Introduction
Ehlers-Danlos Syndrome (EDS) consists of a group of defects of the connective tissue transmitted to a person through genetic inheritance. The disease is primarily a defect of the structural protein collagen. Depending on the extent of this defect the prognosis of the condition can range from favorable to life-threatening; there is no known treatment for the condition; however, it can be managed symptomatically (Lawrence, 2005; Tinkle, 2008).
The condition got its name from a combination of two names of Dr. Edward Ehlers, a Dane and Dr. Henri-Alexandre Danlos, a Frenchman; these two were the first to describe the condition.
Epidemiology
As mentioned before, the condition is hereditary; worldwide, the condition is diagnosed in approximately one in every five thousand births. The condition does not have a race or gender predilection and incidence is evenly distributed in the human population in the world. This had been initially pegged at about one case in every 250,000-500,000; however, these figures have been disputed from an increased volume of medical research information and betterment of diagnostic procedures (Lawrence, 2005).
EDS has six different types; the prevalence of these types is not uniformly distributed (Christos et al, 2006). The condition with the highest representation is the Hypermobility EDS; the second-highest prevalence is that of Classical EDS. The rarity of the condition increases dramatically with the other four categories; for example, less than 10 incidences of Dermatosparaxis EDS have been documented worldwide.
Pathogenesis
The disease is caused by mutation of genes that lead to defects of fibrous and enzyme proteins coded for by the genes. These defects are in the form of changes in collagen protein that affects its strength resulting in the weakening of connective tissues in various organs; various syndromes distinct arise from this weakening in the skin, vasculature, bones and organ tissue parenchyma (William et al, 2005).
Various patterns of inheritance are responsible for the transmission of defective genes to the people having the condition. This can either take an autosomal dominant pattern whereby only one copy of the defective gene is needed to cause the defect. Alternatively, the inheritance can take an autosomal recessive pattern whereby both copies of the genes coding for the offending protein need to be defective so as to express the offending phenotype. The clinical signs experienced are mostly attributed to a reduced amount of Type III collagen.
Clinical presentation
Depending on the system most severely affected by the condition as coded for by the defective genes, there is a wide range of clinical signs associated with EDS. The three most affected organs are the blood vessels, the skin and joints. The skin is usually, smooth and stretchy; bruises occur very easily and wounds heal poorly with excessive formation of scar tissue Blood vessels show poor development and are very fragile thus increasing the possibility of the skin being bruised (Hans-Joachim, 1999; Bieghton et al, 1998).
In all classes of EDS, the joints are affected; defects of the collagen that makes most of the tendons and ligaments that support joints make them less tightly bound thus increasing their normal range of motility dramatically, a condition known as hypermobility. Individuals with hypermobility are very susceptible to joint injuries such as strains, sprains, joint luxations and subluxations and can even suffer from fractures involving articular surfaces. A child presented to a medical professional with signs of EDS often raises suspicions of abuse due to the rarity of the condition and lack of experience in diagnosis (Beighton et al., 1998).
EDS has been classified into six main syndromes based not only on the organ system affected by the specific defective gene causing the disease as identified by genetic testing. The latter is of uttermost importance due to the variation of signs seen by individuals with EDS despite having defects on the same gene.
Hypermobility EDS
Of all the variants of Ehlers-Danlos syndrome, this has the highest prevalence and incidence. It is seen in an average of one in every fifteen to twenty thousand people. The clinical representation of this disease may not immediately drive a physician towards a diagnosis of EDS; many cases may be misdiagnosed as fibromyalgia. The inheritance of this variant is via the autosomal dominant mechanism.
The main system to be affected by this variant is the skeletal system particularly the joints; however, the signs are not isolated here. The joints are basically unstable thus having more probability of injuries and increased range of motion. The skin is also affected by this variant seen as being smooth and bruising very easily. The heart usually has a valvular disease such as prolapse of the mitral valve that can be progressive and potentially fatal.
Complications
The vertebral column can be severely affected by collagen deficiency resulting in deformities such as scoliosis where the spine deviates laterally; or kyphosis where the spine deviates caudally resulting in a hump. Other spinal defects include Arnold-Chiari malformation, Tethered spinal cord syndrome and basilar invagination. The condition may eventually lead to progressive compression of nerves on areas where nerves and plexuses have intimate contact with joints; with accompanying neuropathies such as acroparesthesia and carpal tunnel syndrome.
The effects on joints may also extend to the bones and muscles; conditions such as osteopenia (softening and reduction in density of bone due to loss of the mineral matrix); and weakness of muscles and myalgia are seen. The digestive system may also be involved with conditions such as functional gastritis and irritable bowel syndrome being experienced by an individual with EDS.
