Management of childbearing with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: A scoping review and expert co-creation of evidence-based clinical guidelines.

OBJECTIVE: To co-create expert guidelines for the management of pregnancy, birth, and postpartum recovery in the context of hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). DESIGN: Scoping Review and Expert Co-creation. SETTING: United Kingdom, United States of America, Canada, France, Sweden, Luxembourg, Germany, Italy, and the Netherlands. SAMPLE: Co-creators (n = 15) included expertise from patients and clinicians from the International Consortium on the Ehlers-Danlos syndromes and Hypermobility Spectrum Disorders, facilitated by the Ehlers-Danlos Society. METHODS: A scoping review using Embase, Medline, the Cochrane Central Register of Controlled Trials and CINHAL was conducted from May 2022 to September 2023. Articles were included if they reported primary research findings in relation to childbearing with hEDS/HSD, including case reports. No language limitations were placed on our search, and our team had the ability to translate and screen articles retrieved in English, French, Spanish, Italian, Russian, Swedish, Norwegian, Dutch, Danish, German, and Portuguese. The Mixed Methods Appraisal Tool was used to assess bias and quality appraise articles selected. The co-creation of guidelines was based on descriptive evidence synthesis along with practical and clinical experience supported by patient and public involvement activities. RESULTS: Primary research studies (n = 14) and case studies (n = 21) including a total of 1,260,317 participants informed the co-creation of guidelines in four overarching categories: 1) Preconceptual: conception and screening, 2) Antenatal: risk assessment, management of miscarriage and termination of pregnancy, gastrointestinal issues and mobility, 3) Intrapartum: risk assessment, birth choices (mode of birth and intended place of birth), mobility in labor and anesthesia, and 4) Postpartum: wound healing, pelvic health, care of the newborn and infant feeding. Guidelines were also included in relation to pain management, mental health, nutrition and the common co-morbidities of postural orthostatic tachycardia syndrome, other forms of dysautonomia, and mast cell diseases. CONCLUSIONS: There is limited high quality evidence available. Individualized strategies are proposed for the management of childbearing people with hEDS/HSD throughout pregnancy, birth, and the postpartum period. A multidisciplinary approach is advised to address frequently seen issues in this population such as tissue fragility, joint hypermobility, and pain, as well as common comorbidities, including dysautonomia and mast cell diseases.

Self-reported throat symptoms in Ehlers-Danlos syndromes and hypermobility spectrum disorders: A cross-sectional survey study.

Objectives: This study identified the frequency and severity of dysphagia, dysphonia, and laryngopharyngeal reflux symptoms in people with Ehlers-Danlos syndromes (EDS) or hypermobility spectrum disorders (HSD) and explored differences between diagnostic groups. Methods: Participants were recruited via non-probability convenience sampling. Information was gathered via online survey, including the Reflux Symptom Index (RSI; Belafsky et al., J Voice. 2002;16:274-277), the Eating and Drinking Assessment Tool (EAT-10; Belafsky et al., Ann Otol Rhinol Laryngol. 2008;117:919-924), and the Voice Handicap Index (VHI; Jacobson et al., Am J Speech Lang Pathol. 1997;6(3):66-70). These were analyzed using ANOVAs. Results: There were 1620 participants (96.6% female, 2.8% male) that met the inclusion criteria. The mean age was 38.09 (SD 12.22). 75.51% had hypermobile EDS (hEDS), 17.83% had HSD and 3.33% had classic EDS (cED). The cohort's mean scores were RSI = 22.95 (SD 9.01), EAT-10 = 11.91 (SD 9.66), and VHI score = 31.99 (SD 24.36). The hEDS group had significantly higher mean scores than the HSD group on RSI score and on some RSI items, on EAT-10 score and on all EAT-10 items, and on one VHI item. Conclusion: People with EDS/HSD experience symptoms of acid reflux, dysphagia, and dysphonia to varying degrees with significant differences between hEDS than HSD. Awareness of the impact of EDS/HSD on throat symptoms will enable health care professionals to anticipate throat symptoms more readily in this population, providing individualized and effective management plans. Level of Evidence: IV.

