Version July 2025
INTRODUCTION —
The Ehlers-Danlos syndromes (EDS) are a group of conditions that are characterized by one or more of several common features: skin hyperextensibility, joint hypermobility, and tissue fragility. The conditions are distinguished by family history and clinical criteria, including the degree and nature of involvement of skin, joints, skeleton, and vasculature [1]. While the genetic basis for most types of EDS has been defined, the most common form, hypermobile EDS (hEDS), remains elusive to molecular diagnosis. Genetic testing is therefore used to confirm the diagnosis for all but the hypermobile EDS (hEDS).
The pathogenesis, clinical manifestations, diagnosis, and differential diagnosis of the major forms of EDS will be presented here. An overview of the management of EDS and the principles of genetic counseling and testing are reviewed separately. (See "Ehlers-Danlos syndromes: Overview of the management" and "Genetic testing".)
The relationship between hEDS and hypermobility spectrum disorder (HSD) remains uncertain. A summary of the overlapping and distinctive features of hEDS and HDS is summarized in the table (table 1). There are also distinct types of hypermobility syndromes in children [2]. The clinical manifestations, diagnosis, and management of hEDS is briefly described below and presented in detail separately, along with information on other types of pediatric hypermobility syndromes:
●(See 'Hypermobile EDS' below.)
●(See "Treatment and prognosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)
CLASSIFICATION —
An international classification of the Ehlers-Danlos syndromes (EDS) (table 2) was agreed upon in 2017 [3]. It outlines 13 types of EDS (and their new abbreviations and the former nomenclature):
●Classical (cEDS; classic EDS types I and II) (see 'Classical EDS' below)
●Classical-like EDS (clEDS1) (see 'Classical-like EDS' below)
●Cardiac-valvular (cvEDS) (see 'Other subtypes' below)
●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 'Other subtypes' below)
●Brittle cornea syndrome (BCS) (see 'Other subtypes' below)
●Spondylodysplastic (spEDS) (see 'Other subtypes' below)
●Musculocontractural (mcEDS) (see 'Other subtypes' below)
●Myopathic EDS (mEDS) (see 'Other subtypes' below)
●Periodontal (pEDS; EDS type IX) (see 'Other subtypes' below)
Two other forms of clEDS, called clEDS2 and clEDS3, were described after the 2017 classification [4,5].
This classification scheme is used both clinically and for research purposes. It replaces the older Villefranche classification nomenclature issued in 1998 [1], which was based on a combination of clinical features, biochemical findings, and genetic findings and inheritance. The Villefranche classification was not always able to categorize patients with overlapping features of various EDS types [6]. A numeric classification of EDS (eg, EDS type I) was published in 1988 and is no longer used [1].
EPIDEMIOLOGY —
The overall frequency of the Ehlers-Danlos syndromes (EDS) is estimated at 1 in 5000 [7], with hypermobile EDS (hEDS) being by far the most common, followed by classical EDS (cEDS) and vascular EDS (vEDS) [8]. The exact prevalence of the rarer subtypes is unknown [9]. Studies estimating the prevalence of subtypes of EDS include the following:
●The prevalence of cEDS has been estimated at approximately 1 in 20,000, but the frequency may be higher as some patients with milder forms may go unrecognized [10].
●The prevalence of vEDS 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 [10].
●The frequency of kyphoscoliotic EDS type 1 (kEDS) is estimated at 1 in 100,000 [11].
The epidemiology of hEDS is described separately. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Epidemiology'.)
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, skeleton, vasculature, and eyes [6,8]. In addition, some types of EDS are due to genetic variants that affect the extracellular matrix and its components (such as glycosaminoglycans) and defects in intracellular processing [3]. A variety of different pathogenic variants have been identified for each of the affected genes that may cause an EDS phenotype.
Some forms of EDS are inherited in an autosomal dominant pattern (ie, requiring a single inherited copy of the altered gene for expression of the disease), including the classical and vascular types and arthrochalasia. Most patients with hypermobile (hEDS) appear to follow this pattern, although this has not been confirmed at the molecular level. Spontaneous pathogenic variants 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]), inheritance is autosomal recessive, 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 of EDS (table 2) [8]:
●Classical EDS – Classical EDS (cEDS; Mendelian Inheritance in Man [MIM] #130000 and #130010) is inherited as an autosomal dominant disorder [12,13]. Pathogenic variants are found within the collagen genes COL5A1 and COL5A2 in approximately 90 percent of patients who are diagnosed clinically [14]. In addition, there are rare patients who have pathogenic variants within type I collagen (COL1A1) [3]. Approximately 50 percent of the patients diagnosed with cEDS appear to have a de novo pathogenic variant, and neither parent is affected [13]. Germline mosaicism can occur [15].
