Hypermobile Ehlers-Danlos Syndrome

Criterion 1

Generalized joint hypermobility. The Beighton score [Beighton et al 1973] remains the best-validated tool for assessing joint hypermobility [Juul-Kristensen et al 2017]. In order to reduce false-positive Beighton scores, the 2017 hEDS diagnostic criteria recommend standardized performance of the Beighton test [Malfait et al 2017]. One point is scored for each of the following:

• Passive dorsiflexion of each fifth finger greater than 90°. This should be assessed with the palm and forearm resting on a flat surface, and is considered positive only if the fifth metacarpal-phalangeal joint (MCP) can be extended more than 90°. Ability to extend the tip of the fifth finger to a position proximal to the MCP is insufficient to be called positive if the MCP does not extend more than 90°.
• Passive apposition of each thumb to the flexor surface of the forearm. This should be assessed with the elbow extended and hand pronated.
• Hyperextension of each elbow greater than 10°. This should be measured with a goniometer, with the hand supinated, elbow fully extended, and shoulder abducted to 90°.
• Hyperextension of each knee greater than 10°. This should be measured with a goniometer, with the patient standing and knees fully extended.
• Ability to place the palms flat on the floor with the knees fully extended. This should be assessed with the knees locked in extension and the feet together, and is considered positive only if the total palm of both hands lies flat on the floor just in front of the feet. Slight flexion of the knees, spreading of the feet, failure to get the heels of the palms to the floor, and positioning the hands more than a few inches in front of the feet are common causes for false positive scoring of this point.

The original Beighton publication defines a score of ≥5 as indicative of generalized joint hypermobility [Beighton et al 1973]. However, joint range of motion typically decreases with age, leading to overdiagnosis of children and underdiagnosis of older adults with joint hypermobility. For the purposes of diagnosing hEDS, generalized joint hypermobility is confirmed by a score of [Malfait et al 2017]:

• ≥6 for prepubertal children
• ≥5 for pubertal children and adults up to age 50
• ≥4 for those age >50 years

Multiple other variables including (but not limited to) ethnicity, gender, trauma, surgery, arthritic change, conditioning, and stretching also affect the Beighton score. There is no validated method to account for this variation in assessing generalized joint hypermobility, but the 2017 hEDS diagnostic criteria include an allowance for individuals with acquired limitation of joint mobility [Malfait et al 2017]. Generalized joint hypermobility may be confirmed in an individual whose Beighton score is one point below the age-specific cutoff if there are two or more positive answers to the five-point questionnaire (5PQ) [Hakim & Grahame 2003]. Individuals with prior history of joint hypermobility, suggested by a positive 5PQ (≥2 positive answers) but scoring two or more points below the age-specific Beighton cutoff, should not be considered to have generalized joint hypermobility and should instead be evaluated for HSD [Castori et al 2017].

The 5PQ:

1.

Can you now (or could you ever) place your hands flat on the floor without bending your knees?

2.

Can you now (or could you ever) bend your thumb to touch your forearm?

3.

As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits?

4.

As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?

5.

Do you consider yourself "double-jointed"?

Criterion 2

At least two of the following features (A, B, and/or C) must be present.

Feature A. Five or more of the following systemic manifestations of a more generalized connective tissue disorder (A Systemic Score calculator and a complete description of each component evaluation can be found at the National Marfan Foundation website.):

