Clinical manifestations and diagnosis of Ehlers-Danlos syndromes

INTRODUCTION — Ehlers-Danlos syndrome (EDS) is the term used for a group of relatively rare genetic disorders of connective tissue that are characterized by one or another of several features, including skin hyperextensibility, joint hypermobility, and tissue fragility. The overall frequency of the Ehlers-Danlos syndromes is 1 in 5000, with EDS hypermobile type (hEDS) being by far the most common and some types being quite rare. The disorders are distinguished from one another and can often be diagnosed based upon the family history and clinical criteria, including the degree and nature of involvement of skin, joints, skeleton, and vasculature [1]. The genetic basis for most types of EDS has been defined, other than for the hypermobile type (that is likely genetically heterogeneous), and genetic testing may be useful diagnostically for several of these disorders.

The relationship between hEDS and joint hypermobility syndrome remains uncertain; some experts have suggested that hEDS and joint hypermobility syndrome may be manifestations of the same disorder [2,3] and that hEDS may be a subset of the hypermobility spectrum disorders [4]. (See 'Hypermobile EDS' below and 'Differential diagnosis' below and "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of the major forms of EDS will be presented here. An overview of the management of the Ehlers-Danlos syndromes, the clinical manifestations and treatment of the benign hypermobility syndrome, and overviews of the principles of genetic counseling and testing are reviewed separately. (See "Overview of the management of Ehlers-Danlos syndromes" and "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder" and "Genetic testing".)

CLASSIFICATION — A new international classification of the Ehlers-Danlos syndromes (EDS) (table 1) was agreed upon in 2017 to replace the older Villefranche classification nomenclature [5]. According to this scheme, the 13 types of EDS (and their new abbreviations and the former nomenclature) are:

●Classical (cEDS; classic EDS types I and II) (see 'Classical or classic EDS' below)

●Classical-like EDS (EDSCLL1, EDSCLL2)

●Cardiac-valvular (cvEDS)

●Hypermobile (hEDS; hypermobility EDS, EDS type III) (see 'Hypermobile EDS' below)

●Vascular (vEDS; EDS type IV) (see 'Vascular EDS' below)

●Kyphoscoliotic (kEDS; kyphoscoliosis, EDS type VI) (see 'Kyphoscoliotic EDS' below)

●Arthrochalasia (aEDS; EDS type VIIA and B) (see 'Arthrochalasia EDS' below)

●Dermatosparaxis (dEDS; EDS type VIIC) (see 'Dermatosparaxis EDS' below)

●Brittle cornea syndrome (BCS)

●Spondylodysplastic (spEDS) (see 'Other rare forms of EDS' below)

●Musculocontractural (mcEDS) (see 'Other rare forms of EDS' below)

●Myopathic EDS (mEDS)

●Periodontal (pEDS; EDS type IX)

The hypermobile type, hEDS, is much more common than the other types, with classical and vascular type each being more common than the remainder. Other much less frequently seen forms include the other forms listed above (EDSCLL, cvEDS, kEDS, aEDS, dEDS, BCS, spEDS, mcEDS, mEDS, pEDS) [6].

The Villefranche classification scheme for EDS, which was adopted in 1998, defined six subtypes based upon clinical features, mode of inheritance, and biochemical and genetic findings [1]. This revised nomenclature had replaced the prior approach of identifying the different forms by number (eg, EDS type I) [7]. The clinical diagnoses were based upon a series of major and minor criteria, differing according to EDS type, but additional patients who may have had overlapping features of different types were not easily categorized [8].

GENETICS AND PATHOGENESIS — In most types of Ehlers-Danlos syndrome (EDS), the underlying pathophysiology involves inherited alterations in genes affecting the synthesis and processing of different forms of collagen, which are important in the structure of many tissues and organs, including the skin, tendons, ligaments, vasculature, skeleton, and eyes [6,8]. Some types of EDS are due to disorders of the extracellular matrix and its components (such as glycosaminoglycans) and defects in intracellular processing [5]. A variety of different mutations that may cause an EDS phenotype have been identified for each of the affected genes.

Some forms of EDS are inherited in an autosomal dominant pattern, including the classic and vascular types, arthrochalasia, and most patients with the hypermobile type of EDS, thus requiring a single inherited copy of the abnormal gene for expression of the disease. Spontaneous mutations subsequently associated with an autosomal dominant pattern of inheritance may also occur. In other individuals and some rare types of EDS (eg, kyphoscoliotic EDS [kEDS]), the gene is inherited in an autosomal recessive pattern, with an altered copy from each parent present in those affected clinically. (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Modes of inheritance'.)

The frequency and nature of the genetic abnormalities differ for each type (table 1) [6]:

●Classical EDS – Classical EDS (cEDS; Mendelian Inheritance in Man [MIM] #130000 and #130010) is inherited as an autosomal dominant disorder [9,10]. Mutations are found within the collagen genes COL5A1 and COL5A2 in approximately 90 percent of patients who are diagnosed clinically [11]. Patients with COL5A2 may have more severe features [12]. Approximately 50 percent of the patients diagnosed with cEDS appear to have a de novo mutation, and neither parent is affected [13]. Germline mosaicism can occur [14]. Type V collagen molecules, encoded by the genes in which the mutations reside, interact with type I collagen molecules during collagen fibrillogenesis. Type I collagen is an integral component of the connective tissue, forming skin, tendons, ligaments, bones, and the aorta [15]. In addition, there are rare patients who have mutations within type I collagen (COL1A1) [5].

