The blood vessel is a complex organ with many mechanical and regulatory functions. Abnormalities in the structural characteristics of the extracellular matrix as well as the regulatory functions can results in significant dysfunction. This dysfunction can manifest itself as vascular fragility leading to aneurysms, dissections, and ruptures but it may also result in stenotic lesions.

Many of the conditions have their roots in mutations of the genes responsible for the constitutive proteins of the blood vessel wall, however, probably just as frequently the mutations result in disordered regulation of cell turnover and remodeling. In some cases the underlying abnormality has not been identified, however, the features of the conditions and when they should be suspected are shared with the more definitely identified connective tissue abnormalities and so are included in this chapter.

Beyond the underlying causal abnormality, the primary clinical feature shared by these conditions is the presence of vascular disease in a patient population typically not thought to be a risk: patients who are young and without usually precipitating causes such as hyperlipidemia, hypertension, and diabetes. Typically a familial clustering is also present which should raise concern for these diseases. In addition, the familial nature of these conditions even when a precise genetic syndrome cannot be identified should prompt an evaluation of first-degree relatives.

Ehlers-Danlos Syndrome (EDS) is a collection of connective diseases characterized by hypermobility of the joints and hyperextensible joints. Following the initial description of the condition several subtypes have been identified with different underlying biochemical and genetic causes and different clinical presentations. Vascular manifestations of EDS are primarily limited to the vascular subtype,^1,2 which was known as EDS-IV or Sachs-Barabas syndrome in prior classifications.³ Vascular fragility has been rarely described in other subtypes of EDS (kyphoscoliotic type [EDS-VI] and arthochalasis type [EDS-VII]) and collagen abnormalities, such as osteogenesis imperfecta, but the vast majority of vascular complications in EDS occur in the vascular subtype.^4,5,6 The principal clinical manifestations are vessel rupture and dissection with and without preceding blood vessel dilation. Internal organ rupture, uterus, and colon in particular, are also important causes of morbidity and mortality. Overall prevalence of EDS is estimated to be 1 in between 10 000 and 25 000, with vascular EDS constituting 4% of all EDS cases.^1,7

Pathogenesis

Collagen III is the predominant type of collagen in blood vessel and visceral organ walls.⁸ Abnormalities in collagen III synthesis were first identified by Pope et al.⁹ in EDS-IV in 1975. Causative mutations in the COL3A1 gene coding for the procollagen proα1(III) chain of collagen III have been identified in the vast majority of cases. Over 114 different mutations involving the COL3A1 gene hve been documented in the most complete clinical series, with additional mutations described in smaller series and case reports.¹⁰ The most common mutations aree point mutations leading to a substitution for a glycine within the triple-helical domain.

Procollagen III is formed as a homotripolymer of three identical chains, therefore abnormality of one of the allele results in normal procollagen polymers in only one-eighth of the procollagen polymers that are formed.¹¹ This results in a dominant negative mechanism for the autosomal dominant mode of inheritance seen clinically. With certain mutations, there are no abnormal procollagen strands available for formation of polymers; these mutations phenotypically present with clinical vascular EDS of similar severity. Haploinsuffciency therefore plays a role as well in the autosomal dominant mechanism.¹²

Reduction in the synthesis and deposition of collagen III leads to weakening of the vascular wall.

Clinical Manifestations

The vascular manifestations of EDS IV include dissection and rupture of blood vessels of all sizes from the level of the aorta down to arterioles. Fusiform aneurysms may form, but do not appear to precede dissections and ruptures in the majority of cases.¹³ Thoracic and abdominal vessels appear to be most frequently involved with between 50% and 77% of vascular complications involving those vessels. Vessels of the head and neck are involved in between 10% and 16% of the cases.^10,13,14 Common central nervous system vascular complications are carotid–cavernous sinus fistula formation and vertebral and carotid artery dissections.

Age of presentation with vascular complications is typically in the early twenties, with median age of first vascular complication at 24.6 years. Presentation in childhood is unusual, but has been reported. In available retrospective series approximately 50% of affected individuals will develop a vascular manifestation. Approximately 30% will have a repeat event after first presentation.¹⁰

Rupture of internal organs is the other principal clinical complication of vascular EDS. Approximately 28% will have an internal organ perforation or rupture with the colon, spleen, and uterus most commonly involved.