• Unusually soft or velvety skin. This is an inherently subjective feature. It should be assessed in the absence of recent application of moisturizer, and a high threshold is recommended.
• Mild skin hyperextensibility, assessed at a site lacking excess or loose skin and without evidence of prior trauma by gently pulling until resistance is met. An ideal location is the volar surface of the non-dominant forearm, where the upper limit of normal extensibility is 1.5 cm. Extensor surfaces of joints have excess skin and should not be used. More significant extensibility (e.g. >2.0 cm) should prompt consideration of other EDS types.
• Unexplained* striae at the back, groins, thighs, breast, and/or abdomen in adolescents, men, or prepubertal females (* i.e., without a history of significant gain or loss of body fat or weight)
• Bilateral piezogenic papules* of the heel (* i.e., herniations of subcutaneous heel fat visible upon standing); must be present bilaterally to be considered positive
• Recurrent or multiple abdominal hernias, such as umbilical, curural, inguinal, or femoral. Hiatal hernia does not count toward this feature.
• Atrophic scarring involving at least two sites and without the formation of papyraceous and/or hemosideric scars as seen in classic EDS. Atrophic scarring is defined as scars from linear traumatic lacerations or single surgery that are unusually shallow and/or wider than the original wound. Atrophic scars as the result of multiple incisions, wound infections, or inflammatory conditions do not count toward this feature and elliptical incisions (e.g., for removal of nevi) may be difficult to assess without knowing the size of the original wound.
• Pelvic floor, rectal, and/or uterine prolapse in children, men, or nulliparous women without a known predisposing medical condition
• Dental crowding (including a history of crowding corrected by orthodontia) and high or narrow palate. Both conditions must be positive to count toward this feature.
• Arachnodactyly, defined as either bilateral positive wrist sign or bilateral positive thumb sign
• Arm span to height ≥1.05
• Mitral valve prolapse, based on strict echocardiographic criteria
• Aortic root dilatation with a Z score >+2

Feature B. Positive family history, with one or more first-degree relatives independently meeting the current diagnostic criteria for hEDS. Of note, a first-degree relative meeting prior diagnostic criteria for EDS, hypermobility type or type III EDS does not count toward this feature; the relative must meet current criteria for hEDS.

Feature C. At least one of the following musculoskeletal complications (but see Criterion 3, Note):

• Musculoskeletal pain in two or more limbs, recurring daily for at least three months
• Chronic widespread pain for at least three months
• Recurrent joint dislocations or frank joint instability, in the absence of trauma:
  • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times; OR
  • Medical confirmation of joint instability at two or more sites not related to trauma

Criterion 3

ALL of the following prerequisites must be met:

• Absence of unusual skin fragility, which should prompt consideration of other types of EDS
• Exclusion of other heritable and acquired connective tissue disorders including autoimmune rheumatologic conditions (see Note)
• Exclusion (based on history, physical exam, and/or molecular genetic testing) of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity such as neuromuscular disorders, other heritable connective tissue disorders and skeletal dysplasias (see Differential Diagnosis)

Note: In individuals with an acquired connective tissue disorder (e.g., lupus, rheumatoid arthritis), additional diagnosis of hEDS requires meeting both Features A and B of Criterion 2. Feature C of Criterion 2 (chronic pain and/or instability) cannot be counted toward a diagnosis of hEDS in this situation.

Skin

The skin is often soft and may be mildly hyperextensible.

Piezogenic papules (small herniations of subcutaneous fat through the underlying dermis of the heel occurring only with weight bearing) are common but rarely painful.

Keratosis pilaris may be more common than in the general population [Castori et al 2010a].

Subcutaneous spheroids and molluscoid pseudotumors are not features of this EDS type.

Clinically significant skin morbidity does not occur; its presence should prompt consideration of alternative diagnoses.

Musculoskeletal

Joint instability. Joint laxity and instability and excessive joint motion are frequently evident on routine activity, even in the absence of overt subluxation or dislocation.

• Subluxations and dislocations are common. They may occur spontaneously or with minimal trauma and can be acutely painful. Reduction often occurs spontaneously or can be accomplished by the affected individual or a bystander. For most affected individuals, medical intervention for an acute dislocation is not usually necessary, but pain can last for hours or days after an event.
• All sites can be involved, including the extremities, vertebral column, costo-vertebral and costo-sternal joints, clavicular articulations, and temporomandibular joints.
• Sprains or twisting of the ankles and buckling or "giving out" of the knees are common.
• Iliotibial band syndrome or "snapping hip" is a common symptom, often perceived by the affected individual as hip joint instability [Branson et al 2011].
• Temporomandibular dysfunction ("TMJ syndrome") is relatively common [Hagberg et al 2004, De Coster et al 2005], and can be thought of as a specific example of joint degeneration and osteoarthritis.
• Females tend to have more substantial laxity than males.
• Younger individuals tend to have more substantial laxity than older individuals [Castori et al 2010a].
• Tendinitis and bursitis may occur [Rombaut et al 2010b, Rombaut et al 2011a, Rombaut et al 2011b], especially greater trochanteric bursitis in those with iliotibial band syndrome. EDS does not directly cause inflammation, and these problems are likely secondary to joint instability.