Pediatric joint hypermobility: a diagnostic framework and narrative review.

BACKGROUND: Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD) are debilitating conditions. Diagnosis is currently clinical in the absence of biomarkers, and criteria developed for adults are difficult to use in children and biologically immature adolescents. Generalized joint hypermobility (GJH) is a prerequisite for hEDS and generalized HSD. Current literature identifies a large proportion of children as hypermobile using a Beighton score ≥ 4 or 5/9, the cut off for GJH in adults. Other phenotypic features from the 2017 hEDS criteria can arise over time. Finally, many comorbidities described in hEDS/HSD are also seen in the general pediatric and adolescent population. Therefore, pediatric specific criteria are needed. The Paediatric Working Group of the International Consortium on EDS and HSD has developed a pediatric diagnostic framework presented here. The work was informed by a review of the published evidence. OBSERVATIONS: The framework has 4 components, GJH, skin and tissue abnormalities, musculoskeletal complications, and core comorbidities. A Beighton score of ≥ 6/9 best identifies children with GJH at 2 standard deviations above average, based on published general population data. Skin and soft tissue changes include soft skin, stretchy skin, atrophic scars, stretch marks, piezogenic papules, and recurrent hernias. Two symptomatic groups were agreed: musculoskeletal and systemic. Emerging comorbid relationships are discussed. The framework generates 8 subgroups, 4 pediatric GJH, and 4 pediatric generalized hypermobility spectrum disorders. hEDS is reserved for biologically mature adolescents who meet the 2017 criteria, which also covers even rarer types of Ehlers-Danlos syndrome at any age. CONCLUSIONS: This framework allows hypermobile children to be categorized into a group describing their phenotypic and symptomatic presentation. It clarifies the recommendation that comorbidities should be defined using their current internationally accepted frameworks. This provides a foundation for improving clinical care and research quality in this population.

Prescription Claims for Immunomodulator and Antiinflammatory Drugs Among Persons With Ehlers-Danlos Syndromes.

OBJECTIVE: Joint hypermobility in Ehlers-Danlos Syndromes (EDS) predisposes persons with EDS to frequent subluxations and dislocations, chronic arthralgia, and soft-tissue rheumatism. Epidemiologic trends of rheumatologic conditions among persons with EDS are lacking. Prescription claims databases can reflect underlying disease burdens by using medication claims as disease proxies. We examined the prevalence of prescription claims for commonly prescribed immunomodulator and antiinflammatory (IMD) drugs among persons with EDS compared with their matched control person, and hypothesized peripubertal increases among female persons with EDS. METHODS: We compared the percentages of IMD drug prescription claims among 3,484 persons with EDS (ages 5-62 years) against their age-, sex-, state of residence-, and earliest claim date-matched control persons using 10 years (2005-2014) of private prescription claims data and a minimum 2-year enrollment inclusion criterion. RESULTS: Our cohort comprised 70% adults and 74% female persons. At least 1 IMD medication was prescribed to 65.4% of persons with EDS compared with 47.4% of control persons. We observed 1.3 to 4.2 times higher odds (P < 0.0001) for 5 out of 6 IMD drug classes among persons with EDS compared with matched control persons, except for biologic agents (conditional odds ratio 1.3, 95% confidence interval 0.8-2.0). Peripubertal increases were observed for nonsteroidal antiinflammatory drugs, oral, and injectable steroids. CONCLUSIONS: To our knowledge, our study is the first to examine the full range of IMD drug prescription claim trends among persons with EDS. We believe our research findings can have notable diagnostic and management implications for EDS patients who present with multiple comorbidities and generally require a more granular assessment of their medical conditions.

