What was originally described by Weber (99) as Ehlers-Danlos syndrome (EDS) is in fact a heterogeneous group of clinical syndromes, often with a family history. Ehlers, a Danish dermatologist (26), described a 21-year-old patient who bruised easily, and Danlos, a French physician (21), reported a patient who did not bruise but who had extensive scarring of the skin. Both patients had hypermobile joints and hyper extensible skin (cutis laxa). The first report probably dates from 1682 when van Meekeren (95) described a patient with “extraordinary elasticity of the skin” – It was, however, not until 1960 that it was recognized that some patients with this syndrome had severe vascular problems, in some cases even with spontaneous rupture of non-aneurysmatic arteries and sometimes death (65). Until now there are at least 12 types of EDS described with various genetic characteristics, biochemical defects, and clinical presentations (3, 51, 67). EDS type I (gravis or classic) and above all EDS type Iv (arterial or ecchymotic form) are of interest to surgeons as the patients often present with vascular catastrophes. Another manifestation is gastrointestinal, with spontaneous bowel rupture being a severe outcome (1, 7, 91). A few patients have the combination of bowel perforation and vascular symptoms (15, 40, 80, 82, 87). There seems to be an increased risk of congenital heart disease (58, 64, 90, 97). Not only is there over-representation of aneurysms in the younger age groups, but stenoses have also been reported in the pulmonary arteries (53, 90).
A great step forward in the understanding of the EDS type IV was taken when Pope et al. (69) described a collagen defect as the molecular basis for the disease. Type III collagen (there are at least 13 different types of collagen) is reduced, this collagen being responsible for the tensile strength of arteries. There are several mutations which interfere with various steps in collagen production, which may in part explain the many variations in symptomatology of patients with EDS. New mutations do occur which explains why several cases lack a family history. Histopathologically, the arterial media is thin and the elastic fibres fragmented. For biochemical and genetic details readers should refer to review articles (3.48).
The minimal overall incidence of all types of EDS is 1/150000 (6), which is probably an underestimation because of mild undiagnosed cases. Between 3% and 5% of all are the severe type IV.
Fortunately, this form of EDS is rare but this leads to the problem of awareness and what to do when the patients present; this is true in elective surgery and even more in emergencies. The aim of this review therefore is to summarize our knowledge from a vascular surgical point of view and give some guidelines about how to act when the patients with EDS type IV present.
A review of published reports has disclosed 112 patients with the probable diagnosis of EDS type IV, among whom severe vascular complications have been reported and for whom enough details are given to make an analysis possible (2, 4-8, 10-20.22-25, 28-41,43,45-52,54-57, 59-61, 63, 65-68, 70-72, 74-89,92-94, 96,98, 100, 101). There are further patients with serious vascular complications that are mentioned briefly in papers on genetics and molecular biology but for whom the clinical information is insufficient (46).
There were 61 female patients with a median age of 28 years (range 11-61) and 51 male patients aged 25 years (10-54) at the time of the case report. In 26 patients the familial background was not reported, in 56 there were one or more relatives with EDS, and in 30 a family history of EDS was denied. A total of 96 (85%) had skin symptoms. in eight patients this
©1996 Scandinavian University Press. ISSN IIO2-4151
Table I. Arterial symptoms in 112 patients with EDS
Number of patients Percent of all patients
With each symptom with each symptom
Arterial aneurysm (12 aortic) 54 50
Nonaneurysmatic arterial rupture 42 38
Carotid cavernous fistula 27 24
Gross haematoma (including retro peritoneal, bowel) 21 19
Surgical bleeding 18 17
Arterial dissection (12 aortic) 14 13
Aneurysm rupture 10 9
False aneurysm 6 6
AV-fistula 3 3
Coronary aneurysm 2 2
was denied, and in eight there was a lack of information about the skin. The most common skin symptoms were bruising (71%), followed by thin transparent skin (51%) and cutis laxa (49%). Many had scars of varying ages (30%). Only 16 had no joint symptoms, in 13 patients no report was given, and in the remainder there were varying degrees of hypermobility (75%), in 18 with a tendency to luxation. The hypermobility was often mild and localized to finger joints.