Osteoarthritis. Degenerative joint disease occurs at a younger age than in the general population, possibly because of chronic joint instability resulting in increased mechanical stress.

Bone density. There is very limited and contradictory evidence regarding bone mineral density in hEDS. Dolan et al [1998] found bone density to be reduced by up to 0.9 SD in individuals with EDS compared to healthy controls, but that study did not look specifically at individuals with hEDS. Compared to age- and sex-matched controls, Gulbahar et al [2006] reported bone density reduction of up to 0.5 SD among premenopausal women with joint hypermobility syndrome (now considered identical to hEDS). However, Carbone et al [2000] found no difference in bone density between women with hEDS and normal controls after adjusting for height, weight, and physical activity.

Pain

Chronic pain, distinct from that associated with acute dislocations, is a serious complication of the condition and can be both physically and psychosocially disabling [Sacheti et al 1997, Hagberg et al 2004, Rombaut et al 2010a, Voermans et al 2010a, Rombaut et al 2011a, Rombaut et al 2011b].

It is variable in age of onset (as early as adolescence or as late as the 5th-6th decade), number of sites, duration, quality, severity, and response to therapy.

Severity is typically greater than expected based on physical and radiologic examinations.

Severity sometimes correlates with degree of joint instability and with sleep impairment [Voermans et al 2010a].

Fatigue and sleep disturbance are frequently associated [Rombaut et al 2010b, Voermans et al 2010a, Voermans et al 2010b, Rombaut et al 2011a, Rombaut et al 2011b, Rombaut et al 2012b]. Affected individuals are often diagnosed with chronic fatigue syndrome, fibromyalgia, depression, hypochondriasis, and/or malingering prior to recognition of joint laxity and establishment of the correct underlying diagnosis.

Headaches, especially migraine, are common [Rombaut et al 2010b, Rombaut et al 2011a, Rombaut et al 2011b]. Cervical muscle tension, temporomandibular dysfunction, and stress are some of the likely contributing factors.

Several recognizable pain syndromes are likely:

• Muscular or myofascial pain, localized around or between joints, often described as aching, throbbing, or stiff in quality, may be attributable to myofascial spasm, and palpable spasm with tender points (consistent with fibromyalgia) is often demonstrable, especially in the paravertebral musculature [Castori et al 2010a, Rombaut et al 2010b, Rombaut et al 2011a, Rombaut et al 2011b]. 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, numb, 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 [Camerota et al 2011]. Nerve conduction studies are usually not diagnostic. Skin biopsy may reveal reduction or absence of small nerve fibers, but may be normal. One hypothesis is that neuropathic pain may result from direct nerve impingement (e.g., by subluxed vertebrae, herniated discs, vertebral osteoarthritis, or peripheral joint subluxations). In addition, there may be mild-to-moderate nerve compression within areas of myofascial spasm. Neither of these possibilities has been evaluated clinically.
• Osteoarthritic pain occurs later in life (but earlier than in the general population) and typically presents as aching pain in the joints, frequently associated with stiffness. It is often exacerbated by stasis and by resistance and/or highly repetitive activity.

Hematologic

Easy bruising is quite common, frequently without obvious trauma or injury [Anstey et al 1991, De Paepe & Malfait 2004]. Mildly prolonged bleeding, epistaxis, bleeding from the gums (especially after dental extraction), and menometrorrhagia may also occur.

The underlying cause of the hematologic manifestations is unknown.

• Bleeding time may or may not be prolonged, but no consistent abnormalities of coagulation factors, von Willebrand factor or platelet number, release or aggregation have been reported [Anstey et al 1991, Mast et al 2009].
• Capillary fragility and/or impaired soft tissue integrity may play a role [De Paepe & Malfait 2004].

