This is a genetic disorder that most people have never heard of.
People with this disorder can do things with their bodies that, in past decades, would have got them a job with the circus. Their skin is abnormally stretchy and their joints bend in ways that most of us could not even attempt.
But this is no superpower: their shoulders often pop out of their sockets without warning, their spines may curve dangerously and they often experience chronic pain. In the most dangerous cases, major blood vessels can rupture without warning, with fatal results.
Ehlers-Danlos syndrome is truly life-altering. Yet it is under-diagnosed and little-studied, and many doctors know next to nothing about it. Now, finally, awareness is on the increase. A few celebrities have revealed that they have it: notably Girls creator Lena Dunham, The Good Place actress Jameela Jamil and singer-songwriter Sia. But many medical professionals still know little about it, and as a result many people do not get the help they need.
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“The average time to diagnosis in the UK is 10 years,” says Kay Julier, managing director of Ehlers-Danlos Support UK in Borehamwood, Hertfordshire. “That is completely because doctors just don’t recognise it.”
The experience of Jodie and her three children exemplifies the problem. When her middle child Alice was seven or eight, she started complaining of a recurring backache. This lasted over a month. A friend who worked as a general practitioner (GP) had an informal look and said he suspected Ehlers-Danlos. Jodie took Alice to the local medical practice, and by a stroke of luck the first doctor she saw had a close relative with Ehlers-Danlos, and immediately referred them to a paediatrician.
But then, things stalled. “The paediatric team looked at her and they were umming and ahhing,” says Jodie. “We then spent a good two years at least with people saying ‘Could be this, could be that’.”
Meanwhile the symptoms piled up. Alice’s skin is thin, stretchy and translucent, with prominent veins, and she has low body mass for her age. The back pain spread to her shoulders. “Then the shoulder dislocations started,” says Jodie. “As she’s got older, more and more things have started to come to the surface.”
The lack of awareness of Ehlers-Danlos among medical professionals has been a sore spot for years. It is striking because the syndrome has been known for a long time.
Decades of neglect
Descriptions can be found from the 1680s and 1890s, but the first canonical accounts came from Edvard Ehlers, a Danish dermatologist, in 1901, and the French dermatologist Henri-Alexandre Danlos in 1908. In 1936, the name “Ehlers-Danlos syndrome” was proposed and three cardinal symptoms were identified: joints had to be overly bendy, and skin had to be both stretchy and unusually “friable”, meaning it crumbled easily.
Jameela Jamil is one of the most high profile celebrities who lives with the disease (Credit: Getty Images)
However, this simple picture did not stay simple. Over the coming decades, physicians realised there is more than one type of Ehlers-Danlos syndrome. Quite how many is still uncertain. In 1967, a surgeon claimed there were three subtypes, based on 27 cases with differing symptoms. Two years later, another argued for five subtypes after carefully studying 100 people. By 1988, 11 subtypes had been found
“It’s really been very difficult to define,” says Peter Byers of the University of Washington in Seattle.
What did become clear is that all the subtypes involve problems with connective tissue, which surrounds and supports our internal organs. The tendons and ligaments linking our muscles and bones, and the walls of our major blood vessels, are made in part of connective tissue. The most important proteins in connective tissue are collagens, and one way or another it is collagens that are affected by the Ehlers-Danlos syndromes.
Slowly, geneticists began to identify genes that caused Ehlers-Danlos
The problem was that the early classifications were based on symptoms, which did not necessarily map onto the underlying causes. Perhaps seemingly identical cases were actually caused by mutations in different genes. Different mutations in one gene could also produce distinct symptoms. Slowly, geneticists began to identify genes that caused Ehlers-Danlos. All are either genes for collagen, or for proteins that interact with it.
A 1997 reclassification used some of this genetic information to clarify the subdivisions, merging some of the previous subtypes to give just “six major types”. But this rapidly became out of date as even more Ehlers-Danlos genes were discovered. The total currently stands at 20.