Affected genes encode type V collagen molecules, which 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 [16]. Patients with COL5A2 may have more severe features [17]. (See 'Classical EDS' below.)
●Classical-like EDS – There are three forms of classical-like EDS (see 'Classical-like EDS' below):
•Classical-like 1 – Classical-like 1 EDS (clEDS1) (MIM #606408) results from biallelic pathogenic variants in TNXB and is inherited in an autosomal recessive fashion [18]. Heterozygosity for tenascin X deficiency can be associated with mild features of disease, including joint hypermobility [19].
•Classical-like 2 – Classical-like 2 EDS (clEDS2) (MIM #618000) results from biallelic pathogenic variants in AEBP1 and is inherited in an autosomal recessive fashion.
•Classical-like 3 – Classical-like 3 EDS (clEDS3) is a rare condition due to biallelic pathogenic variants in THBS2 [5] and is inherited in an autosomal recessive fashion.
●Hypermobile EDS – In most patients with hEDS (MIM #130020), inheritance appears to be autosomal dominant, but the underlying genetic abnormality is unknown and unmapped [20]. The pathophysiology of hEDS is described in more detail elsewhere. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder", section on 'Pathophysiology'.)
●Cardiac-valvular EDS – Cardiac-valvular EDS (cvEDS; MIM #225320) is a rare autosomal recessive condition that results from biallelic pathogenic variants (COL1A2) [21] that encode the pro-alpha2(I) chains of type I procollagen. Biallelic pathogenic variants lead to COL1A2 nonsense-mediated messenger ribonucleic acid (mRNA) decay and absence of pro-alpha2(I) collagen chains.
●Vascular EDS – Vascular EDS (vEDS; MIM #130050) is an autosomal dominant condition that results from pathogenic variants COL3A1 that encode the chains of type III procollagen. About 50 percent of identified individuals appear due to de novo pathogenic variants [22]. Most of the pathogenic variants are in the COL3A1 gene, causing an altered procollagen, which results in a "dominant negative effect." Since type III collagen is a homotrimer, an abnormality in half of the pro-alpha1(III) chains will result in greater than half of the resultant type III collagen molecules being abnormal. Heterozygous pathogenic variants that result in haploinsufficiency result in half of the normal production of normal type III procollagen are much rarer; individuals with this type of pathogenic variant may have a milder phenotype and may not be diagnosed unless genetic testing is performed because of an affected family member [23]. Individuals who have missense mutations that lead to substitution of glycine by a larger amino acid (valine, aspartic acid, glutamic acid, arginine, or tryptophan) have a median age of 30 years of age for identification of aortic/arterial pathology compared with a median age of 36 in individuals with substitutions of glycine in the triple helical domain by smaller residues (alanine, serine, cysteine) [24]. (See 'Vascular EDS' below.)
●Kyphoscoliotic EDS – There are two forms of kyphoscoliosis EDS (see 'Kyphoscoliotic EDS' below):
•Kyphoscoliotic type 1 – Kyphoscoliotic type 1 EDS (kEDS; MIM #225400) is an autosomal recessive disorder due to pathogenic variants in PLOD1, which result in lysyl hydroxylase deficiency [11]. Lysyl hydroxylase is a collagen-modifying enzyme that modifies lysyl residues by hydroxylation. Some of these residues are involved in intermolecular crosslinks between the collagen trimers, increasing the collagen strength; failure to hydroxylate those residues leads to defective crosslink formation.
•Kyphoscoliotic type 2 – Kyphoscoliosis EDS type 2 (MIM #614557) is caused by biallelic pathogenic variants in the FKBP14 gene [25]. This protein may be a molecular chaperone for the PLOD1 enzyme.
●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 [26,27]. Exon 6 codes for the procollagen N-proteinase cleavage site, which enables the processing of the precursor procollagen pro-alpha1(I) or pro-alpha2(I) chains in mature procollagen into collagen. Mutations at these sites lead to retention of the amino-terminal propeptide and defects in collagen fibril formation. (See 'Arthrochalasia EDS' below.)
●Other ultra-rare forms of EDS – The genetic abnormalities seen in other rare forms of EDS are presented in the table (table 2), including ones that lead to dermatosparaxis (MIM #225410), spondylodysplastic EDS (spEDS; MIM #612350), autosomal recessive cardiac-valvular EDS (cvEDS), musculocontractural EDS (mcEDS; MIM #601776), myopathic EDS (mEDS), brittle cornea syndrome (BCS), and periodontal EDS (pEDS).