Gastrointestinal

Functional bowel disorders are common and underrecognized, affecting 33%-67% of individuals with hEDS [Levy et al 1999, Castori et al 2010a].

Gastroesophageal reflux and gastritis may be symptomatic despite maximal doses of proton pump inhibitors with additional H2-blockers and acid-neutralizing medications.

Early satiety and delayed gastric emptying may occur and may be exacerbated by opioid (and other) medications.

Irritable bowel syndrome may manifest with diarrhea and/or constipation, associated with abdominal cramping and rectal mucus.

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 [Rowe et al 1999, Gazit et al 2003, Mathias et al 2011]. Holter monitoring usually shows normal sinus rhythm, but sometimes reveals premature atrial complexes or paroxysmal supraventricular tachycardia. Tilt table testing may reveal neurally mediated hypotension (NMH) and/or postural orthostatic tachycardia syndrome (POTS).

Raynaud syndrome and acrocyanosis occur at an increased frequency, which may be another manifestation of autonomic dysfunction [Castori et al 2010a].

Aortic root dilation, usually of a mild degree, occurs in 11%-33% of individuals with hEDS [Wenstrup et al 2002, McDonnell et al 2006, Atzinger et al 2011]. The severity appears to be much less than occurs in Marfan syndrome, and there is no increased risk of aortic dissection in the absence of significant dilation. Dilation onset is in childhood and is usually stable over time. It is unlikely to progress or to develop later in life [Atzinger et al 2011].

Mitral valve prolapse (MVP) was previously considered a common feature of EDS. Rigorous evaluations using modern diagnostic criteria have been inconsistent, with some studies showing no increase in the frequency of clinically significant MVP [Dolan et al 1997, McDonnell et al 2006, Atzinger et al 2011] and others showing an MVP frequency of 28%-67% [Camerota et al 2014, Kozanoglu et al 2016]. It is possible that mild MVP not meeting diagnostic criteria (and therefore not requiring special monitoring or treatment) may also explain some of the atypical chest pain and palpitations.

Oral/Dental

High, narrow palate and dental crowding are nonspecific features of most heritable disorders of connective tissue. Bifid uvula, submucous cleft palate, and overt cleft palate are not manifestations of hEDS, and should prompt consideration of alternative diagnoses (see Differential Diagnosis).

The frequency of periodontal manifestations such as friability, gingivitis, and gum recession is probably increased but has not been adequately studied specifically in the hypermobile type [Hagberg et al 2004, De Coster et al 2005, Castori et al 2010a]. De Felice et al [2004] reported an abnormally complex oral microvascular network in 12 individuals with classic or hypermobile EDS; potential correlation of this with periodontal disease has not been reported.

Obstetric/Gynecologic

Pregnancy may be complicated by rapid labor and delivery (<4 hours), with small studies suggesting a frequency of 28%-36% [Castori et al 2010a, Castori et al 2012].

Joint laxity and pain typically increase throughout gestation, especially in the third trimester, as normally occurs during pregnancy in unaffected women [Volkov et al 2007, Castori et al 2012].

There is no clear advantage to vaginal vs cesarean delivery. Cesarean delivery may reduce the risk of hip dislocation [Volkov et al 2007, Dutta et al 2011], but carries the same risk for surgical complications as in the general population.

There is no increase in risk for cervical incompetence, and no evidence to support use of prophylactic cerclage [Volkov et al 2007].

No other pregnancy complications are associated with hEDS.

Pelvic prolapse, dysmenorrhea, and dyspareunia occur at increased frequency in hypermobile EDS [McIntosh et al 1995, Castori et al 2010a, Castori et al 2012].

Psychiatric

Psychological dysfunction, psychosocial impairment, and emotional problems are common [Hagberg et al 2004, Rombaut et al 2011a].

Specific manifestations may include depression, anxiety, affective disorder, low self-confidence, negative thinking, hopelessness, and desperation [Hagberg et al 2004, Castori et al 2010a, Baeza-Velasco et al 2011, Branson et al 2011, Rombaut et al 2011a].

Fatigue [Voermans et al 2010b] and pain [Rombaut et al 2011a] exacerbate the psychological dysfunction.

