taunton M, Heckman M, Wilke B. Primary total hip arthroplasty in patients with Ehlers-Danlos syndrome: A retrospective matched-cohort study. Arthroplasty Today. 2020;6(3):386–389. https://dx​.doi.org/10​.1016/j.artd.2020.05.006 . [PMC free article: PMC7303917] [PubMed: 32577483]
• Hakim AJ, Grahame R. A simple questionnaire to detect hypermobility: An adjunct to the assessment of patients with diffuse musculoskeletal pain. International Journal of Clinical Practice. 2003;57(3):163–166. [PubMed: 12723715]
• Hakim A, Grahame R, Norris P, Hopper C. Local anaesthetic failure in joint hypermobility syndrome. Journal of the Royal Society of Medicine. 2005;98(2):84–85. https://www​.ncbi.nlm​.nih.gov/pmc/articles/PMC1079398/ [PMC free article: PMC1079398] [PubMed: 15684369]
• Hakim A, De Wandele I, O’Callaghan C, Pocinki A, Rowe P. Chronic fatigue in Ehlers-Danlos syndrome-hypermobile type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017a;175(1):175–180. https://doi​.org/10.1002/ajmg.c.31542 . [PubMed: 28186393]
• Hakim A, O’Callaghan C, De Wandele I, Stiles L, Pocinki A, Rowe P. Cardiovascular autonomic dysfunction in Ehlers-Danlos syndrome-hypermobile type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017b;175(1):168–174. https://doi​.org/10.1002/ajmg.c.31543 . [PubMed: 28160388]
• Hakim AJ, Tinkle BT, Francomano CA. Ehlers-Danlos syndromes, hypermobility spectrum disorders, and associated co-morbidities: Reports from EDS ECHO. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):413–415. https://doi​.org/10.1002/ajmg.c.31954 . [PubMed: 34793630]
• Halverson CME, Clayton EW, Garcia Sierra A, Francomano C. Patients with Ehlers–Danlos syndrome on the diagnostic odyssey: Rethinking complexity and difficulty as a hero’s journey. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):416–424. https://doi​.org/10.1002/ajmg.c.31935 . [PubMed: 34524722]
• Harvard Health Publishing. Depression and pain. 2017. [March 7, 2022]. https://www​.health.harvard​.edu/mindand-mood​/depression-and-pain .
• Hautala T, Heikkinen J, Kivirikko KI, Myllylä R. A large duplication in the gene for lysyl hydroxylase accounts for the type VI variant of Ehlers-Danlos syndrome in two siblings. Genomics. 1993;15(2):399–404. https://doi​.org/10.1006/geno.1993.1074 . [PubMed: 8449506]
• Henderson FC Sr, Austin C, Benzel E, Bolognese P, Ellenbogen R, Francomano CA, Ireton C, Klinge P, Koby M, Long D, Patel S, Singman EL, Voermans NC. Neurological and spinal manifestations of the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):195–211. https://doi​.org/10.1002/ajmg.c.31549 . [PubMed: 28220607]
• Henderson FC, Francomano CA, Koby M, Tuchman K, Adcock J, Patel S. Cervical medullary syndrome secondary to craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after craniocervical reduction, fusion, and stabilization. Neurosurgical Review. 2019;42(4):915–936. https://doi​.org/10.1007​/s10143-018-01070-4 . [PMC free article: PMC6821667] [PubMed: 30627832]
• Hernandez AMC, Dietrich JE. Gynecologic management of pediatric and adolescent patients with Ehlers-Danlos syndrome. Journal of Pediatric and Adolescent Gynecology. 2020;33(3):291–295. https://doi​.org/10.1016/j​.jpag.2019.12.011 . [PubMed: 31883462]
• Hicks D, Farsani GT, Laval S, Collins J, Sarkozy A, Martoni E, Shah A, Zou Y, Koch M, Bönnemann CG, Roberts M, Lochmüller H, Bushby K, Straub V. Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy. Human Molecular Genetics. 2014;23(9):2353–2363. https://doi​.org/10.1093/hmg/ddt637 . [PubMed: 24334769]
• Hsieh FH. Gastrointestinal involvement in mast cell activation disorders. Immunology and Allergy Clinics of North America. 2018;38(3):429–441. https://doi​.org/10.1016/j​.iac.2018.04.008 . [PubMed: 30007461]
• Hugon-Rodin J, Lebègue G, Becourt S, Hamonet C, Gompel A. Gynecologic symptoms and the influence on reproductive life in 386 women with hypermobility type Ehlers-Danlos syndrome: A cohort study. Orphanet Journal of Rare Diseases. 2016;11(1):124. https://doi​.org/10.1186​/s13023-016-0511-2 . [PMC free article: PMC5020453] [PubMed: 27619482]
