In the classic type, the skin is hyperelastic, fragile and smooth and velvety to touch. Skin is prone to rupturing even after minor trauma. The joints are hyperextendable. Joint dislocations are common. Wound healing is impaired. Other signs and symptoms include:

• Hypotonia and delayed motor development
• Fatigue
• Cramps
• Easy bruising
• Spontaneous vessel ruptures
• Valvular prolapse
• Atrophic scars

In hypermobility type, grotesque contortions are seen, such as bending the thumb backwards to touch the forearm or bending the knee almost at a right angle. Chronic pain, joint dislocations and joint hypermobility are other manifestations. Bowel disorders might also be seen.

The vascular type manifests as

• Thin skin
• Arterial or uterine rupture
• Bruising
• Small joint hyperextensibility

In kyphoscoliosis type, the manifestations are:

• Hypotonia
• Joint laxity
• Congenital scoliosis
• Ocular fragility

In arthrochalasia variant, the following findings are present.

• Severe joint hypermobility
• Mild skin changes
• Scoliosis
• Bruising

The dermatosparaxis type shows up as:

• Severe skin fragility
• Cutis laxa
• Bruising

• Chronic Fatigue Syndrome

  Chronic fatigue is an important contributor to impaired health-related quality of life in Ehlers-Danlos syndrome. There is overlap in the symptoms and findings of EDS and chronic fatigue syndrome. [ncbi.nlm.nih.gov]

  EDS is considered an “invisible disability” and is often misdiagnosed as other conditions including hypochondriasis, depression, and chronic fatigue syndrome. [diseaseinfosearch.org]

  He specializes in the evaluation and treatment of adolescents and young adults with conditions characterized by chronic fatigue, including chronic fatigue syndrome, orthostatic intolerance, and joint hypermobility. [doi.org]

  Fatigue Syndrome Fibromyaligia Postural Orthostatic Tachycardia Syndrome, Dysautonomia Prolong QT interval Chronic Bronchitis, Infection. [patch.com]

  Chronic Fatigue Chronic Fatigue Syndrome, also known as CFS, affects people will all sorts of chronic illness. Those of us with chronic fatigue are also known as #Spoonies. See Christine Miserandino's Spoon Theory for more info on that! [buzzfeed.com]

• Marfanoid Habitus

  Homocystinuria also results in a Marfanoid habitus but presents with inferior and medial displacement of the lens ( downward and inward )! [amboss.com]

  habitus" which is characterized by long, slender fingers (arachnodactyly); unusually long limbs; and a sunken chest (pectus excavatum) or protruding chest (pectus carinatum) majority of patients with kEDS harbor biallelic mutations in PLOD1; recently [gpnotebook.com]

  Marfanoid habitus This may be present in association with EDS (usually incomplete). It is a common finding in hypermobile and kyphoscoliotic EDS but is not necessary for diagnosis of EDS. [online.epocrates.com]

• Easy Bruising

  AEBP1 Comprehensive EDS Panel Hypermobility Type (EDS type III) or Tenascin Deficient Type Marked large and small joint hypermobility, joint pain, easy bruising, easy bleeding, normal scars Dominant TNXB (<5%) (Not available through CDL) Vascular Type [uwcpdx.org]

  Easy bruising. Pes planus. Recurrent joint dislocation.Chronic joint pains. Easy brushing. Varicose veins. Intestinal rupture. Pelvic adhesions. Positve DNA test III-5 Thin, delicate straight nose, thin lips. [laeknabladid.is]

  Skin hyperextensibility, easy bruising, tissue fragility, atrophic scars, loss of muscle tone, Kyphoscoliosis, and osteopenia (bones which are less dense than normal) are also possible clinical manifestations. [rarediseases.about.com]

  Ehlers-Danlos syndrome (EDS) is associated with easy bruising and bleeding complications in the majority. [ncbi.nlm.nih.gov]

  As basic structural support of organs is lost in Ehlers Danlos syndrome, therefore, patient experiences signs such as thin and fragile skin, ability to bend the joints to degrees that are not normally possible, easy dislocation of joints, easy bruising [symptoma.com]

• Mitral Valve Prolapse

  […] problems (mitral valve prolapse and others) Other types of EDS The other types of EDS are extremely rare. [web.archive.org]