●Overlap between EDS and osteogenesis imperfecta – There can be overlap in the clinical manifestations of EDS and osteogenesis imperfecta due to pathogenic variants in COL1A1 or COL1A2, including substitution for glycine at the amino-terminal end of the triple helical domain. Patients may have mildly decreased bone density, short stature, and fractures along with the significant joint hypermobility [28].
CLINICAL MANIFESTATIONS
Common clinical features — 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. The particular manifestations in the skin, joints, and other tissues, including the vasculature, depend upon the specific type of EDS that is present, and some features characteristic of one type may not be seen in patients with a different form of EDS (table 3) [8,29]. Consequently, the clinical diagnostic criteria for the different forms of EDS are distinct from one another. The revised Villefranche classification for EDS included definitions of certain important features, including joint hypermobility and skin hyperextensibility [1]. (See 'Classification' above.)
Joint hypermobility — Joint hypermobility or laxity is the hallmark of most types of EDS (picture 1). This can be generalized (ie, both proximal and distal joints) or predominately limited to distal joints, as can be seen in vascular EDS (vEDS), periodontal EDS (pEDS), and cardiac-valvular (cvEDS). The degree of hypermobility may decrease with age. Consequences of joint hypermobility include recurrent joint dislocations or subluxations, joint pain, and premature degenerative arthritis (ie, osteoarthritis). The clinical evaluation for joint hypermobility is described below. (See 'History and physical examination' below.)
Skin hyperextensibility — Skin hyperextensibility is an abnormal ability to stretch the skin at a neutral site, such as the neck or ventral aspect of the forearm (picture 2) [13]. This is particularly true of the classic form. The hyperextensibility increases with age but is present in children [14].
Skin may appear translucent in certain types (vEDS, spondylodysplastic EDS [spEDS], and brittle cornea syndrome [BCS]) [30]. Additionally, the skin may have a doughy or velvety texture [30], which is most notable in patients with classical-like EDS (clEDS), hypermobile EDS (hEDS), and certain other rare forms.
Patients with skin hyperextensibility can develop easy bruising and abnormal wound healing (see 'Tissue fragility' below). It may also be easy to evert the upper eyelid (Metenier sign) in patients with skin hyperextensibility. The clinical evaluation of skin in patients suspected of having EDS is described below. (See 'History and physical examination' below.)
Tissue fragility — Patients with EDS may have difficulty healing wounds, including abnormal bleeding, difficulty holding sutures, delayed healing, and/or wound dehiscence [31]. Scars may be atrophic (eg, thin and shallow, widened), papyraceous (cigarette paper-like), and/or hemosideric (ie, hyperpigmented from breakdown of red blood cells) (picture 3). Atrophic scarring is particularly common in certain types, including classical (cEDS), cvEDS, and hEDS, but also occurs in the rarer forms of EDS; it is notably not seen in classical-like EDS 1 (clEDS1).
Other clinical features — While the clinical manifestations of EDS differ by type, other features that may be seen in multiple types include the following (table 3):
●Musculoskeletal pain – Musculoskeletal pain is common in patients with joint hypermobility. Patients with EDS who have persistent pain without classic signs of tissue damage or inflammation (eg, focal redness, warmth, and swelling) may be misdiagnosed as hypochondriacal or pathologically depressed. Recurrent mechanical joint pain may lead to increased central pain sensitization and neuropathic pain, with subsequent development of fibromyalgia [32] or, more rarely, complex regional pain syndrome (CRPS) [33]. The clinical manifestations and diagnosis of fibromyalgia and CRPS is described separately:
•(See "Fibromyalgia in children and adolescents: Clinical manifestations and diagnosis".)
•(See "Fibromyalgia: Clinical manifestations and diagnosis in adults".)
•(See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)
●Skeletal changes – Pectus excavatum and a high arched palate can also be present in all forms of EDS.
●Cardiovascular manifestations – Patients with certain types of EDS are at risk of developing cardiovascular manifestations that can cause significant morbidity. Screening for these manifestations in patients with established EDS is discussed elsewhere. (See "Ehlers-Danlos syndromes: Overview of the management", section on 'Cardiovascular complications'.)
•Mitral valve prolapse – Mitral valve prolapse has been reported as a feature of several forms of EDS, including cvEDS. 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'.)
•Aortic root dilation and/or dissection – Aortic root dilation can be seen in certain types of EDS, including cEDS, clEDS3, cvEDS, vEDS, and spEDS. The presence of aortic root dilation should prompt consideration of alternative diagnoses, such as Loeys-Dietz and Marfan syndromes. (See 'Differential diagnosis' below.)