• Inayet N, Hayat JO, Kaul A, Tome M, Child A, Poullis A. Gastrointestinal symptoms in Marfan syndrome and hypermobile Ehlers-Danlos syndrome. Gastroenterology Research and Practice. 2018;2018:4854701. https://doi​.org/10.1155/2018/4854701 . [PMC free article: PMC6087563] [PubMed: 30151001]
• International Consortium (International Consortium on Ehlers-Danlos Syndromes and Related Disorders). Diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS). 2017. [February 14, 2022]. https://www​.ehlers-danlos​.com/heds-diagnostic-checklist/
• Jackson SC, Odiaman L, Card RT, van der Bom JG, Poon MC. Suspected collagen disorders in the bleeding disorder clinic: A case-control study. Haemophilia. 2013;19(2):246–250. https://doi​.org/10.1111/hae.12020 . [PubMed: 23030528]
• Jansen LH. Mode of transmission in Ehlers-Danlos disease. Journal de Génétique Humaine. 1955;4(4):204–218. [PubMed: 13306907]
• Jayarajan SN, Downing BD, Sanchez LA, Jim J. Trends of vascular surgery procedures in Marfan syndrome and Ehlers-Danlos syndrome. Vascular. 2020;28(6):834–841. https://doi​.org/10.1177/1708538120925597 . [PubMed: 32423364]
• Johnson SAM, Falls HF. Ehlers-Danlos syndrome: A clinical and genetic study. Archives of Dermatology and Syphilology. 1949;60(1):82–105. https://doi​.org/10.1001/archderm​.1949.01530010085006 . [PubMed: 18152064]
• Juul-Kristensen B, Schmedling K, Rombaut L, Lund H, Engelbert RHH. Measurement properties of clinical assessment methods for classifying generalized joint hypermobility—A systematic review. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):116–147. https://doi​.org/10.1002/ajmg.c.31540 . [PubMed: 28306223]
• Kalisch L, Hamonet C, Bourdon C, Montalescot L, de Cazotte C, Baeza-Velasco C. Predictors of pain and mobility disability in the hypermobile Ehlers-Danlos syndrome. Disability and Rehabilitation. 2020;42(25):3679–3686. https://doi​.org/10.1080/09638288​.2019.1608595 . [PubMed: 31060411]
• Kapferer-Seebacher I, Pepin M, Werner R, Aitman TJ, Nordgren A, Stoiber H, Thielens N, Gaboriaud C, Amberger A, Schossig A, Gruber R, Giunta C, Bamshad M, Björck E, Chen C, Chitayat D, Dorschner M, Schmitt-Egenolf M, Hale CJ, Hanna D, Hennies HC, Heiss-Kisielewsky I, Lindstrand A, Lundberg P, Mitchell AL, Nickerson DA, Reinstein E, Rohrbach M, Romani N, Schmuth M, Silver R, Taylan F, Vandersteen A, Vandrovcova J, Weerakkody R, Yang M, Pope FM, Byers PH, Zschocke J. Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement. American Journal of Human Genetics. 2016;99(5):1005–1014. https://doi​.org/10.1016/j​.ajhg.2016.08.019 . [PMC free article: PMC5097948] [PubMed: 27745832]
• Karthikeyan A, Venkat-Raman N. Hypermobile Ehlers–Danlos syndrome and pregnancy. Obstetric Medicine. 2018;11(3):104–109. https://doi​.org/10.1177/1753495X18754577 . [PMC free article: PMC6134354] [PubMed: 30214474]
• Kilaru SM, Mukamal KJ, Nee JW, Oza SS, Lembo AJ, Wolf JL. Safety of endoscopy in heritable connective tissue disorders. American Journal of Gastroenterology. 2019;114(8):1343–1345. doi: 10.14309/ajg.0000000000000189. [PubMed: 31185005]
• Kindgren E, Quiñones Perez A, Knez R. Prevalence of ADHD and autism spectrum disorder in children with hypermobility spectrum disorders or hypermobile Ehlers-Danlos syndrome: A retrospective study. Neuropsychiatric Disease and Treatment. 2021;17:379–388. https://doi​.org/10.2147/ndt.S290494 . [PMC free article: PMC7882457] [PubMed: 33603376]
• Klinge PM, McElroy A, Donahue JE, Brinker T, Gokaslan ZL, Beland MD. Abnormal spinal cord motion at the craniocervical junction in hypermobile Ehlers-Danlos patients. Journal of Neurosurgery. 2021;35(1):18–24. https://doi​.org/10.3171/2020​.10.Spine201765 . [PubMed: 34020423]
• Klinge PM, Srivastava V, McElroy A, Leary OP, Ahmed Z, Donahue JE, Brinker T, De Vloo P, Gokaslan ZL. Diseased filum terminale as a cause of tethered cord syndrome in Ehlers-Danlos syndrome: Histopathology, biomechanics, clinical presentation, and outcome of filum excision. World Neurosurgery. 2022;162(June):e492–e502. https://doi​.org/10.1016/j​.wneu.2022.03.038 . [PubMed: 35307588]