Classical type EDS
This is the second most prevalent form of EDS affecting an estimated two to five people in every one hundred thousand. This variant has the most effect on the skin and joint resulting from defects to collagen type-I and type-V.
As mentioned before, the skin is a major point of expression of the defective genes; the phenotypes seen include smoothness and extreme elasticity. The skin heals very poorly with excessive scar tissue formation; additionally, the mechanism of wound contraction is affected resulting in excessively wide scars with a predilection for the elbows, knees and parts of the face.
The joints are also affected by this variant with the typical instability and increased risk of dislocation, particularly the patella and shoulder joints. The ability of infants to support their weight on unstable joints results in poor development of muscle tone and will not achieve locomotor activities as efficiently as a normal infant.
Vascular EDS
This is the most severe form of EDS with an average life of 48years in persons diagnosed with this variant. However, there still is no consensus regarding this figure due to the low number of samples used to calculate it as the cases are grossly under-diagnosed and usually at necropsy. The vascular type affects an average of one in every one hundred thousand people (Germain, 2006).
This variant results from a defect on collagen type-III resulting in the weakness of various organs containing this protein. Hypermobility is typically present and more pronounced in the joints of the fingers and the toes. The skin is delicate, thin and translucent; commonly, the veins can be seen coursing on the thoracic region; bruising is also very easy. The blood vessels in the skin and other organs are weak and tend to develop aneurysms easily (Germain, 2006)].
The defective collagen also affects the integrity of other organs and may manifest in ruptures of the arteries, intestines and even the uterus; the final one, in particular, has far-reaching effects on the ability of the person to bear children as the fragility may cause a potentially fatal rupture during pregnancy (Germain, 2006; Krzysztof, 2005).
Diagnosis
Vascular EDS is caused by a defect in the COL3A1 gene responsible for coding for one of the chains that form type-III collagen. The condition can be diagnosed by laboratory examination of skin biopsies to identify this defect on the collagen; this test has a 95% probability of correctly identifying a person with vascular EDS. DNA testing for pregnant mothers for a possible defect in the genotype of the fetus is also available.
Khyphoscoliosis EDS
This variant is extremely rare with less than 60 documented cases; the condition results from a defect of the PLOD gene on chromosome1 of the genome that is responsible for the production of the Lysyl hydroxylase enzyme. The gene is transmitted in an autosomal dominant fashion.
The vertebral column is severely affected by this variant seen as scoliosis in infants; the severity of which is progressive resulting in an inability to walk by the time the person attains the age of twenty. Neonates show poor muscle tone which persists resulting in poor or failure of attainment of motor milestones (Iglesias & T. Renard, 1998).
The skin is very fragile and easily injured; blood vessels and bones may also be affected. The eyes, in particular, are affected by this variant causing them to be extremely fragile which sometimes result in blue tinting of the white area and may even result in rupture of the globe (Royce et al, 1990).
Diagnosis
Measurement of hydroxylysisl pryridinoline in urine samples is very sensitive and specific to this variant and is a useful diagnostic tool. However, for proper and complete diagnosis, several criteria have to be used including the identification of clinical signs typical to the condition.
A pregnant mother can undergo prenatal testing involving an amniocentesis and DNA examination of the fetal cells especially in families with a laboratory-confirmed history of this variant of EDS (Krzysztof, 20050).
Arthrochalasia EDS
This is a very rare variant of EDS with less than 30 documented cases worldwide; it results from defects of either of two building blocks of collagen type-I known as proa1(I) type-A and proa2(I) type-B. The defective genes are inherited in an autosomal dominant fashion.
The main feature that makes this condition a distinct variant is the occurrence of bilateral congenital luxation of the hip joints seen at birth; this is accompanied by severe generalized joint hypermobility with possible early osteoarthritis.
Other systems are also involved; the skin is typically hyperelastic, fragile and easily damaged; and heals with excessive scarification. The vertebral column may exhibit kyphosis and scoliosis; there may be general fragility of tissues and osteopenia. The condition is diagnosed via clinical manifestation, demonstration of defective collagen in skin biopsies and DNA analysis for defective genes.
Dermatosparaxis EDS
This is an extremely rare form of the syndrome with less than 10 documented cases worldwide. The condition is inherited in an autosomal dominant fashion; and results from defects in the enzyme procollagen-I N-terminal peptidase. Although the skin does not scar as severely as in other variants, it is extremely fragile and bruises as easily. Additionally, looseness of the skin leads to sagging giving even young people individual an aged face. The joints are also involved and are unstable and hypermobile. Diagnosis involves documentation of clinical manifestation and confirmation by demonstration of defective proteins in skin biopsies.