  If mitral valve prolapse is diagnosed, monitoring and screening are indicated to address subacute bacterial endocarditis precautions. [emedicine.medscape.com]

  Ehlers-Danlos syndrome Cardiovascular Features of heart valve defects (particularly mitral valve prolapse) Features of aneurysms/dissections of the iliac, splenic, renal arterties, or the aorta Berry/saccular aneurysms of the cerebral arteries → features [amboss.com]

  " mitral valve prolapse in the ecocardiographic study. [ncbi.nlm.nih.gov]

• Spontaneous Rupture of Membranes

  Problems during delivery Due to the fragility of connective tissue, those with EDS are more prone to prelabour spontaneous rupture of membranes (SROM), including preterm SROM. [patient.info]

• Joint Dislocation

  The joints are hyperextendable. Joint dislocations are common. Wound healing is impaired. [symptoma.com]

  Causes generalized joint hypermobility, frequent joint dislocations, skin hyperelasticity, easy bruising, tissue fragility, low muscle tone and low bone mineral density. [gillettechildrens.org]

  Eye involvement Scoliosis common (curved spine) Arthrochalasia Type VII A and B 3% of all cases Noticeable joint hypermobility but less skin involvement Spontaneous joint dislocation common Dermatosparaxis Type VII C Other Type V 5% Extensive skin hyperelasticity [dermnetnz.org]

  Hypermobility type (formerly type III) Joint hypermobility is the major manifestation of this form of Ehlers-Danlos syndrome. Any joint can be affected, and dislocations are frequent. [medicinenet.com]

• Osteoporosis

  […] prevalent in hypermobile EDS, shows a higher prevalence in a study of patients with hypermobility.2 Its correlation has been demonstrated with chronic fatigue syndrome, fibromyalgia7 anxiety, depression, panic attacks, agoraphobia2,6,8 dysautonomia and osteoporosis [reumatologiaclinica.org]

  […] syndrome A lot - including some interesting biochemical anomalies known to be heavily influenced by nutrition Here is a partial list of overlapping features found in most of the disorders listed above: Mitral valve prolapse Low Bone Densities Osteopenia Osteoporosis [ctds.info]

  There was also generalized osteoporosis and supernumerary fingers that the authors have not found described in medical literature. In the familial antecedents there were thoracic alterarions of the same type, but they could not be studied. [archbronconeumol.org]

• Hyperextensible Joints

  Ehlers-Danlos syndrome (EDS) is a group of heritable disorders characterised by vast clinical heterogeneity ranging from the classic constellation of symptoms including skin hyperextensibility, joint hypermobility and skin fragility to the exceedingly [ncbi.nlm.nih.gov]

  Ehlers-Danlos syndrome (EDS) is a rare hereditary disorder that results in skin hyperextensibility, joint hypermobility, and tissue fragility. This syndrome is caused by a gene defect which results in faulty collagen synthesis. [medcomic.com]

  Both children manifested hyperelastic velvety skin, hyperextensible joints, papyraceous scars, flat feet and ectopic bone formation. [jclinepi.com]

  Clinical manifestations of EDS are most often joint and skin related and may include: Joints Joint hypermobility; loose/unstable joints which are prone to frequent dislocations and/or subluxations; joint pain; hyperextensible joints (they move beyond [ednf.org]

  Her father had full-blown Ehlers-Danlos syndrome of the classic type featuring skin hyperextensibility, widened atrophic scars, and joint hypermobility. [jpeds.com]

• Arthralgia

  Arthralgia is a predominant chief complaint that might lead to a diagnosis of HEDS patients. Similarly, arthralgia is also a major complaint in many rheumatological conditions (i.e. [nature.com]

  Correspondence to: R Grahame rodney.grahame{at}uclh.nhs.uk Joint hypermobility syndrome (JHS), previously known as benign joint hypermobility syndrome (BJHS), is a heritable disorder of connective tissue that comprises symptomatic hypermobility predisposing to arthralgia [doi.org]

  […] walking Osteopenia (low bone density) Stretchy ligaments and tendons Tearing of tendons or muscles Deformities of the spine, such as: Scoliosis (curvature of the spine), Kyphosis ( thoracic hump), tethered spinal cord syndrome Myalgia (muscle pain) and arthralgia [fmcpaware.org]