• Knight I. The role of narrative medicine in the management of joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2015;169C(1):123–129. https://doi​.org/10.1002/ajmg.c.31428 . [PubMed: 25821096]
• Komi DEA, Khomtchouk K, Santa Maria PL. A review of the contribution of mast cells in wound healing: Involved molecular and cellular mechanisms. Clinical Reviews in Allergy & Immunology. 2020;58(3):298–312. https://doi​.org/10.1007​/s12016-019-08729-w . [PubMed: 30729428]
• Kosashvili Y, Fridman T, Backstein D, Safir O, Bar Ziv Y. The correlation between pes planus and anterior knee or intermittent low back pain. Foot & Ankle International. 2008;29(9):910–913. https://doi​.org/10.3113/FAI.2008.0910 . [PubMed: 18778669]
• Krahe AM, Adams RD, Nicholson LL. Features that exacerbate fatigue severity in joint hypermobility syndrome/Ehlers-Danlos syndrome—hypermobility type. Disability and Rehabilitation. 2018;40(17):1989–1996. https://doi​.org/10.1080/09638288​.2017.1323022 . [PubMed: 28482708]
• Kulas Søborg M-L, Leganger J, Rosenberg J, Burcharth J. Increased need for gastrointestinal surgery and increased risk of surgery-related complications in patients with Ehlers-Danlos syndrome: A systematic review. Digestive Surgery. 2017;34(2):161–170. https://dx​.doi.org/10.1159/000449106 . [PubMed: 27931023]
• Langhinrichsen-Rohling J, Lewis CL, McCabe S, Lathan EC, Agnew GA, Selwyn CN, Gigler ME. They’ve been BITTEN: Reports of institutional and provider betrayal and links with Ehlers-Danlos syndrome patients’ current symptoms, unmet needs and healthcare expectations. Therapeutic Advances in Rare Disease. 2021;2:1–12. https://doi​.org/10.1177​/26330040211022033 .
• Last JM ed. Dictionary of epidemiology. Fourth ed. New York: Oxford University Press; 2001.
• Lam CY, Palsson OS, Whitehead WE, Sperber AD, Tornblom H, Simren M, Aziz I. Rome IV functional gastrointestinal disorders and health impairment in subjects with hypermobility spectrum disorders or hypermobile Ehlers-Danlos syndrome. Clinical Gastroenterology and Hepatology. 2021;19(2):277–287.e273. https://doi​.org/10.1016/j​.cgh.2020.02.034 . [PubMed: 32109633]
• Louie A, Meyerle C, Francomano C, Srikumaran D, Merali F, Doyle JJ, Bower K, Bloom L, Boland MV, Mahoney N, Daoud Y, Singman EL. Survey of Ehlers-Danlos patients’ ophthalmic surgery experiences. Molecular Genetics & Genomic Medicine. 2020;8(4) https://dx​.doi.org/10.1002/mgg3.1155 . [PMC free article: PMC7196452] [PubMed: 31989797]
• Lum YW, Brooke BS, Black JH 3rd. Contemporary management of vascular Ehlers-Danlos syndrome. Current Opinion in Cardiology. 2011;26(6):494–501. https://doi​.org/10.1097/HCO​.0b013e32834ad55a . [PubMed: 21852761]
• Maitland A. Mast cell activation syndrome. In: Jovin D, editor. Disjointed: Navigating the diagnosis and management of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. 1st ed. San Francisco: Hidden Stripes Publications; 2020. pp. 217–231.
• Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers-Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):8–26. https://doi​.org/10.1002/ajmg.c.31552 . [PubMed: 28306229]
• Mathias CJ, Low DA, Iodice V, Owens AP, Kirbis M, Grahame R. Postural tachycardia syndrome—Current experience and concepts. Nature Reviews: Neurology. 2011;8(1):22–34. https://doi​.org/10.1038/nrneurol​.2011.187 . [PubMed: 22143364]
• Mathias CJ, Owens A, Iodice V, Hakim A. Dysautonomia in the Ehlers-Danlos syndromes and hypermobility spectrum disorders—With a focus on the postural tachycardia syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):510–519. https://doi​.org/10.1002/ajmg.c.31951 . [PubMed: 34766441]
• Maxwell AJ. Dysautonomia. In: Jovin D, editor. Disjointed: Navigating the diagnosis and management of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. 1st ed. San Francisco: Hidden Stripes Publications; 2020. pp. 135–215.
• McKusick VA. Heritable disorders of connective tissue. 1st ed. St. Louis: C.V. Mosby Company; 1956.
