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4 Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders The Ehlers-Danlos syndromes (EDS) are a group of heritable disorders of connective tissue (HDCTs) that share joint hypermobility and skin in- volvement. Other organ systems are involved to greater or lesser degrees, depending on the type of EDS. Hypermobility spectrum disorders (HSD) are included in this discussion because of their similarities with EDS, especially hypermobile EDS (hEDS), although they do not meet the diagnostic criteria for EDS. This chapter describes the history, diagnosis, and characteristics of EDS/HSD, and reviews their treatment, management, and selected as- sociated physical and mental secondary impairments, many of which can limit activities and restrict participation of affected individuals in work and school. An overview EDS and HSD is provided in Annex Table 4-1 at the end of the chapter. Throughout this chapter, hEDS and HSD are considered together as âhEDS/HSDâ because of their clinical similarities. Diagnostic criteria prior to 2017 would not have distinguished between hEDS and HSD, so much of the research on these disorders cited in this report is based on a mix of the two. The term âEDS/HSDâ includes HSD with other types of EDS when it encompasses hEDS. HISTORY OF EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY SPECTRUM DISORDERS Parapia and Jackson (2008) present a historical review of EDS/HSD. The first report of a patient with joint hypermobility and skin laxity was published in 1892 by Tschernogobow, who presented two patients to the Moscow and Venereology and Dermatology Society (Tschernogobow, 73
74 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 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 de- layed 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. McKusickâs 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 pedi- grees 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 rec- ognized (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 ob- servation 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 HDCTsâthe 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 tran- spire before an updated nosology would be published in 2017, identifying 13 distinct types of EDS, including hEDS (Malfait et al., 2017) (Table 4-1). By 2017, the molecular cause of 12 of the then 13 types of EDS/HSD had been identified (Table 4-1). In 2018, another gene associated with classical-like EDS (type 2) was identified: bi-allelic alterations in the AEBP1 gene lead to defective collagen assembly and abnormal connective tissue structure (Blackburn et al., 2018). Identification and understanding of the genetic basis of the 13 EDS types, several of which have two or more sub- types, 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 acceler- ate the search for the hEDS gene(s) and increase the likelihood of finding
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 75 TABLE 4-1â Clinical Classification of the Ehlers-Danlos Syndromes, Inheritance Pattern, and Genetic Basis Clinical EDS Abbre- subtype viation IP Genetic basis Protein 1 Classical EDS cEDS AD Major: COL5A1, COL5A1 Type V collagen Rare: COL1A1 Type I c.934C>T, p.(Arg312Cys) collagen 2 Classical-like EDS clEDS AR TNXB Tenascin XB 3 Cardiac-valvular cvEDS AR COL1A2 (biallelic mutations Type I that lead to COL1A2 collagen NMD and absence of pro Î±2(I) collagen chains) 4 Vascular EDS vEDS AD Major: COL3A1 Type III collagen Rare: COL1A1 Type I c.934C>T, p.(Arg312Cys) collagen c.1720C>T, p.(Arg574Cys) c.3227C>T, p.(Arg1093Cys) 5 Hypermobile EDS hEDS AD Unknown Unknown 6 Arthrochalasia EDS aEDS AD COL1A1, COL1A2 Type I collagen 7 Dermatosparaxis dEDS AR ADAMTS2 ADAMTS-2 EDS 8 Kyphoscoliotic EDS kEDS AR PLOD1 LH1 FKBP14 FKBP22 9 Brittle Cornea BCS AR ZNF469 ZNF469 syndrome continued
76 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE TABLE 4-1â Continued Clinical EDS Abbre- subtype viation IP Genetic basis Protein 10 Spondylodysplastic spEDS AR B4GALT7 Î²4GalT7 EDS B3GALT6 Î²3GalT6 SLC39A13 ZIP13 11 Musculocontractural mcEDS AR CHST14 D4ST1 EDS DSE DSE 12 Myopathic EDS mEDS AD COL12A1 Type XII or collagen AR 13 Periodontal EDS pEDS AD C1R C1r C1S C1s SOURCE: Malfait et al., 2017, p. 10. Â© 2017 Wiley Periodicals, Inc. NOTE: AD, autosomal dominant; AR, autosomal recessive, IP, inheritance pattern; NMD, nonsense-mediated mRNA decay. them, the International Consortium on the Ehlers-Danlos Syndromes & Hypermobility Spectrum Disorders convened in 2016 to refine the diagnos- tic 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 hy- permobility type would not meet the new, more restrictive criteria under the 2017 nosology; thus, the concept of âhypermobility spectrum disordersâ 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 symp- tomatic hypermobility are considered to have HSD. The diagnostic distinc- tion between HSD and hEDS may not be clinically meaningful, however, as both groups may experience the same types of physical and mental im- pairments and potential functional limitations (Aubry-Rozier et al., 2021).
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 77 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 com- plications (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 al- pha 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 cur- rently 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 observa- tions have prompted a call for further studies to reassess the 2017 diag- nostic 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 compa- rable 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 clinicianâs awareness that EDS/HSD should be considered. Once a patient has been recognized as having joint hypermobility, the differential
78 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 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) pres- ent 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 hypermobil- ity associated with EDS/HSD. The clinical diagnostic criteria for 12 other types of EDS are provided on the Ehlers-Danlos Society website,1 but because of the overlap of symp- toms among many types of EDS and HSD, definitive diagnosis includes confirmation through genetic testing of those types for which the respon- sible genes have been identified. The classical type (cEDS) and vascular type (vEDS) of EDS have their own sets of diagnostic criteria (Byers et al., 2017); diagnostic criteria for the 10 rarer types were published in 2017 (Malfait et al., 2017). Research consistently describes the challenges and delays involved in establishing a correct diagnosis and receiving proper management for hEDS/HSD (Halverson et al., 2021; Knight, 2015). People with hEDS/HSD commonly report receiving incorrect or incomplete diagnoses, and studies TABLE 4-2 Selected Hypermobility Assessment Scales Scale Reference Carter and Wilkinson Scale Carter and Wilkinson, 1964 Beighton and Horan Scale Beighton and Horan, 1970 Beighton Scoring System Beighton et al., 1973 RotÃ©s Querol Bulbena et al., 1992; RotÃ©s Querol, 1983 Contompasis McNerney and Johnston, 1979 Hospital del Mar Bulbena et al., 1992 Lower Limb Assessment Score Meyer et al., 2017 Upper Limb Hypermobility Assessment Tool Nicholson and Chan, 2018 5-Item Questionnaire (self-report) Hakim and Grahame, 2003 7-Item Questionnaire (self-report) Bulbena et al., 2014 1âSee https://www.ehlers-danlos.com/eds-types (accessed May 25, 2022).
