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Ehlers Danlos Syndrome

Ehlers-Danlos Syndrome

The Ehlers-Danlos syndrome refers to a group of rare, inherited connective tissue disorders that affect collagen structure and function, marked by hyperplasticity of skin, tissue fragility and hyper-flexible joints.


Presentation

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:

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

In kyphoscoliosis type, the manifestations are:

In arthrochalasia variant, the following findings are present.

The dermatosparaxis type shows up as:

Easy Bruising
  • Vascular Ehlers-Danlos Syndrome (VEDS), previously called Ehlers-Danlos syndrome type-IV, is a heterogeneous group of heritable connective tissue disorders characterized by thin, translucent skin, easy bruising, arterial, intestinal, and/or uterine fragility[ncbi.nlm.nih.gov]
  • Ehlers-Danlos syndrome (EDS) is associated with easy bruising and bleeding complications in the majority.[ncbi.nlm.nih.gov]
  • bruising, and variable musculoskeletal symptoms.[ncbi.nlm.nih.gov]
  • 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.[symptoma.com]
  • In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising.[ncbi.nlm.nih.gov]
Marfanoid Habitus
  • 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]
  • habitus (i.e. tall, slim physique, span:height ratio 1.3, upper:lower segment ratio Abnormal skin: striae, hyperextensibility, thin skin, papyraceous scarring Eye signs: drooping eyelids, myopia, antimongoloid slant Varicose veins or hernia or uterine[medical-dictionary.thefreedictionary.com]
  • Marfanoid habitus. Talipes equinovarus. Refractive errors (myopia, hypermetropia). Skin fragility (easy bruising, friable skin, poor wound healing), widened atrophic scarring. Scleral and ocular fragility/rupture. Microcornea. Facial dysmorphology.[patient.info]
  • habitus Microcornea Osteopenia/porosis Positive family history Arthrochalasis Generalized joint hypermobility with recurrent subluxations Skin hyperextensibility AD COL1A1, COL1A2 (recurrent mutations) Congenital bilateral hip dislocation Tissue fragility[ojrd.biomedcentral.com]
Mitral Valve Prolapse
  • These are outward signs of this syndrome which seem harmless while some of the more serious symptoms might concern the skin, digestive processes, and even mitral-valve prolapse a heart condition.[fmcpaware.org]
  • Additional features include fatigue, development of hernias, increased risk of aortic root dilation, and mitral valve prolapse. Postural orthostatic tachycardia syndrome (POTS) is a type of dysautonomia that may affect patients with EDS.[medcomic.com]
  • valve prolapse, which creates an increased risk for infective endocarditis during surgery, as well as possibly progressing to a life-threatening degree of severity of the prognosis of mitral valve prolapse) Difficulty regulating own body temperature[medicalmarijuana.com]
  • Results of consultations in ophthalmology and cardiology eliminated the possibility of detached retina or mitral valve prolapse. The genetics and rheumatology consults confirmed a diagnosis of EDS type II or III.[cda-adc.ca]
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]
  • […] 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]
  • […] for 3/12 in four or more joints Minor criteria Current/historic Brighton score of 1, 2 or 3/9 (0, 1, 2, 3/9 if 50 years old) Arthralgia for minimum of 3 months in 1-3 joints, or back pain for minimum of 3 months, or spondylosis/spondylolysis/spondylolisthesis[medical-dictionary.thefreedictionary.com]
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]
  • Clinical manifestations of an Ehlers-Danlos syndrome 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[ehlers-danlos.com]
Cutis Laxa
  • Through a survey of more than 20 patients with a specific subgroup of autosomal recessive congenital cutis laxa (ARCL), namely ATP6V0A2-related cutis laxa, we noted that the clinical findings on three patients included pretibial pseudo-ecchymotic skin[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]
  • Chernogubow: Über einen Fall von Cutis laxa. (Presentation at the first meeting of Moscow Dermatologic and Venerologic Society, Nov 13, 1891.) Monatshefte für praktische Dermatologie, Hamburg, 1892, 14: 76. E. L. Ehlers: Cutis laxa.[whonamedit.com]
  • laxa AR 12 15 ELN Cutis laxa, Supravalvular aortic stenosis AD 72 105 FBLN5 Cutis laxa, Macular degeneration, age-related AD/AR 13 21 FBN1 MASS syndrome, Marfan syndrome, Acromicric dysplasia, Geleophysic dysplasia AD 919 2548 FBN2 Congenital contractural[blueprintgenetics.com]
  • […] of cutis laxa, or OHS, is caused by mutations in ATP7A and was discussed earlier.[nature.com]
Thin Skin
  • 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]
  • skin transparent skin thin nose protruding eyes thin lips sunken cheeks small chin collapsed lung heart valve problems Doctors may use a series of tests to diagnose EDS (except for hEDS), or rule out other similar conditions.[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]
  • People with vEDS may have: 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[nhs.uk]
Delayed Wound Healing
  • wound healing Kyphoscoliotic EDS Kyphoscoliotic EDS (kEDS) is rare.[nhs.uk]
  • wound healing with atrophic scarring. [3] People with lax joints and multiple scars were first described in the medical writings of Hippocrates, dating back to 400 BCE. [ 4 ] In 1892, Dr.[emedicine.medscape.com]
Acrogeria
  • 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]
  • The skin on the extremities appears prematurely aged, hence the term acrogeria, and the subcutaneous veins are highly visible.[ojrd.biomedcentral.com]
  • The skin of the hands and of the back appears to age prematurely (acrogeria). The eyes are widely spaced, the nose is narrow, the ear lobes are atrophied and the hair is thin.[cda-adc.ca]
  • […] hypermobility Chronic Pain [11] Recurring joint dislocations Chronic joint/limb pain Positive family history Vascular [7] [12] AD Type IV Thin, translucent skin Arterial/intestinal/uterine fragility or rupture Extensive bruising Characteristic facial appearance Acrogeria[physio-pedia.com]
Subcutaneous Nodule
  • Ehlers-Danlos syndrome a congenital hereditary syndrome of joint hyperextensibility, hyperelasticity and fragility of the skin, poor wound healing leaving parchment-like scars, capillary fragility and subcutaneous nodules after trauma.[medical-dictionary.thefreedictionary.com]
Blue Sclera
  • Functional bowel disorders (functional gastritis, irritable bowel syndrome) Gastroparesis Nerve compression disorders (carpal tunnel syndrome, acroparesthesia, neuropathy) Vascular skin conditions: Raynaud's phenomenon, Livedo reticularis Blue sclera[medicalmarijuana.com]
  • Blue sclerae. There are fourteen minor criteria. Minimal criteria required to suggest BCS are the first major criterion, plus either: at least one other major criterion; or three minor criteria. Spondylodysplastic EDS Major criteria are: 1.[raredr.com]
  • 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]
  • Weakness of supporting structures This is due to weak, lax, and less-effective connective tissues, and can manifest as: Eye signs: drooping eyelids or antimongoloid slant, blue sclera, myopia Muscle hypotonia: muscles may feel doughy on palpation Mitral[online.epocrates.com]
  • OI is characterized by bone fragility specifically, however additional features can include blue sclerae, progressive skeletal changes and hearing loss. Some individuals may demonstrate features of both EDS and OI.[invitae.com]
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]
Peripheral Neuropathy
  • Patients with hypermobility type display skin hyperextensibility and joint laxity, which can result in chronic joint instability, dislocation, peripheral neuropathy, and severe musculoskeletal pain.[ncbi.nlm.nih.gov]