Cause of mortality in EDS is vascular in 79% and because of organ and bowel complications in 18%. Ruptures of thoracic and abdominal vessels are responsible for more than 76% vascular deaths. Central nervous system hemorrhage is responsible for at least 9% of deaths. Life expectancy is 48 years, although individuals living to 73 years of age have been reported.¹⁰

Beyond the clinical complications of vascular EDS, there are several phenotypic features which may help with diagnosis. Joint hypermobility and skin hyperextensibility typical of the other EDS types is not a prominent feature of vascular EDS. Mild hyperextensibility of the small joints may be present. The skin rather than being hyperextensible is typically very thin and pale and in some cases can be translucent. As a result the subcutaneousveins become prominent, particularly over the chest and abdomen. Capillary fragility leads to easy bruisability. In extreme cases recurrent bruising can lead to subcutaneous hemosiderin deposits. The reduction in subcutaneous fat in some cases results in a characteristic delicate facial appearance with a pinch nose, sunken eyes and hollow cheeks.

Diagnosis

Although the phenotypic features are often cited in the diagnosis of vascular EDS, the sensitivity and specificity of these findings are not known and exclusion or diagnosis of vascular EDS based upon them solely is difficult. Of the clinical features bruisability is nearly uniformly present in affected individuals, however, other features such as translucent skin, typical facial features and joint hypermobility are not reliably present.¹³ In most cases, the diagnosis of vascular EDS is made following an incident event or based upon family history.¹⁰ Suspicion of vascular EDS should therefore be raised if an aneurysm, rupture or dissection occurs in a young person without obvious precipitating cause. The presence of abnormalities in multiple vascular beds should strongly raise the need to evaluate further for the diagnosis of vascular EDS (see Figure 15-1).

Screening of children and parents of the afflicted patient should always be performed. The need for screening of additional relatives depends upon the initial screening results, taking into account the autosomal dominant nature of inheritance.

Definitive diagnosis at this time relies upon identifying a disease-causing mutation in the COL3A1 gene or the identification of abnormal structure or quantity of collagen α1(III) chains in dermal fibroblast cell culture. Theoretically genetic analysis of the COL3A1 gene may miss some mutations in the promoter regions of the COL3A1 gene which lead to decreased transcription, since current sequencing techniques only sequence the exons of the COL3A1 gene. To date, there have been no proven cases of EDS IV caused by this type of mutation. Complete deletion of the COL3A1 gene in one allele leading to vascular EDS can usually be identified on genetic testing by the absence of variation in the typical polymorphism in the COL3A1 found during sequencing.

Pathological Findings

The macroscopic and microscopic vascular complications in vascular EDS are attributed to the qualitative and/or quantitative abnormalities of Collagen III. Medium and large vessels such as the branches of the aortic arch, descending thoracic aorta and abdominal aorta and its distal branches are commonly affected. The macroscopic changes include single or multiple tears, dissection, rupture with massive hemorrhage and/or pseudoaneurysm formation, aneurysms of peripheral, coronary and other muscular arteries, and tortuous arteries and varicose veins. Aortic tears and dissection with false channels are common but true aortic aneurysmal formation is less frequently observed.¹⁵ In our experience, the pattern of vascular interruption is similar to other causes of aortic dissection (Figure 15-2). Complete transmural transverse tearing of the vessel can result in rupture; incomplete disruption can produce a dissection plane typically in outer third of the medial layer of the aorta. The microscopic findings are limited to a minimal degree of cystic medial degeneration (CMD) (Figure 15-2). CMD is characterized by loss of smooth muscle cells, fragmentation, and loss of elastic fibers and accumulations of proteoglycans within the medial layer. A marked decrease in Type III collagen in the skin and the wall of the cerebral artery can be demonstrated by immunohistochemical staining techniques.¹⁶ (Figure 15-2) At the ultrastructural level considerable variation in collagen fibril diameter and an overall decrease in the cross sectional area of collagen fibrils in arterial walls has been reported.¹⁷