●Classical-like EDS – There are two forms: classical-like 1 (EDSCLL1) and classical-like 2 (EDSCLL2). EDSCLL1 is due to tenascin X deficiency (MIM #606408, resulting from a mutation in the TNXB gene), which appears to be inherited in an autosomal recessive fashion [16]. Heterozygosity for tenascin X deficiency can be associated with mild features of disease, including joint hypermobility [17]. EDSCLL2 is due to autosomal recessive mutations in AEBP1 (MIM #618000).

●Hypermobile EDS – In most patients with hypermobile EDS (hEDS; MIM #130020), inheritance appears to be autosomal dominant, but the underlying genetic abnormality is unknown and unmapped [18].

●Cardiac-valvular EDS – Cardiac-valvular EDS (cvEDS; MIM #225320) is a rare autosomal recessive condition that results from a mutation in the gene for type I collagen (COL1A2) [19]. Biallelic mutations lead to COL1A2 nonsense-mediated messenger ribonucleic acid (mRNA) decay and absence of pro-alpha 2(I) collagen chains.

●Vascular EDS – Vascular EDS (vEDS; MIM #130050) is an autosomal dominant condition that results from mutations in type III procollagen; 50 percent of cases appear due to de novo mutations [20]. Most of the mutations are in the COL3A1 gene, causing an altered procollagen, which results in a "dominant negative effect." Since type III collagen consists of a homotrimer, an abnormality in half of the type III procollagen molecules will result in greater than half of the resultant type III collagen molecules being abnormal. Haploinsufficiency mutations that result in half of the normal production of type III procollagen are much rarer; individuals with this type of mutation may have a milder phenotype and may not be diagnosed unless genetic testing is performed because of an affected family member [21]. Individuals who have missense mutations leading to substitution of glycine for a larger amino acid have a median age of 30 years of age for aortic/arterial pathology compared with a median age of 36 in individuals with other types of pathogenic variants [22].

●Kyphoscoliotic EDS – Kyphoscoliosis EDS type 1 (kEDS; MIM #225400) is an autosomal recessive disorder due to mutations in PLOD1, which result in lysyl hydroxylase deficiency [23]. Lysyl hydroxylase is a collagen-modifying enzyme that forms crosslinks between the collagen trimers, increasing the collagen strength. Kyphoscoliosis EDS Type 2 (MIM #614557) is caused by biallelic pathogenic variants in the FKBP14 gene [24].

●Arthrochalasia EDS – Arthrochalasia is an autosomal dominant form of EDS (MIM #130060) that is caused by a loss of exon 6 in either COL1A1 (EDS VIIA) or COL1A2 (EDS VIIB) resulting in structural defects in type I collagen [25,26]. Exon 6 codes for the procollagen N-proteinase cleavage site, which enables the precursor procollagen of either the alpha-1 or alpha-2 chains of type I collagen to be modified into mature collagen. The result of mutations affecting this region is abnormal weak collagen.

●Dermatosparaxis EDS – Dermatosparaxis is a rare form of EDS (MIM #225410) that is inherited in an autosomal recessive fashion. It is due to mutations in the ADAMTS2 gene, which result in deficiency of procollagen I N-terminal peptidase [27].

The genetic abnormalities in other rare forms of EDS have also been described. Among these are spondylodysplastic EDS (spEDS; MIM #612350), an autosomal recessive disorder due to mutations in the zinc transporter gene SLC39A13 or genes involved in glycosaminoglycan synthesis (B4GALT7, B3GALT6); autosomal recessive cardiac-valvular EDS (cvEDS) due to specific mutations in COL1A2; musculocontractural EDS (mcEDS; MIM #601776), an autosomal recessive disorder caused by mutations in the CHST14 or DSE genes; myopathic EDS (mEDS) due to autosomal dominant or recessive mutations within the gene COL12A1 (coding for type XII collagen). In addition, brittle cornea syndrome (BCS) is due to autosomal recessive mutations in the ZNF469 or PRDM5 genes, and periodontal EDS (pEDS) is due to heterozygous (one copy) mutations within the complement genes C1R or C1S. In addition, there can be overlap between osteogenesis imperfecta and EDS due to pathogenic variants in COL1A1 or COL1A2 in whom mildly decreased bone density, short stature, and fractures along with the typical features of EDS are present [28]; these variants include glycine substitutions at the procollagen N-proteinase cleavage sites.

CLINICAL MANIFESTATIONS AND DIAGNOSIS

Overview — A variety of clinical features are seen in the different forms of Ehlers-Danlos syndrome (EDS), often resulting in skin hyperextensibility, joint hypermobility, and tissue fragility (see 'Joint hypermobility' below and 'Skin hyperextensibility' below). The particular manifestations in the skin, joints, and other tissues, including the vasculature, depend upon the specific type of EDS that is present. Some features characteristic of one type may not be seen in patients with a different form of EDS [6,29]. Consequently, the clinical diagnostic criteria for the different forms of EDS are distinct from one another. The utility of genetic testing for confirmation of the diagnosis also varies between types.