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 79 document an average 11â12 yearsâ delay in establishing a correct diagnosis (Halverson et al., 2021; Knight, 2015; Terry et al., 2015). Even once diag- nosed, 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 gas- trointestinal disorders, respiratory difficulties, nonmigraine headaches, and cognitive dysfunction or impairment, sometimes referred to as âbrain fogâ (Maitland, 2020). Dysfunction of the autonomic nervous system (dysauto- nomia) 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 impair- ment, 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 physi- cal functioning and mental symptoms and functioning (e.g., cognitive func- tion, 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
80 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE nature of HDCTs and a general lack of knowledge about these disorders among health care providers, undoubtedly contributes to the delayed di- agnosis and misdiagnosis often experienced by individuals with EDS/HSD. The problem is bidirectional, with patients caught in the middle. Clinicians trained to address âphysicalâ disorders may inappropriately refer a patient presenting with âunexplainedâ 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 va- riety 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 hyper- mobility 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 gastrointes- tinal 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 inappropri- ately 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 criti- cal 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
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 81 successful only partially if at all. For example, appropriate treatment of gastrointestinal symptoms could involve treatment for immune system dys- function and dysautonomia. Appropriate treatment for pain requires iden- tification and treatment of underlying pathology, as well as interventions to control the pain. Appropriate treatment for symptoms of anxiety could involve treatment of dysautonomia in addition to interventions to address the anxiety. It is clear that individuals with multisystem disorders such as HDCTs require care from multidisciplinary teams to investigate all of the potential causes of their symptoms (both physical and mental) (Miklovic and Sieg, 2022; Mittal et al., 2021). CHARACTERISTICS OF EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY SPECTRUM DISORDERS Clinical Picture The natural history of EDS/HSD is variable. The range and severity of clinical course are best understood in the context of each specific type of EDS and HSD. Nevertheless, as a group, patients with EDS/HSD share general features of joint hypermobility, skin hyperextensibility, and tissue fragility that may affect organ systems, blood vessels, skin, joints, and ligaments (Bloom et al., 2017). It is important to note that specific mani- festations may depend on the type of EDS/HSD, with hallmark features, such as vascular rupture (seen in vEDS), being specific to a particular type. Additional features of pain; fatigue; cognitive dysfunction; dysautonomia; and gastrointestinal, respiratory, and immune dysfunction are often un- derappreciated in EDS/HSD, particularly given their waxing and waning nature in affected individuals. Results of a large survey of patientsâ lived experience with hEDS/HSD show the multimorbidity nature of these condi- tions, with individuals reporting 15â25 symptoms involving different organ systems and having substantial impact on daily functioning (Murray et al., 2013). Schubart and colleagues (2019a) identified three symptom clusters: a pain-dominant cluster, a high symptom burden cluster, and a mental fatigue cluster. The percentage of participants in the pain-dominant subgroup was similar in all EDS/HSD diagnostic subtypes, while the percentage in the high symptom burden subgroup was higher in the cEDS and hEDS/HSD subtypes, and the percentage in the mental fatigue subgroup was higher in the vEDS and ârare/unclassifiedâ EDS subtypes (Schubart et al., 2019a). EDS/HSD patients often appear healthy but report a constellation of symptoms that may be difficult for clinicians to recognize as being re- lated. Therefore, as described previously, delayed or misdiagnosis is com- mon, and may significantly and negatively impact the clinical course. At the time of diagnosis, patients are likely to have a history of multiple
82 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE articular dislocations or subluxations, poor wound healing, easy bruising, and atypical scarring. Such features are often present in childhood but may be considered ânormalâ for the family or attributed to external factors; in severe cases, child abuse may be suspected. Severe types may also present in relatively young patients with such dramatic manifestations as spontane- ous organ rupture or vascular dissection, as is seen in patients with vEDS (Shalhub et al., 2019). Often children show hypersensitivity; difficulties in eating, which may lead to eating disorders; and more fears and anxiety than are found in the general population (Baeza-Velasco et al., 2022; Ezpeleta et al., 2018). Profound changes in body composition that occur with puberty in- clude, for example, increased musculoskeletal growth and changes in brain development (including cognitive maturation and psychosocial matura- tion) and in the cardiovascular system. These changes are mediated by hormones that can affect all organ systems. In many individuals with EDS/ HSD, particularly those types manifesting hypermobility, puberty is associ- ated with the onset or worsening of secondary impairments, especially in females, and may be a period of disease amplification (Tinkle et al., 2017). These impairments include increased gastrointestinal dysmotility (Dhingra et al., 2021a), respiratory complications (Bascom et al., 2021b), postural tachycardia syndrome (POTS) (Coupal et al., 2019), MCAD (Zierau et al., 2012), increased musculoskeletal pain (Dhingra et al., 2021b; Feldman et al., 2020; Mu et al., 2019), chronic fatigue (Pacey et al., 2015), and neu- ropsychiatric diagnoses (Kindgren et al., 2021; Tran et al., 2020), among others. Importantly, one study found that in vEDS, mortality was increased 3-fold in males under age 20 as a result of unanticipated vascular events (Pepin et al., 2014). A recent study assessed the health-related quality of life (HRQoL) and mental health of children and adolescents aged 4â18 with a variety of HDCTsâMFS, LDS, hEDS, and other EDS typesâthrough child- and parent-reported questionnaires (Warnink-Kavelaars, et al., 2022). Parents also reported on the impact of their childâs condition on the family and themselves. Overall, children and adolescents with HDCTs reported âin- creased pain, decreased physical functioning and general health, a negative mental health state, [and] limitations in school-related and leisure activities and participation with friends and familyâ; those with hEDS also reported low self-esteem compared with representative general-population samples (Warnink-Kavelaars, et al., 2022, p. 6). With respect to parental and family impact, parents of children with hEDS reported increased distress and limi- tations on their personal time and family activities relative to the compari- son sample. Children and adolescents with hEDS and their parents had the lowest scores on all but a few of the HRQoL subscales. Mu and colleagues (2019) also found that children and adolescents with hEDS/HSD had lower
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 83 HRQoL scores compared with healthy controls, and that pain and fatigue were the primary predictors of HRQoL. These findings emphasize the need for psychosocial support among children diagnosed with EDS/HSD and their families. Epidemiology Epidemiology addresses the distribution and determinants of health-re- lated states or events in specified populations and the impact of approaches for treating or controlling health problems (Last, 2001, p. 61). This disci- pline provides a framework for answering many of the questions posed in the committeeâs statement of task: the prevalence of HDCTs; the status of diagnosis, treatment, and prognosis for those disorders; their age at onset and gender distribution; laboratory and diagnostic tests for the disorders; their usual clinical course for adults and children; the likelihood, frequency, and duration of changes in the clinical or medical severity of symptoms, such as flare-ups or remissions; the possibility and likelihood of reducing the work-related severity of symptoms; the treatments or circumstances that may lead to vocationally relevant improvement; and secondary impairments that result from either the disorders or their treatments. Incidence By definition, all HDCTs are present at birth, as the underlying caus- ative genetic variant exists within an individualâs genome. Some HDCTs are recognized at birth because of their distinct and severe manifestations, whereas the manifestations of many HDCTs evolve over time, with shifting distributions in the population. As discussed previously, delays in diagnosis are well recognized. Prevalence As reported in Chapter 2, all types of EDS combined are thought to occur in about 1 in 5,000 people (Pyeritz, 2000; Steinmann et al., 2002). Among all types of EDS, hEDS likely accounts for 80â90 percent of cases (Tinkle et al., 2017). Rarer EDS types include vEDS, with an estimated prevalence of 1/50,000 (Byers, 2019). All other EDS types are extremely rare (Steinmann et al., 2002); musculocontractural EDS and dermatosp- araxis EDS, for example, are estimated to have a prevalence of less than 1/1,000,000 (Orphanet, 2022a,b). Preferred sources of epidemiologic information include large case series and population-based datasets. Current inferences of prevalence are sub- ject to ascertainment and referral bias, and must be viewed with caution.
