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Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder

Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder
Literature review current through: Jan 2024.
This topic last updated: Jan 18, 2024.

INTRODUCTION — The hypermobile type of Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) are among a group of conditions characterized by joint hypermobility and other frequently shared clinical features (table 1 and table 2). Many of the patients with hEDS and HSD were historically described as having joint hypermobility syndrome (JHS), a term no longer used to classify patients since a major revision of the criteria for JHS and the Ehlers-Danlos syndromes (EDS) in 2017 [1,2].

HSD includes those individuals with a hypermobility-related condition who do not fulfill either the more stringent criteria for hEDS or criteria for another of the hereditary disorders of connective tissue (HDCT) [3,4].

An overview of the epidemiology, pathogenesis, clinical manifestations, and diagnosis of hEDS and HSD in adults and similar conditions in older children and adolescents are presented here. The management of these conditions is described separately. (See "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

Overviews of the clinical manifestations, diagnosis, and management of the other, rarer types of EDS; the clinical manifestations and treatment of Marfan syndrome and Loeys-Dietz syndrome and other related disorders; osteogenesis imperfecta; and Stickler syndrome are also presented separately:

EDS (see "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes" and "Overview of the management of Ehlers-Danlos syndromes")

Marfan syndrome and related disorders (see "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders")

Osteogenesis imperfecta (see "Osteogenesis imperfecta: An overview")

Stickler and Marshall syndromes (see "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes')

TERMINOLOGY — The nomenclature for conditions characterized by joint hypermobility has evolved in an effort to better describe different patient populations (table 2). An international committee of experts updated terminology in 2017 [1,2]. The hypermobile type of Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) are defined as follows (table 1):

Hypermobile Ehlers-Danlos syndrome – hEDS is the most common type of Ehlers-Danlos syndrome (EDS) and is characterized by the general features of EDS with less severe manifestations (eg, milder skin stretch and scarring) (table 3). At this time, no single pathogenic gene variants have been found that explain the cause and inheritance of hEDS. (See 'Diagnosis' below.)

Hypermobility spectrum disorder – The term HSD is now used to describe those individuals with a symptomatic hypermobility-related condition who do not fulfill either the comparatively more stringent criteria for hEDS, which generally include involvement of at least one other body system in addition to musculoskeletal complications, or criteria for another of the hereditary disorders of connective tissue (HDCT) [3,4]. The joint involvement can be single, pauci and regional, or generalized. Notably, for patients with HSD, the term "spectrum" is used to highlight the variety of phenotypic patterns of disease presentations that can arise in this group, but it is not intended to suggest a scale of severity of symptoms.

In clinical practice, people living with HSD and hEDS often have similar concerns, whether musculoskeletal, visceral, autonomic, anxiety-related, or others, and these issues were reviewed in detail by the international consortium in a series of reports [5]. Joint hypermobility syndrome (JHS) is now an outdated term but was previously used to describe patients with generalized joint hypermobility and related symptoms; these patients are now categorized as having either hEDS or HSD. The term JHS will be used in this topic review where pre-2017 descriptions or criteria for JHS were used to define patients for inclusion in studies.

A pediatric and adolescent diagnostic framework for pediatric joint hypermobility was published in 2023 (table 4) [6,7]. The two main categories of pediatric hypermobility are as follows:

Pediatric generalized joint hypermobility (pGJH) – Patients have joint hypermobility but do not have musculoskeletal complications

Pediatric generalized hypermobility spectrum disorder (pgHSD) – Patients have joint hypermobility and do have musculoskeletal complications

Subtypes of pGJH and pgHSD are described below. (See 'Pediatric hypermobility syndromes' below.)

EPIDEMIOLOGY — Joint hypermobility is common, with up to one in five individuals in the general population having localized or generalized hypermobility [8]. At this frequency, joint hypermobility can be considered a physical trait rather than a disorder. Hypermobility is more common in females and in people with a family history of hypermobility [9]. Joint flexibility is greater during childhood and adolescence and decreases with age [6].