In the previous medical history quite a few patients had undergone abdominal, hernia, and gynecological operations without any problems being reported. Others had had severe problems with bleeding, ruptures, and friable tissues both in hernia surgery and during delivery. Nine of the patients were operated on for spontaneous rupture of the colon. Some patients presented with an acute abdomen with intense pain, but often without positive findings at various investigations. They were often misdiagnosed as acute pancreatitis, for example.
All kinds of vascular problems indicating fragile vessels have been reported (Table I). The high incidence of spontaneous carotid cavernous fistulas is remarkable, otherwise a rarity. Aneurysms developed at all locations in large and medium sized arteries and often multiple aneurysms were present in one patient. False aneurysms were also seen after minor trauma. Spontaneous rupture of vessels with bleeding was common, both from aneurysmal as well as non-aneurysmal arteries. Development of a large haematoma after rupture of small vessels was often seen in the thigh, in the popliteal fossa and in the shoulder region. Varicose veins were common. In many of the patients there was extensive bleeding, particularly during relatively “simple” operative procedures because of extremely friable vessels.
Table II. Cause of death in patients with EDS (56 deaths of 112 patients; 50%)
Cause No. (%) of patients
Non-aneurysmal arterial rupture 32 (57)
- Aortic ·14
- Hearth · 1
- Other ·17
Rupture of aneurysm 14 (26)
- Aortic · 6
Heart failure 2 (4)
Perforation bowel 2 (4)
Cerebral hemorrhage after balloon
Occlusion 2 (4)
Postangiographic bleeding 1 (2)
Gangrene after ligation of femoral artery 1 (2)
Cerebral infarction after carotid ligation 1 (2)
Unknown (woman aged 42, necropsy refused) 1 (2)
Because of the vascular problems angiography was often done (51), in many patients (21) with complications resulting in perforation, dissection, and life-threatening bleeding, sometimes ending with femoral artery ligation or death.
The mortality in the group of reported patients with vascular problems was high. Fifty-six had died by the time of publication of the case report (50%). In most of the remaining patients the follow up time was limited, and in some it was not even indicated. The mortality among women was 54%, and among men 44%. Most patients died from bleeding complications (Table II). Two died from ischaemic complications after ligation of a major artery and two died from spontaneous perforation of the colon, again pointing to the combination of severe vascular and gastrointestinal problems
In patients who survived there did not seem to be any reduction in thrombogenicity despite the bleeding tendency. Graftocclusions and deep vein thrombosis developed in some patients (19, 63).
SUMMARY OF SOME TYPICAL PUBLISHED CASES
- A woman aged 37 years, (6), with no family history of EDS had skin bruising, transparent skin with cutis laxa, and hypermobile joints. Two deliveries had ended with total perineal tears. A spontaneous carotid cavernous fistula was cured by ligation of the internal carotid artery. At caesarian section there were friable tissues and heavy bleeding and difficulty with haemostasis ending up with hysterectomy. About a year later she came to hospital with severe abdominal pain and died quickly. At necropsy a rupture of the internal iliac artery was found and the only causative factor was playing with her children.
- A woman aged 28 years (12) who had no family history of EDS had thin skin, which bruised easily, but no joint problems. She had varicose veins, which bled repeatedly on minor trauma. At operation for the varicose veins the femoral vein and deep femoral artery were torn. They were both ligated and the occluded femoral vein was bypassed with the saphenous vein. Two years later she developed what was considered to be a pentonsillar abscess, which at incision bled considerably. After pressure there was haemostasis but a fistula developed between the external carotid artery and the internal jugular vein. Operation disclosed a thin vein that had to be oversewn with pieces of muscle and the artery was ligated. Her immediate postoperative course was uneventful.
- A boy aged 14 years (55) had hypermobile joints, cutis laxa, and tendency to bruise. His father, three brothers, and one sister had signs of EDS. Lower back pain of sudden onset was followed by collapse and the development of a large retroperitoneal haematoma that required transfusions. Aortography was attempted but it was not possible to pass the catheter. Severe