84 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE There is now a genetic test with which to identify many, although not all, of the EDS subtypes (Malfait et al., 2017). An epidemiologic approach to estimating the population prevalence of each EDS subtype with identified pathogenic variants would be to test for this variant in a general-population sample. As noted in Chapter 2, there currently is no identified gene (pathogenic variant) for hEDS/HSD. Estimates of the prevalence of these disorders there- fore derive from screening using standardized tests, such as the Beighton scoring system, and other clinical criteria (Castori et al., 2017). Mulvey and colleagues (2013) estimate a general-population prevalence of joint hypermobility of 18 percent, determined using a validated self-administered screening tool (Hakim and Grahame, 2003), with chronic widespread pain being present in a subset of these cases, perhaps indicating that the true prevalence of hEDS/HSD is much higher than 1/5,000. A recent estimate of the prevalence of EDS/HSD derives from a national electronic cohort study and nested case control study conducted in Wales, United Kingdom. To derive this estimate, the researchers identified persons who were assigned a coded diagnosis of EDS/HSD or joint hypermobility syndrome (an older diagnostic term that includes both HSD and hEDS) between 1990 and 2017, finding a point prevalence of 10 cases in a practice of 5,000 patients (Demmler et al., 2019). Outpatient records were classified according to the READ 2 criteria and inpatient records according to the International Classification of Diseases, 10th edition (ICD-10). Age and Gender Effects hEDS/HSD are recognized in equal proportions in boys and girls. Increased joint hypermobility is seen in pubertal females (Quatman et al., 2008). Clinicians have observed the emergence of a female predominance in symptomatic EDS in the peripubertal period. The above-cited national co- hort study of individuals with EDS/HSD in Wales, United Kingdom, showed a gender difference of 8.5 years in the mean age at diagnosis: the highest proportion of males was first identified at ages 5â9, while the highest pro- portion of females was diagnosed at ages 15â19 (Demmler et al., 2019). Overall, among 6,021 identified individuals, 30 percent were male and 70 percent female. This finding is supported by large case control studies of U.S. private insurers showing increased prescription drug claims for females beginning peripubertally (Bascom et al., 2021b; Dhingra et al., 2021a). Of note, a community-based survey conducted by Mulvey and colleagues (2013) found a progressive decline in the prevalence of joint hypermobility throughout adulthood (Mulvey et al., 2013).
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 85 Manifestations The 2017 report of the International Consortium on Ehlers-Danlos Syndromes & Hypermobility Spectrum Disorders provides a detailed re- view of clinical findings for EDS/HSD, organized by organ system and derived from clinical experience, case series, and some large population samples (Bloom et al., 2017; Hakim et al., 2021). Annex Tables 5-3â5-12 list many of the physical and mental impairments associated with EDS/ HSD. Studies cited below provide epidemiologic evidence for specific organ system manifestations associated with these disorders. This research shows greater prevalence of symptoms and diagnoses involving diverse organ systems among persons with EDS/HSD than was previously thought. These findings provide growing evidence that EDS/HSD should be viewed as a disorder not only with musculoskeletal manifestations but also with diverse, multiâorgan system manifestations, including orthostatic intolerance (De Wandele et al., 2014a,b; 2014b; Hakim et al., 2017b; Roma et al., 2018; Rowe et al., 1999; Rowe, 2022), gastrointestinal symptoms, neurologic manifestations, respiratory manifestations (Bascom et al., 2021a,b; Chohan et al., 2021), and psychiatric manifestations (Bulbena et al., 2017). Notably, the pathophysiologic relationship between EDS/HSD and many of these manifestations and comorbid conditions is unclear, and the evidence linking them is primarily associative; many are also common in chronic conditions that are not characterized by connective tissue dysfunction. Further research is needed to understand the pathogenetic sequence for these manifestations and the implications for primary/secondary/tertiary prevention and disease state management. Multisystem manifestations are often significant, but may vary both among individuals and throughout an affected individualâs lifetime. Not only do the physical and mental secondary impairments experienced by individuals with EDS/HSD differ from person to person, but the presence and severity of the impairments also may fluctuate (wax and wane) over time. A growing body of literature suggests that comorbid conditions, such as orthostatic intolerance and immune dysregulation, collectively contribute to disease severity and thus to an individualâs experience and associated disability (Copetti et al., 2019; Kalisch et al., 2020; Krahe et al., 2018). Individuals with versus those without hEDS/HSD also develop migraines earlier, have more days with migraines per month, and experience more accompanying symptoms (Puledda et al., 2015). Patients will likely experience musculoskeletal and other disease mani- festations throughout life. Joint hypermobility contributes to articular in- stability, with subluxation or dislocation leading to pain and premature degenerative arthritis over time. Hand and wrist pain can compromise fine motor skills, making it difficult to perform such activities as keyboarding
86 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE and other fine motor tasks that may be required for work or school. Pes planus (flat feet, usually associated with ankle pronation) is common in all forms of EDS/HSD and may further contribute to joint instability and pain; moderate to severe pes planus has been associated with knee and intermittent lower back pain (Kosashvili et al., 2008). Clinically significant and progressive scoliosis may develop, particularly in the kyphoscoliotic, classical, and arthrochalasia types of EDS as well as hEDS/HSD (Yonko et al., 2021). In addition, EDS/HSD patients are at increased risk of cranio- cervical and other spinal instability and such central nervous system pa- thologies as Chiari 1 malformation, intracranial hypertension, tethered cord syndrome, and syringomyelia (Henderson et al., 2017; Klinge et al., 2021, 2022). Myopia is common but nonspecific, and there is an increased risk for retinal detachment, glaucoma, strabismus, cataract, amblyopia, cornea scarring or rupture, and blindness (Louie et al., 2020). EDS/HSD is also associated with immune dysfunction, including MCAD, as well as primary immune deficiencies, which in turn can contribute to immune-mediated pa- thology in one or multiple organ systems (Brock et al., 2021; Sordet et al., 2005). Acute catastrophic events experienced during the course of disease are most likely to be seen in patients with vEDS, cEDS, or kyphoscoliotic EDS (kEDS) (Bowen et al., 2017; Brady et al., 2017; Byers et al., 2017). Such events include stroke, arterial dissection, spontaneous cerebrospinal fluid leak, ruptured aneurysm, spontaneous rupture of bladder, diverticu- lum, incarcerated hernia, intestinal intussusception, gastric perforation, and peripartum uterine rupture (Castori et al., 2015; Gilliam et al., 2020). Gastrointestinal problems can be pronounced and contribute to high levels of health impairment and functional limitations in patients with hEDS/HSD. Individuals who experience frequent episodes of gastroinstes- tinal distress require access to a restroom whenever necessary at work or school. These problems are amplified by the presence of POTS or MCAD (Chelimsky and Chelimsky, 2018; Hsieh, 2018; Inayet et al., 2018; Lam et al., 2021; Mehr et al., 2018; Tai et al., 2020; Wilder-Smith et al., 2019). Genitourinary conditions are also common and can affect activities and participation (Nee et al., 2019). For example, urinary incontinence can make it difficult to stand for extended periods of time without leakage. A study of gynecologic symptoms in hEDS/HSD indicated high frequencies of menorrhagia, dysmenorrhea, and dyspareunia (Hugon-Rodin et al., 2016). Urogynecological problems are amplified by comorbid POTS and MCAD, and hEDS/HSD symptoms may increase before and during menses (Patel and Khullar, 2021; Peggs et al., 2012). Adolescents with EDS/HSD may also experience severe gynecological symptoms (Hernandez and Dietrich, 2020). Since the first clinical report in 1988, several psychopathological con- ditions, especially anxiety and depression, have been reported consistently in individuals with EDS/HSD (Baeza-Velasco et al., 2011; Bathen et al.,
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 87 2013; Berglund et al., 2015; Bulbena et al., 2017; Bulbena et al., 1988; Bulbena et al., 2015). Chronic pain is also common among individuals with EDS/HSD (Voermans et al., 2010a), with studies finding a prevalence of between 43 percent (Kalisch et al., 2020) and 99 percent (Murray et al., 2013). Individuals with EDS/HSD commonly experience severe fatigue as well (Voermans et al., 2010b). Depression is common among individuals with other chronic conditions, including pain, and dysautonomias can cause symptoms commonly associated with anxiety. As noted, EDS/HSD may manifest in several organ systems, and these manifestations can result in impaired quality of life (Berglund et al., 2015) and employment difficulties. A survey of 455 persons with hEDS/HSD showed that 55 percent were currently employed, and 24 percent were working only part-time as a result of their disorder (Murray et al., 2013), while 12 percent (54 of 466 respondents) indicated they were not working because of hEDS/HSD-associated limitations. Among those who were work- ing, half had to change roles or take on less responsibility because of their diagnosis. Of the 119 student respondents, 18 percent were unable to attend school full-time, and 32 percent reported not being enrolled in school at all because of their EDS/HSD diagnosis. The most common manifestations of EDS/HSD that impact quality of life are chronic pain (joint and limb), chronic fatigue, and hypermobility (Murray et al., 2013). Other organ systems that may be affected by EDS/ HSD include the gastrointestinal, nervous, ocular, respiratory, and urogeni- tal systems. All of these manifestations, along with anxiety, depression, and fibromyalgia, can affect an individualâs participation in work, school, and other activities (Murray et al., 2013). In particular, hEDS/HSD appear to be associated with greater pain and work impairment (De Baets et al., 2021), whereas cEDS has a greater effect on activities of daily living; both types of EDS/HSD were found to result in greater perceived disability than is evident in the general population (Bogni et al., 2015). hEDS/HSD are also associ- ated with mobility disability, which was found to be more prevalent among individuals who are older, have more fatigue, and have a higher body mass index (Kalisch et al., 2020). Mobility issues can be an impediment to working for individuals with hEDS/HSD who need a wheelchair or have difficulty accessing public transportation, and some pain medications used for EDS/HSD have sedative side effects that preclude driving. Obstructive sleep apnea occurs among those with EDS/HSD more frequently than in the general population and is associated with greater fatigue, particularly dur- ing the day, and poorer quality of life (Gaisl et al., 2017); daytime sleepiness can affect an individualâs ability to work regular hours. POTS, a frequent manifestation of EDS/HSD, is associated with a variety of persistent symp- toms, such as cognitive impairments (e.g., in attention and recall), fatigue, low energy, headaches, and sleep disturbances, and can have substantial
88 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE effects on various aspects of quality of life (Mathias et al., 2021; Vernino et al., 2021), including employment and household tasks. Individuals with EDS/HSD report that their pain and fatigue can make working difficult, requiring reduced hours or different jobs, and in some cases leading them to leave a job or be terminated (Palomo-Toucedo et al., 2020). TREATMENT AND MANAGEMENT There is no cure for EDS/HSD, and management strategies rely on pre- venting and mitigating symptoms and treating associated physical and men- tal 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 relation- ship 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 thera- peutic 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 polypharmacyâa 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
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 89 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 prevent- ing 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 impor- tant for those with expertise in EDS/HSD to educate other members of the patientâs 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 signifi- cant 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 coun- seled 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 vascu- lar 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 (DâHondt 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 pa- thology 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 re- quire 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,
90 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE surgical) as needed. In addition, patients with many of the rarer forms of EDS have cardiovascular involvement with functional consequences neces- sitating lifelong specialist management (Brady et al., 2017). Given the risk of retinal detachment, lens luxation, and cornea break- down, all EDS patients should undergo baseline ophthalmologic evaluation that is repeated at regular intervals to assess for evidence of corneal, lenticu- lar, 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 gen- eral 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 sco- liosis 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, dys- tonias, or Tarlov cysts (Henderson et al., 2017). Evaluation should include advanced imaging, such as magnetic resonance imaging.
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 91 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 con- ditions. 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 tachy- cardia and/or palpitations, and contribute to a number of secondary neu- rological 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 assessmentâspirometry with flow-volume loops and assessment of bron- chodilator responsiveness. Psychological assessment is important to screen for the presence of anxiety, phobic features, and depression since they frequently go unno- ticed, and can interfere with daily life functions and even adherence to treatments. Individuals with EDS/HSD often have been classified as âso- matizersâ by clinicians unfamiliar with the disorders (Bulbena-CabrÃ© 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 patientsâ outcomes (Bulbena-CabrÃ© 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-CabrÃ© 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 (associa- tive 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 consid- eration of specific transient states, such as the perioperative or peripartum
92 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 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 typeâspecific mani- festations, such as bleeding, poor wound healing, cardiovascular involve- ment, 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 inpa- tient vascular surgery procedures was statistically greater for EDS/HSD pa- tients (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 lo- cal 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 intend- ing to use local anesthetics for pain control in these patients. In 2017, the Patient-Centered Outcomes Research Instituteâfunded EDS Comorbidity Coalition conducted a research prioritization exercise; among 80 research ideas proposed, one of the 3 highest priorities was the issue of local an- esthetic 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 anes- thesias. 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 res- cues compared with opioid-based anesthesia and postsurgical management (RamÃrezâPaesano et al., 2021). The examples given above, supported by the committee membersâ experience, indicate that persons with EDS/HSD have particular risks as- sociated 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
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 93 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 un- diagnosed, 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, regard- less of the best surgical interventions, they may have an elevated risk of postoperative complications (Guier et al., 2020; Kulas SÃ¸borg et al., 2017; Louie et al., 2020; Yonko et al., 2021) and decreased likelihood of surgical success (Rombaut et al., 2011; Yonko et al., 2021). In addition to those risks, moreover, surgical intervention and anesthesia may provoke POTS and MCAD. To limit surgical morbidity, all conservative (i.e., nonsurgical) measures should be exhausted before surgery for individuals with EDS/HSD is contemplated (see Table 4-3). Patients contemplating pregnancy should be counseled about the risk of obstetrical complications (Byers, 2019; Byers et al., 2017; Eagleton, 2016; Karthikeyan and Venkat-Raman, 2018; Pepin et al., 2000; Pezaro et al., 2018). Preterm labor or premature rupture of membranes may oc- cur 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 differ- ent, 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, relax- ation techniques and mindfulness-based exercises can be helpful.