Data on the prevalence of symptomatic, disabling, joint hypermobility-related conditions like hypermobile Ehlers Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) are limited. In a cohort study in Wales using diagnostic codes, the prevalence of joint hypermobility syndrome (JHS) and all types of Ehlers-Danlos syndrome (EDS) showed a combined prevalence of 1 in 500 and a prevalence of hEDS of approximately 1 in 3200 [10].

PATHOPHYSIOLOGY — The pathophysiologic basis of hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) is not understood. Unlike the other types of EDS, no structural abnormality in collagen or related proteins or in the genes encoding such molecules has yet been identified. Research to identify potential genetic, epigenetic, and metabolic markers within populations of people with hEDS and HSD is ongoing.

The pattern of occurrence of HSD or hEDS in families is generally consistent with dominant inheritance, but the penetrance of signs and symptoms is highly variable among family members. Detailed family studies have identified multiple pedigrees in which HSD, hEDS, or both segregated as a single dominant trait with incomplete penetrance and variable expression [9].

The lack of a well-defined biologic marker in HSD and hEDS contrasts with most other hereditary disorders of connective tissue (HDCT), including other forms of Ehlers-Danlos syndrome (EDS) and Marfan syndrome, for which abnormalities in collagen and fibrillin biology and associated genetic mutations are well documented. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Genetics and pathogenesis' and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Genetics'.)

Many comorbid conditions are associated with HSD and hEDS that appear either unrelated or only indirectly related to connective tissue abnormalities but may contribute to the pathogenesis of the clinical syndrome (table 5). In addition, hEDS and HSD may also share common pathophysiology with chronic fatigue syndrome, fibromyalgia, and "long COVID" based on similar symptoms and comorbid conditions [11].

CLINICAL MANIFESTATIONS

Joint hypermobility — The major clinical features of both hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) include joint hypermobility and symptoms related to the musculoskeletal changes (picture 1A-D). Joint hypermobility is defined as having a greater range of motion in joints than normal, which can be appreciated on examination as well as patient history. (See 'Assessing joint hypermobility' below.)

Musculoskeletal complications — Pain in hEDS and HSD is multifactorial; it may arise as a consequence of recurrent soft tissue injuries, dislocations, and nerve entrapment, and through abnormal neuropathic mechanisms of central and peripheral sensitization [12,13]. Musculoskeletal manifestations may include:

Recurrent joint sprains and ligament and tendon injuries.

Episodes of recurrent joint instability, including subluxations (incomplete dislocation) or dislocations. Dislocations often arise from minor trauma. The more commonly affected joints include the carpometacarpal joint at the thumb and the shoulder, hip, and ankle. The patellar ligament may be so lax as to allow the patella to displace laterally or medially. Less often, some individuals dislocate joints by minor self-manipulation.

Poor proprioception, coordination difficulties, and loss of balance [14].

Mechanical pain related to biomechanical differences, especially in the lower limbs.

Persistent chronic pain in one or many joints.

Complex widespread musculoskeletal pain with evidence of central sensitization and neuropathic qualities. This may share similarities with fibromyalgia. (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases".)

Features of the Marfanoid body habitus (a range of skeletal disproportions associated with increased length and decreased breadth of long bones) (table 6). (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Skeletal findings'.)

Signs of a connective tissue disorder in hypermobile Ehlers-Danlos syndrome — In hEDS, there is fragility of skin and supportive connective tissues and some features common to other hereditary disorders of connective tissue (HDCT), although the severity of these latter manifestations varies between the different disorders [2]. Skin and soft tissue abnormalities include:

Hyperextensible skin (picture 2), the texture of which is usually soft and velvety/silky. In children, significant skin transparency would need referral for genetic evaluation.

Easy bruising.

Wide, paper-thin scars, not "atrophic" like those seen in rarer classical type of Ehlers-Danlos syndrome (EDS).

Multiple stretch marks (striae atrophicae), typically arising during the adolescent growth spurt.

Recurrent abdominal wall hernias.

