INTRODUCTION

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.

PATIENTS 

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.

VASCULAR PROBLEMS

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.

OUTCOME

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

1. 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.
2. 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.
3. 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 bleeding and several attempts to obtain haemostasis and to reconstruct the artery finally led to ligation of the femoral artery. Six months later he died suddenly. The necropsy showed several dilatations of the aorta, and fistulas between the aorta and the vena cava as well as the left common iliac artery and vein. He died from a tear in the aorta just below the diaphragm with extensive haemorrhage.
4. A woman aged 36 years (85) with no family history and with no hyperelastic skin or hypermobile joints had a tendency to bruise. At the age of 5 she had a rectal haemorrhage, which required transfusions. At the age of 15 she had an acute abdomen which necessitated colon resection because of an intra­mural haematoma. At the age of 29, cholecystectomy was done with difficulty because of friable tissue and extensive bleeding. At 36 she had a massive upper gastrointestinal bleeding and endoscopy suggested a duodenal ulcer. This led to an emergency laparotomy, at which a ruptured aneurysm of the hepatic artery was found. The tissues were friable with great difficulties. The aneurysm was excluded with ligation. A splenic artery aneurysm was discovered but not operated on. Ten months later she again had massive upper gastrointestinal bleeding. ‘This time the bleeding was caused by intragastric rupture of the splenic artery aneurysm. To control bleeding the aorta was clamped, the spleen removed, and at release of the clamp the anterior wall of the aorta was transsected. Repeated attempts to obtain haemo­stasis with sutures, pledgets, and finally a dacron prosthesis were unsuccessful because of con­tinuous suture tears and the patient died on the table.

PERSONAL SERIES

The genetic abnormality of this family is a single base mutation of type III collagen (COL3A1) with substitution of glycine 589 for glutamic acid as pub­lished elsewhere, (57), Fig. 1 shows the pedigree.

         I     1.             Died at 36 years of age from a bacterial endo­carditis verified at autopsy.

         I     2.             Died 71 years old.

       II     1.             Bruised easily, and had nose bleeds, classic skin symptoms and hypermobile joints. After operation for a gastric ulcer he developed a deep vein thrombosis. He was operated on for varicose veins       without complications. He had several episodes of acute abdominal pain without diagnosis. At the age of 71 he abruptly developed chest pain and died suddenly after a few hours observation. Necropsy showed a ruptured aneurysm of the aortic arch and two abdominal aortic, and one com­mon iliac, aneurysms.

        II     2.             Died 30 years old in a car accident.

        II     3.             Lives healthy 76 years old and is negative for the mutation.

       III     1.             A 46-year-old woman bruised easily and had the typical skin features of EDS IV. She first had a missed Abortion with an ancephalic child followed by the first normal delivery which did not cause any bleeding. At the second delivery she had a cervical rupture which was sutured successfully. The third child died on the first day of prune belly syndrome having been delivered by caesarean section during which the uterine artery was torn and ligated. The fourthchild, that carries the mutation, was born two months prema­turely after spontaneous rupture of the membranes. The delivery was complicated by a paracervical haematoma that was   conserva­tively treated. At the ages of 41 and 44 years, respectively. she had two episodes of severe abdominal pain with abrupt onset for which no cause was found. On the second occasion she developed moderate hypertension and an uneventful renal angiogram  showed no vascular abnormalities but multiple  renal arteries. At the age of 46 she had a spontaneous haemorrhage in the rectus sheath that was successfully  treated conservatively.

       III     2.             A healthy male aged 45 and woman aged  40 years with symptoms limited to mild  bruising and two & 3          deliveries with  only moderate bleeding

       IV     I.              At the age of 13 this boy developed sudden and intense abdominal pain while motor­ cycling.   Ultrasonographic examination showed no signs of an aneurysm. He devel­oped peritonitis and underwent laparotomy.    A large retroperitoneal haematoma, friable tissues, and a ruptured aorta were found.  When the surgeon tried to place a vascular clamp more proximally, the aorta was torn and the patient died.  Necropsy showed dis­section from the aortic cusp to the iliac bifurcation. Microscopy showed EDS type IV.

       IV     2.            This 4-year-old girl was born with bilateral dislocated hip and a persistent ductus arteriosus. Surgery has been postponed. She has the mutation.