94 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE TABLE 4-3 Surgical and Anesthetic Recommendations for Joint Hypermobility Syndrome/Ehlers- Danlos Syndrome Hypermobility Type (JHS/EDS-HT) Evidence Ref. Recommendation Surgical procedure (1) Orthopedic surgery is Voermans Consider more conservative paradoxically associated with et al., treatments as an alternative to pain worsening in JHS/EDS-HT; 2010a non-life-threatening operations. anecdotal observations suggest a low success rate for abdominal surgery in functional disorders. (2) Although soft tissue fragility Burcharth (a) Perform skin closure in is not severe in JHS/EDS-HT, and two layers (cutaneous and delayed wound healing with Rosenberg, subcutaneous) without excessive consequent suture widening, 2012; tension. suture dehiscence and Castori, (b) Use generous sutures, deep postsurgical hernias are possible 2013a stitches and steri-strips as complications. reinforcement devices. (c) Leave sutures twice as long as normally recommended. (3) Minor bleeding disorders are Jackson et Consider preoperative common in JHS/EDS-HT. al., 2013 prophylaxis with desmopressin (1-deamino-8-D-arginine vasopressin), especially in patients with a positive history for mucosal bleeding (nose, gingivae, bowel, bladder, etc.) and/or easy bruising. (4) Episiotomy is associated with an Castori et Consider cesarean section as increased risk for pelvic prolapses al., 2012b first-choice delivery procedure. in JHS/EDS-HT women. Anesthetic procedure (5) Dysautonomia is a major feature Mathias et (a) Consider to carry out in JHS/EDS-HT and may need al., 2011 appropriate investigations (e.g. special anesthetic considerations. tilt test) before any intervention in order to properly plan the anesthetic procedure, especially in patients with cardiovascular symptoms. (b) In case of confirmed dysautonomia, consider prophylactic early fluid loading and phenylephrine infusion. (6) JHS/EDS-HT patients often Arendt- Consider alternative anesthetic display resistance to intradermal Nielsen et procedures or double the lidocaine infiltrations and topical al., 1990; anesthetic dose. EMLA cream. Hakim et al., 2005
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 95 TABLE 4-3 Continued Evidence Ref. Recommendation (7) Epi/peridural anesthesia may be None1 Favor total anesthesia in case of hampered by severe spondylosis major surgery. and/or scoliosis, and could be complicated by intraspinal hypotension due to increased meningeal weakness in JHS/ EDS-HT. (8) Temporomandibular De Coster Perform intubation with care joint dysfunction and et al., and consider the use of pediatric occipitoatlantoaxial instability 2005; devices also in adults. may be more common in JHS/ Milhorat et EDS-HT. al., 2007 Postsurgery recovery (9) Muscle deconditioning due to Castori et Consider early physical therapy inactivity rapidly worsens chronic al., 2012a support in case of surgery with pain and fatigue in JHS/EDS-HT. postoperative bed rest for >7 days. 1 Reports specifically describing such likely complications are lacking. However, mild scoliosis and premature spondylosis are commonly encountered in the JHS/EDS-HT clinic, while some preliminary studies indicate that generalized joint hypermobility is associated with orthostatic headache. SOURCE: Castori, 2013b. Copyright Â© 2013 Karger Publishers, Basel, Switzerland. Psychosocial support and education are cornerstones of EDS/HSD man- agement. The Ehlers-Danlos Society provides an abundance of information for both providers and patients, including community resources and sup- port 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 adminis- tration of standardized instruments (Schubart et al., 2022), support the
96 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 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 individu- als 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 rea- sonable 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 tri- als. 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 as- sistive devices, among others.
EHLERS-DANLOS SYNDROMES AND HYPERMOBILITY DISORDERS 97 FINDINGS AND CONCLUSIONS Findings 4-1. The Ehlers-Danlos syndromes (EDS) are a group of multisystem, heritable disorders of connective tissue (HDCTs) that share com- mon elements of joint hypermobility and skin and soft tissue in- volvement. Hypermobility spectrum disorders (HSD) are also multisystem connective tissue disorders that are clinically similar to hypermobile EDS (hEDS) with respect to their manifestations and management. 4-2. Many factors, including underdiagnosis, lead to an underestimate of the prevalence of EDS/HSD. 4-3. EDS/HSD can manifest in physical and mental secondary impair- ments in any organ system and often in multiple organ systems in a given individual. 4-4. The type and severity of physical and mental manifestations as- sociated with EDS/HSD often vary both among individuals and throughout an affected individualâs lifetime. Epidemiologic evidence supports multiâorgan system manifestations, high treatment burden, and high disease burden. 4-5. The pathophysiologic relationships between EDS/HSD and many of their manifestations and comorbid conditions are unclear, and the evidence linking them is primarily associative. 4-6. Diagnosis of EDS/HSD is based on established clinical criteria, and most, though not all, types can be confirmed through genetic testing. 4-7. Diagnosis of hEDS and HSD is based solely on clinical criteria, since neither has a known genetic test. Understanding of and diagnostic criteria for hEDS and HSD continue to evolve. 4-8. There are currently no curative treatments for EDS or HSD. Management of the disorders involves early diagnosis and recogni- tion; monitoring; and treatment of the manifestations in multiple organ systems, including treatment of associated physical and men- tal secondary impairments present at the time of identification and preventive measures to lessen or prevent problems that may develop over time. 4-9. The prognosis and clinical course of EDS/HSD depend on individual patient factors, which vary greatly among affected individuals and are often related to the severity of disease-associated physical and mental impairments, as well as the EDS/HSD type. 4-10. Individuals with vascular EDS (vEDS) have a decreased life ex- pectancy, with a median survival age of 46 for males and 54 for females.
