Overview and Variability of Symptoms
Ehlers-Danlos syndrome (EDS) refers to a group of 13 inherited disorders of connective tissue . Although each subtype has its own diagnostic criteria, they share core clinical features, including joint hypermobility, skin hyperextensibility, and tissue fragility . In other words, joints tend to move beyond their normal range (loose joints or “double-jointed”), the skin may stretch more than usual (sometimes with a velvety soft texture), and the tissues (skin, blood vessels, organs) are fragile and easily injured . These traits lead to typical symptoms such as: frequent sprains, subluxations, or joint dislocations, skin that bruises or bruises easily, atrophic or slow-healing scars (often thin and “cigarette paper” scars), and chronic musculoskeletal pain . Many patients also report constant fatigue and even difficulty concentrating, reflecting the systemic impact of EDS.
It is important to note that the severity and combination of symptoms vary greatly from person to person and by EDS subtype. Some individuals present with only mild symptoms (e.g., slightly loose joints and slightly stretchy skin) and may never be diagnosed. Others, however, experience severe or even life-threatening manifestations. Even within the same subtype, two people can have very different symptoms. For example, while some people experience only hyperflexibility and occasional pain, others have recurrent dislocations, orthopedic deformities, prolapsed organs, or vascular ruptures. This variability contributes to diagnostic difficulties and means that EDS can manifest itself subtly in some and dramatically in others. In addition, chronic pain and fatigue are frequently reported symptoms in several types of EDS, impacting quality of life and sometimes being confused with other diseases. Below, we highlight the common and rare clinical manifestations of each major EDS subtype, from mildest to most severe.
Symptoms by EDS Subtype
Hypermobile EDS (hEDS)
The hypermobile subtype is the most common, accounting for approximately 80–90% of EDS cases. Its defining feature is generalized joint hypermobility, often leading to frequent dislocations or subluxations, sprains, and chronic musculoskeletal pain. Large joints (knees, shoulders, ankles, etc.) may become partially or completely dislocated with minor trauma or everyday movements, causing microtears and persistent pain. Joint and muscle pain tends to be chronic and may be out of proportion to the objective findings, possibly related to ligamentous laxity and reflex spasms. The skin in hEDS is usually smooth/velvety and slightly extensible, but usually without significant atrophic scarring, unlike other subtypes. Bruising occurs easily in some patients, although skin fragility is less marked than in classic EDS. Many individuals with hEDS also present with systemic manifestations: for example, autonomic dysfunction (postural dizziness, postural tachycardia), gastrointestinal disturbances (reflux, irritable bowel syndrome, gastroparesis), and allergic tendencies or mast cell activation. Additionally, conditions such as anxiety, depression, and other neurovegetative complaints are more common in hypermobile EDS. This constellation of symptoms causes many hEDS patients to experience intense fatigue and need to adjust their daily activities. It is worth noting the variability: some can lead a near-normal life with only moderate hyperlaxity, while others may require mobility aids, orthoses, and frequent medical support due to debilitating pain and joint instability.
Classical EDS (cEDS)
Classic EDS is marked by prominent cutaneous manifestations in addition to joint hypermobility. The skin is hyperextensible (stretching well beyond normal) and has a soft, “velvety” or dough-like texture. Skin lesions heal slowly and form characteristic thin, wrinkled atrophic scars, often compared to cigarette paper. Because of the fragility of the skin, sutures can tear easily, leading to enlarged scars. Bruising (bruising) often occurs after even minor trauma. The joints are generally hypermobile as in hEDS, predisposing to dislocations and pain, although the pain may be less widespread than in the hypermobile form. Additional cutaneous findings include molluscoid pseudotumors (small fleshy lumps at sites of pressure or scarring) and subcutaneous spheroids (hard nodules of calcified adipose tissue beneath the skin). Herniations (umbilical, inguinal) may also occur due to fragility of the supporting tissues. People with classic EDS sometimes have minor facial features, such as drooping eyelids or epicanthal folds, and excessively soft skin on the face. Together, fragile skin, abnormal scars, and joint hyperlaxity form the classic diagnostic triad of this subtype. The severity varies: some individuals have only hyperflexibility and somewhat elastic skin, while others have chronic wounds, deformities due to retractile scars, and multiple surgeries to correct unstable joints.