Workup

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.

Pericardial Effusion
  • On the second day, haemodynamics suddenly deteriorated because of a rapid accumulation of bloody pericardial effusion, and the patient died.[ncbi.nlm.nih.gov]
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.[ojrd.biomedcentral.com]

Treatment

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.

Prognosis

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.

Etiology

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.

Epidemiology

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.

Sex distribution
Age distribution

Pathophysiology

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.

Prevention

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.

Summary

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.

Patient Information

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.

References

Article

  1. Patel AB, Renge RL. Ehler-Danlos syndrome. Indian pediatrics. Aug 2002;39(8):784-785.
  2. Parikh F, Sivaramakrishnan A, Pai-dhungat JV. Type VI Ehler Danlos Syndrome. The Journal of the Association of Physicians of India. Aug 2004;52:631.
  3. Ciarloni L, Perrigouard C, Lipsker D, Cribier B. [Ehler-Danlos syndrome type VIII]. Annales de dermatologie et de venereologie. Mar 2010;137(3):194-197.
  4. Wenstrup RJ, Florer JB, Willing MC, et al. COL5A1 haploinsufficiency is a common molecular mechanism underlying the classical form of EDS. American journal of human genetics. Jun 2000;66(6):1766-1776.
  5. Wenstrup RJ, Florer JB, Davidson JM, et al. Murine model of the Ehlers-Danlos syndrome. col5a1 haploinsufficiency disrupts collagen fibril assembly at multiple stages. The Journal of biological chemistry. May 5 2006;281(18):12888-12895.
  6. Eder J, Laccone F, Rohrbach M, et al. A new COL3A1 mutation in Ehlers-Danlos syndrome type IV. Experimental dermatology. Mar 2013;22(3):231-234.
  7. Araki T, Samejima T, Sako T. [Ehler-Danlos syndrome occurring in a family]. Seikeigeka. Orthopedic surgery. Oct 1966;17(10):822-826.
  8. Bathen T, Hangmann AB, Hoff M, Andersen LO, Rand-Hendriksen S. Multidisciplinary treatment of disability in ehlers-danlos syndrome hypermobility type/hypermobility syndrome: A pilot study using a combination of physical and cognitive-behavioral therapy on 12 women. American journal of medical genetics. Part A. Dec 2013;161A(12):3005-3011.
  9. Bergqvist D, Bjorck M, Wanhainen A. Treatment of vascular Ehlers-Danlos syndrome: a systematic review. Annals of surgery. Aug 2013;258(2):257-261.
  10. Jones ML. Orthodontic treatment in Ehlers-Danlos syndrome. British journal of orthodontics. Jul 1984;11(3):158-162.

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Last updated: 2018-06-21 19:15