gene. some other cases can be caused by variations in the dse gene. myopathic eds (meds) bethlem myopathy 2, formally known as myopathic eds (meds), is characterized by three major criteria: congenital muscle hypotonia and/or muscle atrophy that improves with age, proximal joint contractures of the knee, hip, and elbow, and hypermobility of distal joints (ankles, wrists, feet, and hands). four minor criteria may also contribute to a diagnosis of meds. this disorder can be inherited through either an autosomal dominant or an autosomal recessive pattern. molecular testing must be completed to verify that mutations in the col12a1 gene are present; if not, other collagen-type myopathies should be considered. periodontal eds (peds) periodontal eds (peds) is an autosomal-dominant disorder characterized by four major criteria of severe and intractable periodontitis of early-onset (childhood or adolescence), lack of attached gingiva, pretibial plaques, and family history of a first-degree relative who meets clinical criteria. eight minor criteria may also contribute to the diagnosis of peds. molecular testing may reveal mutations in c1r or c1s genes affecting the c1r protein. cardiac-valvular eds (cveds) cardiac-valvular eds (cveds) is characterized by three major criteria: severe progressive cardiac-valvular problems (affecting aortic and mitral valves), skin problems such as hyperextensibility, atrophic scarring, thin skin, and easy bruising, and joint hypermobility (generalized or restricted to small joints). four minor criteria may aid in diagnosis of cveds. cveds is an autosomal recessive disorder, inherited through variation in both alleles of the gene col1a2. signs and symptoms this group of disorders affects connective tissues across the body, with symptoms most typically present in the joints, skin, and blood vessels. however, as connective tissue is found throughout the body, eds may result in an array of unexpected impacts with any degree of severity, and the condition is not limited to joints, skin, and blood vessels. effects may range from mildly loose joints to life-threatening cardiovascular complications. due to the diversity of subtypes within the eds family, symptoms may vary widely between individuals diagnosed with eds. musculoskeletal musculoskeletal symptoms include hyperflexible joints that are unstable and prone to sprain, dislocation, subluxation, and hyperextension. there can be an early onset of advanced osteoarthritis, chronic degenerative joint disease, swan-neck deformity of the fingers, and boutonniere deformity of the fingers. tearing of tendons or muscles may occur. deformities of the spine, such as scoliosis (curvature of the spine), kyphosis (a thoracic hump), tethered spinal cord syndrome, craniocervical instability (cci), and atlantoaxial instability may also be present. there can also be myalgia (muscle pain) and arthralgia (joint pain), which may be severe and disabling. trendelenburg's sign is often seen, which means that when standing on one leg, the pelvis drops on the other side. osgood–schlatter disease, a painful lump on the knee, is common as well. in infants, walking can be delayed (beyond 18 months of age), and bottom-shuffling instead of crawling occurs. individual with eds showing hypermobile fingers, including the "swan-neck" malformation on the 2nd–5th digits, and a hypermobile thumb individual with eds displaying hypermobile thumb individual with eds displaying hypermobile metacarpophalangeal joints kyphoscoliosis of the back of someone with kyphoscoliosis eds severe joint hypermobility in a girl with eds arthrochalasia type male, late adolescent, with hypermobile type skin the weak connective tissue causes abnormal skin. this may present as stretchy or in other types simply be velvet soft. in all types, some increased fragility occurs, but the degree varies depending on the underlying subtype. the skin may tear and bruise easily, and may heal with abnormal atrophic scars; atrophic scars that look like cigarette paper are a sign seen including in those whose skin might appear otherwise normal. in some subtypes, though not the hypermobile subtype, redundant skin folds occur, especially on the eyelids. redundant skin folds are areas of excess skin lying in folds. other skin symptoms include molluscoid pseudotumors, especially on pressure points, petechiae, subcutaneous spheroids, livedo reticularis, and piezogenic papules are less common. in vascular eds, skin can also be thin and translucent. in dermatosparaxis eds, the skin is extremely fragile and saggy. atrophic scar in a case of eds translucent skin in vascular eds individual with eds displaying