•Arterial aneurysm and/or dissection – Patients with some types of EDS are at risk of developing arterial aneurysms and/or dissections, including vEDS, kyphoscoliosis EDS (kEDS), and periodontal EDS (pEDS) [34].
●Hematologic manifestations – Bleeding complications, ,such as bruising, epistaxis, bleeding after tooth extraction, muscle hematoma, and menorrhagia, are more common among patients with various types of EDS, especially vEDS and cEDS [35].
●Gastrointestinal manifestations – Various types of functional gastrointestinal disorders have been reported in patients with EDS, including irritable bowel syndrome and functional dyspepsia [36,37]. Pelvic floor prolapse may affect the uterus, vagina, and/or rectum in certain subtypes of EDS, including hEDS and clEDS. Rupture of certain internal organs (eg, esophagus, small or large bowel, bladder, uterus) can also occur in some subtypes, most commonly vEDS but also clEDS1, clEDS2, kEDS, and pEDS [38].
●Ocular manifestations – Myopia, astigmatism, blue sclera, and floppy eyelids can also be seen but are not specific, and retinal detachment can occur [39]. Keratoconus and corneal perforation are features of some of the rarer subtypes.
●Other features – Pes planus is common in all forms of EDS. Piezogenic papules, or fat herniations through fascia on heels or sides of feet (picture 4), may be seen in several subtypes of EDS. Resistance to local anesthesia can be seen [40]. Females frequently report dysmenorrhea and dyspareunia [41].
Features suggestive of certain subtypes — The clinical manifestations that characterize and distinguish each of the major forms of EDS and the approach to their diagnosis are summarized in the table (table 3) and discussed in detail separately. (See 'Considerations by EDS subtype' below.)
EVALUATION
When to suspect EDS — The diagnosis of Ehlers-Danlos syndrome (EDS) 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, unusual scars, and easy bruising [10]. This diagnosis should also be considered in any young individual who experiences spontaneous rupture of certain organs (eg, gut or uterus), dissection of a major artery, or spontaneous pneumothorax.
History and physical examination — Patients with suspected EDS require a detailed history and comprehensive physical examination, with special attention to the following components:
●History – We ask patients about a personal and family history of symptoms related to EDS, including skin fragility, easy bruising, joint hypermobility, spontaneous organ rupture, and dissection of major blood vessels.
●Skin – We look for evidence of atrophic scarring and bruising, and we examine skin texture, translucency, extensibility, and integrity. We test the skin extensibility at multiple sites (eg, elbow, neck, forearm, and dorsum of the hand). Translucency may be difficult to appreciate in patients with darker skin tones.
●Joint hypermobility – Hypermobility of the peripheral joints and spine is assessed with the Beighton hypermobility scale, which is a widely used scoring system for epidemiologic research and clinical use [42,43]. Patients are asked to perform the specific maneuvers as follows (figure 1):
•Passive dorsiflexion of the fifth finger >90 degrees with forearm flat, performed bilaterally
•Passive apposition of the thumb to the flexor aspect of the forearm, performed bilaterally
•Hyperextension of elbow >10 degrees, performed bilaterally
•Hyperextensibility of the knee >10 degrees, performed bilaterally
•Flexion of waist with palms on the floor (and with the knees fully extended)
To score the Beighton hypermobility scale, one point each is awarded for the ability to perform each of the maneuvers (table 4). In adults, a score of ≥5 of the maximum total of nine points is used to define hypermobility in criteria for EDS [13,20]; in children between the ages of 6 and 18 who have not reached skeletal maturity, the threshold is ≥6.
●Other bony abnormalities – We look for evidence of any bony abnormalities that can be seen in EDS (eg, pectus excavatum) as well as those that may suggest an alternative diagnosis (eg, very tall stature and overgrowth of long bones in Marfan syndrome).
Laboratory testing — Genetic testing is routinely done to diagnose or confirm a clinical diagnosis of EDS. Testing involves sequencing a panel of genes associated with EDS and other connective tissue disorders. The increasing use of genetic testing is in part due to the recognition that even some of the most experienced clinicians may not be able to clinically diagnose specific genetic types of EDS with high certainty, as well as decreased cost of genetic testing and, in some countries, increased insurer coverage of such testing. In addition, identification of a causative variant(s) allows extended family testing, stratification of risk for some complications, information for family planning, and, in some instances, identification of an unexpected condition.
When patients meet the classification criteria for a type of EDS that is associated with a known genetic variant, we refer them to genetics to consider testing. (See 'When to refer' below.)