Pelvic floor weakness with rectal and/or vaginal prolapse, and bladder dysfunction (dysuria, urgency, frequency, urge, and stress incontinence).

Other common symptoms and comorbidities — Patients with hEDS and HSD may experience a variable array of other associated symptoms and comorbid conditions that are not part of the diagnostic criteria but can have a major impact on activities of daily living and quality of life in people with hEDS or HSD if not remedied [5,15]. These symptoms and disorders include chronic widespread pain [13], fatigue [16], autonomic dysfunction [17], and gastrointestinal dysmotility [18].

In children and adolescents, the more common comorbid associations include pain, fatigue, disorders of gut-brain interaction (DGBI), dysautonomia, disorders of the bladder, and anxiety [6]. (See 'Pediatric hypermobility syndromes' below.)

Common symptoms and comorbid conditions often associated with hEDS and HSD include the following (table 5):

Fatigue – Disabling, persistent fatigue may be due to a combination of chronic pain, poor sleep due to pain, and autonomic dysfunction [16]. Fatigue in patients with hEDS and HSD shares many similarities with chronic fatigue syndrome. (See "Clinical features and diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome".)

Mood disorders – Patients may experience comorbid anxiety, depression, and phobia (eg, fear of movement). Anxiety states are overrepresented in patients with hEDS and HSD. One factor may be the concerns of patients regarding the multiple comorbidities associated with joint hypermobility for which the relationship with HSD and hEDS is often not appreciated [19-22].

Autonomic dysfunction – There is a strong association of joint hypermobility syndrome (JHS) and hEDS with primary cardiovascular autonomic dysfunction [23,24], bowel anatomic and autonomic dysfunction [25-29], and bladder dysfunction [30,31]. Cardiovascular autonomic dysfunction includes orthostatic intolerance, orthostatic hypotension, or postural tachycardia syndrome (when accompanied by a significant increase in heart rate). These can lead to symptoms including palpitations, chest pain, and presyncope or syncope. Exacerbating factors include postural change, exertion, dehydration, and heat exposure. Patients may also experience abnormal sweating.

Neurologic symptoms – Patients may develop symptoms related to spinal instability, nerve entrapment, or peripheral neuropathy, resulting in worsening pain or autonomic dysfunction. This may be exacerbated by movements, such as when moving the cervical spine [32]. Patients may also have chronic headaches or migraines [33].

Gastrointestinal and genitourinary symptoms – Gastrointestinal and genitourinary symptoms are present in over half of patients with hEDS and HSD [34] and may be influenced in part by autonomic dysfunction. Symptoms may include:

Bowel symptoms suggestive of DGBI or irritable bowel syndrome, including alternating constipation and diarrhea, bloating, nausea, and pain. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults".)

Bowel dysmotility, especially slow-transit constipation.

Heavy and painful menstrual bleeding.

Functional bladder disorders, including interstitial cystitis/bladder pain syndrome. (See "Interstitial cystitis/bladder pain syndrome: Clinical features and diagnosis".)

Symptoms during pregnancy and childbirth — Based on a small number of studies, patients with hEDS and HSD may experience higher rates of complications during pregnancy compared with the general population, including onset or worsening of the following [35-37]:

Increased ligament laxity leading to joint pain, joint dislocations, and soft tissue injury in areas including but not limited to the low back, pelvic girdle, ankles, and feet

Injury to the pelvic girdle and hips from malposition in labor and/or prolonged strain

Abdominal wall herniation

Pelvic floor weakness and prolapse

Bladder obstruction due to prolapse

Rapid progression of labor

Higher risk of tearing of the vaginal wall

Poor wound healing

Decreased efficacy of local anesthetics and epidurals

Delayed resolution of musculoskeletal pain, potentially leading to chronic pain

Fatigue

Postural tachycardia syndrome

Gastroesophageal reflux

Varicose veins

Difficulty caring for an infant (eg, lifting, carrying) due to the above issues

Management considerations for people with hEDS and HSD who are pregnant or postpartum are detailed elsewhere. (See "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Management in pregnancy and childbirth'.)