The diagnosis of EDS in one of its forms should be suspected when a patient presents with some combination of features seen in one or several of the types of EDS, including joint hypermobility, multiple joint dislocations, translucent skin, poor wound healing, easy bruising, and unusual scars. This diagnosis should also be considered in any young individual who experiences spontaneous rupture of an organ (eg, gut or uterus) or dissection of a major blood vessel. Referral to a clinical geneticist or other expert in EDS may be warranted for assistance in the diagnostic evaluation and management, particularly with respect to genetic testing. (See 'When to refer' below.)

Joint dislocations or subluxations are common in most forms of EDS, and joint pain and premature degenerative arthritis are often consequences of the disorder. Pes planus is common in all forms, and pectus excavatum and a high arched palate can also be present in all of the forms of EDS. Musculoskeletal pain is common in patients with joint hypermobility, and complex regional pain syndrome has been described as a rare complication with both the hypermobility and classic forms of EDS [30]. Resistance to local anesthesia can be seen [31]. EDS patients, often appearing fit and healthy, may be misdiagnosed as hypochondriacal or pathologically depressed. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)

Myopia can also be seen but is not specific, and retinal detachment can occur. Bleeding complications, such as epistaxis, bleeding after tooth extraction, muscle hematoma, and menorrhagia, are also more common among patients with various subtypes of EDS [32].

The clinical manifestations that characterize and distinguish each of the major forms of EDS and the approach to their diagnosis are each discussed separately. (See 'Classical or classic EDS' below and 'Hypermobile EDS' below and 'Vascular EDS' below and 'Kyphoscoliotic EDS' below and 'Arthrochalasia EDS' below and 'Dermatosparaxis EDS' below.)

Definitions — The revised Villefranche classification for EDS included definitions of certain important features, including joint hypermobility and skin hyperextensibility [1].

Joint hypermobility — Joint hypermobility or laxity is the hallmark of most types of EDS. This can involve both proximal and distal joints or may be seen predominantly in distal joints (such as in vascular EDS [vEDS]). The assessment of the joints is done using the Beighton hypermobility scale, which is widely used in assessing hypermobility of peripheral joints and the spine, and is the scoring system most often used in epidemiologic research [33,34]. One point is awarded for the ability to perform each of four maneuvers involving the extremities (bilaterally), and one point is awarded for having an unusually flexible spine. A score of at least five of the maximum total of nine points is used to define hypermobility in criteria for EDS [13,18]. The following maneuvers are performed:

●Passive dorsiflexion of the fifth finger >90 degrees with forearm flat

●Passive apposition of the thumb to the flexor aspect of the forearm

●Hyperextension of elbow >10 degrees

●Hyperextensibility of the knee >10 degrees

●Flexion of waist with palms on the floor (and with the knees fully extended)

Skin hyperextensibility — Skin hyperextensibility is defined as the capacity to stretch the skin for 4 cm or more at a neutral site, such as the neck or ventral aspect of the forearm, until feeling resistance [10]. This is particularly true of the classic form. The hyperextensibility increases with age but is present in children [11].

Mitral valve prolapse — Mitral valve prolapse has been reported as a feature of several forms of EDS. However, older estimates of the frequency of mitral valve prolapse should be interpreted with caution, as the criteria defining mitral valve prolapse have evolved, and studies prior to 1989 may have overestimated its prevalence. (See "Mitral valve prolapse: Clinical manifestations and diagnosis", section on 'Diagnostic evaluation'.)

Classical or classic EDS

●Clinical manifestations – Classical EDS (cEDS), the severity of which can vary, is the term used collectively for the conditions formerly referred to as EDS gravis (EDS I) and EDS mitis (EDS II) [13]. EDS type I was characterized by more severe joint hypermobility and skin laxity than type II, but these two forms previously described as distinct types have subsequently been recognized as describing the range of findings along a continuum. The prevalence of cEDS has been estimated at approximately 1 in 20,000, but some patients with milder forms may go unrecognized, and the frequency may be higher [9,10].

Both large and small joint hypermobility are typically seen, although the degree of hypermobility may decrease with age. In one study of 40 patients from 28 families, 8 of 40 (20 percent) of the patients lacked evidence of joint hypermobility [35]. Joint dislocations may be frequent and recurrent; joint subluxations of the shoulder, patella, and temporomandibular joints are often self-managed by the patient and may resolve spontaneously. Joint effusions sometimes occur, and patients can develop osteoarthritis. Skeletal abnormalities, including thoracolumbar scoliosis, may be seen in some patients.

The characteristic skin findings include velvety ("doughy") hyperextensible and fragile skin, which extends easily and snaps back upon release but may split easily with trauma; abnormal wound healing, with delayed healing and widened atrophic scars; and increased bruisability. The upper eyelid may be everted easily (Metenier sign) due to hyperextensibility of the eyelid. Other skin features include piezogenic papules (fat herniations through fascia on sides of feet), molluscoid pseudotumors (bluish-gray to violaceous, spongy 1 to 2 cm nodules over easily traumatized bony areas such as the shin, forearm, and Achilles tendon, which represent herniations of subcutaneous fat through atrophic dermal scars), and subcutaneous spheroids (several mm diameter, hard, calcified, subcutaneous nodules due to fat necrosis) [36].