• McKusick VA. Heritable disorders of connective tissue. 4th ed. St. Louis: C.V. Mosby Company; 1972.
• McNerney JE, Johnston WB. Generalized ligamentous laxity, hallux abducto valgus and the first metatarsocuneiform joint. Journal of the American Podiatry Association. 1979;69(1):69–82. https://doi​.org/10.7547/87507315-69-1-69 . [PubMed: 759483]
• Meester J, Verstraeten A, Schepers D, Alaerts M, Van Laer L, Loeys BL. Differences in manifestations of Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome. Annals of Cardiothoracic Surgery. 2017;6(6):582–594. https://doi​.org/10.21037/acs.2017.11.03 . [PMC free article: PMC5721110] [PubMed: 29270370]
• Mehr SE, Barbul A, Shibao CA. Gastrointestinal symptoms in postural tachycardia syndrome: A systematic review. Clinical Autonomic Research. 2018;28(4):411–421. https://doi​.org/10.1007​/s10286-018-0519-x . [PMC free article: PMC6314490] [PubMed: 29549458]
• Meyer KJ, Chan C, Hopper L, Nicholson LL. Identifying lower limb specific and generalised joint hypermobility in adults: Validation of the Lower Limb Assessment Score. BMC Musculoskeletal Disorders. 2017;18(1):514. https://doi​.org/10.1186​/s12891-017-1875-8 . [PMC free article: PMC5719901] [PubMed: 29212541]
• Miklovic T, Sieg V. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Ehlers Danlos syndrome. https://www​.ncbi.nlm​.nih.gov/books/NBK549814/ [PMC free article: PMC549814] [PubMed: 31747221]
• Milhorat TH, Bolognese PA, Nishikawa M, McDonnell NB, Francomano CA. Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and Chiari malformation type I in patients with hereditary disorders of connective tissue. Journal of Neurosurgery: Spine. 2007;7(6):601–609. https://doi​.org/10.3171/spi-07/12/601 . [PubMed: 18074684]
• Mittal M, Mina DS, McGillis L, Weinrib A, Slepian PM, Rachinsky M, Buryk-Iggers S, Laflamme C, Lopez-Hernandez L, Hussey L, Katz J, McLean L, Rozenberg D, Liu L, Tse Y, Parker C, Adler A, Charames G, Bleakney R, Veillete C, Nielson CJ, Tavares S, Varriano S, Guzman J, Faghfoury H, Clarke H. The GoodHope Ehlers Danlos Syndrome Clinic: Development and implementation of the first interdisciplinary program for multi-system issues in connective tissue disorders at the Toronto General Hospital. Orphanet Journal of Rare Diseases. 2021;16(1):357. https://doi​.org/10.1186​/s13023-021-01962-7 . [PMC free article: PMC8353438] [PubMed: 34376220]
• Moonesinghe SR, Mythen MG, Das P, Rowan KM, Grocott MP. Risk stratification tools for predicting morbidity and mortality in adult patients undergoing major surgery: Qualitative systematic review. Anesthesiology. 2013;119(4):959–981. https://doi​.org/10.1097/ALN​.0b013e3182a4e94d . [PubMed: 24195875]
• Mu W, Muriello M, Clemens JL, Wang Y, Smith CH, Tran PT, Rowe PC, Francomano CA, Kline AD, Bodurtha J. Factors affecting quality of life in children and adolescents with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders. American Journal of Medical Genetics. Part A. 2019;179(4):561–569. https://doi​.org/10.1002/ajmg.a.61055 . [PMC free article: PMC7029373] [PubMed: 30703284]
• Müller T, Mizumoto S, Suresh I, Komatsu Y, Vodopiutz J, Dundar M, Straub V, Lingenhel A, Melmer A, Lechner S, Zschocke J, Sugahara K, Janecke AR. Loss of dermatan sulfate epimerase (DSE) function results in musculocontractural Ehlers-Danlos syndrome. Human Molecular Genetics. 2013;22(18):3761–3772. https://doi​.org/10.1093/hmg/ddt227 . [PubMed: 23704329]
• Mulvey MR, Macfarlane GJ, Beasley M, Symmons DPM, Lovell K, Keeley P, Woby S, McBeth J. Modest association of joint hypermobility with disabling and limiting musculoskeletal pain: Results from a large-scale general population–based survey. Arthritis Care & Research. 2013;65(8):1325–1333. https://doi​.org/10.1002/acr.21979 . [PubMed: 23401475]
• Murray B, Yashar BM, Uhlmann WR, Clauw DJ, Petty EM. Ehlers-Danlos syndrome, hypermobility type: A characterization of the patients’ lived experience. American Journal of Medical Genetics. Part A. 2013;161A(12):2981–2988. https://doi​.org/10.1002/ajmg.a.36293 . [PubMed: 24254846]
• Nakajima M, Mizumoto S, Miyake N, Kogawa R, Iida A, Ito H, Kitoh H, Hirayama A, Mitsubuchi H, Miyazaki O, Kosaki R, Horikawa R, Lai A, Mendoza-Londono R, Dupuis L, Chitayat D, Howard A, Leal GF, Cavalcanti D, Tsurusaki Y, Saitsu H, Watanabe S, Lausch E, Unger S, Bonafé L, Ohashi H, Superti-Furga A, Matsumoto N, Sugahara K, Nishimura G, Ikegawa S. Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. American Journal of Human Genetics. 2013;92(6):927–934. https://doi​.org/10.1016/j​.ajhg.2013.04.003 . [PMC free article: PMC3675233] [PubMed: 23664117]
• National Institute of Allergy and Infectious Diseases. Hereditary alpha tryptasemia and hereditary alpha tryptasemia syndrome FAQ. 2018. [March 4, 2022]. https://www​.niaid.nih​.gov/research/hereditary-alpha-tryptasemia-faq .