  Migraines and headaches, including postural headaches from spontaneous intracranial hypontension Fibromyalgia symptoms: Myalgia and arthralgia Other, less common signs and complications may include: Osteopenia (low bone density) Talipes equinovarus (club [medicalmarijuana.com]

• Blue Sclera

  Other eye symptoms may include nearsightedness ( myopia ), a blueish tint in the white part of the eyes (blue sclera), and retinal detachment. [rarediseases.info.nih.gov]

  However, there is no reason to think that environmental influences would not be important factors, especially since many of the individual features of connective tissue disorders, such as mitral valve prolapse, blue sclerae, pectus excavatum, dislocated [ctds.info]

  sclerae, small jaw, hypertrichosis Dominant COL1A1, COL1A2 Arthrochalasia, type VII A/B (Exon 6 COL1A1/2 ) Dermatosparaxis Type (EDS type VIIC) Soft and very thin, fragile skin (tearing of the skin), stretchy skin, easy bruising, joint hypermobility [uwcpdx.org]

  Blue sclera. Thin, translucient, fragile skin. Easy bruising. Pes planus. Recurrent joint dislocation.Chronic joint pains. Easy brushing. Varicose veins. Intestinal rupture. Pelvic adhesions. [laeknabladid.is]

• Acrogeria

  A slightly extensible, thin and translucent skin, associated with dysmorphic facies, acrogeria, multiple ecchymoses, hypermobility of the small joints, dorsal kyphosis, genu valgum, flat feet, elongated upper limbs, and low muscle tone were all evident [ncbi.nlm.nih.gov]

  Disease definition Ehlers-Danlos syndrome type IV, also known as the vascular type of Ehlers-Danlos syndrome (EDS), is an inherited connective tissue disorder defined by characteristic facial features (acrogeria) in most patients, translucent skin with [orpha.net]

  Other manifestations that may be found in the Vascular Type include: acrogeria (premature aging of the skin of the hands and feet); early onset varicose veins; arteriovenousfistula (an opening between an artery and vein), carotid-cavernousfistula (abnormal [tadcoalition.org]

• Cutis Laxa

  KEYWORDS: ATP6V0A2-related cutis laxa; Ehlers-Danlos-like skin lesions; autosomal recessive cutis laxa; type 2A (ARCL2A) [ncbi.nlm.nih.gov]

  […] recessive 1B EFEMP2 Del Dup NGS Cutis laxa, autosomal recessive IC LTBP4 Del Dup NGS Cutis laxa, autosomal recessive IIA ATP6V0A2 Del Dup NGS Cutis laxa, autosomal recessive IIIA ALDH18A1 Del Dup NGS Cutis laxa, autosomal recessive, type IIB & type IIIB [ctgt.net]

  Van Meekeren: De dilatabilitate extraordinaria cutis. In: Observations Medico-Chirugicales. Chapter 32. Amsterdam, 1682. N. A. Chernogubow: Über einen Fall von Cutis laxa. [whonamedit.com]

  Orphanet: 209 Medscape entry on Cutis Laxa [en.wikipedia.org]

  laxa AR 14 16 ELN Cutis laxa, Supravalvular aortic stenosis AD 78 113 FBLN5 Cutis laxa, Macular degeneration, age-related AD/AR 13 22 FBN1 MASS syndrome, Marfan syndrome, Acromicric dysplasia, Geleophysic dysplasia 3 AD 1465 2679 FBN2 Congenital contractural [blueprintgenetics.com]

• Thin Skin

  Thin, translucent skin (especially noticeable on the chest/abdomen) Easy bruising (spontaneous or with minimal trauma) Characteristic facial appearance (thin lips and philtrum, small chin, thin nose, large eyes) Acrogeria (an aged appearance to the extremities [uwcpdx.org]

  […] hypermobile EDS (hEDS) loose joints easy bruising muscle pain muscle fatigue chronic degenerative joint disease premature osteoarthritis chronic pain heart valve problems Symptoms of vascular EDS fragile blood vessels thin skin transparent skin thin [healthline.com]

  Symptoms include: Skin that bruises very easily, thin skin with visible small blood vessels, particularly on the upper chest and legs fragile blood vessels that can bulge or tear, resulting in serious internal bleeding, a risk of organ problems, such [metro.co.uk]