skin hyperelasticity piezogenic papules on the heel of an individual with hypermobile eds skin hyperelasticity in the wrist cardiovascular thoracic outlet syndrome arterial rupture valvular heart disease, such as mitral valve prolapse, creates an increased risk for infective endocarditis during surgery. this may progress to a life-threatening degree. heart conduction abnormalities have been found in those with hypermobility form of eds. dilation and/or rupture (aneurysm) of ascending aorta cardiovascular autonomic dysfunction such as postural orthostatic tachycardia syndrome raynaud's phenomenon varicose veins heart murmur heart conduction abnormalities other manifestations hiatal hernia gastroesophageal reflux poor gastrointestinal motility dysautonomia gorlin's sign (touch tongue to nose) anal prolapse flat feet tracheobronchomalacia / tracheal collapse collapsed lung (spontaneous pneumothorax) nerve disorders (carpal tunnel syndrome, acroparesthesia, neuropathy, including small fiber neuropathy) insensitivity to local anesthetics arnold–chiari malformation platelet aggregation failure (platelets do not clump together properly) mast cell disorders (including mast cell activation syndrome and mastocytosis) pregnancy complications: increased pain, mild to moderate peripartum bleeding, cervical insufficiency, uterine tearing, or premature rupture of membranes hearing loss may occur in some types eye: nearsightedness, retinal tearing and retinal detachment, keratoconus, blue sclera, dry eye, sjogren's syndrome, lens subluxation, angioid streaks, epicanthal folds, strabismus, corneal scarring, brittle cornea syndrome, cataracts, carotid-cavernous sinus fistulas, macular degeneration craniocervical instability: caused by trauma(s) to the head and neck areas such as concussion and whiplash. ligaments in neck are unable to heal properly, so the neck structure does not have the ability to support the skull, which can then sink into the brain stem, blocking the flow of cerebrospinal fluid, leading to issues related to the autonomic nervous system failing to work properly. osteoporosis and osteopenia are associated with eds and symptomatic joint hypermobility there is some evidence that eds may be associated with greater than expected frequencies of neurodevelopmental disorders such as attention deficit hyperactivity disorder (adhd) and other learning, communication and motor issues, including autism spectrum conditions and tourette syndrome. gorlin's sign in a case of eds keratoglobus in a case of eds with brittle cornea syndrome because it is often undiagnosed or misdiagnosed in childhood, some instances of eds have been mischaracterized as child abuse. the pain may also be misdiagnosed as a behavior disorder or munchausen by proxy. the pain associated with eds ranges from mild to debilitating. causes the collagen fibril and eds: (a) normal collagen fibrils are of uniform size and spacing. fibrils from a person with dermatosparaxis (b) show dramatic alterations in fibril morphology with severe effects on the tensile strength of connective tissues. a person with classical eds (c) shows composite fibrils. fibrils from a tnx-deficient person (d) are uniform in size and no composite fibrils are seen. tnx-null (e) fibrils are less densely packed and not as well aligned to neighboring fibrils. every type of eds except the hypermobile type (which affects the vast majority of people with eds) can be positively tied to specific genetic variation. variations in these genes can cause eds: collagen primary structure and collagen processing: adamts2, col1a1, col1a2, col3a1, col5a1, col5a2 collagen folding and collagen cross-linking: plod1, fkbp14 structure and function of myomatrix: tnxb, col12a1 glycosaminoglycan biosynthesis: b4galt7, b3galt6, chst14, dse complement pathway: c1r, c1s intracellular processes: slc39a13, znf469, prdm5 variations in these genes usually alter the structure, production, or processing of collagen or proteins that interact with collagen. collagen provides structure and strength to connective tissue. a defect in collagen can weaken connective tissue in the skin, bones, blood vessels, and organs, resulting in the features of the disorder. inheritance patterns depend on the specific syndrome. most forms of eds are inherited in an autosomal dominant pattern, which means only one of the two copies of the gene in question must be altered to cause a disorder. a few are inherited in an autosomal recessive pattern, which means both copies of the gene must be altered for a person to be affected. it can also be an individual (de novo or "sporadic") variation. sporadic variations occur