Hypermobile Ehlers-Danlos Syndrome

Clinical characteristics.

Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, functional bowel disorders, cardiovascular autonomic dysfunction, swallow and phonation disorders, sleep disorders including apnea, migraine, entrapment and peripheral neuropathies, inflammation from mast cell activation disorders, anxiety disorders, and urogynecologic disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications.

Diagnosis/testing.

The diagnosis of hEDS is established in an adult proband based on 2017 international clinical diagnostic criteria. Currently, no underlying genetic, epigenetic, or metabolomic etiology has been identified for hEDS.

Management.

Treatment of manifestations: Tailored treatment with exercise to increase core and extremity muscle strength and tone, proprioception, and joint stability; braces and splints to improve alignment and control; occupational therapy for assistive devices (e.g., wide-grip writing utensils, home and work ergonomics); physical therapy for assistive devices (e.g., wheelchair or scooter, suitable mattress, soft neck collar); pain management tailored to cause and symptoms; platelet disorders may respond to tranexamic or mefenamic acid; nutrition advice for micronutrient deficiencies; gastritis, gastroparesis, and gastroesophageal reflux disease may require intensive pharmacotherapy; therapies for other gastrointestinal, cardiovascular, ocular, neurologic, and urogynecologic manifestations; orthodontic, maxillofacial, and ENT management for narrow palate, crowded teeth, temporomandibular joint laxity and dysfunction, and disorders of swallow and phonation; standard treatment of periodontal disease; avoidance of triggers for mast cell activation disorder and pharmacotherapy or monoclonal biologic therapy as needed; counseling and pharmacotherapy for neurobehavioral and psychiatric manifestations.

Surveillance: Assess for joint manifestations, pain, disability, bleeding issues, functional bowel disorders, autonomic dysfunction, oral health needs, phonation and respiratory issues, sleep issues, vision issues, headaches and other neurologic manifestations, inflammatory disease, neurobehavioral and psychiatric manifestations, and urogynecologic manifestations annually or at each visit. Dual-energy x-ray absorptiometry in those with height loss greater than one inch, atypical/low trauma fractures, or radiographs suggestive of osteopenia. Follow-up echocardiography in those with aortic root dilatation.

Agents/circumstances to avoid: High-impact activity may increase the risk of acute subluxation/dislocation and acute and chronic pain. Chiropractic adjustment and yoga are not contraindicated but like all other physical treatments must be performed in ways that avoid iatrogenic subluxations or dislocations. Autonomic concerns, gastrointestinal disorders, and intolerances may preclude use of medications or their excipients (e.g., common analgesics in someone with slow gastrointestinal transit, vasodilator in a person with orthostatic intolerance).

Pregnancy management: Preconceptual (e.g., musculoskeletal health and medication use), antenatal (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum (e.g., birth choices, mobility in labor, anesthesia), and postpartum (e.g., wound healing, pelvic health, newborn/infant care) issues should all be addressed.

Genetic counseling.

Hypermobile EDS is inherited in an autosomal dominant manner with variable expression of signs and variable severity of symptoms among affected family members. Most individuals diagnosed with hEDS have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin manifestations despite the absence of serious complications. Each child of an individual with hEDS has a 50% chance of inheriting hEDS. Because the gene(s) and pathogenic variant(s) responsible for hEDS have not been identified, prenatal and preimplantation genetic testing are not possible.

Suggestive Findings

Hypermobile EDS should be suspected in adult probands (individuals who have reached biologic maturity) with the following clinical features [Malfait et al 2017]:

• Joint instability including subluxations and dislocations
• Musculoskeletal pain
• Soft, hyperextensible skin, with atypical stretchmarks and/or scarring
• Dental crowding and a high or narrow-arched palate
• Abdominal hernias
• Pelvic organ prolapse
• A marfanoid body habitus
• Mitral valve prolapse and/or aortic root dilatation
• Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

In addition, hEDS is associated with clinical manifestations that are not included in the published diagnostic criteria including [Hakim et al 2021]:

