Ehlers (1901) and Danlos (1970) first described a clinical syndrome that was characterised by lax skin and hypermobile joints. Since then, with the identification and study of thousands of cases, many other manifestations of the syndrome have become known. The Ehlers-Danlos syndrome (EDS) is now recognised as an abnormality of collagen structure and synthesis with varying inheritance that produces a whole variety of symptoms and signs. There are at least ten distinct subtypes but, because many cases are asymptomatic and remain undiagnosed, the true incidence is unknown. It probably represents the commonest inheritable disorder of connective tissue.
Connective tissue, as its name implies, has a vital function in binding the tissues of the body together and maintaining their integrity. Collagen fibres in particular form a meshwork throughout tissue, imparting strength, and rigidity to it. The deficiencies in connective tissue and collagen fibres associated with EDS are therefore manifested by uncharacteristic weakness and elasticity of body tissues. This is most obviously demonstrated by the laxity and fragility of the skin and stretch ability of tendons allowing the characteristic joint mobility. In the skeletal system joints may dislocate easily and deformities of the hips, spine and chest may occur, whilst stretching of the abdominal wall leads to hernia formation. Any hollow tube or organ whose walls are subjected to intermittent or constant rises in internal pressure may be affected. Varicose veins may form in the legs due to stretching of their weakened walls and large arteries may dilate due to the high pressure blood within them, forming aneurysms for the same reason. Similarly, although much more rarely seen, the gut wall can stretch and cause either a generalised dilatation or focal outpouchings, called diverticula. These can give rise to problems by interfering with the absorption of nutrients or by rupturing and causing peritonitis.
Ehlers-Danlos syndrome rarely causes complications in the urinary tract and these tend to appear as case reports in medical journals. Four cases with multiple cysts in the kidneys are reported, although these may in fact have been separately inherited lesions and unrelated to the patients EDS. Dilatation of the ureters that drain the kidneys into the bladder has also been seen but the commonest problem is an outpouching of the bladder wall or bladder diverticulum.
The first case of bladder diverticulum was reported in 1942 and since then there have been at least 24 others in the journals. All have been male with an age range of between 18 months and 49 years, with 80% presenting with symptoms before their sixteenth birthday. Presentation is variable and urinary tract infection, dysuria (pain on passing urine), haematuria (blood in the urine), lower abdominal swelling, bladder stones and bladder rupture have been reported. There may of course be many more patients with EDS whose diverticula never cause symptoms and go undetected. Bladder diverticula have been seen in several of the different subtypes Classical, Hypermobility, Vascular, and Kyphscoliosis, (l, ll, lll, lV, Vl, lX). Their association with a variant of EDS linked to the X chromosome is now becoming increasingly recognised after finding them in 5 male members of the same family and 5 out of 7 cases of EDS type lX (now known as 'occipital horn syndrome).
The pressure inside the bladder remains low while it is filling but rises significantly when urine is passed (voiding). It is probable that this rise in pressure stretches the bladder wall in susceptible in individuals and causes the diverticulum to form. One explanation for the complete absence of diverticula in female patients is the significantly higher voiding pressures generated by male bladders. Obstruction of the bladder outflow causing abnormally high voiding pressures has been suggested but in spite of carefully investigating several patients for this, it has only been seen in one.
Although the diverticulum may rarely enlarge sufficiently to cause an obvious swelling in the lower abdomen, the main cause of symptoms is due to retention of urine in the diverticulum and an inability of the bladder to empty completely on voiding. Thus the bladder contents are never completely flushed out, which may allow bacteria to gain a foothold and infection to develop.
As well as causing symptoms of general malaise and a raised temperature, infection and inflammation in the bladder and bladder outflow (urethra) can cause lower abdominal pain and a nasty burning pain on voiding (dysuria). Bladder irritation leads to a need to void more frequently (frequency) and the bladder lining can bleed (haematuria), which may be severe due to the increased bleeding tendency in EDS. Accumulation of debris in the bladder may also lead to the formation of bladder stones, which promote infection and inflammation. Pain in the back and a high temperature suggest kidney involvement with the infection and patients with this complication may become quite ill.
The management priorities in-patients with the above symptoms are to initially eradicate infection with antibiotics (which may need to be given intravenously in a severe case), then investigate them to look for the underlying cause and finally to plan definitive treatment. An ultrasound scan is normally the first line investigation. It enables good visualisation of both the bladder and the kidneys and certainly any diverticula and bladder stones should be spotted by an experienced operator. A plain X-ray of the area can be used to demonstrate stones. Various other X-rays are then available if further information or clearer visualisation is required.
Fifteen of the cases of diverticulum reported in the journals were treated by surgical excision of the diverticulum. These were found to have a characteristic appearance when studied under the microscope. Unfortunately of the 15 patients at least 10 developed recurrent diverticula after surgery and adequate follow up information is lacking in the remainder. As well as giving these poor results, delicate friable tissues, per-and post-operative bleeding, may complicate surgery itself and poor wound healing. It should therefore be reserved for severe or symptomatic cases or for those patients in whom the kidneys are also involved and their function is threatened. Less invasive surgery may be required to remove bladder stones but in the majority of patients infection can be controlled by administering regular low dose antibiotics (prophylactic antibiotics). In some patients asymptomatic bladder diverticula are discovered incidentally during investigation of another problem. In this situation it is debatable whether any treatment at all is required.
As the urinary tract complications of EDS are comparatively rare, it is important to emphasise in this discussion that EDS patients are no less susceptible to commoner urinary tract diseases than the rest of the population. Thus urinary tract infection and high fever in a child may be due to another underlying problem, dysuria in a young female to simple cystitis, difficulty passing urine in an older man due to an enlarged prostate and haematuria in older people of both sexes may herald bladder cancer. All of these problems require careful investigation and treatment and are familiar to most doctors. Nonetheless, the possibility of an underlying diverticulum in symptomatic males with EDS warrants at least an ultrasound scan to exclude it. It is of course very important for doctors to be aware of EDS in-patients they are treating, particularly if surgery is to be required.
In conclusion, Ehlers-Danlos syndrome rarely causes problems in the urinary tract, although hidden abnormalities my be present in many more patients than present with symptoms. The commonest of these is a bladder diverticulum, and this should always be suspected as a cause of haematuria or urinary infection in young males. Surgery to remove the diverticulum should be reserved for those cases in which symptoms are severe and poorly controlled with medication or in whom kidney function is threatened. The presence of EDS in-patients being treated for common urinary tract problems will impact on their treatment, particularly if surgery is involved.
The views expressed are those of the author(s) and should not be construed to represent the opinions or policy of the Ehlers-Danlos Support UK or its Trustees.