Presentation and physical therapy management of upper cervical instability in patients with symptomatic generalized joint hypermobility: International expert consensus recommendations.

Experts in symptomatic generalized joint hypermobility (S-GJH) agree that upper cervical instability (UCI) needs to be better recognized in S-GJH, which commonly presents in the clinic as generalized hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome. While mild UCI may be common, it can still be impactful; though considerably less common, severe UCI can potentially be debilitating. UCI includes both atlanto-occipital and atlantoaxial instability. In the absence of research or published literature describing validated tests or prediction rules, it is not clear what signs and symptoms are most important for diagnosis of UCI. Similarly, healthcare providers lack agreed-upon ways to screen and classify different types or severity of UCI and how to manage UCI in this population. Consequently, recognition and management of UCI in this population has likely been inconsistent and not based on the knowledge and skills of the most experienced clinicians. The current work represents efforts of an international team of physical/physiotherapy clinicians and a S-GJH expert rheumatologist to develop expert consensus recommendations for screening, assessing, and managing patients with UCI associated with S-GJH. Hopefully these recommendations can improve overall recognition and care for this population by combining expertise from physical/physiotherapy clinicians and researchers spanning three continents. These recommendations may also stimulate more research into recognition and conservative care for this complex condition.

The power of patient-led global collaboration.

In late 2017, the global nonprofit, The Ehlers-Danlos Society (TEDS), was awarded a "Pipeline to Proposal" Tier A award from the Patient-Centered Outcomes Research Institute (PCORI). The goal of this application was to form a team of patients, researchers, other community support groups and stakeholders who are focused on establishing the Ehlers-Danlos Comorbidity Coalition to address the common health issues associated with this group of high morbidity, high disease burden conditions. The ongoing Coalition that is now funded by individual donors and expanding in its mission and members, is an example of successful collaboration spanning over borders and priorities.

Dysautonomia in the Ehlers-Danlos syndromes and hypermobility spectrum disorders-With a focus on the postural tachycardia syndrome.

Dysautonomia (autonomic dysfunction) occurs in the Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD). Symptoms include palpitations, dizziness, presyncope, and syncope, especially when standing upright. Symptoms of orthostatic intolerance are usually relieved by sitting or lying and may be exacerbated by stimuli in daily life that cause vasodilatation, such as food ingestion, exertion, and heat. Neurocardiovascular dysautonomia may result in postural tachycardia syndrome (PoTS), a major cause of orthostatic intolerance. It is defined by a rise in heart rate of >30 beats per minute (bpm) in adults and >40 bpm in teenagers while upright, without a fall in blood pressure (BP; orthostatic hypotension). In some, it can be compounded by the presence of low BP. For many, there is delay in clinicians recognizing the nature of the symptoms, and recognizing EDS or HSD, leading to delays in treatment. The onset of PoTS may be linked to an event such as infection, trauma, surgery, or stress. Gastrointestinal and urinary bladder involvement may occur, along with thermoregulatory dysfunction. In some, the mast cell activation syndrome may be contributary, especially if it causes vasodilatation. This paper reviews neurocardiovascular dysautonomia with an emphasis on PoTS, its characteristics, associations, pathophysiology, investigation, and treatment.

Initial description and evaluation of EDS ECHO: An international effort to improve care for people with the Ehlers-Danlos syndromes and hypermobility spectrum disorders.

The Ehlers-Danlos Society Extension for Community Health Care Outcomes (EDS ECHO) is a portfolio of teleconferencing programs developed around the principles and practices of Project ECHO®, aimed at increasing awareness of Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders (HSD) among clinicians, enhancing their confidence in the assessment and management of these complex conditions, and generating networks of clinicians across specialties. We assessed the outcomes of the first EDS ECHO program, launched in April 2019, with two hub locations: Indiana University Health, Indianapolis, Indiana, USA, and The Royal Society of Medicine, London, UK. Clinicians were surveyed before and 6 months after their participation. We describe the initial outcomes of the first four EDS ECHO programs, each comprising nine sessions. Participants reported increased levels of knowledge and confidence in providing care (93% and 95%, respectively) and an increase in referral network participation (65%). Additionally, 80% reported that their interest in EDS and HSD increased; 57% reporting a great increase. Also, 59% reported a decrease in feeling overwhelmed by EDS and HSD, and nearly half reported a decrease in their level of frustration because of participating in EDS ECHO. Clinicians participating in EDS ECHO programs know more, have more confidence in their ability to provide care, and feel energized by their participation.