• Chronic fatigue
• Easy bruising
• Functional bowel disorders (gastroesophageal reflux, gastritis, early satiety, delayed gastric emptying, irritable bowel syndrome, constipation)
• Additional cardiovascular manifestations (autonomic dysfunction, Raynaud phenomenon, acrocyanosis)
• Reduced efficacy of local anesthetics
• Laryngeal and breathing disorders including apnea
• Neurologic complications (migraine, Chiari I malformation, cerebrospinal fluid leaks, craniocervical instability and associated cord and nerve root pathology, tethered cord, entrapment and peripheral neuropathy, small fiber neuropathy)
• Mast cell activation disorders and immune deficiency including primary immune deficiency
• Anxiety disorders
• Autism and attention-deficit/hyperactivity disorder
• Urogynecologic manifestations (dysmenorrhea, menorrhagia, interstitial cystitis, urinary incontinence, pelvic organ prolapse)

Establishing the Diagnosis

The diagnosis of hEDS can be established in an adult proband based on clinical diagnostic criteria [Malfait et al 2017]. The 2017 clinical diagnostic criteria were developed for the diagnosis of adults; many of the clinical features arise over time and may not be present in childhood and adolescence. A clinical diagnostic classification for symptomatic joint hypermobility in younger individuals was developed by Tofts et al [2023]. Using this system, affected children are classified as having pediatric generalized hypermobility or pediatric hypermobility spectrum disorder with combinations of comorbid concerns and/or mild skin concerns (see Differential Diagnosis), with the recommendation that younger individuals should be monitored for evolving clinical manifestations and reevaluation for hEDS should be done when the individual reaches biologic maturity.

No underlying genetic etiology has been identified for hEDS, and thus molecular genetic testing cannot be used to establish the diagnosis.

The clinical diagnosis of hEDS can be established in an adult proband (an individual who has reached biologic maturity) with all three of the following criteria:

1.

Generalized joint hypermobility with a Beighton score of:

a.

≥5 for adolescents who have reached biologic majority and adults age ≤50 years

b.

≥4 for those age >50 years

2.

Evidence of two of the following: systemic manifestations of a more generalized connective tissue disorder, family history, and musculoskeletal complications

3.

Exclusion of alternative diagnoses

Clinical Description

Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, swallow and phonation disorders, functional bowel disorders, cardiovascular autonomic dysfunction, migraine, entrapment and peripheral neuropathies and dystonia, urogynecologic disorders, anxiety disorders, and inflammation from mast cell activation disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications.

Joint hypermobility and joint instability. Excessive joint range of motion with or without instability in the form of subluxations and/or dislocations is evident in the history and on examination. Younger individuals tend to have more joint laxity than older individuals, and females tend to have more joint laxity than males. Joint laxity with instability, with or without reduced proprioception, increases the risk of the following complications:

• Acute joint / soft tissue injury that can last for hours or days after an event. All sites can be involved, including the extremities, vertebral column, costovertebral and costosternal joints, clavicular articulations, and temporomandibular joints. A person may also develop abnormal movement patterns and experience reduced physical function when compensating for joint instability and injury, including fear of movement (kinesiophobia) [Pacey et al 2013, Engelbert et al 2017, Simmonds 2021].
• Chronic joint / soft tissue injury. Osteoarthritis and chronic tendinopathies and bursitis may occur at a younger age than in the general population, possibly because of chronic joint instability resulting in increased mechanical stress. Temporomandibular joint (TMJ) dysfunction is relatively common and is an example of joint degeneration and osteoarthritis [Willich et al 2023]. Hip degenerative disease can lead to conditions such as femoroacetabular impingement [Clapp et al 2021]. Recurring displacement of the patella may contribute to chondromalacia [al-Rawi & Nessan 1997].