DIAGNOSIS AND EVALUATION

When to suspect hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder — Hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) should be considered in patients presenting with evidence of hypermobility on examination as well as other symptoms including (see 'Clinical manifestations' above):

Arthralgia, soft tissue injuries, or musculoskeletal pain

Joint subluxations or dislocations

Fatigue

Anxiety

Autonomic dysfunction

Gastrointestinal dysfunction

Skin changes (eg, hyperextensible skin, abnormal scarring) in hEDS only

Assessing joint hypermobility

Questions about hypermobility — The presence of generalized joint hypermobility, including its presence historically, may be suspected in adult patients over the age of 18 years who answer "yes" to two or more questions in a simple five-part questionnaire (table 7) [38]:

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

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

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

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

Do you consider yourself double-jointed?

This five-part questionnaire has not been validated in people under 18 years of age [39].

Hypermobility on physical examination — Physical examination for hypermobility should include a comprehensive musculoskeletal examination, including any symptomatic joints as well as the temporomandibular joints, shoulders, elbows, hands, wrists, spine, hips, knees, ankles, and feet.

In patients who are over five years of age, joint hypermobility is assessed using the Beighton score. The score depends upon the presence of joint hypermobility in the hands, elbows, lumbar spine, and knees using specific examination techniques (figure 1 and table 8) [40-42]. One point is awarded for the ability to perform each of nine maneuvers (including four maneuvers tested bilaterally and evaluation of the spine).

The specific maneuvers used to obtain a Beighton score include:

Passive apposition of the thumb to the volar aspect of the ipsilateral forearm

Passive hyperextension of fingers, demonstrated by passive dorsiflexion of the fifth metacarpophalangeal joint to at least 90 degrees

Hyperextension of the elbow to at least 10 degrees

Hyperextension of the knee to at least 10 degrees

Flexion of the spine with placement of the palms flat on the floor without bending the knees

Scores need to be assessed in the context of age- and sex-matched norms. For the 2017 hEDS criteria, generalized joint hypermobility requires a score of ≥6 in children (over five years old who have not reached skeletal maturity, up to 18 years old), ≥5 in adolescents and younger adults, and ≥4 in adults aged 50 years and over. Robust normative reference data exists for children and adolescents [43]. However, according to an analysis of population data, use of these definitions may still fail to identify males with unusually high levels of joint hypermobility while overdiagnosing young females as having joint hypermobility [43]. (See 'Diagnosis' below.)

While the Beighton criteria are limited to the hands, elbows, lumbar spine, and knees, supplemental clinical assessment tools for the upper limb (Upper Limb Hypermobility Assessment Tool [ULHAT]), lower limb (Lower Limb Assessment Score [LLAS]), and foot (Foot Posture Index [FPI]) are now available [44-46].

Diagnosis — The diagnosis of HSD and hEDS is made clinically; there are no diagnostic laboratory tests for HSD or hEDS.

Hypermobile Ehlers Danlos syndrome — The diagnosis of hEDS can be made clinically, based upon the clinical history and physical examination, using the 2017 international criteria (table 3) [2]. The criteria describe the combinations of musculoskeletal and other historical and clinical findings that may be used to make the diagnosis.

hEDS is diagnosed if an adult individual fulfills:

Criterion 1 – Presence of generalized joint hypermobility, based on the Beighton hypermobility score (figure 1 and table 8) and the five-part hypermobility questionnaire (table 7) [38]. (See 'Assessing joint hypermobility' above.)

Criterion 2 – At least two of sections A, B, and C in criterion 2 (other tissue signs, family history, and joint pain or joint instability).

Criterion 3 – The absence of another hereditary disorder of connective tissue (HDCT) or other cause for relevant signs or symptoms found. (See 'Features suggesting an alternative diagnosis' below and 'Differential diagnosis' below.)

There are currently no diagnostic laboratory tests (eg, blood tests, molecular genetic analyses, imaging, or histopathology) for hEDS.