Notes on classification;
While the above classification may seem very distinct, the true nature is that there is a wide range of clinical signs that this disease can exhibit that make it hard to differentiate one variant from the other simply using clinical examination; this can easily lead to the wrong diagnosis of the condition.
Management and follow-up
As mentioned before, there is no known cure for the condition; the only thing that can be done is to make sure that the person avoids situations that may lead to physical harm; such as working with sharp objects. Wounds on the skin should be approached with great attention to avoid complications such as disfiguring scar formation; in this case, surgical treatment may be made difficult by the inability of the skin to hold sutures thus causing wound dehiscence. The skin should get extra protection from irradiation by the sun by staying in the shade (wearing hats) and sunscreen (Beighton et al, 1998).
People diagnosed with the condition should avoid activities that would lead to overextension of joints such as physical contact sports (football, wrestling) or those that put extra strain on joints such as rock-climbing. In addition to this, a physician may be compelled to prescribe braces for severely affected joints; some may also require surgical reconstruction. Physical therapy may be necessary to strengthen muscles that lack tone and suffer from disuse atrophy; and occupational therapy to enable a person to take better care of themselves and to operate with their disability (Tinkle, 2008).
It is important to screen expectant mothers for telltale genes that may predict the occurrence of EDS; from here, the choice between elective termination and preparing to raise a sick infant loom large. In parents already raising such a child, they should be given maximum information about the condition so as to take care of their child better and to give it adequate emotional support during the difficult periods that may take a toll on the esteem of such a person.
Summary
- Ehlers-Danlos syndrome is a defect of collagen, a protein forming connective tissue in any organs
- The defect is caused by defects in genes coding for the protein; therefore, the syndrome is hereditary
- The syndrome is rare; with a varying rarity of the different variants; some are extremely rare with less than 10 documented cases
- The syndrome affects various organs and can have life-threatening effects
- The most commonly affected organs are the skin and the joint resulting in soft fragile skin and hypermobility of joints
- There is no known cure for the syndrome, however, the symptoms can be managed
- The syndrome can be diagnosed by demonstrating the defective protein in connective tissue biopsies or defective genes in the genome; prenatal detection of the condition in fetuses is also possible.
References
- Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ (1998): Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK): American Journal of Medical Genetics 77 (1): 31–7.
- Christos D. Karkos, Vishal Prasad, Umasankar Mukhopadhyay, George J. L. Thomson and Alan R. Hearn (2000): Rupture of the Abdominal Aorta in Patients with Ehlers-Danlos Syndrome: Annals of Vascular Surgery, Volume 14, Number 3, 2000
- Germain D. P. (2006): The vascular Ehlers-Danlos syndrome: Current Treatment Options in Cardiovascular Medicine, Volume 8, Number 2, 2006
- Hans-Joachim Mentzel, Jörg Seidel, Susanna Vogt, Lothar Vogt and Werner A. Kaiser (1999): Vascular complications (splenic and hepatic artery aneurysms) in the occipital horn syndrome: report of a patient and review of the literature: Pediatric Radiology, Volume 29, Number 1, 1999
- Iglesias J. L. and T. Renard (1998): Diaphragmatic hernia in an 8-year-old with Ehlers-Danlos syndrome: Pediatric Surgery International, Volume 13, Number 8, 1998
- Krzysztof M. Kuczkowski (2005): Ehlers–Danlos syndrome in the parturient: an uncommon disorder–common dilemma in the delivery room: Archives of Gynecology and Obstetrics, Volume 273, Number 1, 2005
- Lawrence E.J (2005): The clinical presentation of Ehlers-Danlos syndrome: Advanced Neonatal Care 5 (6): 301–14.
- Royce P.M., B. Steinmann, A. Vogel, U. Steinhorst and A. Kohlschuetter (1990): Brittle cornea syndrome: An heritable connective tissue disorder distinct from Ehlers-Danlos syndrome type VI and fragilitas oculi, with spontaneous perforations of the eye, blue sclerae, red hair, and normal collagen lysyl hydroxylation. European Journal of Pediatrics, Volume 149, Number 7, 1990
- Tinkle Brad (2008). Issues and Management of Joint Hypermobility: A Guide for the Ehlers-Danlos Syndrome Hypermobility Type and the Hypermobility Syndrome. Left Paw Press, Greens Fork, Melanie Pepin. Journal of Genetic Counseling
- William J; Berger, Timothy; Elston, Dirk (2005): Andrews’ Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. Page 512