Psychological distress exacerbates pain [Baeza-Velasco et al 2011, Branson et al 2011].

Fear of pain and/or joint instability may lead to avoidance behavior (kinesiophobia) and exacerbate dysfunction and disability [Baeza-Velasco et al 2011, Branson et al 2011].

Affected individuals may feel misunderstood, disbelieved, marginalized, and alone [Baeza-Velasco et al 2011].

Resentment, distrust, and hostility may develop between the affected individual/family and the health care team (in both directions), adversely affecting the therapeutic relationship [Branson et al 2011].

Ocular

Detailed and systematic evaluation of ocular findings in 44 eyes of 22 individuals with hEDS was compared to age- and gender-matched controls [Gharbiya et al 2012]. Findings included the following:

• Subjective and objective measures of xerophthalmia were rare, but more common in hEDS than controls. It is unknown whether this represents an intrinsic feature of EDS or possibly an indirect association (e.g., a side effect of medication).
• Clinically insignificant minor lens opacities were found in 13% of EDS eyes, compared to none among controls.
• High myopia (more than -6.0 diopters) and vitreous degeneration were found in 16% of EDS eyes and none of the controls. There was no difference in frequency of mild or moderate myopia between EDS and control eyes.
• There was no significant difference in axial length of the globe between EDS and control eyes.
• EDS eyes averaged slightly increased corneal curvature compared to controls, but there was no overt keratoconus.

Neurologic & Neuromuscular

Delayed onset and/or resistance to local anesthesia is a frequent complaint [Hakim et al 2005, Castori et al 2010a].

Dysautonomia may manifest as functional bowel disorders, cardiovascular autonomic dysfunction, and/or Raynaud syndrome/acrocyanosis.

Poor balance is common, with increased incidence of falls and occasionally fear of falling [Rombaut et al 2011c].

Diminished joint position sense has been reported at the knees, but not the shoulders. Vibration sensation is normal [Rombaut et al 2010a].

It is unclear whether weakness is an associated feature. Some studies suggest normal muscle strength [Castori et al 2010a, Rombaut et al 2010b], while others have demonstrated decreased ankle power [Galli et al 2011], reduced passive muscle tension, and increased Achilles tendon compliance [Rombaut et al 2012a, Rombaut et al 2012b]. One study reported lower-extremity weakness, but the findings could also be explained by reduced motor effort secondary to pain and/or fatigue [Rombaut et al 2012b].

Individuals with hEDS tend to have a slower-than-normal gait with shorter gait length [Cimolin et al 2011, Galli et al 2011, Rombaut et al 2011c].

Kinematic studies are normal at the hips and knees [Galli et al 2011], but the ankles demonstrate excess plantar flexion at ground contact and decreased dorsiflexion during motion [Cimolin et al 2011, Galli et al 2011, Rigoldi et al 2012].

In a series of 2,813 individuals with Chiari malformation type 1, 12.7% were felt to also have a hereditary disorder of connective tissue, including many with hEDS [Milhorat et al 2007]. Among those with independently confirmed EDS, Chiari malformation was found in only one (4.7%) of 21 individuals with hypermobile EDS [Castori et al 2010a] and one (5.5%) of 18 individuals with headache and unspecified types of EDS [Jacome 1999]. The incidence of Chiari malformation among individuals with EDS has not been systematically studied, and the clinical relevance of this potential association is uncertain.

Disability

Functional and psychosocial impairment are common, manifesting with decreased sport-related physical activity, diminished health-related quality of life, and significant impact on daily function [Rombaut et al 2010b, Voermans et al 2010a, Rombaut et al 2011a, Rombaut et al 2011b].

Pain, fatigue, and sleep disturbance all may contribute to disability and functional impairment [Rombaut et al 2010b, Voermans et al 2010a, Rombaut et al 2011a, Voermans & Knoop 2011].

Other

Fragility of soft tissues with spontaneous ruptures or tears of internal organs is, by definition, not a feature of hEDS. Such manifestations should prompt consideration of other hereditary connective tissue disorders (see Differential Diagnosis).