Something had to shift. In 2014, a support group called the Ehlers-Danlos National Foundation, since renamed the Ehlers-Danlos Society, launched an international consortium of researchers to study Ehlers-Danlos and related disorders. The aim was to revise the classification again, and to devise international guidelines for caring for people with the disorder. There is also now an international register for people with the syndrome.
The consortium’s formation was significant, because previously the few researchers working on Ehlers-Danlos each pursued their own research agendas rather than collaborating, says Fransiska Malfait of Ghent University in Belgium. “It’s never been a sexy topic,” she says, but nowadays the research is more coordinated.
Ehlers-Danlos Syndrome doesn't just affect skin and joints – it can also leave pateints in immense pain (Credit: Getty Images)
The new classification duly came out in 2017 in a special issue of the American Journal of Medical Genetics. It recognised 13 subtypes of Ehlers-Danlos. The following year, a 14th subtype was found, albeit in just four people. Malfait says more will likely turn up.
However, most subtypes are rare. Two get the most attention: hypermobile Ehlers-Danlos Syndrome (hEDS) is the most common, and vascular Ehlers-Danlos is by far the most dangerous.
In vascular Ehlers-Danlos, the changes to connective tissue weaken heart valves and arteries. This is life-threatening: major blood vessels can rip open without warning. It is caused by mutations in a single collagen gene called COL3A1. The mortality rate is high: in a study of 231 people, 39% died, with a median age of death of 31 years. Patients are advised to avoid violent exercise to minimise the risk of ruptures, and to carefully manage their blood pressure.
The vascular subtype is the only form of Ehlers-Danlos that may be treatable with drugs. A drug called celiprolol has shown promise in clinical trials: it seems to reduce the risk of blood vessels rupturing. However, one downside is that many people cannot tolerate the recommended dose, which may limit the drug’s usefulness.
Jodie soon started to worry that Alice might have vascular Ehlers-Danlos. Some of her symptoms suggested as much. Doctors had also discovered that Alice has a mitral valve prolapse: the valve between two of the chambers of her heart does not close properly, so some blood flows backwards every time her heart pumps. In fact this is more common in hypermobile Ehlers-Danlos, but it alarmed everyone.
Confusion means we still do not know how common Ehlers-Danlos syndrome is
Jodie wanted to get a genetic test to find out if Alice had vascular Ehlers-Danlos, but she says “that was when we started running into obstacles, because nobody wants to send you for genetic tests, because it’s expensive”. After a year of pestering the paediatrician, they got an appointment in the genetics department, only to be seen by an assistant who refused to perform any tests. “She didn’t fit the right categories,” Jodie says. “Her face isn’t pointy enough, her eyes aren’t big enough, her chin isn’t under-pronounced enough.” For these reasons, the geneticist said it probably wasn’t vascular Ehlers-Danlos.
Instead, Alice now has a diagnosis of hypermobile Ehlers-Danlos. This has none of the dangers of the vascular subtype, but in other ways it is even more problematic.
Unlike every other form of Ehlers-Danlos, the hypermobile subtype has not been associated with any genes. That means we do not understand why some people have it. It is not even clear exactly who has it and who doesn’t.
The difficulty arises because of another syndrome called hypermobile spectrum disorder (HSD), previously known as benign joint hypermobility syndrome. People with HSD have unusually bendy joints, like in Ehlers-Danlos, but they do not have any of the other symptoms of Ehlers-Danlos like fragile skin. However, because no genes have been identified for either disorder, we do not know where to draw the line.
An immune cell overreaction can be one sympton of Ehlers-Danlos syndrome (Credit: Getty Images)
It is not even clear that we should be dividing people into just those two categories: hypermobile Ehlers-Danlos and HSD might encompass a range of distinct disorders that have not yet been recognised. “Hypermobile Ehlers-Danlos syndrome is clearly not one entity,” argues Byers.
