ehlers–danlos syndromes ehlers–danlos syndromes ehlers–danlos syndromes (eds) are a group of 13 genetic connective-tissue disorders in the current classification, with the latest type discovered in 2018. symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. these may be noticed at birth or in early childhood. complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis. ehlers–danlos syndromes (eds)individual with eds displaying skin hyperelasticitypronunciation/ˈeɪlərz ˈdænlɒs/ specialtymedical geneticssymptomsoverly flexible joints, stretchy skin, abnormal scar formationcomplicationsaortic dissection, joint dislocations, osteoarthritisusual onsetchildhood or teens depending on type.durationlifelongtypeshypermobile, classic, vascular, kyphoscoliosis, arthrochalasia, dermatosparaxis, brittle cornea syndrome, otherscausesgeneticrisk factorsfamily historydiagnostic methodgenetic testing, physical examinationdifferential diagnosismarfan syndrome, cutis laxa syndrome, familial joint hypermobility syndrome, loeys–dietz syndrome, hypermobility spectrum disordertreatmentsupportiveprognosisdepends on specific disorderfrequency1 in 5,000 eds occurs due to variations of more than 19 genes that are present at birth. the specific gene affected determines the type of eds. some cases result from a new variation occurring during early development, while others are inherited in an autosomal dominant or recessive manner. typically, these variations result in defects in the structure or processing of the protein collagen. diagnosis is often based on symptoms and confirmed by genetic testing or skin biopsy, but people may initially be misdiagnosed with hypochondriasis, depression, or chronic fatigue syndrome. a cure is not yet known and treatment is supportive in nature. physical therapy and bracing may help strengthen muscles and support joints. some forms of eds result in a normal life expectancy, but those that affect blood vessels generally decrease it. the hypermobile type of eds (heds) affects at least one in 5,000 people globally; other types occur at lower frequencies. the prognosis depends on the specific disorder. excess mobility was first described by hippocrates in 400 bc. the syndromes are named after two physicians, edvard ehlers and henri-alexandre danlos, who described them at the turn of the 20th century. types in 2017, 13 subtypes of eds were classified using specific diagnostic criteria. according to the ehlers–danlos society, the syndromes can also be grouped by the symptoms determined by specific gene mutations. group a disorders are those that affect primary collagen structure and processing. group b disorders affect collagen folding and crosslinking. group c are disorders of structure and function of myomatrix. group d disorders are those that affect glycosaminoglycan biosynthesis. group e disorders are characterized by defects in the complement pathway. group f are disorders of intracellular processes, and group g is considered to be unresolved forms of eds. hypermobile eds (heds) hypermobile eds (heds, formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. it may lead to frequent joint subluxations (partial dislocations) and dislocations. in general, people with this variant have skin that is soft, smooth, and velvety and bruises easily, and may have chronic muscle and/or bone pain. it affects the skin less than other forms. it has no available genetic test. heds is the most common of the 19 types of connective tissue disorders. since no genetic test exists, providers have to diagnose heds based on what they know about the condition and the patient's physical attributes. other than the general signs, attributes can include faulty connective tissues throughout the body, musculoskeletal issues, and family history. along with these general signs and side effects, patients can have trouble healing. women who are pregnant should be warned about things such as pre-labor rupture of membranes, drop in blood pressure with anesthesia, precipitate birth (very fast, active labor), malposition of bleeding, and more. new mothers with heds should pay extra attention to taking care of their babies. mothers may have trouble taking care of babies because of the risk of dropping a baby due to weak connective tissue in arms and legs, falling, postpartum depression (more than the general population), and healing from the birthing process. the medical university of south carolina discovered a gene variant common with heds patients. genetics of hypermobile eds while 12 of the 13 subtypes of eds have genetic variations that can be tested for by genetic testing, there is no known genetic cause of heds. recently, several labs and research initiatives have been attempting to uncover a potential heds gene. in 2018, the ehlers–danlos society began the hypermobile ehlers–danlos genetic evaluation (hedge) study. the ongoing study has screened over 1,000 people who have been diagnosed with heds by the 2017 criteria to evaluate their genome for a common mutation. to date, 200 people with heds have had whole genome sequencing, and 500 have had whole exome sequencing; this study aims to increase those numbers significantly. promising outcomes of this increased screening have been reported by the norris lab, led by russell norris, in the department of regenerative medicine and cell biology at medical university of south carolina. using crispr cas-9 mediated genome editing on mouse models of the disease, the lab has recently identified a "very strong candidate gene" for heds. this finding, and a greater understanding of cardiac complications associated with the majority of eds subtypes, has led to the development of multiple druggable pathways involved in aortic and mitral valve diseases. while this candidate gene has not been publicly identified, the norris lab has conducted several studies involving small population genome sequencing and come up with a working list of possible heds genes. a mutation in col3a1 in a single family with autosomal dominant heds phenotype was found to cause reduced collagen secretion and an over-modification of collagen. in 35 families, copy number alterations in tpsab1, encoding alpha-tryptase, were associated with increased basal serum tryptase levels, associated with autonomic dysfunction, gastrointestinal disorders, allergic and cutaneous symptoms, and connective tissue abnormalities, all concurrent with heds phenotype. lastly, tenascin x, an extracellular matrix protein important for collagen mutation encoded by the tnxb gene, has been associated with heds in patients with tenascin x deficiency. another way the norris lab is attempting to find this gene is by looking at genes involved in the formation of the aorta and mitral valves, as these valves are often prolapsed or malformed as a symptom of eds. because heds is such a complex, multi-organ disease, focusing on one hallmark trait has proven successful. one gene found this way is dzip1, which regulates cardiac valve development in mammals through a cby1-beta-catenin mechanism. mutations at this gene affect the beta-catenin cascade involved in development, causing malformation of the extracellular matrix, resulting in loss of collagen. a lack of collagen here is both consistent with heds and explains the "floppy" mitral and aortic valve heart defects. a second genetic study specific to mitral valve prolapse focused on the pdgf signaling pathway, which is involved in growth factor ligands and receptor isoforms. mutations in this pathway affect the ability to localize cilia in various cell types, including cardiac cells. with the resulting ciliopathies, structures such as the cardiac outflow tract, heart tube assembly, and cardiac fusion are limited and/or damaged. classical eds (ceds) classical eds (formerly categorized as type 1) is characterized by extremely elastic skin that is fragile and bruises easily and hypermobility of the joints. molluscoid pseudotumors (calcified hematomas that occur over pressure points) and spheroids (cysts that contain fat occurring over forearms and shins) are also often seen. a side complication of the hyperelasticity presented in many eds cases makes wounds closing on their own more difficult. sometimes, motor development is delayed and hypotonia occurs. the variation causing this type of eds is in the genes col5a2, col5a1, and less frequently col1a1. it involves the skin more than heds. in classical eds, large variation in symptom presentation is seen. because of this variance, eds has often been underdiagnosed. without genetic testing, healthcare professionals may be able to provide a provisional diagnosis based on careful examination of the mouth, skin, and bones, as well as by neurological assessment. a good way to begin the diagnosis process is looking at family history. eds is an autosomal dominant condition, so is often inherited from parents. genetic testing remains the most reliable way to diagnose eds. no cure for type 1 eds has been found, but a course of non-weight-bearing exercise can help with muscular tension, which can help correct some eds symptoms. anti-inflammatory drugs and lifestyle changes can help with joint pain. lifestyle choices should also be made with children who have eds to try to prevent wounds to the skin. protective garments can help with this. in a wound, deep stitches are often used and left in place for longer than normal. vascular eds (veds) vascular eds (formerly categorized as type 4) is identified by skin that is thin, translucent, extremely fragile, and bruises easily. it is also characterized by fragile blood vessels and organs that can easily rupture. affected people are frequently short, and have thin scalp hair. it also has characteristic facial features, including large eyes, an undersized chin, sunken cheeks, a thin nose and lips, and ears without lobes. joint hypermobility is present, but generally confined to the small joints (fingers, toes). other common features include club foot, tendon and/or muscle rupture, acrogeria (premature aging of the skin of the hands and feet), early-onset varicose veins, pneumothorax (collapse of a lung), the recession of the gums, and a decreased amount of fat under the skin. it can be caused by the variations in the col3a1 gene. rarely, col1a1 variations can also cause it. kyphoscoliosis eds (keds) kyphoscoliosis eds (formerly categorized as type 6) is associated with severe hypotonia at birth, delayed motor development, progressive scoliosis (present from birth), and scleral fragility. people may also have easy bruising, fragile arteries that are prone to rupture, unusually small corneas, and osteopenia (low bone density). other common features include a "marfanoid habitus" characterized by long, slender fingers (arachnodactyly), unusually long limbs, and a sunken chest (pectus excavatum) or protruding chest (pectus carinatum). it can be caused by variations in the gene plod1, or rarely, in the fkbp14 gene. arthrochalasia eds (aeds) arthrochalasia eds (formerly categorized as types 7a and b) is characterized by severe joint hypermobility and congenital hip dislocation. other common features include fragile, elastic skin with easy bruising, hypotonia, kyphoscoliosis (kyphosis and scoliosis), and mild osteopenia. type-i collagen is usually affected. it is very rare, with about 30 cases reported. it is more severe than the hypermobility type. variations in the genes col1a1 and col1a2 cause it. dermatosparaxis eds (deds) dermatosparaxis eds (formerly categorized as type 7c) is associated with extremely fragile skin leading to severe bruising and scarring; saggy, redundant skin, especially on the face; hypermobility ranging from mild to serious; and hernias. variations in the adamts2 gene cause it. it is extremely rare, with around 11 cases reported. brittle-cornea syndrome (bcs) brittle-cornea syndrome is characterized by the progressive thinning of the cornea, early-onset progressive keratoglobus or keratoconus, nearsightedness, hearing loss, and blue sclerae. classic symptoms, such as hypermobile joints and hyperelastic skin, are also seen often. it has two types. type 1 occurs due to variations in the znf469 gene. type 2 is due to variations in the prdm5 gene. classical-like eds (cleds) classical-like eds is characterized by skin hyperextensibility with velvety skin texture and absence of atrophic scarring, generalized joint hypermobility with or without recurrent dislocations (most often shoulder and ankle), and easily bruised skin or spontaneous ecchymoses (discolorations of the skin resulting from bleeding underneath). it can be caused by variations in the tnxb gene. spondylodysplastic eds (speds) spondylodysplastic eds is characterized by short stature (progressive in childhood), muscle hypotonia (ranging from severe congenital to mild later-onset), and bowing of limbs. it can be caused by variations in both copies of the b4galt7 gene. other cases can be caused by variations in the b3galt6 gene. people with variations in this gene can have kyphoscoliosis, tapered fingers, osteoporosis, aortic aneurysms, and problems with the lungs. other cases can be caused by the slc39a13 gene. those with variations in this gene have protuberant eyes, wrinkled palms of the hands, tapering fingers, and distal joint hypermobility. musculocontractural eds (mceds) musculocontractural eds is characterized by congenital multiple contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot), characteristic craniofacial features, which are evident at birth or in early infancy, and skin features such as skin hyperextensibility, bruising, skin fragility with atrophic scars, and increased palmar wrinkling. it can be caused by variations in the chst14