Hypermobility spectrum disorder — A diagnosis of HSD is made in the presence of the same musculoskeletal concerns as seen in hEDS but with the absence of sufficient additional features to make a diagnosis of hEDS or other HDCT or another primary cause for joint instability, such as a myopathy, neuropathy, or a bone dysplasia (see 'Features suggesting an alternative diagnosis' below and 'Differential diagnosis' below). A key difference between HSD and hEDS is the distribution of hypermobility; in HSD, it can be generalized, local/regional, or peripheral (small joints), while in hEDS, the criteria require the hypermobility to be generalized (table 9) [3,4].

Pediatric hypermobility syndromes — A pediatric and adolescent diagnostic framework for pediatric joint hypermobility was published in 2023 (table 4 and form 1 and algorithm 1) [6,7]. It was designed for children ages five years and older and adolescents up to age 18 years old who have not reached biologic maturity (defined as skeletal maturity with growth velocity under 1 cm/year on two measurements taken three months apart, or mature bone age radiograph). The need for this framework arose for several reasons:

Joint flexibility is greater in younger people and decreases as children grow.

It is unclear how best to determine the significance of skin texture and elasticity in younger people.

Many of the clinical features in the adult hEDS 2017 criteria appear over time (eg, stretch marks, scarring) and may not be present in the younger person.

Comorbidities with generalized joint hypermobility are different in younger people.

Patients with pediatric generalized joint hypermobility (pGJH) have joint hypermobility without musculoskeletal complications, whereas patients with pediatric generalized hypermobility spectrum disorder (pgHSD) have joint hypermobility with musculoskeletal complications. There are also different subtypes and features based on the presence or absence of common comorbidities and skin involvement (table 4 and form 1). Our approach to diagnosis of pGJH and pgHSD is summarized in this algorithm and is aligned with published guidelines (algorithm 1).

These conditions can only be diagnosed in the absence of other conditions related to joint hypermobility, such as other types of Ehlers-Danlos syndrome (EDS) or genetically-based connective tissue diseases, skeletal dysplasia, and chromosomal microdeletions. (See 'Features suggesting an alternative diagnosis' below.)

Children who are under five years of age have greater joint flexibility because their epiphyses have not yet fully ossified. The Beighton score and criteria for pediatric joint hypermobility should not be used. hEDS and HSD cannot be formally diagnosed in this younger group, who should be kept under clinical observation with management of any developmental or functional issues until they can be assessed after the fifth birthday. This approach does not apply to the rarer syndromic types of EDS and other heritable disorders of connective tissue where specific concerns may be present from birth and pre- or post-natal genetic testing can be used for diagnosis in children at risk.

Features suggesting an alternative diagnosis — Because of the lack of definitive diagnostic tests for hEDS and HSD and the potential for serious complications from disorders that may resemble these conditions (see 'Differential diagnosis' below), some patients will benefit from evaluation by an expert in hypermobility disorders or medical genetics to exclude another disorder before establishing a firm diagnosis. The presence of any of the following features would suggest a need for such a referral:

Physical appearance

Low muscle tone (floppy infant, delayed motor development)

Hypertelorism (wide-set eyes), bifid uvula, or cleft palate

Significant kyphoscoliosis

Height less than the third percentile

Hand and foot deformities

Skin findings

Unusual skin fragility

Extensive widened atrophic scars

Significant sagging skin

Premature aged appearance

Severe bruising and hematomas

Comorbid conditions

Intellectual disability

Organ rupture, including large bowel perforation

Young-onset unexplained aortic root dilation, arterial dissection, or aneurysm

Multiple hernias (excluding umbilical, as this is common in infants)

Recurrent pneumothoraces

Severe periodontal disease

Severe myopia

Severe corneal thinning, retinal detachment

WHEN TO REFER — Any health care practitioner can acquire the skills to assess for signs and symptoms of joint hypermobility, hypermobility spectrum disorder (HSD), and hypermobile Ehlers-Danlos syndrome (hEDS). Any medical practitioner can make a formal diagnosis and should seek assistance from specialists as required and based on the nature of the complications. In particular, referral to a subspecialist may be indicated in the following scenarios depending on the clinical presentation and/or other suggestive diagnostic testing:

Referral to evaluate for other causes of joint hypermobility (eg, genetics to evaluate other types of Ehlers-Danlos syndrome (EDS) or other hereditary disorders of connective tissue [HDCT]) (see 'Features suggesting an alternative diagnosis' above)

Referral to evaluate for other causes of joint pain (eg, rheumatology to evaluate for inflammatory arthritis)

Further evaluation and/or subspecialist referral may also be indicated in the evaluation of comorbid symptoms and conditions (eg, consideration of testing and cardiology evaluation for patients with suspected postural tachycardia syndrome). (See 'Other common symptoms and comorbidities' above.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) includes the conditions that have generalized joint hypermobility as a clinical feature, particularly Marfan syndrome, Loeys-Dietz syndrome, osteogenesis imperfecta, and other types of the Ehlers-Danlos syndromes (EDS) [47]. A variety of clinical features may suggest the possibility of another, potentially serious disorder and the need for evaluation by an expert in medical genetics (see 'Features suggesting an alternative diagnosis' above). Other diagnostic considerations of particular importance are:

Joint hypermobility – Patients with joint hypermobility alone can be distinguished from HSD and hEDS by the absence of additional symptoms and findings. (See 'Diagnosis and evaluation' above.)

Marfan syndrome – Joint hypermobility and the marfanoid habitus (table 6) are features of Marfan syndrome. Other findings or complications may include scoliosis, kyphosis, dilatation of the aortic root and aortic arch, aortic dissection, ectopia lentis, and dural ectasia. Additional studies may be required in patients in whom this distinction is uncertain based upon clinical grounds alone, such as ophthalmologic consultation, echocardiography, and genetic testing. There are many Marfan-like conditions that are rare and have similar features to Marfan [48]. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

Loeys-Dietz syndrome – Loeys-Dietz syndrome is an important group of autosomal dominant conditions that may present with joint hypermobility but also exhibit major cardiovascular involvement, with aortic aneurysms and arterial tortuosity; hence, it is very important to consider these in the differential diagnosis. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'TGFBR1 or TGFBR2 mutation: Loeys-Dietz syndrome'.)

Loeys-Dietz syndrome can generally be distinguished from hEDS and HSD by clinical features and genetic testing; clinical features that may suggest one of the subtypes of this syndrome and indicate a need for referral and genetic testing include [49]:

The triad of hypertelorism, cleft palate, or bifid uvula, and arterial tortuosity or aneurysm

Early-onset aortic aneurysm often combined with joint hypermobility and other skeletal abnormalities, and/or blue sclerae, thin skin with atrophic scars, easy bruising, bicuspid aortic valve, patent ductus arteriosus, or cardiac septal defects

Aortic root dilatation and dissection, familial (autosomal dominant) thoracic aortic aneurysms, and early-onset aortic or arterial dissection

Marfan syndrome-like phenotype (not meeting criteria for Marfan syndrome)

Features similar to EDS-vascular type but with negative biochemical and genetic testing for this condition (see "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Vascular EDS')

Other types of Ehlers-Danlos syndromes – EDS are a group of conditions generally characterized by skin hyperelasticity and fragility and joint hypermobility. The rarer variants of EDS, including classical EDS and vascular EDS, should be considered in patients with more florid skin abnormalities (eg, atrophic scarring or marked hyperextensibility or fragility) or severe scoliosis, or when there is a strong family history of easy bleeding, including hematoma, or vascular collapse [2]. The diagnosis of EDS, other than hEDS, may be made clinically and confirmed or excluded by genetic testing or by analysis of collagen obtained from cultured fibroblasts following skin biopsy. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Clinical manifestations and diagnosis'.)