Additional features include fatigue, development of hernias, cervical insufficiency, and uterine prolapse. Vascular complications are rare but have been reported, and valvular heart disease is uncommon. The frequency of aortic root dilatation has been reported as 6 percent [37]. Mitral valve prolapse has been observed in 6 percent of patients as well [38] (see 'Mitral valve prolapse' above). Carotid artery tortuosity has also been noted in approximately 19 percent of patients [39]. Pulmonary complications, including spontaneous pneumothorax, are reported. Gastrointestinal and bladder diverticula may occur [29]. Mild decreased bone density and vertebral abnormalities have been reported [40].

●Diagnosis – The diagnosis is made clinically, based upon the family history and physical examination. It can be made in the presence of the major criteria along with any minor criterion, or it can be made in the presence of the major skin criterion and either generalized joint hypermobility and/or three or more minor criteria [5,41]:

•Major criteria – Skin hyperextensibility and widened atrophic papyraceous (cigarette paper-like) scars with poor wound healing, joint hypermobility.

•Minor criteria – Soft doughy skin, easy bruising, fragile skin, molluscoid pseudotumors, subcutaneous spheroids, complications of joint hypermobility, epicanthal folds, hernias, and a positive family history.

•Diagnostic testing – The diagnosis can be confirmed by deoxyribonucleic acid (DNA) sequencing of COL5A1 and COL5A2. Patients who fulfill the clinical criteria should be referred to a clinical geneticist, who may order the testing for confirmation and for genetic counseling purposes.

Classical-like EDS

●Classical-like 1 – Classical-like 1 (EDSCLL1) consists of joint hypermobility, joint subluxations, and hyperextensible velvety skin but with normal wound healing. Some patients can have myopathic features. A subset of patients with a contiguous gene defect including both TNXB and the CYP21A2 genes can have endocrinologic features with ambiguous genitalia, an elevated 17-hydroxyprogesterone level, and genitourinary and cardiac valvular abnormalities [16,17]. Gastrointestinal ruptures have been reported rarely [42].

●Classical-like 2 – Classical-like 2 (EDSCLL2) is similar to classical EDS, and the major features are joint and skin laxity, joint dislocations, abnormal wound healing with atrophic scars, mitral valve prolapse, aortic root dilation, and, rarely, bowel rupture [43].

Hypermobile EDS

●Clinical manifestations – The major physical features of hypermobile EDS (hEDS) include large- and small-joint and spine hypermobility; frequent joint dislocations, often affecting a shoulder, the patella, or the temporomandibular joint; and chronic joint pain, which often develops, may resemble fibromyalgia, and can have an adverse impact on the quality of life [44]. Patients may also develop scoliosis and premature osteoarthritis. The frequency of the hypermobility form of EDS is unknown, although it is at least 1 in 5000 [18].

The skin is sometimes soft and smooth, but usually not to the degree seen in cEDS, where it is typically described as velvety; only mild hyperextensibility is evident, if present. Wound healing is normal. Molluscum pseudotumors do not occur, unlike patients with classic EDS. Piezogenic papules may be seen. Keratosis pilaris/hyperkeratosis of the extensor surfaces and striae can occur [45]. Skin changes are generally modest compared with classic EDS, but small, postsurgical, wide, nonpapyraceous scars can occur [45].

Other features and complications include delayed gastric emptying and irritable bowel syndrome. Autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS), which can be detected by tilt table testing, can occur [46,47]. Such patients may experience syncope, sleep disturbance including apnea, swelling and varicosities of legs, headache including "brain fog," and poor proprioception [48]. Autonomic instability can also be associated with postural acrocyanosis after several minutes of standing in some patients [49]. One report has also suggested an association with occipitoatlantoaxial hypermobility and Chiari type I malformation [50]. Headaches are reported in approximately one-third of patients (including migraines, tension-type headaches, headache from cerebrospinal fluid leakage, headache from Chiari malformation, and cervicogenic headache [from cervical spine hypermobility]) [51]. Resistance to local anesthetic drugs and opioids has been reported.

Mild aortic root dilatation can be seen in 12 percent of patients, and the frequency of mitral valve prolapse has been reported as 6 percent [38]. However, a subsequent study did not find aortic dilation or the frequency of mitral valve prolapse to be any greater than the general population [52]. (See 'Mitral valve prolapse' above.)

The clinical syndrome of hEDS is discussed in detail separately. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)

●Diagnosis – The diagnosis is made clinically. The 2017 international diagnostic criteria for hEDS have three criteria, all of which must be present:

•Generalized joint hypermobility

•Two or more of A, B, or C

-A. Five or more of the following: Soft velvety skin; mild skin hyperextensibility; striae (without weight gain or loss); bilateral piezogenic heel papules; abdominal hernias (multiple); atrophic scarring (not as severe as seen in cEDS or vEDS); prolapse of pelvic floor, rectum or uterus; dental crowding and high palate; arachnodactyly (positive wrist and/or thumb sign); arm-span-to-height ratio >1.05; mitral valve prolapse or aortic root dilatation defined as a z score >2 standard deviations above the mean

-B. Positive family history in first-degree relatives diagnosed with these criteria

-C. Daily musculoskeletal pain in two or more extremities (for at least three months) or chronic pain for three months or more, recurrent joint dislocations, or atraumatic joint instability

•No evidence of skin fragility or other connective tissue disorders.