98 SELECTED HERITABLE DISORDERS OF CONNECTIVE TISSUE 4-11. Diagnosis and management of EDS and HSD involve specialists across multiple physical and mental health disciplines. 4-12. Delayed diagnosis may result in a lack of or inappropriate man- agement that may exacerbate physical and mental manifestations of EDS/HSD. Unanticipated risks and harms may attend routine procedures and therapies that carry EDS/HSD-specific risks, such as tissue fragility and physiologic reactivity resulting from autonomic and immune dysregulation. 4-13. EDS/HSD can affect individualsâ everyday physical and mental func- tioning, particularly as a result of limitations associated with pain, fatigue, and anxiety. 4-14. Secondary impairments in any of the body systems can be severe and affect the functioning of individuals with EDS/HSD. 4-15. Physical and mental secondary impairments associated with EDS/ HSD often manifest or worsen during puberty, especially in fe- males. Males with vEDS are at higher risk for complications during puberty. 4-16. Pregnancy can be a high-risk condition in some individuals with EDS; women with vEDS have an increased risk of uterine rupture or peripartum hemorrhage. 4-17. Following trauma or surgery, individuals with versus those without EDS/HSD often have a worse trajectory in terms of both length of recovery and frequency of complications. Conclusions 4-1. EDS and HSD have multiple clinical manifestations that, individu- ally or in combination, can cause functional limitations of varying severity. Some manifestations may become apparent only with age, and the types and severity of manifestations may vary throughout an affected individualâs lifetime. 4-2. Development of a screening tool to identify EDS/HSD could provide timely diagnosis of the disorders and help mitigate the negative effects of delayed diagnosis and EDS/HSD-specific risks that may attend routine procedures and therapies. 4-3. Management of EDS/HSD requires a multidisciplinary approach and involves early diagnosis of the multisystem findings, treatment of associated physical and mental secondary impairments, and mea- sures to reduce or prevent problems that may present over time. 4-4. More research is needed on the pathophysiological mechanisms of EDS/HSD and their comorbid conditions and the implications for appropriate management and outcomes of the many secondary impairments associated with EDS/HSD.
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ANNEX TABLE 4-1â 114 Overview of Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders Documentation (e.g., laboratory tests, diagnostic Selected HDCTs Description criteria) Hypermobile EDS The hypermobile type of EDS is an autosomal-dominant disorder Diagnostic criteria (hEDS) that presents with phenotypic variability. Common signs and Simultaneous presence of three symptoms include joint hypermobility, affecting large and small criteria: joints; soft, smooth skin that may be slightly elastic, with easy 1. Generalized joint hypermobility bruising and unexplained striae; piezogenic papules of the heel; 2. Evidence of syndrome features, chronic musculoskeletal pain (as differentiated from acute due to musculoskeletal complications, and/ injury); early-onset osteoarthritis; osteopenia; gastrointestinal issues or family history (dysmotility, bloating, nausea, vomiting, heartburn, constipation); 3. Exclusion of alternative diagnoses migraine headaches; dysfunction of theÂ nervous system, including Laboratory genetic (mutation) pain and postural orthostatic tachycardia syndrome. Rapid testing labor and delivery, psychological dysfunction, and psychosocial Genetic etiology remains unresolved impairments are common. Classical EDS The classical type of EDS is an autosomal-dominant connective Diagnostic criteria tissue disorder associated with skin hyperextensibility, articular International EDS Consortium hypermobility, and tissue fragility with peculiar âcigarette- Laboratory genetic (mutation) paperâ scars. Clinical findings include mild short stature; testing narrow maxilla; myopia;Â ectopia lentis; small, irregularly placed COL5A1 teeth; mitral valve prolapse;Â aortic root dilatation;Â inguinal orÂ umbilical hernia;Â spontaneous bowel rupture;Â bowel diverticula;Â osteoarthritis;Â joint hypermobility and dislocations (hip, shoulder, elbow, knee, or clavicle);Â pes planus;Â fragile skin; cigarette-paper scars;Â dystrophic scarring; poor wound healing;Â molluscoid pseudotumors; skin hyperextensibility; hypotonia in infancy; muscle fatigue and cramps; and premature birth following premature rupture of fetal membranes.
Classical-like EDS type 1 Classical-like EDS type 1 is either an autosomal-recessive disorder Diagnostic criteria due to mutations in the gene encoding TNXB or a contiguous gene- Similar to classical form of EDS deletion syndrome that includes TNXB and CYP21A2. Characteristic but lacks skin scarring and has findings include childhood onset, mitral valve prolapse and autosomal-recessive inheritance quadricuspid aortic valve (deletion syndrome), hiatal hernia and Laboratory genetic (mutation) other gastrointestinal issues, urogenital anomalies in the deletion testing syndrome (ambiguous genitalia, bicornuate uterus, renal agenesis, TNXB urethral prolapse), joint hypermobility and subluxations, arthralgia, Contiguous deletion that includes piezogenic papules and brachydactyly of the feet, leg edema, TNXB and CYP21A2 hyperextensible skin with no scarring, proximal muscle weakness Other laboratory findings and atrophy, and chronic fatigue. Serum, absence of TNX Electromyogram with myopathic pattern Elevated serum 17-hydroxyproges- terone level (seen in patients with contiguous gene defect) Classical-like EDS type 2 Classical-like EDS type 2 is an autosomal-recessive disorder that Diagnostic criteria falls in the EDS spectrum, associated with joint hypermobility, Similar to classical form of EDS but skin laxity, delayed wound healing, abnormal scarring, and aortic with autosomal-recessive inheritance dilation. Clinical findings include joint laxity with dislocations, Laboratory genetic (mutation) redundant and hyperextensible skin, poor wound healing with testing abnormal scarring, piezogenic papules,Â osteoporosis, micrognathia, AE-Binding Protein 1 (AEBP1) ptosis, mitral valve prolapse and aortic dilation, bowel rupture, gut Other laboratory findings dysmotility, hernias, pes planus, and hallux valgus. Transmission electron microscopy of skin shows irregular disrupted collagen fibrils with moderate variation in collagen size continued 115
ANNEX TABLE 4-1â Continued 116 Documentation (e.g., laboratory tests, diagnostic Selected HDCTs Description criteria) Cardiac-valvular EDS The cardiac-valvular type of EDS is an ultrarare autosomal- Diagnostic criteria recessive disorder characterized by generalized peripheral joint Findings of EDS hypermobility, moderate to severe cardiac valvular disease Suspected if patient presents with (particularly the mitral valve), skin hyperextensibility, variable severe cardiovascular involvement atrophic scarring, easy bruising, lower-eyelid ptosis, inguinal that is progressive hernias, bilateral flatfeet with hindfoot pronation, genu recurvata, Laboratory genetic (mutation) and hypoplasia of the interphalangeal creases. testing Recessively inherited COL1A2 nonsense (null mutations) Vascular EDS (vEDS) The vascular form of EDS is an autosomal-dominant disorder Diagnostic criteria defined by the major complications of arterial and bowel rupture, Suspected if patient, particularly and uterine rupture during pregnancy. Clinical features include younger than age 40, presents short stature; thin lips; lobeless ears; keratoconus; pinched- with one of the following: arterial appearing, thin nose;Â periodontal diseaseÂ and early loss of aneurysms, dissection, or rupture; teeth; mitral valve prolapse; intracranial aneurysms; spontaneous intestinal rupture; uterine rupture pneumothorax and hemoptysis; inguinal hernias; spontaneous during pregnancy; family history of rupture of bowel; uterine rupture during pregnancy; uterine and vEDS bladder prolapse; joint laxity of the distal phalanges with acro- Laboratory genetic (mutation) osteolysis; hip dislocations; clubfeet; fragile skin with paper-thin testing scars and prominent vascular markings, poor wound healing, COL3A1 molluscoid pseudotumorsÂ and acrogeria; and scalp alopecia. Death often occurs before the fifth decade.