without any inheritance. diagnosis a diagnosis can be made by an evaluation of medical history and clinical observation. the beighton criteria are widely used to assess the degree of joint hypermobility. dna and biochemical studies can help identify affected people. diagnostic tests include collagen gene-variant testing, collagen typing via skin biopsy, echocardiogram, and lysyl hydroxylase or oxidase activity, but these tests are not able to confirm all cases, especially in instances of an unmapped variation, so clinical evaluation remains important. if multiple members of a family are affected, prenatal diagnosis may be possible using a dna information technique known as a linkage study. knowledge about eds among all kinds of practitioners is poor. research is ongoing to identify genetic markers for all types. differential diagnosis several disorders share some characteristics with eds. for example, in cutis laxa, the skin is loose, hanging, and wrinkled. in eds, the skin can be pulled away from the body, but is elastic and returns to normal when let go. in marfan syndrome, the joints are very mobile and similar cardiovascular complications occur. people with eds tend to have a "marfanoid" appearance (e.g., tall, skinny, long arms and legs, "spidery" fingers), but physical appearance and features in several types of eds also have characteristics including short stature, large eyes, and the appearance of a small mouth and chin, due to a small palate. the palate can have a high arch, causing dental crowding. blood vessels can sometimes be easily seen through translucent skin, especially on the chest. the genetic connective tissue disorder loeys–dietz syndrome also has symptoms that overlap with eds. in the past, menkes disease, a copper metabolism disorder, was thought to be a form of eds. people are commonly misdiagnosed with fibromyalgia, bleeding disorders, or other disorders that can mimic eds symptoms. because of these similar disorders and complications that can arise from an unmonitored case of eds, a correct diagnosis is important. pseudoxanthoma elasticum is worth consideration in diagnosis. management no cure for ehlers–danlos syndromes is known, and treatment is supportive. close monitoring of the cardiovascular system, physiotherapy, occupational therapy, and orthopedic instruments (e.g., wheelchairs, bracing, casting) may be helpful. this can help stabilize the joints and prevent injury. orthopedic instruments are helpful for the prevention of further joint damage, especially for long distances. people should avoid activities that cause the joint to lock or overextend. a physician may prescribe casting to stabilize joints. physicians may refer a person to an orthotist for orthotic treatment (bracing). physicians may also consult a physical and/or occupational therapist to help strengthen muscles and to teach people how to properly use and preserve their joints. aquatic therapy promotes muscular development and coordination. with manual therapy, the joint is gently mobilized within the range of motion and/or manipulations. if conservative therapy is not helpful, surgical joint repair may be necessary. medication to decrease pain or manage cardiac, digestive, or other related conditions may be prescribed. to decrease bruising and improve wound healing, some people have responded to vitamin c. medical care workers often take special precautions because of the sheer number of complications that tend to arise in people with eds. in vascular eds, signs of chest or abdominal pain are considered trauma situations. cannabinoids and medical marijuana have shown some efficacy in reducing pain levels. in general, medical intervention is limited to symptomatic therapy. before pregnancy, people with eds should have genetic counseling and familiarize themselves with the risks pregnancy poses. children with eds should be given information about the disorder so they can understand why they should avoid contact sports and other physically stressful activities. children should be taught that they should not demonstrate the unusual positions they can maintain due to loose joints, as this may cause early degeneration of the joints. emotional support along with behavioral and psychological therapy can be useful. support groups can be immensely helpful for people dealing with major lifestyle changes and poor health. family members, teachers, and friends should be informed about eds so they can accept and assist the child. pain management successful treatment of chronic pain in eds requires a multidisciplinary team. the ways to manage pain can be to modify pain management techniques used in the normal