Vascular EDS (vEDS)
Vascular EDS is one of the most severe subtypes, as it significantly affects blood vessels and internal organs. Individuals with vEDS tend to have exceptionally thin, translucent skin, through which veins can easily be seen beneath the surface, especially in areas such as the chest and abdomen. The face may have distinctive features: a narrow nose, thin lips, prominent eyes, and small earlobes, giving a typical facial appearance. Bruising occurs very easily due to extreme capillary fragility. However, the hallmark of vEDS is arterial and organ fragility – medium- and large-caliber arteries may rupture spontaneously, without obvious prior aneurysm, leading to catastrophic internal bleeding. Sudden arterial ruptures at a young age (e.g., dissection or rupture of the aorta, coronary arteries, or renal arteries) are a constant threat in this subtype. There is also an increased risk of rupture of hollow organs, such as spontaneous perforation of the large intestine (colon) or uterine rupture during pregnancy. Women with vEDS face high-risk pregnancies due to the possibility of rupture of the uterus or placental vessels. The joints in vEDS may not be as loose as in the hypermobile or classic subtypes – often the hypermobility is restricted to the small joints (fingers) while the larger joints are less affected. In summary, vEDS can present as a relatively silent form (thin skin, some hyperlaxity) to a dramatic presentation with fatal internal bleeding, which is why it requires close medical monitoring. Unfortunately, serious vascular complications in vEDS can occur early in life, significantly reducing the patient’s life expectancy and quality of life.
Other Rare Subtypes of EDS
In addition to the three main subtypes above, there are other rare forms of EDS – each with unique, often more specific, manifestations. In general, these subtypes are much less prevalent, but they are important to recognize:
• Classic-Like EDS (clEDS) – Presents with signs similar to the classic form (hyperextensible skin, loose joints, and easy bruising), but without significant atrophic scarring. There may also be mild muscle weakness and deformities of the feet (flat feet) or hands, as well as prolapse of internal organs (e.g., uterine or rectal prolapse) in some cases. This subtype is associated with mutations in the TNXB (tenascin X) gene.
• Cardiac Valvular EDS (cvEDS) – Characterized by a combination of classic symptoms (hyperextensible skin, atrophic scars, easy bruising, joint hypermobility) associated with progressive valvular heart problems. Patients may develop severe heart valve insufficiency (such as mitral or aortic valve), often requiring surgical repair. Other findings include chest deformities (pectoralis carinatum or excavatum) and congenital clubfeet. This subtype is extremely rare and inherited as an autosomal recessive disorder (related to mutations in COL1A2).
• Kyphoscoliotic EDS (kEDS) – Characterized by severe muscular hypotonia from birth, motor delay, and early progressive scoliosis (abnormal curvature of the spine present in childhood). Joint hypermobility is widespread, and dislocations frequently occur. Due to the deficiency in the structure of type VI collagen, there is great fragility of the ocular tissues: fragility of the ocular sclera (white of the eye) may occur, predisposing to rupture of the ocular globe after minimal trauma. Other findings include a small ocular globe (microcornea) and mild facial dysmorphism. This subtype may also present with vascular fragility and a tendency to aneurysms, although not as marked as in vEDS. kEDS related to the PLOD1 gene (lysyl-hydroxylase enzyme) has recessive inheritance and is extremely rare, with few cases described in the world.
• Arthrochalastic EDS (aEDS) – It is characterized by generalized joint hypermobility of an extreme degree, to the point that multiple dislocations occur spontaneously. A classic finding is bilateral congenital dislocation of the hips – that is, babies are born with dislocated hips due to laxity. The skin is hyperextensible and fragile, although scars may not be as atrophic as in classic EDS. Muscle hypotonia, delayed motor development, and spinal deformities (kyphosis/scoliosis) may also be present during growth. This subtype, caused by mutations in type I collagen genes (COL1A1/COL1A2), is extremely rare and is inherited as an autosomal dominant trait.