Arthrochalasia EDS The arthrochalasia typeÂ of EDS,Â formerly EDS type 7A and 7B, Diagnostic criteria is an autosomal-dominant disorder that is distinguished from Severe joint hypermobility, congenital other types ofÂ EDSÂ by the markedly increased frequency of hip dislocation, facial dysmorphism, congenital hip dislocation and extreme joint laxity with recurrent osteopenia, kyphoscoliosis joint subluxations and minimal skin involvement. Clinical findings Laboratory genetic (mutation) include mild to moderate short stature; midface hypoplasia; testing severe joint dislocations with recurrent joint subluxations; early- COL1A1 onset osteoarthritis; osteopenia with increased risk for fractures; COL1A2 kyphoscoliosis and scoliosis; congenital hip dislocations; thin, hyperextensible, atrophic scars; hypotonia with gross-motor developmental delay. Dermatosparaxis EDS Dermatosparaxis EDS is an autosomal-recessive disorder of Diagnostic criteria connective tissue resulting from deficiency of procollagen Autosomal-recessive inheritance peptidase. Characteristic findings include extreme skin fragility Minimal criteria for diagnosis with congenital and postnatal skin tears, soft and doughy skin include extreme skin fragility and with hyperextensibility and atrophic scars, excessive skin at joints characteristic facial findings with increased palmar creases, and severe bruisability with risk Laboratory genetic (mutation) for hematomas and hemorrhage. Facial findings include delayed testing closure of the anterior fontanel, blue sclera, epicanthal folds, ADAMTS2 blepharochalasis, prominent lips, hypodontia, and discolored teeth. Other laboratory findings Other findings include umbilical and inguinal hernias, short stature, Collagen fibrils demonstrate joint laxity, osteopenia, delayed motor milestones, organ system hieroglyphic patternÂ abnormalities due to visceral fragility (diaphragmatic and bladder rupture, rectal prolapse), and prematurity. continued 117
ANNEX TABLE 4-1â Continued 118 Documentation (e.g., laboratory tests, diagnostic Selected HDCTs Description criteria) Kyphoscoliotic EDS type 1 Kyphoscoliotic EDS type 1 is an autosomal-recessive disorder Diagnostic criteria resultant from mutations in the gene PLOD1. Characteristic findings Autosomal-recessive inheritance include marfanoid habitus, keratoconus, microcornea, myopia, Major criteria: Congenital muscular retinal detachment, ocular rupture, glaucoma, blindness, tooth hypotonia (progressive or early- crowding, gastrointestinal hemorrhage, bladder prolapse, joint laxity onset kyphoscoliosis) with dislocations, osteoporosis, congenital scoliosis and progressive Generalized joint hypermobility with kyphosis, arachnodactyly, pes planus, talipes equinovarus, thin dislocations/subluxations (shoulders, skin, moderate scarring, molluscoid pseudotumors, decreased hips, and knees in particular) fetal movements, and premature rupture of membranes. Risks Laboratory genetic (mutation) include rupture of medium-size arteries, cardiac failure, decreased testing pulmonary function, recurrent pneumonias, and respiratory PLOD1 insufficiency secondary to chest deformity. Other laboratory findings Increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by high-performance liquid chromatographyÂ Kyphoscoliotic EDS type 2 Kyphoscoliotic EDS type 2 is an autosomal-recessive disorder Diagnostic criteria caused by mutations in the gene encoding FKBP14. Characteristic Autosomal-recessive inheritance findings include hearing loss, myopia, occasional cleft palate, Major criteria: tricuspid valve insufficiency, aortic rupture and arterial dissection, Congenital muscular hypotonia subdural hygroma, insufficiency of cardiac valves, restrictive lung Congenital or early-onset disease due to severe scoliosis, hernias, bladder diverticulum, kyphoscoliosis progressive kyphoscoliosis, hypermobility of large and small joints, Generalized joint hypermobility pes planus, equinovarus, hyperelastic skin, easy bruising, follicular Laboratory genetic (mutation) hyperkeratosis, muscular atrophy, and myopathy. testing FKBP14 Other laboratory findings Normal pyridinoline excretion in urineÂ Electromyography: myopathic pattern in adulthood
Brittle cornea syndrome type 1 Brittle cornea syndrome type 1, one of the EDS, is an autosomal- Diagnostic criteria recessive disorder due to mutations in the gene ZNF469. Corneal topography, anterior Characteristic findings include marfanoid habitus, macrocephaly, segment optical coherence hearing loss, myopia, brittle cornea (extreme thinning of the cornea, tomography, corneal pachymetryÂ with risk of tearing or rupture leading to blindness), keratoconus, Ocular manifestations with keratoglobus, blue sclera, dentinogenesis imperfecta, mitral valve extraocular findings of deafness, prolapse, joint laxity, hip dislocations and dysplasia, scoliosis, developmental hip dysplasia, and skin scarring, molluscoid pseudotumor, excessively wrinkled skin joint hypermobility (particularly palms and soles), and red hair. Laboratory genetic (mutation) testing ZFN469 Other laboratory findings Normal lysyl hydroxylase activityÂ Normal dermal hydroxylysine contentÂ Brittle cornea syndrome type 2 Brittle cornea syndrome type 2, one of the EDS, is an autosomal- Diagnostic criteria recessive disorder due to mutations in the gene PDRM5. Corneal topography, anterior Characteristic findings include hearing loss due to hypercompliant segment optical coherence tympanic membranes, myopia, brittle cornea with corneal thinning tomography, corneal pachymetry and risk of rupture, blue sclera, keratoconus, megalocornea, Ocular manifestations with sclerocornea, cornea plana, keratoglobus, hernias, small-joint extraocular findings of deafness, hypermobility, increased fracture incidence, hip dysplasia, myalgias, developmental hip dysplasia, and skin hyperelasticity, and poor wound healing. joint hypermobility Laboratory genetic (mutation) testing PDRM5 continued 119
ANNEX TABLE 4-1â Continued 120 Documentation (e.g., laboratory tests, diagnostic Selected HDCTs Description criteria) Spondylodysplastic EDS 1 type Spondylodysplastic EDS type 1 is an autosomal-recessive disorder Diagnostic criteria caused by mutations in the B4GALT7 gene. Characteristic findings Progressive short stature include dysmorphic features, sparse hair, blue sclera, occasional Poor muscle tone pectus excavatum, large-joint laxity, kyphoscoliosis, spatulate Bowing of lower extremities fingers, talipes equinovarus, hypotonia, hyperextensible skin, Characteristic facial features cutis laxa, mild developmental delay (occasional), and multiple Radiographic findings radiographic abnormalities. Laboratory genetic (mutation) testing B3GALT7 Other laboratory findings Galactosyltransferase I deficiency in fibroblastsÂ Spondylodysplastic EDS type 2 Spondylodysplastic EDS type 2 is an autosomal-recessive disorder Diagnostic criteria caused by mutations in the B3GALT6 gene. Characteristic findings Progressive short stature include dysmorphic features, sparse hair, blue sclera, occasional Poor muscle tone pectus excavatum, large-joint laxity, kyphoscoliosis, spatulate Bowing of lower extremities fingers, talipes equinovarus, hypotonia, hyperextensible skin, cutis Characteristic facial features laxa, and multiple radiographic abnormalities. Radiographic findings Laboratory genetic (mutation) testing B3GALT6