Management

There is no specific treatment for the underlying biochemical abnormality at this time. In the absence of complications the treatment is primarily targeted at reducing factors that may aggravate the known complications of vascular EDS. Vigilant control of blood pressure and the avoidance of activities that would tend to increase blood pressure excessively, for example, competitive sports and weightlifting are prudent, however, unproven. Activities that place the patient at risk for trauma, for example, contact sports, skiing, should also be avoided given the fragility of the blood vessels and organs. Avoidance of agents that impair hemostasis such aspirin and other nonsteroidal anti-inflammatory drugs is also typically recommended. Avoiding increased intraluminal pressure in the organs from straining may require the routine use of laxatives and stool softeners.

Because of the rarity of vascular EDS, there is no proven approach to the management of vascular complications. The marked fragility of the tissues and the high frequency of arterial tears and anastomotic breakdown that develops with surgical manipulation place all interventions at high risk. For this reason a conservative approach is generally recommended to manage non-life-threatening complications using compression and transfusions. Mortality rates associated with operative vascular intervention has been as high as 40% in retrospective series.¹⁰ Surgical intervention can be performed successfully in some cases, so surgery should not be denied when conservative approaches are unlikely to work. The incidence of surgical complication remains high, with excessive bleeding being the most frequent complication. Late problems such as graft anastomosis aneurysms and anastomotic ruptures are very frequent affecting 40% of repairs.¹³

The use of percutaneous interventions with stents, covered stents and coils has also been performed with success in some patients with vascular EDS.^{18,19,20,21,22} The precise role of such interventions is yet to be determined. Care must be taken with the vascular access in such cases, as there have been cases in which the procedure has been successful in treating the vascular complication, only to have the patient die from exsanguinations at the vascular entry site or other sites remote from the site of intervention.^23,24,25 Consideration of these complications should be made in planning any intervention^26,27 and wherever possible evaluation and planning should be undertaken by noninvasive means. Invasive angiography in a series of thirteen patients resulted in serious complication in three patients (23%).¹³

The role of surveillance imaging of the vasculature in patients with vascular EDS is uncertain. In many cases, the vascular complications are not preceded by aneurysm development or other features identifiable by noninvasive imaging. However, in a minority of cases, there is aneurysm or dissection before rupture. That combined with recent successes with percutaneous intervention suggests that routine surveillance imaging of the vasculature may have value.

The elastic fibers also form an essential component of the blood vessel wall, particularly in the elastic arteries such as the aorta and its major branches.²⁸ Marfan syndrome (MFS) is caused by mutations on the FBN1 gene on chromosome 15.²⁹ Fibrillin is an important component of the microfibrils and is closely coupled to the extracellular elastic fibers.^30,31,32 Not surprisingly, most if not all of the vascular manifestations of MFS are therefore limited to the aorta and to much lesser degree the major branches of the aorta.

Pathogenesis

Shortly following the identification of fibrillin-1 in 1986, the FBN1 gene on chromosome 15 was identified as the causative mutation through linkage analysis and genetic sequencing. Subsequently, over 600 mutations of the fibrillin gene have been identified as causing MFS (http://www.umd.be:2030/). A MFS-2 locus has also been suggested on chromosome 3 involving the TGF-β receptor gene, however, the distinction between MFS-2 and Loeys-Dietz Syndrome (LDS) remains to be clarified and will be discussed later in this chapter.³³

Genotype-to-phenotype correlation remains weak, with only mutations in the region of exons 24 to 32 appearing to result in the particularly severe neonatal form of MFS.^34,35 Beyond this finding the correlations are not strong enough to be useful in predicting clinical course.

Expression of MFS is an autosomal dominant pattern with some degree of variance in penetration. There have been no well documented cases of complete lack of phenotypic expression of a disease causing FBN1 mutation, although in some cases the penetrance can be very mild.