Pain. Pain is variable in age of onset (childhood to late adulthood), location, duration, quality, severity, and response to therapy. Chronic pain, distinct from that associated with acute injury, can be physically and psychosocially disabling [Chopra et al 2017]. Fatigue and sleep disturbance are frequently associated with pain. Headaches, especially migraines, are common. Cervical muscle tension, temporomandibular dysfunction, and stress may be contributing factors. Several recognizable pain syndromes are reported:

• Muscular or myofascial pain, localized around or between joints, often described as aching, throbbing, or stiff in quality, may be attributable to myofascial spasm. Palpable spasm with tender points (consistent with fibromyalgia) is often demonstrable, especially in the paravertebral musculature [Fairweather et al 2023]. Myofascial spasm possibly occurs in response to chronic joint instability, but this has not been systematically studied. Myofascial release often provides temporary relief.
• Neuropathic pain, variably described as electric, burning, shooting, tingling, or hot or cold discomfort, may occur in a radicular or peripheral nerve distribution or may appear to localize to an area surrounding one or more joints [Chopra et al 2017]. Nerve conduction studies are usually not diagnostic. Skin biopsy may reveal reduction or absence of small nerve fibers [Fernandez et al 2022]. Neuropathic pain may result from direct nerve impingement due to subluxated vertebrae, herniated discs, vertebral osteoarthritis, or joint subluxations and dislocations. In addition, there may be mild-to-moderate nerve compression within areas of myofascial spasm or compression, for example, as seen in thoracic outlet syndrome [Levine & Rigby 2018].
• Pain may arise from tissue damage, including tendon injury and cartilage tears.
• Visceral pain arising from the gastrointestinal tract and urogynecologic tissues are common presenting concerns.
• Osteoarthritic pain typically presents as aching pain in the joints, frequently associated with stiffness. It is often exacerbated by activity.

Skin. The skin is often soft and mildly hyperextensible. Piezogenic papules (small herniations of subcutaneous fat through the underlying dermis of the heel occurring only when weight-bearing) are common but rarely painful. Atypical stretchmarks (e.g., across the back, chest, axilla), atrophic scars, and easy bruising are common findings [Doolan et al 2023]. Spontaneous bruising without obvious trauma or injury is common and can be mistaken for nonaccidental trauma [Castori 2015].

Hematologic. Mildly prolonged bleeding, epistaxis, bleeding from the gums, and menorrhagia may also occur. The bleeding time may or may not be prolonged, and abnormalities of von Willebrand factor and platelet function have been reported. Capillary fragility and/or impaired soft tissue integrity may also play a role [Jesudas et al 2019].

Gastrointestinal (GI). Functional GI disorders, now termed disorders of gut-brain interaction, are common and underrecognized in individuals with hEDS [Thwaites et al 2022]. Gastroesophageal reflux and gastritis may persist despite polytherapy with maximal doses of proton pump inhibitors, H2 blockers, and acid-neutralizing medications. Early satiety and delayed gastric emptying may occur and may be exacerbated by opioids and other medications. Irritable bowel syndrome may manifest with diarrhea and/or constipation, bloating, abdominal cramping, and rectal mucus. Anorectal manifestations include rectocele, rectal prolapse, and hemorrhoids. GI manifestations are associated with cardiovascular autonomic manifestations, mast cell activation disorders, and nutritional deficiencies [Lam et al 2022]. Abdominal wall herniation may be present. In individuals with unexplained GI and pelvic pain, the symptoms may be arising from nerve entrapment in the abdominal wall or from vascular compression syndromes [Sandmann et al 2021].

Cardiovascular

• Autonomic dysfunction. Many affected individuals report atypical chest pain, palpitations at rest or on exertion, and/or orthostatic intolerance with syncope or near syncope [Hakim et al 2017, Roma et al 2018]. Clinic room testing may demonstrate postural hypotension and/or postural tachycardia. Ambulatory 24-hour monitoring of heart rate, blood pressure, and symptoms is also an effective method of identifying autonomic dysfunction. Tilt table testing with ancillary supplementary testing such as catecholamine levels can delineate the nature and relationships of hypotension, tachycardia, and syncope, revealing, for example, neurally mediated hypotension [Cheshire & Goldstein 2019].
• Mitral valve prolapse (MVP). The incidence of MVP was 7% in one study of 258 individuals with either hEDS or hypermobility spectrum disorder [Rashed et al 2022]. A similar incidence of MVP was reported in a study of 209 individuals with hEDS or classic EDS (cEDS) [Asher et al 2018]. Studies suggest that MVP is mild, nonprogressive, and does not require routine monitoring.
• Aortic root dilatation. The incidence of aortic root dilatation was 15% in one study of 258 individuals with either hEDS or hypermobility spectrum disorder [Rashed et al 2022]. A study of 95 children diagnosed with hEDS or cEDS showed approximately 2% had aortic root dilatation [Paige et al 2020]. The same 2% incidence of aortic root dilatation was found in a study of 62 adults with hEDS [Pietri-Toro et al in 2023].
• Abdominal vascular compression syndromes such as median arcuate ligament syndrome and superior mesenteric artery syndrome have been identified as a cause of pain, disordered eating, and GI dysfunction in individuals with hEDS. In those with GI manifestations that cannot be readily attributed to structural malfunction, autonomic dysfunction, or inflammation of the GI tract, abdominal compression syndromes should be considered; symptoms can improve significantly following decompressive surgery [Sandmann et al 2021].