• Nee J, Kilaru S, Kelley J, Oza SS, Hirsch W, Ballou S, Lembo A, Wolf J. Prevalence of functional GI diseases and pelvic floor symptoms in Marfan syndrome and Ehlers-Danlos syndrome: A national cohort study. Journal of Clinical Gastroenterology. 2019;53(9):653–659. https://doi​.org/10.1097/MCG​.0000000000001173 . [PMC free article: PMC6642856] [PubMed: 30672816]
• Nicholls AC, Oliver J, Renouf DV, McPheat J, Palan A, Pope FM. Ehlers-Danlos syndrome type VII: A single base change that causes exon skipping in the type I collagen alpha 2(I) chain. Human Genetics. 1991;87(2):193–198. https://doi​.org/10.1007/bf00204180 . [PubMed: 1712342]
• Nicholson LL, Chan C. The Upper Limb Hypermobility Assessment Tool: A novel validated measure of adult joint mobility. Musculoskeletal Science and Practice. 2018;35:38–45. https://doi​.org/10.1016/j​.msksp.2018.02.006 . [PubMed: 29510315]
• NLM (U.S. National Library of Medicine). ClinicalTrails.gov. 2022. [February 11, 2022]. https:​//clinicaltrials.gov/
• NORD (National Organization for Rare Disorders). Rare disease database: Ehlers-Danlos syndrome. 2017. [May 16, 2022]. https:​//rarediseases​.org/rare-diseases/ehlers-danlos-syndrome/
• Okajima T, Fukumoto S, Furukawa K, Urano T. Molecular basis for the progeroid variant of Ehlers-Danlos syndrome. Identification and characterization of two mutations in galactosyltransferase I gene. Journal of Biological Chemistry. 1999;274(41):28841–28844. https://doi​.org/10.1074/jbc.274.41.28841 . [PubMed: 10506123]
• Orphanet. Dermatosparaxis Ehlers-Danlos syndrome. 2022a. [February 16, 2022]. https://www​.orpha.net/consor4​.01/www/cgi-bin/Disease_Search​.php?lng​=EN&data_id​=4045&Disease​_Disease_Search_diseaseGroup​=Dermatosparaxis-EDS&Disease​_Disease_Search_diseaseType​=Pat&Disease(s)​/group%20of%20diseases​=Dermatosparaxis-Ehlers-Danlos-syndrome&title​=Dermatosparaxis​%20Ehlers-Danlos​%20syndrome&search​=Disease_Search_Simple .
• Orphanet. Musculocontractural Ehlers-Danlos syndrome. 2022b. [February 16, 2022]. https://www.orpha.net/consor4.01/www/cgi-bin/Disease_Search.php?lng=EN&data_id=3480&Disease_Disease_Search_diseaseGroup=Musculocontractural-EDS&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Musculocontractural-Ehlers-Danlos-syndrome&title=Musculocontractural%20Ehlers-Danlos%20 syndrome&search=Disease_Search_Simple .