•Caveats – Joint hypermobility is more common in females and young children. In addition, as patients get older, joint hypermobility may lessen, although joint pain may persist or worsen, especially with the development of arthritis and following surgical intervention. In this situation, the history of previous joint laxity is noted. A positive Beighton score is defined as >6 in prepubertal children, >5 in postpubertal individuals, and >4 in patients older than 50 [5].

•Diagnostic testing – Genetic testing is not available.

Vascular EDS

●Clinical manifestations – Vascular EDS (vEDS) is potentially life-threatening and differs from the classic and hypermobility forms most dramatically in the increased risk for these patients of spontaneous vascular or visceral rupture and the absence of large-joint hyperextensibility. Small (more distal) joints, however, may exhibit mild hypermobility. The prevalence of the vascular form of EDS is not well studied, but estimates based upon available data suggest a frequency of at least 1 in 100,000, accounting for approximately 4 percent of all EDS cases [20].

Arterial rupture may involve the iliac, mesenteric, cerebrovascular, splenic, or renal arteries or the aorta [22]. Preexisting aneurysms are rarely detected prior to a rupture, as the aneurysms are typically pseudoaneurysms. Complications in affected individuals also include significant risk for spontaneous rupture of internal organs (such as the intestine and gravid uterus) and muscles. Maternal mortality during pregnancy is approximately 12 percent, although delivery is often uneventful [20].

The skin is thin and may appear translucent with a prominent venous pattern (especially on the chest and abdomen), atrophic scars, increased bruisability, and varicosities. Wound dehiscence may occur postoperatively. However, the skin is only mildly hyperextensible. Minor trauma leads to extensive bruising.

Skeletal abnormalities include acrogeria, characterized by a lack of subcutaneous fat in the distal extremities, and a particular facial appearance with prominent eyes, thin face and nose, and lobeless ears (not seen in all). Gingival recession is common. Short stature may be seen but is not typical. Clubfoot has been reported in 12 percent of neonates with vEDS, and 3 percent have congenital hip dislocations [20]. Amniotic band sequence has been reported in affected individuals [53]. Emphysema also has been observed on imaging [54].

Eighty percent of individuals experience a major vascular event or rupture of an internal organ by age 40 years. There is a shortened lifespan with a median age of death of 48 years [20].

●Diagnosis – The following criteria have been proposed [5,55]:

•Major criteria – Arterial rupture in a young individual, intestinal rupture (in the absence of risk factors), uterine rupture, carotid-cavernous sinus fistula, and positive family history (with a known pathogenic mutation in COL3A1).

•Minor criteria – Increased bruising (atraumatic, in unusual places), thin translucent skin, characteristic facial appearance (thin face, large-appearing eyes, thin lips, thin nose), acrogeria, hypermobility of small joints, tendon and muscle rupture, talipes equinovarus, congenital hip dislocation, early-onset varicosities, spontaneous pneumothorax, gingival recession, keratoconus.

•Diagnostic testing – A positive family history, arterial rupture, sigmoid colon rupture, or spontaneous pneumothorax in someone with other features listed above would warrant diagnostic testing. In addition, individuals with the minor features may also warrant such testing.

Sequence and deletion/duplication testing of the COL3A1 gene has a high sensitivity.

Kyphoscoliotic EDS

●Clinical manifestations – Kyphoscoliotic EDS type 1 (kEDS) typically presents in newborns with muscle hypotonia associated with joint laxity, often leading to an initial evaluation by a neurologist [56]. Kyphoscoliosis may be present at birth and develops in nearly all patients. Progressive kyphoscoliosis can result in respiratory complications and often requires surgery. Patients with this form exhibit joint hypermobility and can experience recurrent joint dislocations. Osteoporosis can be seen, and clubfoot deformity may occur in approximately 30 percent. The skin is hyperextensible and typically velvety, pale, and translucent, with poor wound healing. Approximately 50 percent may have atrophic scarring and 50 percent may have severe bruising [57]. Vascular fragility may be present and spontaneous vascular rupture may occur.

Ocular involvement may occur, including the presence of scleral fragility, risk of rupture of ocular globe, keratoconus, retinal detachment, and glaucoma.

The frequency is estimated at 1 in 100,000 [23].

Kyphoscoliotic EDS type 2 is due to biallelic variants in FKBP14 [24]. Individuals with this have progressive kyphoscoliosis, hypotonia, myopathic features, joint hypermobility, hernias, hyperelastic skin, and hearing loss [24].

●Diagnosis – The following criteria have been proposed [5,57]:

•Major features – Early-onset severe congenital hypotonia; progressive kyphoscoliosis, which is present at birth or occurs during the first year of life; generalized joint laxity.

•Minor features – Hyperextensible skin, easy bruising, marfanoid habitus, rupture of medium-sized arteries, osteopenia, blue sclerae, hernias, pectoral anomaly, talipes equinovarus, myopia.