Oral/dental. High, narrow palate and dental crowding are common in individuals with hEDS. Gastroesophageal reflux may cause dental erosion. Many individuals with hEDS report poor efficacy of local anesthetic, often first realized during dental treatment and requiring additional dosage or alternative methods of analgesia [Schubart et al 2019]. In addition, many have TMJ dysfunction, which can impede oral assessment [Willich et al 2023], and oral and TMJ concerns may impede use of positive pressure therapies for apnea [Gaisl et al 2017, Sedky et al 2019]. Severe periodontal disease and early-onset dental decay not accounted for by lifestyle is not common in individuals with hEDS and should prompt assessment for periodontal EDS (see Differential Diagnosis) [Lepperdinger et al 2021].

ENT. Hypermobile EDS is associated with variable laryngeal and upper airway inflammation, dysphagia, and dysphonia. Individuals with hEDS are also more likely to report severe airway disease [Williams et al 2023]. Gastroesophageal reflux and mast cell activation disorders both contribute to pharyngeal and throat inflammation.

Sleep disturbance. Sleep can be disrupted in individuals with hEDS due to pain and cardiovascular autonomic disturbance. Sleep disorders also appear to be common in hEDS, including obstructive sleep apnea, insomnia, hypersomnia, and periodic limb movement disorder [Gaisl et al 2017, Domany et al 2018, Sedky et al 2019]. Sleep apnea may be underrecognized in women with hEDS, as it is in the general population [Shepertycky et al 2005].

Ocular. Detailed and systematic evaluation of ocular findings in several small cohorts and case control studies have demonstrated that xerophthalmia (dry eye), high myopia (more than −6 diopters), increased lens curvature (but not keratoconus), eyelid laxity, minor lens opacities, and convergency insufficiency are more common in individuals with hEDS. Minor increases in corneal curvature and lens opacities are incidental findings in those with hEDS and do not cause problems with vision [Asanad et al 2022].

Neurologic/neuromuscular. Neurologic and neuromuscular diseases reported to be more common in those with hEDS include headaches (primarily migraines, TMJ dysfunction-induced headaches, and relating to neck pathology), intracranial hypertension, intracranial hypotension (e.g., due to cerebrospinal fluid leak), Chiari I malformation, craniocervical instability leading to cervicomedullary syndrome, dystonia, tethered cord, Tarlov cysts, nerve entrapment and deformation neuropathies, reduced proprioception, small fiber neuropathy, and autonomic dysfunction [Hamonet et al 2016, Henderson et al 2017, Malhotra et al 2020, Fernandez et al 2022, Zingman et al 2022].

Mast cell activation disorders (MCAD) and immune deficiencies. MCAD reported in individuals with hEDS include single-organ disease such as asthma, urticaria, and gastroenteritis, as well as multiorgan systemic involvement such as mast cell activation syndrome and anaphylaxis. MCAD may contribute to several of the clinical manifestations of hEDS, including headache, upper and lower airway inflammation, gastrointestinal and urologic manifestations, autonomic dysfunction, and joint inflammation [Afrin 2021, Brock et al 2021, Monaco et al 2022]. Primary immune deficiencies such as complement and immunoglobulin deficiencies are also reported in individuals with hEDS.

Neurobehavioral/psychiatric manifestations (neurodivergence). Autism and attention-deficit/hyperactivity disorder are reported to occur more frequently in those with hEDS and impact psychological, social, and emotional processes [Baeza-Velasco 2021, Csecs et al 2022].