DISCUSSION AND GUIDELINES

Although EDS type IV is rare, it is important that any surgeon should recognize it because of the severe vascular complications; these may occur spontaneously, during trauma, or usually during operations. The characteristics of the disease must be known to be able to suspect it: it is likely to be hereditary, it has specific skin and joint charac­teristics, and there is often a history of previous sur­gical or obstetric problems with bleeding. The bleeding tendency is vascular in origin and most patients have normal platelet function and coagu­lation system although a few patients with platelet (44) and coagulation defects (9, 27) have been reported. Whether this is part of the syndrome or simultaneous disorders is not known. Their normal humoral haemo­static function is further emphasized in that they have the same problems with thrombotic diseases, both arterial and venous, as do other patients (19, 63, 73, 84, 85).A recent text-book suggestion that “all patients with EDS should be followed from an early age with noninvasive techniques to assess the aorta for aneu­rysm” (62) does not seem to be practicable. Firstly, although an aneurysm may be diagnosed, the thera­peutic attitude must be conservative and elective sur­gery is rarely indicated. Secondly, the absence of an aneurysm does not exclude the risk of dissection and the rupture of a non-aneurysmal artery. A surveillance program would probably be more of a hindrance than a help to the patients because of the anxiety that it would create.

• The surgeon must recognize these patients. If they do not know that they have EDS themselves the typical skin and joint symptoms should, even if they are mild, make the surgeon suspicious. On the other hand, if a surgical procedure has been complicated because of friable tissues and vessels, EDS should be suspected even if there are no familial, skin or joint manifestations. Diagnostic steps must then be taken to be better prepared in the future. One problem obviously is the heterogeneous expression of the disease.
• Modern genetic testing should be used to obtain a correct diagnosis, which is the prerequisite for optimal treatment and adequate information.
• Patients known to have EDS who develop acute abdominal or chest pain should be suspected of having a vascularcatastrophe, an intramural bowel haematoma or spontaneous bowel rupture until otherwise disproved.
• In case of vascular problems angiography is contra-indicated unless absolutely necessary for adequate treatment. Atangiography the smallest possible catheter should be used, preferably with a soft tip. At contrast injection a jet effect, that may injure the intima, must be avoided. The investigation method of choice should be color coded Doppler ultrasonography, magnetic resonance angiography and computed tomography; in some cases intra­venous digital subtraction angiography may be used.
• The risk for vascular complications seems to increase early after seemingly uncomplicated gen­eral surgical operationsor childbirth, probably caused by increased collagenolysis. This phenom­enon must be kept in mind.
• The surgeon must be extremely conservative and where there are relative indications, surgery should be avoided, forexample for hernia or var­icose veins.
• When bleeding is encountered there should be a primarily conservative attitude, and if the bleeding is localized compression and transfusions should be tried, even in the case of rupture of a large vessel such as the femoral or popliteal artery. The use of DDAVP (synthetic vasopressin analogue) to stimulate the release of von Willebrand factor could improve haemostasis.
• If operation is thought necessary this should be centralized, for both elective and if possible emerg­ency operations the patient or the surgeon should be transported either by ambulance or helicopter, whichever is considered to be optimal.
• Any operation must be done with extreme care and an atraumatic technique. There may already be difficulties at the time of the skin incision because of the friability of the skin with risk for tearing far more than was intended by the incision. Vascular clamps should be avoided because of their tendency to tear vessels. In extremities the use of tourniquets is one possibility. Intraluminal balloon control could be attempted but shear force must be avoided. When ligation is necessary it could be done with umbilical tape or using a dacron or expanded polytetrafluoroethylene (ePTFE) patch between the vessel and ligature, the aim being to distribute the pressure to a broad area and to avoid the tearing force of a suture. Ligation should be made just to stop blood flow. Suture with the use of synthetic pledgets or pledgets made from muscles or fascia could be tried. When a graft is necessary it is probably wise to use interrupted sutures to avoid tearing as much as possible. If possible anastomoses or repaired vessels should be covered with a cuff made of Dacron or ePTFE to secure pressure from the outside.
• New endovascular interventions may be tried when appropriate. This means haemostasis with various types of embolization procedures when there is a haemorrhage or the use of graft-covered stents for the treatment of arteriovenous fistulas, pseudo-aneurysms,  or  even  aneurysms.  It must, however, be remembered that serious  compli­cations could follow, particularly at the entry site of the vessel, normally the femoral artery. Per­foration by guide wires or dissection are other dangers, as are tears from vascular stents. When percutaneous techniques are tried a competent vascular surgeon must be in attendance.
• It may be possible to use intraluminal grafts fixed with a band ligature.
• Skin sutures should be kept in place much longer than normal because of the tendency of the wound to dehisce. Smaller wounds should preferably be closed with surgical tape, again to avoid tearing of sutures. Despite meticulous wound care the scars are often widened and stretched.
• In some countries there are EDS support groups of patients and relatives. This is a way to improve the management of the disease and to support the families.