COL1-related overlap disorder: A novel connective tissue disorder incorporating the osteogenesis imperfecta/Ehlers-Danlos syndrome overlap.

The 2017 classification of Ehlers-Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re-define this OI/EDS overlap as a missing EDS type. Twenty-one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS-related features. OI-related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N-proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.

Resistance to local anesthesia in people with the Ehlers-Danlos Syndromes presenting for dental surgery.

BACKGROUND: People with the Ehlers-Danlos Syndromes (EDS), a group of heritable disorders of connective tissue, often report experiencing dental procedure pain despite local anesthetic (LA) use. Clinicians have been uncertain how to interpret this apparent LA resistance, as comparison of EDS and non-EDS patient experience is limited to anecdotal evidence and small case series. The primary goal of this hypothesis-generating study was to investigate the recalled adequacy of pain prevention with LA administered during dental procedures in a large cohort of people with and without EDS. A secondary exploratory aim asked people with EDS to recall comparative LA experiences. METHODS: We administered an online survey through various social media platforms to people with EDS and their friends without EDS, asking about past dental procedures, LA exposures, and the adequacy of procedure pain prevention. Among EDS respondents who both received LA and recalled the specific LA used, we compared agent-specific pain prevention for lidocaine, procaine, bupivacaine, mepivacaine, and articaine. RESULTS: Among the 980 EDS respondents who had undergone a dental procedure LA, 88% (n = 860) recalled inadequate pain prevention. Among 249 non EDS respondents only 33% (n = 83) recalled inadequate pain prevention (P < 0.001 compared to EDS respondents). The agent with the highest EDS-respondent reported success rate was articaine (30%), followed by bupivacaine (25%), and mepivacaine (22%). CONCLUSIONS: EDS survey respondents reported nearly three times the rate of LA non-response compared to non-EDS respondents, suggesting that LAs were less effective in preventing their pain associated with routine office dental procedures.

Use of Cluster Analysis to Delineate Symptom Profiles in an Ehlers-Danlos Syndrome Patient Population.

CONTEXT: The Ehlers-Danlos Syndromes (EDSs) are a set of rare heritable disorders of connective tissue, characterized by defects in the structure and synthesis of extracellular matrix elements that lead to a myriad of problems including joint hypermobility and skin abnormalities. Because EDS affects multiple organ systems, defining clear boundaries and recognizing overlapping clinical features shared by disease phenotypes is challenging. OBJECTIVES: The objective of this study was to seek evidence of phenotypic subgroups of patients with distinctive symptom profiles and describe these resulting subgroups. METHODS: Data were extracted from a repository assembled 2001-2013 by the National Institute on Aging Intramural Research Program. Agglomerative hierarchical clustering was used to form distinct subgroups of patients with respect to the domains of pain, physical and mental fatigue, daytime sleepiness, and nighttime sleep. Domains were selected based on literature review, clinician expertise, and guidance from patient advisors. RESULTS: One hundred seventy-five patients met all inclusion criteria. Three subgroups were identified. The Pain Dominant subgroup (39 patients) had the highest mean pain values, but lowest mean values of other symptoms. The High Symptom Burden subgroup (71 patients) had high mean values in all domains. The Mental Fatigue subgroup (65 patients) had a high mean value for mental fatigue and daytime sleepiness, but a lower mean value for pain. CONCLUSION: The subgroups aligned with clinical observation of the heterogeneous nature of EDS, with overlapping symptoms between subtypes and a wide divergence in degree of symptoms within subtypes. This exploratory study helps characterize the various phenotypes and comorbidities of patients with EDS.

Exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type.

PURPOSE: To explore exercise beliefs and behaviours of individuals with Joint Hypermobility syndrome/Ehlers-Danlos syndrome - hypermobility type and to explore patient experiences of physiotherapy. METHODS: A cross sectional questionnaire survey design was used to collect quantitative and qualitative data from adult members of the Hypermobility Syndromes Association and Ehlers-Danlos Syndrome Support UK. Descriptive and inferential statistics were used to analyse the data. Qualitative data was analysed thematically. RESULTS: 946 questionnaires were returned and analysed. Participants who received exercise advice from a physiotherapist were 1.75 more likely to report high volumes of weekly exercise (odds ratio [OR] = 1.75, 95% confidence interval [CI] = 1.30-2.36, p < 0.001) than those with no advice. Participants who believed that exercise is important for long-term management were 2.76 times more likely to report a high volume of weekly exercise compared to the participants who did not hold this belief (OR = 2.76, 95% CI = 1.38-5.50, p = 0.004). Three themes emerged regarding experience of physiotherapy; physiotherapist as a partner, communication - knowledge, experience and safety. CONCLUSION: Pain, fatigue and fear are common barriers to exercise. Advice from a physiotherapist and beliefs about the benefits of exercise influenced the reported exercise behaviours of individuals with Ehlers-Danlos syndrome - hypermobility type in this survey. Implications for rehabilitation Exercise is a cornerstone of treatment for Ehlers-Danlos syndrome/Ehlers-Danlos syndrome - hypermobility type. Pain, fatigue and fear of injury are frequently reported barriers to exercise. Advice from physiotherapists may significantly influence exercise behaviour. Physiotherapists with condition specific knowledge and good verbal and non-verbal communication facilitate a positive therapeutic experience.

Contemporary approach to joint hypermobility and related disorders.

PURPOSE OF REVIEW: Joint hypermobility is a common, although largely ignored physical sign. Joint hypermobility is often asymptomatic but may be a feature of an underlying genetic disorder with systemic manifestations. The present article presents a comprehensive approach to considering joint hypermobility and clinically related issues in children and adults. RECENT FINDINGS: Ehlers-Danlos syndrome (EDS) is an umbrella term for various Mendelian connective tissue disorders sharing joint hypermobility, skin hyperextensibility, and tissue fragility. Hypermobile EDS is the default diagnosis in many individuals and still lacks of any confirmatory test. There is also a continuous spectrum of phenotypes between asymptomatic, nonsyndromic joint hypermobility, and hypermobile EDS. In 2017, a new international classification of EDSs, joint hypermobility, and related disorders was published. EDSs are now classified in 13 different variants because of mutations in 19 genes. The gap between joint hypermobility and hypermobile EDS is filled by the descriptive diagnosis of 'hypermobility spectrum disorders'. Alongside the new criteria recommendations for the assessment and management of selected issues related to joint hypermobility such as fatigue and physical therapy have also been published by expert panels. SUMMARY: Asymptomatic, nonsyndromic joint hypermobility, hypermobility spectrum disorders and EDS (particularly, the hypermobile type) are the most common phenotypes in children and adults with joint hypermobility. Their prompt recognition is crucial to the appropriate application of evidence-based management and the reduction in burden of ill health.

The 2017 international classification of the Ehlers-Danlos syndromes.

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.

A framework for the classification of joint hypermobility and related conditions.