• Pacey V, Tofts L, Adams RD, Munns CF, Nicholson LL. Quality of life prediction in children with joint hypermobility syndrome. Journal of Paediatrics and Child Health. 2015;51(7):689–695. https://doi​.org/10.1111/jpc.12826 . [PubMed: 25622801]
• Palomo-Toucedo IC, Leon-Larios F, Reina-Bueno M, Vázquez-Bautista MDC, Munuera-Martínez PV, Domínguez-Maldonado G. Psychosocial influence of Ehlers-Danlos syndrome in daily life of patients: A qualitative study. International Journal of Environmental Research and Public Health. 2020;17(17):6425. https://doi​.org/10.3390/ijerph17176425 . [PMC free article: PMC7503231] [PubMed: 32899328]
• Parapia LA, Jackson C. Ehlers-Danlos syndrome—A historical review. British Journal of Haematology. 2008;141(1):32–35. https://doi​.org/10.1111/j​.1365-2141.2008.06994.x . [PubMed: 18324963]
• Patel M, Khullar V. Urogynaecology and Ehlers-Danlos syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):579–585. https://doi​.org/10.1002/ajmg.c.31959 . [PubMed: 34799982]
• Peggs KJ, Nguyen H, Enayat D, Keller NR, Al-Hendy A, Raj SR. Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome. International Journal of Gynaecology and Obstetrics. 2012;118(3):242–246. https://doi​.org/10.1016/j​.ijgo.2012.04.014 . [PMC free article: PMC3413773] [PubMed: 22721633]
• Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. New England Journal of Medicine. 2000;342(10):673–680. https://doi​.org/10.1056​/nejm200003093421001 . [PubMed: 10706896]
• Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, Byers PH. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genetics in Medicine. 2014;16(12):881–888. https://doi​.org/10.1038/gim.2014.72 . [PubMed: 24922459]
• Pezaro S, Pearce G, Reinhold E. Hypermobile Ehlers-Danlos syndrome during pregnancy, birth and beyond. British Journal of Midwifery. 2018;26(4):217–223. https://doi​.org/10.12968/bjom​.2018.26.4.217 .
• Pinnell SR, Krane SM, Kenzora JE, Glimcher MJ. A heritable disorder of connective tissue. Hydroxylysine-deficient collagen disease. New England Journal of Medicine. 1972;286(19):1013–1020. https://doi​.org/10.1056​/nejm197205112861901 . [PubMed: 5016372]
• Puledda F, Viganò A, Celletti C, Petolicchio B, Toscano M, Vicenzini E, Castori M, Laudani G, Valente D, Camerota F, Di Piero V. A study of migraine characteristics in joint hypermobility syndrome a.k.a. Ehlers-Danlos syndrome, hypermobility type. Neurological Sciences. 2015;36(8):1417–1424. https://doi​.org/10.1007​/s10072-015-2173-6 . [PubMed: 25791889]
• Pyeritz RE. Ehlers-Danlos syndromes. Goldman L, Bennett JC, editors. Philadelphia: W.B. Saunders; Cecil Textbook of Medicine. (21st) 2000;1:1119–1120.
• Quatman CE, Ford KR, Myer GD, Paterno MV, Hewett TE. The effects of gender and pubertal status on generalized joint laxity in young athletes. Journal of Science and Medicine in Sport. 2008;11(3):257–263. https://doi​.org/10.1016/j​.jsams.2007.05.005 . [PMC free article: PMC2453596] [PubMed: 17597005]
• Ramírez-Paesano C, Juanola Galceran A, Rodiera Clarens C, Gilete Garcsía V, Oliver Abadal B, Vilchez Cobo V, Ros Nebot B, Julián González S, Cao López L, Santaliestra Fierro J, Rodiera Olivé J. Opioid-free anesthesia for patients with joint hypermobility syndrome undergoing craneo-cervical fixation: A case-series study focused on anti-hyperalgesic approach. Orphanet Journal of Rare Diseases. 2021;16(1):172. https://doi​.org/10.1186​/s13023-021-01795-4 . [PMC free article: PMC8045305] [PubMed: 33849631]
• Roma M, Marden CL, De Wandele I, Francomano CA, Rowe PC. Postural tachycardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome. Autonomic Neuroscience. 2018;215:89–96. https://doi​.org/10.1016/j​.autneu.2018.02.006 . [PubMed: 29519641]
• Rombaut L, Malfait F, De Wandele I, Cools A, Thijs Y, De Paepe A, Calders P. Medication, surgery, and physiotherapy among patients with the hypermobility type of Ehlers-Danlos syndrome. Archives of Physical Medicine and Rehabilitation. 2011;92(7):1106–1112. https://doi​.org/10.1016/j​.apmr.2011.01.016 . [PubMed: 21636074]
• Ronchese F. Dermatorrhexis: With dermatochalasis and arthrochalasis (the so-called Ehlers-Danlos syndrome). American Journal of Diseases of Children. 1936;51(6):1403–1414. https://doi​.org/10.1001/archpedi​.1936.01970180149012 .
• Rotés Querol J. Reumatología clínica. Barcelona: Espaxs; 1983.
• Rowe P. Paper commissioned by the Committee on Heritable Disorders of Connective Tissue and Disability. National Academies of Sciences, Engineering, and Medicine; Washington, DC: 2022. The functional impact of orthostatic intolerance in Ehlers-Danlos syndrome.
• Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. Journal of Pediatrics. 1999;135(4):494–499. https://doi​.org/10.1016​/s00223476(99)70173-3 . [PubMed: 10518084]
• Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, van Haren B, Miller WL, Bristow J. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. New England Journal of Medicine. 2001;345(16):1167–1175. https://doi​.org/10.1056/NEJMoa002939 . [PubMed: 11642233]
• Schubart JR, Schaefer E, Hakim AJ, Francomano CA, Bascom R. Use of cluster analysis to delineate symptom profiles in an Ehlers-Danlos syndrome patient population. Journal of Pain and Symptom Management. 2019a;58(3):427–436. https://doi​.org/10.1016/j​.jpainsymman.2019.05.013 . [PMC free article: PMC6708773] [PubMed: 31153935]
• Schubart JR, Schaefer E, Janicki P, Adhikary SD, Schilling A, Hakim AJ, Bascom R, Francomano CA, Raj SR. Resistance to local anesthesia in people with the Ehlers-Danlos syndromes presenting for dental surgery. Journal of Dental Anesthesia and Pain Medicine. 2019b;19(5):261. https://dx​.doi.org/10​.17245/jdapm.2019.19.5.261 . [PMC free article: PMC6834718] [PubMed: 31723666]
• Schubart JR, Mills SE, Schaefer EW, Bascom R, Francomano CA. Longitudinal analysis of symptoms in the Ehlers-Danlos syndromes. American Journal of Medical Genetics. Part A. 2022;188(4):1204–1213. https://doi​.org/10.1002/ajmg.a.62640 . [PMC free article: PMC10433231] [PubMed: 34994522]
• Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, Byers PH. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. American Journal of Human Genetics. 2004;74(5):917–930. https://doi​.org/10.1086/420794 . [PMC free article: PMC1181985] [PubMed: 15077201]
• Seneviratne SL, Maitland A, Afrin L. Mast cell disorders in Ehlers-Danlos syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):226–236. https://doi​.org/10.1002/ajmg.c.31555 . [PubMed: 28261938]
• Sestak Z. Ehlers-Danlos syndrome and cutis laxa: An account of families in the Oxford area. Annals of Human Genetics. 1962;25(4):313–321. https://doi​.org/10.1111/j​.1469-1809.1962.tb01768.x . [PubMed: 13910947]
• Shalhub S, Byers PH, Hicks KL, Charlton-Ouw K, Zarkowsky D, Coleman DM, Davis FM, Regalado ES, De Caridi G, Weaver KN, Miller EM, Schermerhorn ML, Shean K, Oderich G, Ribeiro M, Nishikawa C, Behrendt CA, Debus ES, von Kodolitsch Y, Powell RJ, Pepin M, Milewicz DM, Lawrence PF, Woo K. A multi-institutional experience in the aortic and arterial pathology in individuals with genetically confirmed vascular Ehlers-Danlos syndrome. Journal of Vascular Surgery. 2019;70(5):1543–1554. https://doi​.org/10.1016/j​.jvs.2019.01.069 . [PMC free article: PMC8240141] [PubMed: 31126764]
• Song B, Yeh P, Nguyen D, Ikpeama U, Epstein M, Harrell J. Ehlers-Danlos syndrome: An analysis of the current treatment options. Pain Physician. 2020;23(4):429–438. [PubMed: 32709178]
• Sordet C, Cantagrel A, Schaeverbeke T, Sibilia J. Bone and joint disease associated with primary immune deficiencies. Joint, Bone, Spine: Revue du Rhumatisme. 2005;72(6):503–514. https://doi​.org/10.1016/j​.jbspin.2004.07.012 . [PubMed: 16376804]
• Steinmann B, Royce PM, Superti-Furga A. The Ehlers-Danlos syndrome. In: Steinmann B, Royce PM, editors. Connective tissue and its heritable disorders: Molecular, genetic, and medical aspects. 2nd ed. New York: Wiley‐Liss, Inc; 2002. https://doi​.org/10.1002/0471221929.ch9 .
• Tahir F, Bin Arif T, Majid Z, Ahmed J, Khalid M. Ivabradine in postural orthostatic tachycardia syndrome: A review of the literature. Cureus. 2020;12(4):e7868. https://doi​.org/10.7759/cureus.7868 . [PMC free article: PMC7255540] [PubMed: 32489723]
• Tai FWD, Palsson OS, Lam CY, Whitehead WE, Sperber AD, Tornblom H, Simren M, Aziz I. Functional gastrointestinal disorders are increased in joint hypermobility-related disorders with concomitant postural orthostatic tachycardia syndrome. Neurogastroenterology and Motility. 2020;32(12):e13975. https://doi​.org/10.1111/nmo.13975 . [PubMed: 32803794]
• Terry RH, Palmer ST, Rimes KA, Clark CJ, Simmonds JV, Horwood JP. Living with joint hypermobility syndrome: Patient experiences of diagnosis, referral and self-care. Family Practice. 2015;32(3):354–358. https://doi​.org/10.1093/fampra/cmv026 . [PMC free article: PMC4445137] [PubMed: 25911504]
• Tinkle BT. Symptomatic joint hypermobility. Best Practice & Research: Clinical Rheumatology. 2020;34(3):101508. https://doi​.org/10.1016/j​.berh.2020.101508 . [PubMed: 32249022]
• Tinkle B, Castori M, Berglund B, Cohen H, Grahame R, Kazkaz H, Levy H. Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers-Danlos syndrome type III and Ehlers-Danlos syndrome hypermobility type): Clinical description and natural history. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2017;175(1):48–69. https://doi​.org/10.1002/ajmg.c.31538 . [PubMed: 28145611]
• Tobias N. Archives of Dermatology and Syphilology. 4. Vol. 30. 1934. Danlos syndrome associated with congenital lipomatosis; pp. 540–551. https://doi/0​.1001/archderm​.1934.01460160054008 .
