Introduction

There are many problems that surround us on a daily basis; however, the worst of them come due to illness. With the spread of many diseases on a regular basis, people are getting themselves admitted to many different hospitals to get treated. Most people get themselves checked for some of the common diseases known to mankind. These diseases can have multiple lines of action, with easy diagnosis and treatment options. Therefore, when someone presents with any disease which is a little out of the ordinary, they get easily missed as well as misdiagnosed, such is the case with  Ehlers-Danlos Syndrome.

Ehlers-Danlos Syndrome is a rare genetic disorder, which involves the many systems of the body, but mostly the musculoskeletal system. There are many types of this disease and it becomes extremely hard for physicians to diagnose this condition due to its vague symptoms. People, who live with this condition, usually have no clue what degree of pathogenesis is happening inside of their body, neither do they know the right kind of care they need.

In recent times, there has been a lot of work done by many societies formed to promote awareness about Ehlers-Danlos Syndrome. It is known as a heterogeneous group of disorders that presents with joint hyper flexibility, skin fragility, as well as hyperextensibility. There have also been many research societies established to learn and explore more about this disease and come up with better management and treatment options. The people who suffer from this rare genetic disorder sometimes do not require a lot of medications and have a good prognosis; however, some individuals suffer all their life without properly getting diagnosed.

It is really important to spread awareness about this disease so that more people who have similar symptoms can recognize their condition and be able to use conventional methods in order to prevent themselves from any serious issues. The following article touches on the many important aspects of this disease so that it can help people identify this syndrome earlier than usual.

What is the pathophysiology of this disease? Why does it happen?

As mentioned, Ehlers-Danlos Syndrome is a genetic disorder and the main problems arise due to the mutations that occur in the DNA of the ones suffering from this condition. This genetic defect can therefore be passed on to the offspring’s and hence can play a big role in its occurrence in a family. There are many different types of conditions associated with this disorder which is why it is largely grouped into many different classes.

All the different types of this disease present themselves in different ways and forms, has different pathologies associated with them, different treatment options as well as different rates of prognosis.

In order to understand, how and where the abnormality occurs in the body, it is vital to understand what happens without mutations in the genetic makeup. The main defect apparent seen in this condition is due to problems in the formation as well as alignment of connective tissue. This connective tissue is called collagen and has many different types present in the body, each of them having different functions in the body.

There are 13 different sub-types of collagen found in the body. These collagen fibrils are organized in a specialized manner and provide strength to the blood vessels, skin, joints, and bone. Irregularities in the shape or arrangement of these collagen fibrils are what results in disruptions in the structure of these particular tissues and organs in the body. These fibrils can be abnormally large or short or sometimes they are not even formed.

With the many different types of EDS discovered, it has been discovered that at least 6 of them are due to defects in the synthesis of collagen.

• Decreased production of type III collagen and defects in it are seen in the vascular form (Type IV) of EDS, which is an autosomal condition, and have the highest chances of appearing in offspring’s of those with this condition. The mutations occur in the genes that decode collagen type III, which increases the fragility of the arterial, intestinal and can be associated with uterine ruptures resulting in the premature death of the fetus.
• In type V and VI forms of EDS, there are specific enzyme deficiencies such as hydroxylase and Lysyl oxidase, which hinder collagen synthesis as a whole.
• Type VII also presents with an enzyme deficiency. This enzyme is important for activating the pro-collagen state by removing the terminal peptides off with the help of the proteases.
• It has been seen that type IX to be associated with abnormal copper metabolism, this leads to a number of problems in the body.
• In type X, cell-to-cell adhesion molecules such as fibronectin do not function properly, which contributes to loose lax skin in patients of EDS.

Type I and type II have the classic variety of EDS. The genetic mutations involved are different from the rest of the types. In these two types of EDS, the main problem occurs when a genetic transmission of information is hindered due to low levels of mRNA.

Signs and symptoms

There are a range of signs and symptoms that appear in people suffering from EDS. Since there are a lot of variations in the different types of EDS, it can be the reason why not many physicians can diagnose it on the first go. Apart from the usual physical signs, most often the other symptoms are due to the damage happening internally. Here is a list of signs and symptoms that can help narrow down the search for EDS.

• More than normal joint flexibility
• Extremely stretchable skin
• Slow and impaired wound healing, due to fibroblast defect. Therefore easy scarring
• Bending of the spine (kyphoscoliosis)
• Hearing loss
• Muscle pain and weakness
• Easily get fatigued
• Problems standing for long hours
• Joint dislocations
• Dental problems are common in these individuals such as hypodontia of permanent teeth
• Difficulty maintaining proper posture
• Problems maintaining gait
• Postural incontinence
• Gastrointestinal issues; diarrhea
• Frequent anxiety attacks

Prevalence

Since Ehlers-Danlos Syndrome is a rare genetic disorder, its prevalence is less. However, it can also be due to less reporting of this disease since many people with this condition can stay undiagnosed all their life.