Occasionally, other types of laboratory testing may helpful in distinguishing certain types of EDS. As an example, the ratio of lysyl pyridinoline to hydroxylysylpyridinoline in urine is elevated in patients with kyphoscoliotic EDS type 1 (kEDS) and spondylodysplastic EDS (spEDS). However, this cannot be used for prenatal diagnosis. Transmission electron microscopy of skin is not routinely performed but may be helpful in supporting a diagnosis for patients with variants of unknown significance and for dermatosparaxis EDS (dEDS) [44,45]. (See 'Considerations by EDS subtype' below.)
Additional testing in selected patients — Screening for complications of established EDS, including evaluation for possible cardiac valvular disease and ocular comorbidities, is described separately. (See "Ehlers-Danlos syndromes: Overview of the management", section on 'Monitoring'.)
DIAGNOSIS
Confirming the diagnosis — Ehlers-Danlos syndrome (EDS) is primarily a clinical diagnosis based on physical examination and family history. The classification criteria are commonly used in clinical practice (see 'Classification' above). Patients who fulfill the classification criteria should be referred to a clinical geneticist, who may order confirmatory genetic testing and/or facilitate genetic counseling. Increasingly, genomic testing deploys a panel of genes rather than testing single genes individually. As an example, an EDS gene panel may include all of the known EDS genes together with some of the disorders in the differential diagnosis (eg, Marfan syndrome and Loeys-Dietz syndrome). (See 'When to refer' below.)
Considerations by EDS subtype — Certain disease manifestations are more or less common in various subtypes of EDS, as summarized in the table (table 3) and described in detail below.
Classical EDS
●Clinical manifestations – The severity of disease varies in classical EDS (cEDS), including the degrees of joint hypermobility and skin laxity.
•Skeletal and joint manifestations – Both large and small joint hypermobility are typically seen, although in one study of 40 patients from 28 families, 20 percent of the patients lacked evidence of joint hypermobility [46]. 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. Patients can develop osteoarthritis. Skeletal abnormalities, including thoracolumbar scoliosis, and mildly decreased bone density have been also reported [47].
•Skin manifestations – The characteristic skin findings include velvety ("doughy") hyperextensible and fragile skin; abnormal wound healing, with delayed healing and widened atrophic scars; and increased bruisability. This may lead to the development of piezogenic papules, molluscoid pseudotumors, and/or subcutaneous spheroids. (See 'Skin hyperextensibility' above.)
•Cardiovascular manifestations – Vascular complications are rare but have been reported. Valvular heart disease is uncommon, with mitral valve prolapse observed in 6 percent of patients [48]. Aortic root dilation has been reported in 6 percent of patients [49]. The incidence of carotid artery tortuosity appears similar in patients with EDS and healthy controls [50].
•Other manifestations – Additional features include fatigue, spontaneous pneumothorax, development of hernias, cervical insufficiency, and uterine prolapse. Gastrointestinal and bladder diverticula may occur [29].
●Diagnosis – The diagnosis of cEDS 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 [3,51]:
•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
The diagnosis can be confirmed by deoxyribonucleic acid (DNA) sequencing and deletion/duplication analysis of COL5A1 and COL5A2 and rarely COL1A1; this is usually done with a genetic panel that includes genes related to other subtypes of EDS and other genetic conditions that may present similarly.
Classical-like EDS
●Clinical manifestations
•Classical-like 1 – Clinical features of classical-like 1 (clEDS1) include joint hypermobility, joint subluxations, and hyperextensible velvety skin but with normal wound healing. Some patients can have myopathic features (eg, hypotonia, decreased muscle mass). Gastrointestinal ruptures have been reported rarely [52]. 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 [18,19].
•Classical-like 2 – Classical-like 2 (clEDS2) is similar to classical EDS, with the exception that atrophic scarring is present and myopathic features are not. Foot deformities and osteopenia are reported. Bowel rupture has rarely been reported [53].
•Classical-like 3 – Classical-like 3 (clEDS3) is similar to classical EDS with the exception of the development of cerebral aneurysms and tendon rupture [5].
●Diagnosis – The diagnosis of clEDS is made clinically, based upon the family history that is compatible with autosomal recessive inheritance and physical examination. All three major criteria must be present to make a diagnosis.