Other conditions with widespread or localized musculoskeletal pain (eg, fibromyalgia, injuries of tendons and ligaments) can usually be distinguished from hEDS and HSD by the lack of generalized joint hypermobility and by the presence of features suggesting these conditions on the medical history and examination.

SUPPLEMENTAL AND POSTDIAGNOSTIC EVALUATION — Additional testing may be required to either help establish the diagnosis (eg, by excluding other conditions) or to further characterize symptoms or abnormal findings identified in the history and physical examination; testing depends upon the specific clinical findings. Screening blood tests are not required in the absence of clinical features suggesting a disorder other than or in addition to hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD).

Indications for testing depend upon the clinical presentation and may include:

Laboratory evaluation for fatigue – Thyroid function tests, celiac screening, and iron studies should be performed in patients presenting with fatigue. Patients with muscle fatigue or significant postexercise myalgia may require specialist assessment to evaluate for milder myopathies that may present with exercise intolerance and poor recovery.

Musculoskeletal imaging for select patients – Imaging of affected regions of the musculoskeletal system may be indicated in patients suspected of degenerative joint changes, subluxation, dislocation, or a congenital anatomic defect. Imaging studies may demonstrate degenerative disease, vertebral listhesis, or joint subluxation. Static images may appear normal. Thus, dynamic ultrasound and weightbearing images with joints placed in extreme ranges of movement may be more informative.

In patients with height less than the third percentile, a radiographic skeletal survey may be needed to rule out skeletal dysplasia. (See "Skeletal dysplasias: Approach to evaluation".)

Bone mineral density testing for suspected low bone mass – Patients with a personal history of low-trauma fracture or pediatric patients with a family history of early osteoporosis should undergo bone mineral density testing to assess for osteopenia and osteoporosis. Osteoporosis that is familial, diagnosed early, or otherwise unexplained should prompt assessment for osteogenesis imperfecta, which is associated with hypermobile joints. (See "Screening for osteoporosis in postmenopausal women and men" and "Osteogenesis imperfecta: An overview".)

Echocardiography for suspected cardiac or aortic disease – Echocardiography should be performed in patients with a heart murmur, those in whom Marfan syndrome or Marfan-like disorder or Loeys-Dietz syndrome is suspected, and children with dysmorphology or non-musculoskeletal anomalies to evaluate for congenital cardiac disease, mitral valve disease, or abnormalities of the aorta or other heart valves. (See "Mitral valve prolapse: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of thoracic aortic aneurysm" and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Aortic disease' and "Clinical manifestations and diagnosis of chronic aortic regurgitation in adults".)

Assessment of orthostatic hypotension and tachycardia – Patients suspected of postural orthostatic tachycardia syndrome should be assessed clinically with orthostatic pulse and blood pressure testing (increase in pulse of >30 beats per minute for adults) in changing position from lying supine to standing and/or a fall >20 mmHg in systolic pressure from lying to standing). Patients with abnormal testing should be referred to an expert on these conditions to undergo more detailed assessment. (See "Postural tachycardia syndrome" and "Mechanisms, causes, and evaluation of orthostatic hypotension".)

Genetic evaluation for patients with developmental disability – Referral to a clinical geneticist for full evaluation is recommended for any patient with severe developmental delay or learning disability before making a diagnosis of HSD. This includes pediatric patients with intellectual disability, significant attentional or specific learning difficulties (developmental coordination disorder, language difficulties), or additional congenital anomalies. Workup for developmental disability should include a comparative genomic hybridization array. Generalized joint hypermobility and/or joint laxity is associated with many chromosomal conditions, including duplications and deletions, and some syndromes (eg, Kabuki, trisomy 21) have joint hypermobility and laxity as a feature. (See "Developmental-behavioral surveillance and screening in primary care" and "Down syndrome: Clinical features and diagnosis".)