  The vascular type manifests as Thin skin Arterial or uterine rupture Bruising Small joint hyperextensibility In kyphoscoliosis type, the manifestations are: Hypotonia Joint laxity Congenital scoliosis Ocular fragility In arthrochalasia variant, the following [symptoma.com]

• Delayed Wound Healing

  Patients with vascular EDS are at higher risk for uterine rupture and postpartum hemorrhage. 8 Some further complications of delivery in EDS include abnormal fetal presentations, delayed wound healing, uterus atonia, hemorrhage, pelvic prolapse, deep [rheumatologyadvisor.com]

  History revealed skin hyperextensibility since early childhood, presence of easy bruisability & delayed wound healing but there was no dislocation of joints or relevant family history. His development milestones were apparently normal. [ncbi.nlm.nih.gov]

  wound healing with atrophic scarring. [3] Depending on the type, EDS can be diagnosed through laboratory studies or clinical examination. [emedicine.medscape.com]

• Subcutaneous Nodule

  The disorder started at approximately age 22 with the development of subcutaneous nodules. Hyperextensibility of the skin in this region developed within the subsequent five years. [jamanetwork.com]

  It is characterized by an unusual hyperelasticity and fragility of the skin and blood vessels, hypermobility of the joints, pseudotumors over the bony prominences, and disseminated, movable subcutaneous nodules. The subcutaneous nodules may calcify. [dxy.cn]

  nodules due to herniation of subcutaneous fatty tissue and resemble lipomas histologically. [ncbi.nlm.nih.gov]

  These are subcutaneous nodules due to herniation of subcutaneous fatty tissue and resemble lipomas histologically. The "reverse Namaskar sign" [6] [Figure 4], a valuable diagnostic sign has been described by Premalatha in patients with EDS. [idoj.in]

  These five cardinal signs are skin fragility, blood vessel fragility, skin hyperelasticity, joint hypermobility, and characteristic subcutaneous nodules. [malacards.org]

The clinical evaluation and family history are important diagnostic tools. The qualitative and quantitative analysis, sequencing and biochemical testing can establish the type of Ehlers Danlos syndrome present in the patients. Deletion and duplication testing can also be done to pinpoint the mutations that have occurred. Prenatal diagnosis pre implantation genetic diagnosis (PGD) for at-risk pregnancies can also be done.

• Platelet Aggregation Abnormal

  ROTEM™), platelet aggregation abnormalities can be expected in about 26% of patients [[ 21 ]]. New measures of platelet function such as PFA-100™ or Multiplate™ show normal values and should not be used routinely. [ncbi.nlm.nih.gov]

  ROTEM™), platelet aggregation abnormalities can be expected in about 26% of patients [[21]]. New measures of platelet function such as PFA-100™ or Multiplate™ show normal values and should not be used routinely. [ojrd.biomedcentral.com]

Conservative treatment of Ehlers Danlos syndrome is possible with the following:

• Braces for joint support to prevent dislocation
• Appropriate therapy for gastritis/reflux /delayed gastric emptying/irritable bowel syndrome
• Beta-blockers for progressive aortic enlargement
• Analgesics for chronic pain
• Pain-oriented counseling
• Exercise to improve muscle tone [8]
• Calcium and vitamin D supplements to increase bone density
• Echocardiogram for pregnant women with known aortic root dilation.
• Genetic counseling

Symptomatic treatment of bone, gastrointestinal, dental, and hematologic manifestation should be done accordingly [9] [10].

The surgical treatment is delayed in favor of physiotherapy for as long as possible. Long-term improvement in shoulder stability with Achilles tendon allograft reconstruction of the joint capsule has been reported.

The prognosis is poor for the patients suffering from the vascular variety of Ehlers Danlos syndrome. Complications leading to morbidity and sudden death are often seen.

Prognosis is better for the other types of Ehlers Danlos syndrome, although there is reduced quality of life.

Based on the clinical and molecular patterns, Ehlers Danlos syndrome has been subdivided into six clinical forms.

Classical

Genes other than those coding for collagen have been hypothesized to be involved in the classical type of Ehlers Danlos syndrome. In 30 to 50% of these cases, mutations in the genes COL5A1 AND COL5A2 that encode type V collagen have been observed [4] [5]. It is autosomal dominant.

Hypermobility

It is also an autosomal dominant disorder. The gene involved in its causation has not been detected as yet.