Spondylodysplastic EDS type 3 SpondylodysplasticÂ EDS type 3 is an autosomal-recessive disorder Diagnostic criteria caused by mutations in the zinc transporter gene SLC39A13. The Progressive short stature disorder is characterized by moderate short stature; protuberant Poor muscle tone eyes; high-arched palate with bifid uvula; hypodontia; sparse hair; Bowing of lower extremities joint laxity; finger contractures; fine-wrinkled palms; hypothenar Characteristic facial features muscle atrophy; inability to adduct thumbs; short fingers; pes Radiographic findings planus; thin, hyperelastic skin; abnormal scars with poor healing; Laboratory genetic (mutation) delayed wound healing; muscle weakness; osteopenia; mild testing intellectual disability; and radiographic abnormalities. SLC39A13 Other laboratory findings Lysyl pyridinoline/hydroxylysyl pyridinoline (LP/HP) ratio approximately 1Â (nl LP/HP: 0.2â+â0.03) Musculocontractural EDS type 1 Musculocontractural EDS type 1 is an autosomal-recessive disorder Diagnostic criteria caused by mutations in the CHST14 gene. Characteristic findings Congenital malformations include wasted body build; dysmorphic facies with prominent ears; Contractures of hands and feet hearing impairment; blue sclera; strabismus; myopia; glaucoma; Dysmorphic features microcornea; retinal detachment; anterior chamber abnormality; Laboratory genetic (mutation) cleft palate; cardiac valvular anomalies; atrial septal defect; testing hemopneumothorax; pectus excavatum; hernias; constipation; CHST14 duodenal obstruction; hydronephrosis; recurrent cystitis; congenital contractures that include adducted thumbs and distal arthrogryposis; joint laxity and dislocations; tendon abnormalities; scoliosis; progressive talipes valgus and planus; hyperextensible, fragile, transparent skin with atrophic scarring; delayed wound healing; hyperalgesia; recurrent subcutaneous infections; low muscle mass and gross motor delay; and developmental delay in some. continued 121
ANNEX TABLE 4-1â Continued 122 Documentation (e.g., laboratory tests, diagnostic Selected HDCTs Description criteria) Musculocontractural EDS type 2 Musculocontractural EDS type 2 is an autosomal-recessive Diagnostic criteria disorder caused by mutations in the DSE gene. Characteristic Clinical findings findings include hypotonic facies with prominent and abnormally Laboratory genetic (mutation) shaped ears, hypertelorism, blue sclera, mitral valve prolapse testing and regurgitation, mixomatous degeneration of mitral valve, DSE eventration of abdominal wall after surgery, hernia, uterine and Other laboratory findings bladder prolapse in females, arachnodactyly, camptodactyly, talipes Adulthood, abnormal muscle fiber equinovarus, delayed wound healing with atrophic scars, recurrent pattern in histology large subcutaneous hematomas, postecchymotic calcifications, generalized muscle weakness, pain, and occasional cerebral atrophy. Myopathic EDS The myopathic type of EDS, also known as Bethlem myopathy-2, is Diagnostic criteria an autosomal-dominant disorder due to mutations in the gene that Clinical findings encodes type XII collagen (COL12A1) and recessive mutations in Laboratory genetic (mutation) the gene COL6A1. Characteristic findings include muscle weakness testing present in childhood that improves with age but is followed by COL12A1 (autosomal-dominant) some deterioration, distal hyperlaxity and flexion contractures, joint COL6A1 (autosomal-recessive) hypermobility, and hypertrophic scars. Other laboratory findings Increased serum creatine kinase Fibroblasts show a reduction of and disorganization in type XII collagen in the extracellular matrix
Periodontal EDS type 1 Periodontal EDS typeÂ 1 is an autosomal-dominant disorder caused Diagnostic criteria by heterozygous mutations in the C1R gene, with the defining Early-onset severe periodontitis feature of severe periodontal inflammation. Characteristic findings Generalized lack of attached gingiva include significant gingivitis with gum inflammatory destruction Pretibial plaques of dental attachments and premature loss of teeth; tall stature; Family history in a first-degree acrogeric facies; cerebral and aortic aneurysm; scoliosis; joint relativeÂ laxity; hypermobility; and thin, atrophic skin with easy tearing and Laboratory genetic (mutation) bruisability, pretibial hyperpigmentation, and pretibial plaques. testing C1R Other laboratory findings Electron microscopy: Abnormally enlarged endoplasmic reticulum cisternaÂ Abnormal variation in collagen fibril diameterÂ Periodontal EDS type 2 Periodontal EDS typeÂ 2 is an autosomal-dominant disorder caused Diagnostic criteria by heterozygous mutation in the C1S gene. Characteristic findings Early-onset severe periodontitis include aggressive periodontitis with gingival recession, tooth loss, Generalized lack of attached gingiva hernias, prominent subcutaneous vasculature, irritable bowel and Pretibial plaques gastrointestinal symptoms, scoliosis, spinal osteoarthritis, joint Family history in a first-degree hypermobility and pain, skin fragility, pretibial hyperpigmentation, relativeÂ abnormal scarring, and increased incidence of cancer. Laboratory genetic (mutation) testing C1S continued 123
ANNEX TABLE 4-1â Continued 124 Documentation (e.g., laboratory tests, diagnostic Selected HDCTs Description criteria) Hypermobility spectrum Hypermobility spectrum disorders are a wide spectrum of related Diagnostic Criteria disorders (HSD) disorders with joint hypermobility (JH) of unknown molecular Ability of a joint or group of joints to etiology. HSD is used as a diagnosis after other well-defined move beyond physiologic limits types of EDS, including hEDS, are excluded. Joint hypermobility is Exclusion of other well-defined defined as the ability of a joint or group of joints to move passively etiologies for joint hypermobility or actively beyond normal physiologic limits. It can be an isolated finding in some individuals. There are four types of JH: generalized (joint) HSD (G-HSD), peripheral (joint) HSD, localized (joint) HSD, and historical (joint) HSD. Individuals with HSD are predisposed to joint trauma, including dislocations, subluxations, and damage to joint tissues; increased occasional and recurrent musculoskeletal pain; decreased muscle mass; and decreased proprioception. G-HSD can be also associated with extra-articular complications that include anxiety disorders, orthostatic tachycardia, a variety of functional gastrointestinal disorders, and pelvic and bladder dysfunction often similar to what is seen in hEDS. NOTE: HDCT = heritable disorder of connective tissue and disability. SOURCES: Bertoli-Avella et al., 2015; Callewaert, 2019; Doyle et al., 2012; Frischmeyer-Guerrerio et al., 2013; Greally, 2020; Gupta et al., 2002; Lindsay et al., 2012; Loeys and Dietz, 2018; Loeys et al., 2005, 2010; Matyas et al., 2014; Regalado et al., 2011; Rienhoff et al., 2013; Tan et al., 2013; Van Hemelrijk et al., 2010.