•Major criteria – Skin hyperextensibility with velvety texture, joint hypermobility, and easy bruising [3]
•Minor criteria – Foot deformities (eg, brachydactyly with excessive skin, pes planus, hallux valgus, piezogenic papules), hand deformities (acrogeric hands, mallet finger, clinodactyly, brachydactyly), leg edema (without having a cardiac cause), mild proximal and distal muscle weakness, axonal polyneuropathy, hand and foot muscle atrophy, pelvic organ prolapse (ie, vaginal, uterus, rectal)
The diagnosis can be confirmed with DNA sequencing and deletion/duplication analysis of TNXB, AEBP1, and THBS2.
Hypermobile EDS — The clinical manifestations and diagnosis of hypermobile EDS (hEDS) are described separately. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)
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 spontaneous vascular or visceral rupture and the absence of large-joint hyperextensibility. 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 51 years [54].
•Arterial aneurysms and dissections – Arterial dissection and/or rupture may involve the aorta and/or the iliac, mesenteric, cerebrovascular, splenic, or renal arteries [24].
•Organ or muscle rupture – Affected individuals have an increased risk of spontaneous rupture of internal organs and muscles (eg, the intestine and gravid uterus). A review showed that maternal mortality during pregnancy is approximately 6 percent, although delivery is often uneventful [22,55,56].
•Skin manifestations – The skin is thin and may appear translucent with a prominent venous pattern (especially on the chest and abdomen). There may be varicosities, extensive bruising with minor trauma, atrophic scars, and postoperative wound dehiscence. However, the skin is only mildly hyperextensible. Acrogeria, characterized by a lack of subcutaneous fat in the distal extremities, can be seen. Occasionally, there is a particular facial appearance with prominent eyes, a thin face and nose, and lobeless ears.
•Skeletal and joint manifestations – Smaller, more distal joints (eg, those in the hands and feet) may exhibit mild hypermobility. Clubfoot has been reported in 12 percent of neonates with vEDS, and 3 percent have congenital hip dislocations [22].
•Other manifestations – Gingival recession is common. Short stature may be seen but is not typical. Amniotic band sequence has been reported in affected individuals [57]. Emphysema also has been observed on imaging [58]. Pulmonary nodules and hemoptysis may be seen [59].
●Diagnosis – While the following criteria have been proposed [3,60], we use these as a pathway to genetic testing for diagnostic confirmation:
•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 variant 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
A positive family history, arterial rupture, sigmoid colon rupture, or spontaneous pneumothorax in someone with other features listed above would warrant diagnostic testing for variants in the COL3A1 gene. 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.
Rare subtypes
Kyphoscoliotic EDS
●Clinical manifestations
•Kyphoscoliotic EDS type 1 – Kyphoscoliotic EDS (kEDS) type 1 is caused by bi-allelic pathogenic variants in PLOD1. It typically presents in newborns with muscle hypotonia associated with joint laxity, often leading to an initial evaluation by a neurologist [61]. 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 kEDS 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 half of patients have atrophic scarring and severe bruising [11]. 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.
•Kyphoscoliotic EDS type 2 – kEDS type 2 is due to biallelic variants in FKBP14 [25]. Individuals with this have progressive kyphoscoliosis, hypotonia, myopathic features, joint hypermobility, hernias, hyperelastic skin, and sensorineural hearing loss [25].
●Diagnosis – The following criteria have been proposed [3,11]:
•Major criteria – Early-onset severe congenital hypotonia; progressive kyphoscoliosis, which is present at birth or occurs during the first year of life; generalized joint laxity.
•Minor criteria – 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, which may be done in several ways. The mean value of the ratio of lysyl pyridinoline to hydroxylysylpyridinoline in urine is higher in patients with kEDS caused by PLOD1 pathogenic variants (approximately 6.0), compared with normal individuals (approximately 0.2); however, the ratio is also normal in individuals with kEDS due to pathogenic variants in FKBP14, and testing is not widely available. 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.
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), and muscle hypotonia [26]. 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, hyperextensible skin, and a combination of the other clinical features noted [3].
•Major criteria – Congenital bilateral hip dislocation, severe generalized joint laxity with multiple subluxations and/or dislocations, and skin hyperextensibility
•Minor criteria – Muscle hypotonia, kyphoscoliosis, osteopenia (mild), tissue fragility with atrophic scarring, easy bruisability
The diagnosis can be confirmed by COL1A1 and COL1A2 DNA sequencing with analysis of exon 6.
Other subtypes — Several other very rare forms of EDS have been described [62-64]; their precise frequency is uncertain (table 2).
●Dermatosparaxis EDS (dEDS) – Features of dEDS include severe skin fragility, sagging redundant skin, and large hernias [65,66]. 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 in infancy, and with increasing age there is striking distal wrinkling. Unlike most other forms of EDS, it may be associated with infantile fractures [47]. Its frequency is unknown. 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.