Psychiatric manifestations in individuals with hEDS include depression, anxiety disorders, affective disorder, low self-confidence, negative thinking, hopelessness, and desperation. Fatigue and pain exacerbate the psychological dysfunction, and psychological distress exacerbates pain [Bulbena et al 2017, Bulbena-Cabré et al 2021, Eccles et al 2022]. In addition to anxiety disorders, many with hEDS experience a reactive state of anxiety and low mood due to the symptoms and challenges of managing multiple morbidities and the impact these have on daily activities and quality of life. Affected individuals often feel misunderstood, disbelieved, and marginalized. Many with hEDS report difficult encounters with health care professionals and experience clinician-associated traumatization. Resentment and distrust may develop between the affected individual/family and the health care team, adversely affecting the therapeutic relationship [Halverson et al 2023].

Gynecologic/obstetric. Pelvic floor manifestations reported in individuals with hEDS include urinary incontinence, fecal incontinence, pelvic organ prolapse, rectal prolapse, pelvic pain, and sexual dysfunction with dyspareunia, with 20%-75% of individuals reporting at least one of these [Glayzer et al 2021, Patel & Khullar 2021, Kciuk et al 2023, Nazemi et al 2023]. Dysmenorrhea and menorrhagia are also more common in individuals with hEDS [Hugon-Rodin et al 2016].

Several studies have reviewed the evidence for medical issues reported in childbearing women with hEDS, including those related to preconception (e.g., musculoskeletal health and medication use), antenatal (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum (e.g., birth choices, mobility in labor, anesthesia), and postpartum (e.g., wound healing, pelvic health, newborn/infant care adjustments) health [Pezaro et al 2021, Nazemi et al 2023]. In a large (n=947, with 1,338 pregnancies) international survey of pregnancy complications in individuals with hEDS, a higher incidence was reported for preeclampsia, eclampsia, preterm rupture of membranes, preterm birth, antepartum hemorrhage, postpartum hemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, post-traumatic stress disorder, precipitous labor, and delivery prior to arrival at planned place of birth [Pearce et al 2023].

Nomenclature

The 1997 Villefranche criteria [Beighton et al 1998] broadened the classification and nomenclature of the Ehlers-Danlos syndromes based on phenotypic and genetic characteristics. The former EDS type III was renamed the hypermobile type. In 2017, the International Consortium on the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders published revised diagnostic criteria, and the name was modified slightly to hypermobile EDS (hEDS) [Malfait et al 2017].

The terms "benign familial articular hypermobility syndrome" and "joint hypermobility syndrome" are no longer used [Grahame et al 2000]. Individuals with hypermobility-related musculoskeletal concerns who do not fulfill the hEDS criteria and are not syndromic in any other way (which would suggest another underlying disorder) are diagnosed with hypermobility spectrum disorders (HSD) [Castori et al 2017, Castori & Hakim 2017].

The 2017 criteria were constructed with adults in mind. Many of these features arise over time and may not be present in childhood and adolescence. In addition, many of the clinical manifestations are common in younger individuals. A framework for the diagnosis in younger people was developed by Tofts et al [2023]. In this framework most individuals with symptomatic joint hypermobility are classified as having HSD, with the guidance that younger individuals should be monitored and that their diagnosis can change as concerns arise or resolve.

Prevalence

A study of health care records in the Welsh population found an hEDS prevalence of approximately 1:3,100 [Demmler et al 2019]. A similar prevalence was found in a study of US hospital admissions [Brooks et al 2021]. The reported prevalence of hEDS is likely underestimated due to missed diagnosis.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hEDS, the evaluations summarized in Table 3 are recommended.