In the last decade, growing attention has been placed on joint hypermobility and related disorders. The new nosology for Ehlers-Danlos syndrome (EDS), the best-known and probably the most common of the disorders featuring joint hypermobility, identifies more than 20 different types of EDS, and highlights the need for a single set of criteria to substitute the previous ones for the overlapping EDS hypermobility type and joint hypermobility syndrome. Joint hypermobility is a feature commonly encountered in many other disorders, both genetic and acquired, and this finding is attracting the attention of an increasing number of medical and non-medical disciplines. In this paper, the terminology of joint hypermobility and related disorders is summarized. Different types of joint hypermobility, its secondary musculoskeletal manifestations and a simplified categorization of genetic syndromes featuring joint hypermobility are presented. The concept of a spectrum of pathogenetically related manifestations of joint hypermobility intersecting the categories of pleiotropic syndromes with joint hypermobility is introduced. A group of hypermobility spectrum disorders is proposed as diagnostic labels for patients with symptomatic joint hypermobility but not corresponding to any other syndromes with joint hypermobility. © 2017 Wiley Periodicals, Inc.

Cardiovascular autonomic dysfunction in Ehlers-Danlos syndrome-Hypermobile type.

Autonomic dysfunction contributes to health-related impairment of quality of life in the hypermobile type of Ehlers-Danlos syndrome (hEDS). Typical signs and symptoms include tachycardia, hypotension, gastrointestinal dysmotility, and disturbed bladder function and sweating regulation. Cardiovascular autonomic dysfunction may present as Orthostatic Intolerance, Orthostatic Hypotension, Postural Orthostatic Tachycardia Syndrome, or Neurally Mediated Hypotension. The incidence, prevalence, and natural history of these conditions remain unquantified, but observations from specialist clinics suggest they are frequently seen in hEDS. There is growing understanding of how hEDS-related physical and physiological pathology contributes to the development of these conditions. Evaluation of cardiovascular symptoms in hEDS should include a careful history and clinical examination. Tests of cardiovascular function range from clinic room observation to tilt-table assessment to other laboratory investigations such as supine and standing catecholamine levels. Non-pharmacologic treatments include education, managing the environment to reduce exposure to triggers, improving cardiovascular fitness, and maintaining hydration. Although there are limited clinical trials, the response to drug treatments in hEDS is supported by evidence from case and cohort observational data, and short-term physiological studies. Pharmacologic therapy is indicated for patients with moderate-severe impairment of daily function and who have inadequate response or tolerance to conservative treatment. Treatment in hEDS often requires a focus on functional maintenance. Also, the negative impact of cardiovascular symptoms on physical and psycho-social well-being may generate a need for a more general evaluation and on-going management and support. © 2017 Wiley Periodicals, Inc.

Chronic fatigue in Ehlers-Danlos syndrome-Hypermobile type.

Chronic fatigue is an important contributor to impaired health-related quality of life in Ehlers-Danlos syndrome. There is overlap in the symptoms and findings of EDS and chronic fatigue syndrome. A proportion of those with CFS likely have EDS that has not been identified. The evaluation of chronic fatigue in EDS needs to include a careful clinical examination and laboratory testing to exclude common causes of fatigue including anemia, hypothyroidisim, and chronic infection, as well as dysfunction of major physiological or organ systems. Other problems that commonly contribute to fatigue in EDS include sleep disorders, chronic pain, deconditioning, cardiovascular autonomic dysfunction, bowel and bladder dysfunction, psychological issues, and nutritional deficiencies. While there is no specific pharmacological treatment for fatigue, many medications are effective for specific symptoms (such as headache, menstrual dysfunction, or myalgia) and for co-morbid conditions that result in fatigue, including orthostatic intolerance and insomnia. Comprehensive treatment of fatigue needs to also evaluate for biomechanical problems that are common in EDS, and usually involves skilled physical therapy and attention to methods to prevent deconditioning. In addition to managing specific symptoms, treatment of fatigue in EDS also needs to focus on maintaining function and providing social, physical, and nutritional support, as well as providing on-going medical evaluation of new problems and review of new evidence about proposed treatments. © 2017 Wiley Periodicals, Inc.