This is an excellent and thorough explanation of EDS and other Connective Tissue Disorders (CTDs):
Joint laxity syndromes can cause many nonspecific and variable symptoms, even among patients with the same condition, making diagnosis difficult.
Many patients see numerous specialists before receiving a proper diagnosis, as many healthcare providers are only familiar with the more extreme forms of the disease (eg, Marfan syndrome, osteogenesis imperfecta) despite milder variants being more prevalent.
This article provides an overview of the spectrum of joint laxity syndromes, examining symptoms, assessment, and workup of patients suspected to have such conditions. It also provides an overview of the role of genetic testing and of the preventive and therapeutic strategies physicians can use to improve the care of their patients.
At least 10% of the general population has some degree of joint laxity, with a tenth of these individuals experiencing pain and disability that can be ameliorated by the astute physician
When more serious signs and symptoms accompany hypermobility, patients are classified as having connective tissue dysplasia (CTD). The most common CTD is EDS, which can cause symptoms ranging from joint hypermobility and fragile skin to rupture of the blood vessels, intestines, and other organs. Patients with EDS and other CTDs often present with a variety of symptoms that affect many body systems.
In addition to musculoskeletal pain or injury, patients may have migraines, menorrhagia, fragile skin with unusual healing, and/or fragile vessels with easy bruising.
Recognition of the heterogeneous spectrum of CTDs has transferred the diagnosis from the narrow aisles of genetics into the main theatre of medicine. As such, emphasis on physician skills has been restored, as timely clinical diagnosis is paramount to ensuring proper treatment and improving quality of life.
Currently, too many patients are written off as hypochondriacs or malingerers as they go from specialist to specialist with a barrage of symptoms and inaccurate diagnoses.
Prompt recognition of CTDs validates patients’ concerns and improves their quality of life, enabling proper steps to be taken to ameliorate their symptoms and protect them from injury, such as nutrition therapy, physical therapy, cognitive-behavioral therapy, and proper medicines (eg, beta-blockers to moderate tachycardia and slow vascular dissection)
This article provides an overview of CTDs, focusing on identification of milder variants—much more likely to be missed.
Here, the article gives 3 case presentations in great detail and with pictures.
Examining the Cases
All 3 case patients have joint laxity syndromes, with the case 1 and 2 patients having milder disease best classified as type I EDS; the many novel genes being found in EDS patients argue for an EDS spectrum rather than clinically distinguishable types
Another problem with CTD diagnosis is that flexibility symptoms may not be correlated with symptoms affecting other parts of the body.
The case 1 and 2 patients had IBS, which is often misdiagnosed as Crohn’s disease or celiac disease. They also had POTS, which causes dizziness and faintness on standing that patients often address by steadying themselves after standing.
Other frequent findings are chronic fatigue and poor focus or brain fog, which tend to manifest after exposure to an environmental trigger, such as trauma, infectious illnesses like mononucleosis (as occurred with the case 1 patient), and a first pregnancy in women.
Therefore, when joint and/or skin laxity is identified, physicians should evaluate for other signs and symptoms that can be indicative of a joint laxity syndrome, such as those outlined in the Table.
When a joint laxity syndrome is properly diagnosed, an appropriate subspecialty referral can be made. Had the condition been diagnosed earlier in the case 1 patient, she would have been spared from multiple unproductive subspecialty visits. The clinical diagnosis was sufficient to provide appropriate interventions and closure for cases 1 and 2, and to guide specific gene testing to diagnose Marfan syndrome in case 3.
The table below is an excellent list of possible signs and symptoms of EDS and other CTD’s:
GENETIC TESTING FOR JOINT LAXITY SYNDROMES
The EDS/CTD spectrum ranges from severe genetic disorders associated with single gene changes to milder, multifactorial disorders that stem from combinations of genetic and environmental factors. Genetic testing can focus on single genes like fibrillin-1 associated with Marfan syndrome in patients with extreme symptoms like case 3, but must examine many genes in patients with broader symptoms
(WES), that analyzes the coding regions (exons) of all 23,000 genes is now the test of choice for milder patients, its $10,000 cost justified by much greater sensitivity than single gene tests that cost between $1000 and $3000 each, even greater than sequencing panels of 15 to 30 genes related to CTD (~$4000) because many new genes related to CTD are being discovered by WES.