Treatment of Manifestations

Musculoskeletal. Improvement in musculoskeletal function includes tailored treatment with exercise to increase core and extremity muscle strength and tone, proprioception, and joint stability. Improved joint stability may be achieved with exercises to increase muscle strength and reduce muscle tension. Emphasis is often placed on improving movement patterns and on physical function. Braces and splints are useful to improve alignment and control. They may allow an injured joint to rest and support joints during normal activities and exercising to allow greater duration, frequency, and level of activities. Occupational and physical therapy can assist in recommending wide-grip writing utensils to reduce finger and hand strain and evaluate home and work ergonomics as well as assistive devices (e.g., wheelchair or scooter, suitable mattress, soft neck collar). Orthopedists, rheumatologists, and podiatrist can assist in additional recommendations for problematic joints such as the fingers, hands, wrists, shoulders, knees, ankles, and feet.

Some individuals will have undergone orthopedic and orthognathic procedures prior to diagnosis. Anecdotally, a lack of awareness of the joint hypermobility and tissue fragility may lead to poorer surgical outcomes, but datasets of outcomes are lacking. Some will require surgical procedures if conservative therapies for hEDS fail or there are significant pathologies present (e.g., impingement disorders, dysplasias, and cord/nerve entrapment with neurologic deficit) [Ericson & Wolman 2017, Henderson et al 2017, Homere et al 2020, Santore et al 2020, Clapp et al 2021, DeLeonibus et al 2023].

Prolotherapy, in which saline and/or other irritants are injected in tendons or around joints to induce scar formation and increase stability, has been objectively shown to be safe and effective in one study [Burling 2019].

Pain. Physical and occupational therapies, dry needling, behavioral therapies, and complimentary therapies are among the treatments reported as most helpful for pain management. Among the pharmacologic options, nonsteroidal anti-inflammatory drugs, acetaminophen, and opioids are reported as the most beneficial [Chopra et al 2017, Demes et al 2020]. To date, there is little or mixed outcome data on efficacy of magnesium, muscle relaxants, and neuropathic analgesia such as duloxetine, gabapentin, and tricyclics for pain treatment in individuals with hEDS, and insufficient published evidence on the efficacy of medical marijuana for hEDS. All of these treatments have been used in clinical practice in the management of pain in individuals with hEDS and must be tailored to the individual needs and adjusted or avoided as required in those with comorbidities.

Hematologic. Platelet disorders may respond to tranexamic or mefenamic acid. For severe bleeding or operative prophylaxis, desmopressin acetate (DDAVP^®) may be beneficial. Micronutrient deficiencies may also be responsible for bleeding (e.g., low vitamin C) and anemia (e.g., folate and vitamin B₁₂).

Gastrointestinal (GI). Gastritis and gastroesophageal reflux disease may require intensive therapy, including proton pump inhibitor twice daily before meals, high-dose H2 blocker at bedtime (e.g., famotidine, 20-40 mg), sucralfate (one gram four times daily), and over-the-counter acid-neutralizing agents. Other treatable causes such as H pylori infection and small intestinal bacterial overgrowth (SIBO) should be investigated and treated. Upper endoscopy is indicated for resistant symptoms, but frequently is normal. Delayed gastric and colonic emptying should be identified and treated, as should causes of anorectal pain and prolapse. Assistance from a gastroenterologist experienced in managing GI dysmotility and pelvic floor pathology is required. Visceral mobilization therapies may also help. Irritable bowel syndrome is treated as usual with dietary modification, fiber, antispasmodics, antidiarrheals, and laxatives as needed. Motility enhancers may be helpful for those with constipation only. Tricyclic antidepressants may be helpful for persons with neuropathic pain. If no cause for abdominal pain is identified following GI evaluation, doppler ultrasound should be considered to evaluate for vascular compression syndromes that may require surgical correction.

Cardiovascular. Standard treatments for neurally mediated hypotension and postural orthostatic tachycardia are advised, including avoidance of sudden postural change, consideration of lower extremity and/or abdominal compression garments, exercise to increase muscle strength and improve tone, supplementation of sodium and water to expand the blood volume, and sometimes pharmacologic treatment with beta-blockers, midodrine, fludrocortisone, ivabradine, and/or other medications initiated by a clinician experienced in autonomic medicine. Commercially available electrolyte tablets can facilitate oral expansion of blood volume.

Other vascular concerns, including significant aortic root dilatation and abdominal and pelvic vascular compression syndromes, require referral to a cardiovascular specialist. Rapid aortic root growth, an indication for intervention, is defined as ≥0.5 cm in one year.