• Tran ST, Jagpal A, Koven ML, Turek CE, Golden JS, Tinkle BT. Symptom complaints and impact on functioning in youth with hypermobile Ehlers-Danlos syndrome. Journal of Child Health Care. 2020;24(3):444–457. https://doi​.org/10.1177/1367493519867174 . [PubMed: 31370685]
• Tschernogobow A. Cutis laxa (presentation at first meeting of Moscow). Dermatologic and Venereology Society, November 13, 1891. Monatshefte für Praktische Dermatologie. 1892;14:76.
• Vernino S, Bourne KM, Stiles LE, Grubb BP, Fedorowski A, Stewart JM, Arnold AC, Pace LA, Axelsson J, Boris JR, Moak JP, Goodman BP, Chémali KR, Chung TH, Goldstein DS, Diedrich A, Miglis MG, Cortez MM, Miller AJ, Freeman R, Biaggioni I, Rowe PC, Sheldon RS, Shibao CA, Systrom DM, Cook GA, Doherty TA, Abdallah HI, Darbari A, Raj SR. Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 National Institutes of Health expert consensus meeting—part 1. Autonomic Neuroscience. 2021;235:102828. https://doi​.org/10.1016/j​.autneu.2021.102828 . [PMC free article: PMC8455420] [PubMed: 34144933]
• Voermans NC, Knoop H, Bleijenberg G, van Engelen BG. Pain in Ehlers-Danlos syndrome is common, severe, and associated with functional impairment. Journal of Pain and Symptom Management. 2010a;40(3):370–378. https://doi​.org/10.1016/j​.jpainsymman.2009.12.026 . [PubMed: 20579833]
• Voermans NC, Knoop H, van de Kamp N, Hamel BC, Bleijenberg G, van Engelen BG. Fatigue is a frequent and clinically relevant problem in Ehlers-Danlos syndrome. Seminars in Arthritis and Rheumatism. 2010b;40(3):267–274. https://doi​.org/10.1016/j​.semarthrit.2009.08.003 . [PubMed: 19878973]
• Warnink-Kavelaars J, de Koning LE, Rombaut L, Menke LA, Alsem MW, van Oers HA, Buizer AI, Engelbert RHH, Oosterlaan J., Pediatric Heritable Connective Tissue Disorder Study Group. Heritable connective tissue disorders in childhood: Decreased health-related quality of life and mental health. American Journal of Medical Genetics. Part A. 2022;188(7):2096–2109. https://doi​.org/10.1002/ajmg.a.62750 . [PMC free article: PMC9321696] [PubMed: 35393672]
• Weil D, D’Alessio M, Ramirez F, de Wet W, Cole WG, Chan D, Bateman JF. A base substitution in the exon of a collagen gene causes alternative splicing and generates a structurally abnormal polypeptide in a patient with Ehlers-Danlos syndrome type VII. EMBO Journal. 1989;8(6):1705–1710. https://doi​.org/10.1002/j​.1460-2075.1989.tb03562.x . [PMC free article: PMC401012] [PubMed: 2767050]
• Wilder-Smith CH, Drewes AM, Materna A, Olesen SS. Symptoms of mast cell activation syndrome in functional gastrointestinal disorders. Scandinavian Journal of Gastroenterology. 2019;54(11):1322–1325. https://doi​.org/10.1080/00365521​.2019.1686059 . [PubMed: 31687861]
• Wile H. The elastic skin man. Medical News (NY). 1883;43:705.
• Yonko EA, Loturco HM, Carter EM, Raggio CL. Orthopedic considerations and surgical outcomes in Ehlers–Danlos syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2021;187(4):458–465. https://dx​.doi.org/10.1002/ajmg.c.31958 . [PubMed: 34845816]
• Zierau O, Zenclussen AC, Jensen F. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Frontiers in Immunology. 2012;3:169. https://doi​.org/10.3389/fimmu.2012.00169 . [PMC free article: PMC3377947] [PubMed: 22723800]