●Spondylodysplastic EDS (spEDS) – Clinical features of spEDS 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 [62]. Keratoconus, cardiac involvement, and vascular events have also been reported [67,68]. 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 [69]. 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 with spEDS versus 0.2 in unaffected patients), but the degree of elevation is not as high as seen with kEDS type 1 (see 'Kyphoscoliotic EDS' above). DNA sequencing of the SLC39A13, B4GALT7, and B3GALT6 genes is available.
●Musculocontractural EDS (mcEDS) – Clinical features of mcEDS 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 [63,64,70]. DNA sequencing of the CHST14 and DSE genes can be performed. Individuals with mcEDS due to the DSE gene may have a milder phenotype [71].
●Periodontal EDS (pEDS) – pEDS is characterized by early severe periodontitis, easy bruising, pretibial pigment deposition, and joint hypermobility. It is due to heterozygous pathogenic variants in C1R and C1S (MIM #130080 and #617174, respectively), which encode two proteins of the complement cascade. All pathogenic variants identified to date are missense alterations that appear to activate the C1r protease activity. One study demonstrated that activation of the complement cascade in this condition can occur independently of triggers by microbial organisms [72]. Vascular complications can occur rarely, including arterial complications, venous insufficiency, and aneurysm development [73]. Sequencing analysis of C1R and C1S is the basis for the diagnosis and, to date, all pathogenic variants are missense alterations. Nonsense heterozygous variants are not pathogenic except in the biallelic setting, in which case they can cause a lupus-like-phenotype. Genetic heterogeneity beyond these two genes seems unlikely [74].
●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. Pathogenic variants can be found in the ZNF469 or PRDM5 genes [75].
●Myopathic EDS (mEDS) – mEDS can be autosomal dominant or autosomal recessive due to pathogenic 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 [3,76]. Pathogenic variants can be found in the COL12A1 gene; however, normal testing for COL12A1 does not exclude this diagnosis [3].
●Cardiac-valvular EDS (cvEDS) – cvEDS is characterized by severe and progressive disease of the aortic and mitral valves, as well as atrophic scarring, skin hyperextensibility, and joint hypermobility, which may be restricted to small joints or more generalized. Other potential features include joint dislocations, pectus and foot deformities, and inguinal hernias. Sequencing and duplication/deletion analysis of COL1A2 can confirm the diagnosis; however, the diagnosis cannot be excluded based on normal testing [3].
DIFFERENTIAL DIAGNOSIS —
Alternative diagnoses to consider in patients who are being evaluated for Ehlers-Danlos syndrome (EDS) include hypermobility spectrum disorder (HSD) and other connective tissue disorders. Several connective tissue disorders share some features with EDS, but clinically distinct features are typically also present [77]. These conditions include those described below:
●Hypermobility spectrum disorder – Hypermobile EDS (hEDS) may be difficult to distinguish from HSD (table 1), which is a much more common condition characterized by musculoskeletal pain and generalized joint hypermobility. Some experts have suggested that hEDS and HSD may be manifestations of the same disorder [78,79] and that hEDS may be a subset of HSD [80]. More information about these conditions is provided separately. (See "Clinical manifestations and diagnosis of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder".)
●Marfan syndrome – Marfan syndrome is inherited in an autosomal dominant pattern, due to pathogenic variants in the FBN1 gene. Like EDS, patients with Marfan syndrome have joint hypermobility and may also have scoliosis and mild aortic dilatation. However, unlike patients with EDS, those with Marfan syndrome often have disproportionate tall stature and overgrowth of the long bones (picture 5), dislocation of the lens (picture 6), pectus excavatum and/or carinatum (picture 7), and progressive aortic dilatation with a propensity to aortic dissection. They do not have the skin findings seen in the classic form of EDS [81]. (See "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders".)
●Cutis laxa – Cutis laxa has several forms, including those with autosomal recessive and dominant inheritance. It is characterized by loose, redundant skin that only slowly returns from distension (picture 8) [82]. Heart valve regurgitation and other vascular involvement can occur, and hernias and emphysema are common. A distinguishing feature is the speed with which stretched skin returns to normal, which is slow in patients with cutis laxa but rapid in patients with EDS.
●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). Distinguishing features of Loeys-Dietz syndrome include cleft palate, bifid uvula, and arterial tortuosity, which are not typically found in patients with EDS [83].
●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 [84].