• Dermatosparaxis EDS (dEDS) – A very rare subtype, defined by extreme fragility of the skin. The skin is very loose, soft, and “moldy” (with a soft, mass-like appearance) and may have a redundant/sagging appearance, especially on the face, resulting in an aged appearance. Minor trauma leads to severe lacerations and extensive bruising, as the skin tears easily. Large hernias (umbilical or inguinal) are common in infancy due to weak connective tissue. Infants may be born with a markedly edematous appearance and redundant skin. This subtype results from mutations in ADAMTS2 (collagen processing enzyme) and has recessive inheritance.
• Fragile Corneal Syndrome (BCS) – Included in the current classification of EDS, fragile corneal syndrome presents mainly ocular manifestations. Individuals have very thin corneas, subject to spontaneous rupture or rupture due to minimal trauma, in addition to corneal deformities such as keratoconus or keratoglobus (changes in the curvature of the cornea). The presence of bluish sclerae (bluish tint in the whites of the eyes) and high myopia is also common. Some features of EDS (mild joint hypermobility and thin skin) may occur, but the predominant ocular picture distinguishes this subtype. It has recessive inheritance linked to genes such as ZNF469 and PRDM5.
• Spondylodysplastic EDS (spEDS) – Presents with a picture of disproportionate short stature, skeletal deformities (e.g., curvature of the long bones of the legs) and significant muscle hypotonia since childhood. The joints may be loose to a variable degree. Osteopenia or moderate bone fragility is common. This subtype is associated with defects in genes involved in glycosaminoglycan synthesis (e.g., B4GALT7, B3GALT6) and is inherited recessively.
• Musculocontractural EDS (mcEDS) – Characterized by multiple congenital contractures (i.e., joints that are fixed/flexed from birth—e.g., clubfeet, hand or knee contractures) and characteristic facial features. The face may have wide-set eyes (hypertelorism), full lips, and low-set ears, among other peculiarities. The skin is hyperextensible and fragile, with a tendency to atrophic scars similar to those in the classic form. With growth, some contractures may improve, but hypermobility in other joints and skin fragility persist. They are caused by mutations in the CHST14 or DSE (dermatan sulfate synthesis pathway) genes, with recessive inheritance.
• Myopathic EDS (mEDS) – In this subtype, signs include hypermobility mainly of the distal joints (hands and feet) and, interestingly, reduced mobility in the large joints due to proximal muscle contractures (elbows, hips, knees). There is congenital muscle hypotonia and/or muscle atrophy at birth, which improves with age (motor strength increases as the child grows). Children may have initial motor delay but later achieve motor milestones. The skin may be flexible and there is mild tissue fragility. Caused by mutations in COL12A1 (collagen XII), and may have dominant or recessive inheritance.
• Periodontal EDS (pEDS) – Its distinctive feature is severe, early-onset periodontal disease. Patients usually develop aggressive periodontitis in adolescence or early adulthood, with inflammation and marked gingival recession that leads to premature tooth loss. The gingiva is very thin and fragile, often with an absence of attached gingiva (insufficiently attached gingiva), which worsens tooth mobility and bone loss around the teeth. In addition, pretibial plaques (dark, atrophic patches on the skin of the shins) are formed, which are characteristic scars of this type. Joint hypermobility is mild to moderate and usually accompanied by a tendency to bruise. pEDS is caused by mutations in the C1R or C1S (collagen complement) genes and has an autosomal dominant inheritance.
(Note: The above subtypes are rare and often require confirmation by genetic testing. Each subtype has major and minor diagnostic criteria that are well-defined in the medical literature. Despite the differences, almost all subtypes present, to a greater or lesser extent, with some degree of joint hyperlaxity, skin or tissue fragility, and symptoms such as pain and fatigue.)
Differential Diagnosis
Because of the wide variety of manifestations, the diagnosis of EDS can be challenging—many signs/symptoms also occur in other diseases. It is essential to differentiate EDS from other connective tissue conditions: for example, osteogenesis imperfecta (OI) type I may resemble EDS (both present with loose joints and minimally traumatic injuries), but OI typically presents with blue sclerae, a history of multiple fractures since childhood, hearing loss, and known mutations in type I collagen genes. Marfan syndrome can cause joint hypermobility and musculoskeletal signs similar to hypermobile EDS, but is distinguished by very tall stature with disproportionate limbs, sternal deformities, possible dislocations of the ocular lens, and especially dilation of the aortic root (ascending aortic aneurysm) – features absent in EDS. Another genetic condition, Loeys-Dietz syndrome, involves vascular fragility and aneurysms as in vascular EDS; however, Loeys-Dietz typically exhibits the characteristic triad of bifid uvula/cleft palate, hypertelorism (widely separated eyes), and diffuse arterial tortuosity with aneurysms in arteries not common in vEDS. Cutis laxa (or elastolysis) may be confused with dermatosparaxis EDS because of the extremely loose skin; However, in cutis laxa the skin slowly returns to its place after being stretched, and there is usually typical pulmonary (emphysema) and facial involvement, as well as different mutations (for example, in FBLN5).