WES = Whole Exome Sequencing
Surprisingly, WES is better covered by insurance companies with over half the author’s patients having zero out-of-pocket costs, and it has the additional advantage of screening genes like those for breast-ovarian cancer (BRCA), undertaken as “incidental findings” that are separately consented.
The more common, milder presentations of CTD can result from single gene mutations that produce milder symptoms, like that in collagen V for case 1, but can also involve mutations in several genes (multifactorial determination) as is increasingly found by WES.
Genetic testing can exclude the presence of an extreme CTD disorder and discriminate between a 10% (multigenic) or 50% (single gene) transmission risk, with severity of affected offspring unpredictable but at least limited to those of milder CTD.
Despite the complications of prognostic and prenatal prediction, gene testing has significantly improved our understanding of EDS and other CTDs. In 100+ CTD patients who have had WES, the author has found over 20 gene changes that were not previously associated with tissue laxity/fragility or dysautonomia, ranging from those causing acute intermittent porphyria to dopamine-beta-hydroxylase that converts norepinephrine to dopamine.
PREVENTIVE HEALTHCARE AND THERAPY FOR JOINT LAXITY SYNDROMES
Joint pain is one of the most common symptoms experienced by patients with joint laxity syndromes due to their hypermobility causing wear and tear on their joints and predisposing them to arthritis. Analgesics can be used to control joint pain in these patients, even when arthritis is present
Effective analgesics are opioids in many cases.
Immune inhibitors with potentially severe side effects should not be prescribed to patients with CTD, since their wear and tear arthritis due to disability is different from that in inflammatory arthritis (eg, lupus, rheumatoid arthritis).
Although it may be tempting for some patients to minimize their physical activity levels, it is important for them to remain active to prevent joint stiffness and pain and to alleviate some of the many other symptoms that accompany EDS and other CTDs (eg, chronic fatigue syndrome, fibromyalgia, IBS, anxiety/depression). Moderate weightlifting and other muscle-building activities can also be helpful, as they strengthen the muscles around the joints and protect them from injuries (and muscle relaxants should be avoided).
Dysautonomia is another common problem among patients with joint laxity syndromes, which can manifest as POTS, excessive fatigue, cardiovascular symptoms (eg, tachycardia, bradycardia, angina), IBS, and other symptoms. Although not validated by controlled trials, several types of therapy are available for dysautonomia, depending on the patient’s presentation
When cardiovascular-related symptoms are present, medication prescribing is best left to the cardiology specialis
However, agents to consider can include beta-blockers or midodrine to counteract sympathetic stimulation, fludrocortisone to aid salt/water repletion of intravascular volume, clonidine for sleep, and assorted medications to control headache, arthralgia, neuralgia, myalgia, and soft tissue and/or visceral pain.
These medications can be opioids in many cases.
Patients who have posterior head and neck pain may benefit from upright head MRI to exclude a Chiari deformation arising from a distensible fourth ventricle and/or cervical spine changes; surgical treatment can be very effective for Chiari deformation.
Many geneticists, physicians, and other healthcare providers continue to view EDS and other CTDs as a group of rare and extreme disorders, only making the diagnosis when very unusual skin or joint findings are observed.
Milder forms of these diseases, however, are more common, their associated dysautonomia and chronic pain often misdiagnosed as chronic fatigue syndrome, fibromyalgia, or anxiety. Recognition that these symptoms reflect an underlying, truly medical condition offers validation to patients who are often dismissed by multiple specialists, providing important opportunities for prevention and therapy.
When patients present with recurrent joint injuries and/or pain, joint hypermobility should be considered and is easily evaluated.
A major criterion for diagnosing joint hypermobility is a positive Beighton score (≥4 out of 9), and when joint hypermobility occurs in combination with 2 or more of the criteria outlined in the Table, a joint laxity syndrome is likely. Such syndromes are genetic, often with environmental factors as triggers for severe symptoms, and genetic testing using WES (Whole Exome Sequencing) is greatly expanding the list of genes that when altered can cause CTD.
At present, gene or DNA testing has limited advantages over the clinical CTD diagnosis in terms of guiding interventions or subspecialist referrals. Nevertheless, it can help determine the risk of transmitting the disease to offspring and in the future may lead to more effective treatments.
Until then, treatment of patients with EDS and other CTDs focuses on prevention of injuries and managing associated symptoms to improve quality of life.
“Managing associated symptoms” can often be accomplished with opioids.