Other symptoms and findings – Depending upon the specific clinical findings that may be present, various blood tests and other laboratory studies may be required. As examples, testing for myopathies; endocrinopathies; hematologic disorders, including clotting abnormalities; inflammation; and autoantibodies for autoimmune rheumatic disease may assist in excluding other conditions suggested based upon clinical findings.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ehlers-Danlos syndromes and joint hypermobility".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Ehlers-Danlos syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

Terminology – New definitions and international criteria were adopted in 2017 for hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD), which are characterized by joint hypermobility and other shared clinical features (table 2). Pediatric specific criteria were added in 2023 and include pediatric generalized joint hypermobility (pGJH) and pediatric generalized hypermobility spectrum disorder (pgHSD). (See 'Terminology' above.)

Epidemiology – Joint hypermobility alone is very common in the general population, affecting approximately 10 to 20 percent of individuals to some degree. Most people with joint hypermobility alone do not experience any problems from the condition. By contrast, patients with joint hypermobility accompanied by symptoms and abnormal musculoskeletal finding are categorized as having hEDS or HSD. The precise prevalence of these disorders is unknown, but one study estimated a combined prevalence of 1 in 500 people in the general population. (See 'Epidemiology' above.)

Pathophysiology – No structural abnormality in collagen or related proteins or in the genes encoding such molecules has been identified in the vast majority of patients with hEDS. (See 'Pathophysiology' above.)

Clinical manifestations – The major clinical features in both HSD and hEDS are joint hypermobility and symptoms and findings related to the musculoskeletal system (table 1). In hEDS, there are also skin changes, including fragility of skin and supportive connective tissues, and some features common to other hereditary disorders of connective tissue (HDCT). Additionally, in both HSD and hEDS, systemic comorbidities are often present, including chronic widespread pain, fatigue, autonomic dysfunction, and gastrointestinal dysmotility (table 5). (See 'Clinical manifestations' above.)

Diagnosis and evaluation – The diagnosis of HSD and hEDS is made clinically; there are no diagnostic laboratory tests for HSD or hEDS. (See 'Diagnosis' above.)

When to suspect hEDS and HSD – Hypermobility syndromes should be considered in patients presenting with evidence of hypermobility on examination as well as other symptoms including arthralgia or diffuse musculoskeletal pain, frequent joint dislocations, fatigue, anxiety, and autonomic dysfunction. The additional presence of skin changes (eg, hyperextensible skin, abnormal scarring) should prompt consideration of hEDS. (See 'When to suspect hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder' above.)

Assessing joint hypermobility – Joint hypermobility can be assessed with a five-item questionnaire for adults and with the Beighton score for joint hypermobility on physical examination in patients who are ages five years and older (table 8). (See 'Assessing joint hypermobility' above.)

Diagnosis – Diagnosis of hEDS is based upon the medical history and physical examination, using the 2017 international criteria (table 3). HSD can be diagnosed in patients with clinical manifestations who do not meet criteria for hEDS. There are separate criteria for pediatric hypermobility syndromes. (See 'Diagnosis' above.)

When to refer – Any health care practitioner can acquire the skills to assess and formally diagnose joint hypermobility, HSD, and hEDS. Referral to a subspecialist may be indicated in certain scenarios, including evaluation for other causes of joint hypermobility (eg, genetics to evaluate for HDCT), and evaluation for other causes of joint pain (eg, rheumatology to evaluate for inflammatory arthritis). (See 'When to refer' above.)

Differential diagnosis – The differential diagnosis includes other types of HDCT characterized by generalized joint hypermobility, particularly Marfan syndrome and other types of Ehlers-Danlos syndrome (EDS). (See 'Features suggesting an alternative diagnosis' above and 'Differential diagnosis' above.)

Supplemental and post-diagnostic evaluation – Additional testing may be required to either help establish the diagnosis (eg, by excluding other conditions) or to further characterize symptoms or abnormal findings identified in the history and physical examination. Testing may include imaging of the peripheral joints and spine, laboratory testing to exclude other disorders, echocardiography, bone mineral density testing, evaluation for autonomic dysfunction, and other studies. (See 'Supplemental and postdiagnostic evaluation' above.)

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Topic 5591 Version 30.0

References

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