This confusion means we still do not know how common Ehlers-Danlos syndrome is. For many years, the standard estimate has been that one in 5,000 people have it. However, the vast majority of those have the poorly-defined hypermobile type. Furthermore, it may be that many people diagnosed with HSD should really be considered as having Ehlers-Danlos, and many others may be undiagnosed.
A study published in late 2019 in the BMJ led by Emma Reinhold, a former GP, analysed medical data from Wales and claimed the prevalence was actually one in 500 – 10 times higher. Malfait and other experts criticised the study because the researchers lumped together people diagnosed with Ehlers-Danlos and joint hypermobility syndrome – the obsolete term for HSD.
In an attempt to resolve the confusion, the Ehlers-Danlos Society has helped to fund a major study called Hedge (Hypermobile Ehlers-Danlos Genetic Evaluation), which aims to find the genetic cause of hypermobile Ehlers-Danlos. The researchers want to collect genetic data from 1,000 people with the subtype. This large sample size is necessary because hypermobile Ehlers-Danlos is thought to be caused by mutations in many genes, each with a small effect, rather than just one. “I think it will be very complex,” says Malfait.
There is also no cure for Ehlers-Danlos
“I think in the next five years we’ll be much closer,” says Lara Bloom, president and CEO of the Ehlers-Danlos Society. “Once those basic, fundamental questions are answered, we can then start thinking about how the community can be diagnosed, managed and cared for.”
Bloom says a further complication is that people with Ehlers-Danlos often have other symptoms – especially if they have the hypermobile subtype. These symptoms can include digestive troubles like diarrhoea or constipation, or even mast cell activation syndrome where immune system cells release chemicals that disrupt many bodily systems.
It is not obvious how these symptoms could be caused by connective tissue damage, and some of them may be coincidental. But they show up a lot, which has led many researchers to suspect that there is a link.
Ehlers-Danlos has no cure, but diagnosis can help patients get crucial support (Credit: Getty Images)
The trouble is, these extra symptoms confuse clinicians. Alice’s older sister Harriet knows this all too well. Her first symptoms were gastrointestinal, leading doctors to diagnose her with irritable bowel syndrome. But she also has a curvature of the spine and hypermobile joints. These point to Ehlers-Danlos, but so far this has not been formally diagnosed. “They still won’t commit to Harriet,” says Jodie. “I’m thinking, for Christ’s sake, it’s genetic.” Her youngest child Owen is also hypermobile, but he shows few other symptoms and she has not tried to get him diagnosed. “The struggle to get the other two diagnosed has really put me off bothering,” she says. “There’s nothing really that wrong with him.”
Help to live life
There is also no cure for Ehlers-Danlos, which Jodie has repeatedly been told is a reason not to diagnose it. “A lot of them will say things like ‘There’s no cure, so does it really matter if you have a diagnosis?’” she says.
In fact the diagnosis does allow people to get crucial support to help them live full lives. Occupational therapists have obtained special seats for Alice and Harriet which support their backs at school. Physiotherapists have helped them tone their stomach muscles, reducing the risk of dislocations and joint damage.
Alice was booked to see a psychotherapist for advice on how to manage the pain, although that has been postponed due to the Covid-19 pandemic. One day, surgery to strengthen her joints may become a possibility, as some surgeons are already experimenting with this.
The complexity and diversity of the syndrome makes it hard to diagnose
Bloom says the most important thing is for everyone with Ehlers-Danlos to have access to everyday support like physiotherapy. “Thousands of people around the world are living with these conditions and are not diagnosed,” she says.
The complexity and diversity of the syndrome makes it hard to diagnose, but she says the fundamental problem is that many medical professionals are taught almost nothing about it. “There is a whole generation that were never taught [about Ehlers-Danlos],” she says. “Then you have the generations that believe they know what Ehlers-Danlos syndrome is, which equates to it being bendy and nothing more. That’s the group that needs to be re-educated.”
Bloom is optimistic, but she concedes it will be an uphill battle. “In some ways, we’re still at the very beginning.”
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