Because of the dominant nature of inheritance earlier proposals of disease mechanisms suggested a dominant negative mechanism with the belief that the abnormal transcript/protein interfered with translation and deposition of normal fibrillin.³⁶ More recent work, however, suggests that haploinsuffciency may also be an important mechanism of disease as well.^37,38

The close association of the microfibrils to the elastic fibers suggested that abnormal microfibril synthesis leads to vascular weakness by causing disarrayed deposition of elastic fibers. However, the relatively normal nature of lung tissue at the time of birth suggested that the effects of the FBN1 mutation persisted beyond the time of elastogenesis. It is now thought that most if not all of the clinical manifestations are caused by loss of the regulatory role of extracellular matrix fibrillin on the signaling activity of TGF-β. Fibrillin is one of the principal extracellular binding sites for TGB-β either directly or through latent TGF-β binding protein. Reduction in the availability of extracellular matrix TGF-β binding sites by loss of FBN1 or alterations in the binding sites on mutant fibrillin results in excessive amounts of TGF-β available for interaction with cell surface receptors. The resulting biochemical changes seen in MFS match those seen with TGF-β over-activity. This underlying mechanism is supported by mouse models demonstrating the amelioration of the features of MFS with TGF-β binding antibodies.³⁹

Clinical Manifestations

Because of the ubiquitous nature of fibrillin throughout the body the manifestations of MFS typically involve several organ systems. Although MFS is frequently associated with the musculoskeletal features of tall height, long limbs and flexibility, its most important manifestations from a diagnostic and prognostic standpoint are cardiovascular and ocular.

The cardiovascular complications of MFS are dominated by pathology of the aorta. Aortic root expansion is initiated at the sinuses of Valsalva and progressively enlarges in aneurysmal fashion to cause aortic dissection, aortic rupture and/or aortic regurgitation. Greater than 80% of patients with MFS will manifest some degrees of aortic enlargement or dissection with the aortic root most frequently involved.⁴⁰ Cardiovascular disease is the cause of death in untreated MFS in 71% of patients with median age of death of 41 years in men and 49 years in women.⁴¹

Vascular disease beyond the aorta is unusual in the absence of aortic dissection with extension into the branches of the aorta (Figure 15-3).^42,43,44,45 Independent involvement of the carotids and neck vessels has been suggested in some case reports, but whether the incidence in MFS exceeds that of the general population is uncertain.⁴⁶ Intracranial aneurysms have also been reported as case reports.⁴⁷ A population based study, however, showed no evidence of increased frequency.⁴⁸

Diagnosis

Many of the features of MFS can be seen in the general population independent of any connective tissue disorder. Therefore, at this time the diagnosis currently depends upon a combination of the presence of the more specific findings such as aortic aneurysm, lens dislocation and family history. The formal diagnostic criteria in use currently were defined in 1996.⁴⁹ The presence of two major clinical features in separate organ systems and evidence of involvement in one additional organ system is required. The presence of a documented family history of MFS or genetic testing documenting a fibrillin mutation can be used to reduce the clinical findings needed to provide a definitive diagnosis. The Ghent criteria have proven to be very specific diagnostic criteria for MFS. In young patients and in patients without family history the criteria may be overly rigorous; therefore, care must be used in excluding the diagnosis of MFS in clinical practice using the Ghent criteria alone. Genetic testing is not definitive as FBN-1 mutations can also lead to other syndromes such as Weill-Marchesani and isolated ectopia lentis; these share some of the features of MFS, but have very different phenotypic features and prognostic implications. Correlation between the genetic findings and clinical features is necessary for determining the significance of DNA testing.

Other diagnoses to consider when presented with vascular findings associated with MFS include annuloaortic ectasia, FAA, and TAAD 1. The presence of features in other organ systems helps to exclude those diagnoses. LDS, which will be discussed in the next section, shares many features of MFS: the absence of lens dislocation and the presence of typical craniofacial abnormalities strongly favor the diagnosis of LDS. In the absence of these features, the diagnosis may require genetic testing. Other conditions such as Stickler syndrome, Schprintzen-Goldberg, and Homocystinuria may share the some of the musculoskeletal features that raise concern for MFS, but these conditions do not normally have the vascular manifestations of MFS.