Vascular

An autosomal dominant disorder, the vascular type arises due to the mutations in COL31A gene encoding the type III collagen [6].

Kyphoscoliosis

Inherited as an autosomal recessive trait, kyphoscoliosis type arises due to the mutations in the genes encoding lysyl hydroxylase, an enzyme responsible for hydroxylation of lysine residues during collagen synthesis.

Arthrochalasia

Having an autosomal dominant pattern of inheritance, the arthrochalasia variant of Ehlers Danlos syndrome arises due to the mutations in COL1A1 or COL1A2 genes, resulting in formation of structurally abnormal pro α 1 or pro α 2 chains that resist cleavage of N-terminal peptides, a crucial step in type I collagen synthesis.

Dermatosparaxis

It is an autosomal recessive disorder, caused by defect in the conversion of procollagen to collagen.

Being a genetic disorder, the incidence of Ehlers Danlos syndromes, worldwide is 1:5,000 people worldwide. The hypermobility and classical variants are more common. Hypermobility Ehlers Danlos syndrome affects 1 in 10,000 to 15,000 while classical type occurs in as many as 1 in 20,000 to 40,000 people worldwide. Other forms of Ehlers Danlos syndrome are even rarer.

The disease is equally prevalent in all races. Ehlers Danlos syndrome is inherited in autosomal pattern [7]. It occurs without the involvement of sex chromosomes, therefore both sexes are equally affected. Although present at birth, it becomes apparent much later.

Median life expectancy for patients with vascular type Ehlers Danlos syndrome is 50 years. Average life span of patients with Ehlers Danlos syndrome is 50 years. Only the spontaneous rupturing of vessels and intestines can pose life threatening risks. Uterine rupture during pregnancy can also endanger maternal and neonatal life.

Collagen is an integral part of the connective tissue. Faulty synthesis and functioning can give rise to hyperextensibility of the skin. As a result, grotesque deformities arise. Joint dislocations become common. Skin becomes lax and prone to injuries.

Collagen deficiency in arterial wall causes thinning of vascular walls which can rupture spontaneously. Being a part of scar tissue, fault in the laying down of scars after injury can lead to delayed wound healing and easy bruising even after minor injuries.

Type I collagen is present in muscles. Its deficiency leads to impairment of motor functions and difficulty in starting and carrying out the movements (hypotonia). Cramps, easy fatigability and malaise ensue. Being part of the connective tissue of the valves, deficient and faulty collagen can also lead to dysfunction of the valves.

The vitreous humor of eye also contains collagen, the deficiency of which can lead to visual disturbances. Being part of the bone and cartilage, deficiency of collagen also induces bony deformities like scoliosis.

Constant surveillance of at risk population with family history of Ehlers Danlos syndrome should be done as a primary preventive measure. Resistance exercise can increase muscle tone. High impact activities should be avoided. Crutches, canes, and walkers should be used but with caution, as they tend to exert pressure on the upper extremities.

Secondary interventions, like calcium and vitamin D supplementation should also be done.

Ehlers Danlos syndromes are a genetically inherited, heterogeneous group of disorders that arise due to abnormality of collagen fibers [1]. There are several different types of Ehlers Danlos syndrome depending upon the type of the abnormality [2][3]. The abnormality may arise in the structure or synthesis of collagen or in the proteins that closely interact with collagen. The defect may also arise in one of the proteins closely associated with collagen, like those taking part in its post transcriptional modification.

Collagen provides basic structural support to the connective tissue and is found in tendons, ligaments, vascular wall, cornea, cartilage, bone, gut, muscles and in the skin in abundance. Therefore, the changes in the structure and functions of collagen can lead to the manifestation of a wide range of clinical symptoms.

Ehlers Danlos syndrome is a syndrome in which anomalies arise in skin and other soft tissues of the body. The basic fault lies in the genetic makeup of the individual therefore, Ehlers Danlos syndrome tends to run in families.

As basic structural support of organs is lost in Ehlers Danlos syndrome, therefore, patient experiences signs such as thin and fragile skin, ability to bend the joints to degrees that are not normally possible, easy dislocation of joints, easy bruising even after minor injuries, bursting of blood vessels, difficulty in starting and maintaining movements, easy fatigability and delayed wound healing.

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