Clinical diagnosis is based on the presence of congenital hypotonia and early-onset kyphoscoliosis along with the joint laxity and/or three minor criteria. Diagnostic testing is necessary to confirm the diagnosis:

•Diagnostic testing – The diagnosis can be made by measurement in urine of the ratio of lysyl pyridinoline to hydroxylysylpyridinoline. The mean value of this ratio in kEDS, caused by mutations in the PLOD1 gene, is approximately 6.0, compared with 0.2 in normal individuals. Activity of the enzyme in fibroblasts (with enzyme activity being below 25 percent of normal) and DNA sequence analysis of the PLOD1 gene or FKBP14 can also be performed. Ocular and cutaneous fragility is seen in PLOD1 and sensorineural hearing loss is seen in FKBP14. Note that the urine crosslinks are normal in individuals with kEDS due to mutations in FKBP14.

Arthrochalasia EDS

●Clinical manifestations – Arthrochalasia EDS (aEDS) is characterized by hypermobility with recurrent subluxations, congenital bilateral hip dislocations, extremity contractures, thoracolumbar scoliosis, short stature (as a complication of the scoliosis), muscle hypotonia, and frequent fractures [25]. Complications include fractures and recurrent dislocations, which can prevent weightbearing. The skin is fragile and hyperelastic and may have a doughy texture. Its frequency is unknown, although this form is extremely rare.

●Diagnosis – The diagnosis is made clinically based upon a combination of the congenital hip dislocations along with the severe generalized joint hypermobility with recurrent dislocations and/or hyperextensible skin and a combination of the other clinical features noted [5].

•Laboratory testing – The diagnosis can be confirmed by COL1A1 and COL1A2 DNA sequencing with analysis of exon 6.

Dermatosparaxis EDS

●Clinical manifestations – Features of dermatosparaxis EDS (dEDS) include severe skin fragility, sagging redundant skin, and large hernias [58,59]. Blue sclerae, typical facial features, and severe bruising can be present. The major complications are related to the severe skin fragility. The skin can have a velvety "doughy" texture. Its frequency is unknown.

●Diagnosis – The diagnosis is made by the combination of the severe skin fragility along with the typical facial features and other features, along with sequencing of the ADAMTS2 gene.

Other rare forms of EDS — Several other very rare forms of EDS have been described [60-62]; their precise frequency is uncertain (table 1).

●Spondylodysplastic EDS (spEDS) – Clinical features of this form include short stature; blue sclera; delayed eruption of teeth and hypodontia; joint laxity and a particular pattern of skeletal findings (platyspondyly, osteopenia, widened metaphyses, flattened epiphyses, small ilia, short broad femoral necks and short metacarpals and phalanges); velvety, hyperextensible, thin skin with prominent veins; and delayed wound healing with atrophic scars [60]. Keratoconus, cardiac involvement, and vascular events have also been reported [63,64]. One report has suggested that the extreme hypermobility of the distal joints and the very soft skin on the hands and feet can be clues to the diagnosis [65]. Laboratory testing in these patients demonstrates that the ratio of lysyl pyridinoline to hydroxylysyl pyridinoline in urine is elevated compared with normal (approximately 0.9 in patients versus 0.2 in normals), but the degree of elevation is not as high as seen with kyphoscoliosis EDS type 1 (see 'Kyphoscoliotic EDS' above). DNA sequencing of the SLC39A13, B4GALT7, and B3GALT6 genes are available.

●Musculocontractural EDS (mcEDS) – Clinical features of this form include specific craniofacial features (broad forehead, small mouth, large fontanelle and micrognathia in infancy; protruding jaw in adolescence; low-set prominent rotated ears, blue sclerae, short nose, thin upper lip, and long philtrum), thumb and finger contractures, club feet, severe kyphoscoliosis, hypotonia, hyperextensible thin skin with easy bruising, atrophic scars, joint laxity, subcutaneous hematoma, and organ fragility [61,62,66]. DNA sequencing of the CHST14 and DSE genes can be performed. Individuals with mcEDS due to the DSE gene may have a milder phenotype [67].

●Periodontal EDS (pEDS) – This form of EDS is characterized by early severe periodontitis, easy bruising, pretibial plaques, and joint hypermobility. It is due to pathogenic variants in C1r and C1s (MIM 130080 and MIM 617174, respectively). One study demonstrated that activation of the complement cascade in this condition can occur independently of triggers by microbial organisms [68]. Vascular complications can occur rarely, including arterial complications, venous insufficiency, and aneurysm development [69].

●Brittle cornea syndrome (BCS) – BCS is characterized by corneal fragility, corneal rupture, blue sclerae, keratoconus, myopia, and joint hypermobility. Additional features can include hearing loss, hand and foot deformities, kyphoscoliosis, hip dysplasia, and bone fragility [70].

●Myopathic EDS (mEDS) – Myopathic (m)EDS can be autosomal dominant or autosomal recessive due to variants in COL12A1 (the gene for type XII collagen). The features include hypotonia, decreased muscle mass, proximal joint contractures, joint hypermobility, skin involvement including atrophic scarring, delay in gross motor milestones, and evidence of myopathy on muscle biopsy. Some individuals will have increased levels of serum creatine kinase [5,71].