●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 [85]. There are several different responsible genes and both autosomal dominant and autosomal recessive forms of disease. 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 an autosomal dominant condition that may be caused by pathogenic variants in several different genes. It 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, but joint dislocations are not typical. While patients with Stickler syndrome and EDS may both have joint laxity, those with Stickler syndrome also have features that are not typical in EDS, such as hearing loss, very high myopia, and the characteristic craniofacial features and cleft palate [86]. (See "Syndromes with craniofacial abnormalities", section on 'Stickler and Marshall syndromes'.)
●Osteogenesis imperfecta – Osteogenesis imperfecta is a group of disorders whose main features are fragile osteopenic bones with recurrent fractures. Inheritance is autosomal dominant or recessive, depending upon the specific type. In some forms, there can be blue sclerae (picture 9), hearing loss, and progressive skeletal deformity. While patients with osteogenesis imperfecta and EDS both have joint laxity, recurrent fractures and osteopenia are rarely seen in EDS. Very rarely, there may be overlap between EDS and osteogenesis imperfecta due to pathogenic variants in COL1A1 or COL1A2. (See "Osteogenesis imperfecta: An overview" and 'Genetics and pathogenesis' above.)
WHEN TO REFER —
We refer patients suspected of having Ehlers-Danlos syndrome (EDS), based upon their clinical presentation and family history, for consultation with an expert in the care of patients with EDS, such as a clinical geneticist. 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. They can also help facilitate any additional referrals that may be necessary for evaluation and monitoring of certain subtypes (eg, cardiology for vascular EDS [vEDS]) and create a coordinated care team to ensure that emergencies are managed effectively. (See "Ehlers-Danlos syndromes: Overview of the management".)
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 topics (see "Patient education: Ehlers-Danlos syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Classification – Ehlers-Danlos syndromes (EDS) is a group of relatively rare disorders of connective tissue that is often characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. An international classification of the EDS outlines 13 subtypes, which can be distinguished based on various clinical features (table 2). (See 'Classification' above.)
●Epidemiology – The overall frequency of EDS is estimated at 1 in 5000, with hypermobile EDS (hEDS) being by far the most common, followed by classic EDS (cEDS) and vascular EDS (vEDS). (See 'Epidemiology' above.)
●Genetics and pathogenesis – Most pathogenic variants in EDS affect genes that control collagen synthesis and processing, the extracellular matrix, or intracellular processing (table 2). (See 'Genetics and pathogenesis' above.)
●Clinical manifestations – Clinical manifestations of EDS vary based on the specific subtype (table 3). (See 'Clinical manifestations' above.)
•Joint hypermobility – Joint hypermobility or laxity is the hallmark of most types of EDS and may be generalized (ie, both proximal and distal joints) or predominately limited to distal joints. (See 'Joint hypermobility' above.)
•Skin hyperextensibility – Skin hyperextensibility (ie, an abnormal ability to stretch the skin at a neutral site) is often seen. In certain EDS subtypes, the skin may also appear translucent or have a doughy or velvety texture. (See 'Skin hyperextensibility' above.)
•Tissue fragility – Patients with EDS may have difficulty healing wounds, including abnormal bleeding, difficulty holding sutures, delayed healing, and/or wound dehiscence. Scars may be atrophic, papyraceous, and/or hemosideric. (See 'Tissue fragility' above.)
●Evaluation
•When to suspect EDS – EDS should be suspected when a patient presents with some combination of features seen in one or several of the types of EDS (eg, joint hypermobility, translucent skin, poor wound healing, unusual scars). EDS should also be considered in any young individual who experiences spontaneous rupture of certain organs (eg, gut or uterus) or dissection of a major blood vessel. (See 'When to suspect EDS' above.)
•History and physical examination – Patients with suspected EDS require a detailed history and comprehensive physical examination, with special attention to family history of EDS and related complications, skin hyperextensibility, and joint hypermobility. (See 'History and physical examination' above.)
•Laboratory testing – Genetic testing is routinely done to diagnose or confirm a clinical diagnosis of EDS. Standard testing includes a panel of genes associated with EDS and other connective tissue disorders. (See 'Laboratory testing' above.)
●Diagnosis – EDS is primarily a clinical diagnosis based on physical examination and family history. The classification criteria are commonly used in clinical practice. Patients who fulfill the classification criteria should be referred to a clinical geneticist, who may order confirmatory genetic testing and/or facilitate genetic counseling. (See 'Confirming the diagnosis' above.)
●When to refer – We refer patients suspected of having EDS, based upon their clinical presentation and family history, for consultation with an expert in the care of patients with EDS, such as a clinical geneticist. (See 'When to refer' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Susan Pauker, MD, FACMG, who contributed to earlier versions of this topic review.