According to research, it has been seen that EDS is reported to be in 1 out of 400,000 people. The most fatal form of EDS is the vascular type which has been estimated to be in 1 out of 50,000 live births.

It has been seen that this syndrome is present equally in males and females, with a slightly more predominance in Caucasians.

All the clinical manifestations of this syndrome are only apparent in individuals when they physically start showing signs of this disease. Therefore, it is mostly diagnosed in people in their teen years or in their twenties.

Procedures of diagnosis

Proper History Taking Is Very Important

The procedures that take place to diagnose this condition unfortunately are based on very vague symptoms. This makes the process of diagnosing this condition very difficult. Since the defect in the formation of collagen exists since birth, there are only a few physical signs that help in its diagnosis.

The first and foremost step knows the history of the person. Anyone with hyperelastic skin and extremely mobile joint should be taken into consideration for having EDS.

Usually, the first signs that appear are joint dislocation, especially of the shoulder. This joint has a wide range of motion and anyone with hypermobile joints can hence dislocate it very easily.

It is then important to further investigate whether the person has problems walking, feels fatigued, and tired a lot. Muscle weakness and pain are also chronic in nature and can give clues. Gastrointestinal dysmotility, urinary incontinence, several scars, as well as the presence of some sort of dental pathology can help to investigate EDS.

There are also certain conditions that can be linked to EDS, such as Multiple Sclerosis, Rectal ulcer syndrome, absence of inferior labial, metaplastic synovial cysts as well as splenic rupture. Therefore, it is important to evaluate these patients for EDS, when presented with these conditions.

It has also been seen in some cases that people with gastric adenocarcinoma can also have type IV EDS.

Imaging Studies

People, who are suspected to have EDS, then have different types of imaging studies to confirm and closely inspect which type of EDS they have. These imaging studies show calcification of nodules. These calcified or hard nodules are movable and are often present in the subcutaneous tissue, hence are a little deep.

MRI when done on patients with hypermobility type of EDS, show specific white matter lesions as well!

Tests to diagnose in the prenatal period

For every different type of EDS, there are different tests that can be performed.

Prenatal genetic testing can be helpful in the diagnosis of type IV EDS. whereas, concentrations of Lysyl hydroxylase can also be done during pregnancy to diagnose type VI EDS.

Histologic Findings

The last step for confirmation of the diagnosis of EDS requires help from histology. In this procedure, a small part of the skin is biopsied to analyze the arrangement of tissues and cells. All the abnormalities in this skin biopsy are noted depending on the arrangement of the collagen fibrils.

A whorled appearance with irregular orientation and size of fibers is noted. Electron microscopy shows striation do the collagen fibers, which are of various sizes.

Treatment options

The treatment options for EDS are not very satisfactory as the main pathology lies in the genetic makeup of the person. However, there are ways to manage this condition from progressing rapidly and overall improving the quality of life of those that are affected by this syndrome.

Medicinal treatment options 

A report showed that people with type VI EDS showed improvements after consuming vitamin C. this greatly improved their scars and also decreased their bleeding time. Therefore, it can all aid to better wound healing and a lot healthier skin.

Patients are also prescribed multiple pain medications (analgesics) to relieve off backache, as well muscle pain. However, a few people have also been advised to switch to opioids due to extreme intolerable pain which cannot otherwise be relieved by analgesics.

Antidepressants are also known to help patients of EDS, to decrease feelings of anxiety and depression.

Most of these patients receive physical therapy to help strengthen their bones and joints. There are many rehabilitation programs that help patients of EDS to regain their musculoskeletal functions. These programs go a long way in helping patients with EDS, through their scapular motor control program.

Surgical interventions

Special care needs to be taken before and after surgery of patients with EDS. There are many instances where a patient with EDS might require surgery.

Type IV, or vascular type of EDS, is what causes high rates of atherosclerosis, and can lead to rupture of vessels. This is a very serious condition and can be linked to uterine rupture or dissection of vessels anywhere in the body. Stroke, as well as gut bleeding, can also occur, which requires immediate treatment. Great importance needs to be taken in order to save from any airway or cervical spine trauma.

As for the rest of the patients with Ehlers- Danlos Syndrome, there are surgical procedures to re-excise scars to give excellent cosmetic results. However, these cosmetic repairs are often weighted to see if they can pose a risk of bleeding out or hemorrhage.

Pregnant women who require a Caesarian section are given local anesthesia rather than general to avoid further complications. Recombinant factor VIIa has shown great results in preventing excessive bleeding in patients with vascular type EDS.

Prognosis

The prognosis of patients with Ehlers-Danlos Syndrome depends on which type of EDS they have. Type IV, which is the vascular type poses a lot of health risks as it is known to cause pathologies in the entire course of the cardiovascular system. These individuals have a shortened life-span as any pathology can occur at any time. Rupture of large vessels, such as the aorta or the splenic artery can have fatal consequences. Prevention of such serious outcomes can be prevented through a good diet and better lifestyle choices. However, they cannot guarantee complete recovery.

The other types are usually not as dangerous, and affected individuals can live a healthy and not a very restricted life.