DIFFERENTIAL DIAGNOSIS — In addition to the other types of Ehlers-Danlos syndrome (EDS), the differential diagnosis includes the joint hypermobility syndrome and other disorders of connective tissue. Hypermobile EDS (hEDS) may be difficult to distinguish from joint hypermobility syndrome, which is a much more common condition characterized by musculoskeletal pain and generalized joint hypermobility. Joint hypermobility syndrome is considered by many experts in rheumatology and in clinical genetics to be indistinguishable from, if not identical to, the most common variant of EDS, EDS-hypermobility type, but the precise relationship between hEDS and joint hypermobility syndrome remains uncertain and molecular genetic confirmation is needed [2,72,73] (see "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder"). Several connective tissue disorders share some features with EDS, but clinically distinct features are typically also present [73]. These conditions include those described below.

Marfan syndrome — Marfan syndrome, like EDS, is typically characterized by joint laxity. It is inherited in an autosomal dominant pattern, due to mutations in the FBN1 gene. Joint hypermobility, scoliosis, and mild aortic dilatation can be seen in patients with Marfan syndrome, as in EDS, but the disproportionate tall stature, dislocation of the lens, pectus carinatum, and progressive aortic dilatation distinguish Marfan syndrome from the different types of EDS. In addition, the skin findings seen in the classic form of EDS are not typical for Marfan syndrome. Features characteristic of Marfan syndrome include overgrowth of long bones, dislocation of the lens, retinal detachment, pectus excavatum and/or carinatum, scoliosis, heart valve dysfunction, and aortic dilatation with a propensity to aortic rupture. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)

Cutis laxa — Cutis laxa is characterized by loose, redundant skin that only slowly returns from distension [74]. Heart valve regurgitation and other vascular involvement can occur. Hernias and emphysema are common. There are several different forms, inherited in both autosomal recessive and dominant fashion. While the skin may be easily stretched in patients with EDS as well, in EDS, it is hyperextensible and returns quickly from distention, differentiating the skin changes in EDS from those of cutis laxa.

Loeys-Dietz syndrome — Loeys-Dietz syndrome involves aortic and other arterial aneurysm and dissection, but also includes generalized arterial tortuosity, hypertelorism (widely spaced eyes), cleft palate, or bifid uvula. Some patients with Loeys-Dietz syndrome may have translucent skin and atrophic scars very similar to the changes seen in patients with vascular EDS (vEDS), but the cleft palate, bifid uvula, and arterial tortuosity seen in Loeys-Dietz syndrome are not typically found in patients with EDS.

Osteogenesis imperfecta — Osteogenesis imperfecta is a group of disorders whose main features are fragile osteopenic bones with recurrent fractures. In some forms, there can be blue sclerae, hearing loss, and progressive skeletal deformity. Joint laxity is common, but the hallmark features of osteogenesis imperfecta, which are the recurrent fractures and osteopenia, are rarely seen in EDS. Inheritance is autosomal dominant or recessive, depending upon the specific type. (See "Osteogenesis imperfecta: An overview".)

Larsen syndrome — Larsen syndrome consists of dislocations of large joints (hips, knees, and elbows), specific craniofacial features (flat midface, depressed nasal bridge, and cleft palate), short stature, and clubfoot [75]. There are both autosomal dominant and autosomal recessive forms. While joint dislocations are seen in both EDS and Larsen syndrome, the specific craniofacial features seen in Larsen syndrome are not seen in patients with EDS.

Stickler syndrome — Stickler syndrome is characterized by specific craniofacial features (flattened midface, cleft palate, micrognathia), high myopia with risk for retinal detachment, hearing loss, and spondyloarthropathy. Affected individuals may have a marfanoid habitus and joint laxity. Joint dislocations are not typical. It is autosomal dominantly inherited with several different genes being responsible. Patients with Stickler syndrome can have joint laxity, but they have other features that are not typical in the various EDS syndromes, such as hearing loss, very high myopia, and the characteristic craniofacial features and cleft palate, which can each be seen in Stickler syndrome. (See "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes'.)

Arterial tortuosity syndrome — Arterial tortuosity syndrome is an autosomal recessive condition characterized by generalized tortuosity of large- and medium-size arteries, with increased risk of aneurysms, dissections, and ischemic stroke. There can be pulmonary artery and aortic stenosis. The skin can be soft and hyperextensible, suggesting EDS, but there is normal wound healing and no increased bruisability. The face can be long with a long philtrum and a high arched palate. Hernias and pectoral anomalies may be present, and keratoconus, joint laxity, arachnodactyly, and joint contractures can be seen. Arterial tortuosity syndrome is distinguished from Loeys-Dietz syndrome based upon the absence of uvular abnormalities or micrognathia, and by molecular genetic testing for abnormalities of the SLC2A10 gene [76].

WHEN TO REFER — Patients suspected of having Ehlers-Danlos syndrome (EDS) based upon their clinical presentation and family history should be referred for consultation with an expert in clinical genetics or the care of patients with EDS for confirmation of the diagnosis and the institution of multidisciplinary management and follow-up care. The evaluation should include a general physical examination, with particular attention to an evaluation of ophthalmologic status; examination of skin texture, translucency, extensibility and integrity; assessment of range of motion of the joints, including determination of the Beighton score (see 'Joint hypermobility' above); and evaluation of other skeletal findings. The geneticist or other EDS expert can help to determine which, if any, genetic testing may be needed to assist in making or confirming the diagnosis.