Oral/dental/ENT. Standard treatment of periodontal disease is advised, noting that many individuals may have more fragile periodontal tissues and often have a poor response to local anesthetic that requires additional doses throughout dental procedures or other analgesia. Treatment may also be hampered in those with temporomandibular joint (TMJ) laxity and dysfunction, craniocervical instability, and intolerance of specific or prolonged head and neck positions.

For TMJ dysfunction, intraoral devices/retainers may be helpful. Oral rest, local myofascial release, and muscle relaxant medications may be beneficial for acute flares. Surgical intervention may be required.

Issues with swallow and phonation should be assessed by an otolaryngologist.

A pulmonology, otolaryngology, or sleep specialist assessment is recommended for apnea.

Ocular. Standard treatment of ocular concerns is advised.

Neurologic/neuromuscular. No specific pharmacologic treatments have been reported for neurologic and neuromuscular diseases in those with hEDS. Standard pharmacologic treatment for neuropathies is advised. Physical therapies are adjusted to account for joint instability, low muscle tone, and fatigue. Surgical stabilization of the craniocervical junction and spinal surgeries require subspecialty expert neurosurgical or orthopedic management.

Mast cell activation disorder. Treatments include avoidance of triggers (though for many this is challenging, as they are common in most environments), use of H1 and H2 antihistamines, aspirin, ketotifen, and the mast cell stabilizers montelukast and sodium cromoglycate. In those with severe disease and/or those unresponsive to these treatments, monoclonal biologic therapy may be appropriate; this treatment requires expert assessment and management.

Neurobehavioral/psychiatric manifestations (neurodivergence). Validation of symptoms can be immensely helpful, as many with hEDS have been accused by health care professionals of malingering or diagnosed with primary psychiatric disorders. Establishing trust, rapport, and a supportive relationship with the affected individual is important. Anxiety and depression are a common result of the many morbidities a person with hEDS may experience. Psychological and/or symptom-oriented counseling can improve adaptation to and acceptance of these issues and their impact on quality of life. Cognitive behavioral therapy can be beneficial but requires active participation. Antidepressants may also be of benefit. Standard behavioral and pharmacologic therapies should be offered for the management of autism and attention-deficit/hyperactivity disorder.

Urogynecologic. There are no specific guidelines for the management of urinary tract and gynecologic manifestations of hEDS. Within the limited peer-reviewed literature, adjustments to pelvic floor therapies may be warranted, and one study showed that connective tissue disorders including hEDS had the same pelvic surgery outcomes as controls [Nazemi et al 2023]. Other potentially more specific treatments include use of antifibrinolytics for pain and bleeding given their platelet effect, and reduced histamine intake, antihistamines, and mast cell stabilizers for mast cell-induced interstitial cystitis [Patel & Khullar 2021].

Surveillance

There are no specific surveillance guidelines for hEDS. Specific concerns should be followed up based on clinical need and standard protocols. See Table 4 for recommended evaluations.

Agents/Circumstances to Avoid

High-impact activity may increase the risk for acute subluxation/dislocation and acute and chronic pain. Some sports, such as tackle football, may not be suitable but should be discussed on an individual basis. Most sports and activities are acceptable with appropriate precautions.

Chiropractic adjustment and yoga are not contraindicated but must be performed in ways that avoid subluxations or dislocations.

Joint hyperextension may not need to be avoided. In a randomized controlled trial of physical therapy among 26 children and adolescents with joint hypermobility and knee pain, those allowed to exercise into hyperextension had similar improvement in pain score and better improvement in psychosocial score compared to those restricted to neutral joint position [Pacey et al 2013].

Autonomic concerns, gastrointestinal disorders, and intolerances, for example, may preclude use of medications or their excipients (e.g., common analgesics in someone with slow gastrointestinal transit, vasodilator in a person with orthostatic intolerance).

Topical agents and adhesives should be used cautiously in those with skin fragility and/or allergy.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Management of women with hEDS should include preconception assessment (e.g., musculoskeletal health and medication use), antenatal evaluation (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum planning (e.g., birth choices, mobility in labor, anesthesia), and postpartum care (e.g., wound healing, pelvic health, newborn/infant care).