Other conditions to consider include nonsyndromic hypermobility syndromes (also called hypermobility spectrum disorders, formerly “benign hypermobility syndrome”), which present with loose joints and musculoskeletal pain but without the skin or systemic changes of EDS. In addition, because of the predominance of nonspecific symptoms such as chronic pain and fatigue, patients with hypermobile EDS are often initially misdiagnosed with conditions such as fibromyalgia, chronic fatigue syndrome, or even psychosomatic disorders. Careful clinical evaluation and, when possible, genetic testing help distinguish EDS from these other conditions. Correct recognition is crucial, because each of these syndromes has specific complications and management—for example, missing the diagnosis of vascular EDS can be dangerous if the person is treated as having only Marfan or ordinary hypertension. In summary, the differential diagnosis of EDS encompasses a spectrum of inherited and acquired connective tissue diseases and requires attention to the unique clinical details of each.
Impact on Quality of Life
Ehlers-Danlos syndrome can profoundly affect patients’ quality of life, ranging from mild discomfort to significant disability. Even in “mild” forms, many individuals suffer from chronic pain—whether it be joint pain from repeated microinjuries or muscle pain from overuse and spasms—which can lead to functional limitations, sleep disturbances, and regular use of painkillers. Chronic fatigue is another common and debilitating symptom, often reported even by young patients, and may be related to sleep disturbances, constant pain, and associated autonomic dysfunction. Due to pain and fatigue, everyday activities (such as walking long distances, standing for long periods of time, exercising, or even household chores) can become strenuous. In subtypes with severe joint instability, patients live with the fear of dislocation or injury with every movement, often avoiding certain physical activities. Some people need to use braces, joint support straps, or wheelchairs to move long distances, especially after multiple orthopedic surgeries or injuries.
From a psychosocial perspective, the impact is also significant. The chronic and unpredictable nature of EDS can lead to anxiety (e.g., constant worry about suffering a new injury or sudden complication) and depression, especially if there is a loss of autonomy or if the patient faces a lack of understanding from the medical community or family about their condition. Many patients report a long journey to obtain a correct diagnosis, seeing several specialists – during which their complaints may be discredited or wrongly attributed to psychogenic causes. After diagnosis, although there is relief in naming the problem, the challenge of dealing with an incurable disease remains. Lifestyle adjustments are necessary: it is often necessary to redesign the work or study routine, taking breaks to rest, adapting the environment (e.g., using ergonomic desks and chairs) and sometimes reducing the workload. In the social sphere, patients with EDS may have to give up sports hobbies or social activities that they previously enjoyed, requiring reorganization of leisure and relationships to overcome physical limitations. Qualitative studies reveal that EDS affects not only the physical level, but also the psychological and social spheres of individuals’ lives . However, with appropriate management – including physical therapy for muscle strengthening, pain control, cardiovascular monitoring when necessary, and emotional support – many patients are able to improve their functionality and find strategies to live better with EDS. Support from multidisciplinary teams and support groups is essential for sharing experiences and tips, and has been encouraged to help EDS patients improve their quality of life and face the daily challenges imposed by this syndrome .
Sources: The above summary was prepared based on specialized references, including guidelines from medical societies and academic reviews on EDS, which detail the common and rare clinical manifestations in each subtype, the interindividual variability of symptoms, differential diagnostic considerations, and implications for the daily life of patients. The information cited reflects current knowledge about EDS, ranging from typical skin and joint signs to serious complications (such as vascular ruptures) and aspects of disease management and prognosis. All direct citations are identified throughout the text, supporting the key points presented.