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 5^th to 6^th 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 10^th to 12^th 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 topics (see "Patient education: Ehlers-Danlos syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Overview – Ehlers-Danlos syndrome (EDS) is the term used for a group of relatively rare disorders of connective tissue, due to inherited alterations in genes affecting the synthesis and processing of different forms of collagen. These conditions are characterized by one or another of several features, including skin hyperextensibility, joint hypermobility, and tissue fragility. The disorders are classified into 13 major types, which can be distinguished from one another clinically, and genetic testing may be useful diagnostically for several of these disorders (table 1). Additional rare variants of EDS have also been described. (See 'Classification' above and 'Overview' above and 'Genetics and pathogenesis' above.)

●When to suspect EDS – EDS should be suspected when a patient presents with some combination of characteristic features, including joint hypermobility, multiple joint dislocations, translucent skin, poor wound healing, easy bruising, hyperextensible skin, and unusual scars; and in any individual who experiences spontaneous rupture of an organ or dissection of a blood vessel. Joint dislocations or subluxations are common in most forms of EDS, and joint pain and premature degenerative arthritis are often consequences of the disorder. Other common features include pes planus, pectus excavatum, and a high arched palate. Musculoskeletal pain is common in patients with joint hypermobility. (See 'Overview' above and 'Definitions' above.)

●Classical EDS – Classical EDS (cEDS), the severity of which can vary, is characterized by skin hyperextensibility; widened atrophic scars; and both large- and small-joint hypermobility, which may decrease with age. Frequent and recurrent joint dislocations are common, osteoarthritis can develop, and scoliosis may be seen. The characteristic skin findings include velvety ("doughy") hyperextensible and fragile skin, which extends easily and snaps back upon release, but may split easily with trauma; abnormal wound healing, with delayed healing and widened atrophic scars; and increased bruisability. Additional features include fatigue, development of hernias, cervical insufficiency and uterine prolapse, and rare vascular complications. Valvular heart disease is uncommon. The diagnosis can be confirmed by DNA sequencing of COL5A1 and COL5A2. (See 'Classical or classic EDS' above.)

●Hypermobility EDS – The major features of hypermobility EDS (hEDS) include large- and small-joint and spine hypermobility, which may lessen with age, and frequent joint dislocations. Chronic joint pain, which may resemble fibromyalgia, is common. Patients may also develop scoliosis and premature osteoarthritis. Skin is sometimes soft and smooth, but usually not to the degree seen in classic EDS, and only mild hyperextensibility is evident, if present. Wound healing is normal, without atrophic scars or evidence of skin or tissue fragility. Other features and complications include delayed gastric emptying, irritable bowel syndrome, and autonomic dysfunction. Aortic root dilatation and mitral valve prolapse are uncommon but can occur. Genetic testing for most patients with this form is not available, but a small subset of patients may have abnormalities in tenascin X DNA. (See 'Hypermobile EDS' above.)

●Vascular EDS – Vascular EDS (vEDS) is potentially life-threatening and is characterized by increased risk of spontaneous vascular or visceral rupture and the absence of large-joint hyperextensibility. Arterial rupture may involve the iliac, mesenteric, cerebrovascular, splenic, or renal arteries or the aorta. Preexisting aneurysms are rarely detected prior to a rupture, as the aneurysms are typically pseudoaneurysms. There is significant risk for spontaneous rupture of internal organs (such as the intestine and gravid uterus) and muscles, and increased risk of maternal mortality during pregnancy. The skin is thin and may appear translucent with a prominent venous pattern, atrophic scars, increased bruisability, and varicosities, but is only mildly hyperextensible. Skeletal abnormalities may also be present. Substantial morbidity and mortality occurs by the fifth decade of life. The diagnosis can usually be confirmed by sequence and deletion/duplication testing of the COL3A1 gene. (See 'Vascular EDS' above.)

●Other forms of EDS – Additional forms of EDS include kyphoscoliotic (kEDS), in which ocular involvement may be present, in addition to muscle hypotonia and joint laxity present at birth, kyphoscoliosis detected during infancy and other skeletal changes, and abnormal skin; arthrochalasia (aEDS), which is characterized by hypermobility with recurrent subluxations, congenital hip dislocations, extremity contractures, thoracolumbar scoliosis, short stature, muscle hypotonia, and frequent fractures; dermatosparaxis (dEDS), with severe skin fragility, sagging redundant skin, and large hernias; and other rare forms (table 1). (See 'Kyphoscoliotic EDS' above and 'Arthrochalasia EDS' above and 'Dermatosparaxis EDS' above and 'Other rare forms of EDS' above.)

●Differential diagnosis – The differential diagnosis of each form of EDS includes the other EDS types and other connective tissue disorders with shared features, including Marfan syndrome, osteogenesis imperfecta, and several other uncommon or rare disorders that can usually be distinguished clinically from EDS. Whether hypermobile EDS (hEDS) and joint hypermobility syndrome represent distinct entities or the same condition remains uncertain. (See 'Differential diagnosis' above.)

●Indications for referral – Patients suspected of having EDS based upon their clinical presentation and family history should be referred for consultation with an expert in clinical genetics or the care of patients with EDS for confirmation of the diagnosis and the institution of multidisciplinary management and follow-up care. The geneticist or other EDS expert can help to determine which, if any, genetic testing may be needed to assist in making or confirming the diagnosis. (See 'Differential diagnosis' above.)