Musculoskeletal complications of hEDS including pain and joint instability may arise for the first time or worsen during pregnancy. In women with hEDS there is a higher incidence of preeclampsia, eclampsia, preterm rupture of membranes, preterm birth, antepartum hemorrhage, postpartum hemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, post-traumatic stress disorder, precipitous labor, and delivery prior to arrival at planned place of birth [Alrifai et al 2023, Pearce et al 2023].

Pregnant women with known aortic root dilatation should have an echocardiogram in each trimester. Echocardiography is not needed if the aortic root is normal prior to pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Hypermobile Ehlers-Danlos syndrome (hEDS) is inherited in an autosomal dominant manner with variable expression of signs and variable severity of symptoms among affected family members.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with hEDS are likely to have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin concerns despite the absence of serious complications.
• A proband with hEDS may be the only family member known to be affected.

Sibs of a proband. The risk to sibs of the proband depends on the clinical status of the proband's parents.

• If a parent of the proband is affected, the risk to the sibs is 50%.
• If both parents are clinically unaffected, the risk to the sibs is likely to be low.

Offspring of a proband

• Each child of an individual with hEDS has a 50% chance of inheriting hEDS.
• Because of marked clinical variability, it is difficult to predict severity among affected offspring.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring) to young adults who are affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from a proband diagnosed with hEDS. For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Because the gene(s) and pathogenic variant(s) responsible for hEDS have not been identified, prenatal and preimplantation genetic testing are not possible at this time.

Molecular Pathogenesis

No pathogenic variants in any genes have as yet been associated with hypermobile Ehlers-Danlos syndrome (hEDS).

Author Notes

Assoc Prof Dr Alan Hakim is an adult certified consultant in Medicine and Rheumatology based in the United Kingdom. Having practiced for more than 30 years in medicine, he has 28 years of experience in rheumatology and translational medicine and 23 years of experience in hypermobility-related disorders. In hospital and community clinical commissioning and administration, he has worked at divisional, director, executive, and board levels. He has project-managed multiple large-scale programs of work across the health sector in the UK. Dr Hakim has published widely in clinical research and education, including more than 100 original scientific and review papers, six books, and multiple chapters and online pages and webinars. He has also held several roles as a Principal and Chief Investigator in pharmaceutical studies related to rheumatic disorders and been awarded numerous major grants in support of his research. He is a Fellow of The Royal College of Physicians, London, UK; an Adjunct Associate Professor in Medicine at The School of Medicine, Penn State, USA; Honorary Consultant at UCLH, London; Chief Medical Officer, Director of Education, Director of Research, and Lead for EDS ECHO at The Ehlers-Danlos Society; and a member of the Steering Committee and Chair of the hEDS/HSD Working Group of the International Consortium on the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders.

Acknowledgments

I first wish to thank all my patients for their insights, in good times and in bad, that they have shared with me over many years regarding living with Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders. Second, I wish to thank Dr Howard Levy, previous author of this review, for nominating me as his successor. Third, I may not have entered the field had I not undertaken research with Prof Tim Spector and Prof Alex MacGregor, and met with Prof Rodney Grahame some 25 years ago. I am grateful to them for helping me establish and develop a subspecialty clinical expertise and a clinical academic career. That in mind, I must thank the Arthritis Research Campaign for funding my initial research fellowship, and all the grant-awarding bodies and donors that have supported me since. Finally, in more recent years I have had the privilege of working with several charitable organizations. In my role as the CMO, Director of Education, and Director of Research at The Ehlers-Danlos Society, I work with a truly dedicated staff and volunteers and with the most incredible array of community and professional colleagues internationally from whom and with whom I continue to learn every day.

Author History

Alan Hakim, BA, MBBChir, MA (2024-present)
Howard P Levy, MD, PhD; Johns Hopkins University School of Medicine (2004-2024)

Revision History

• 22 February 2024 (sw) Comprehensive update posted live
• 31 March 2016 (ha) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 27 April 2010 (me) Comprehensive update posted live
• 1 May 2007 (me) Comprehensive update posted live
• 22 October 2004 (me) Review posted live
• 1 June 2004 (hpl) Original submission

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