Heritable Connective Tissue Disorders and Stroke

Heritable Connective Tissue Disorders and Stroke Silvina B. Tonarelli, MD and Oscar Benavente, MD, FRCP Stroke is a heterogeneous syndrome caused by multiple etiologies. Heritable defects in connective tissue cause a small fraction of ischemic and hemorrhagic stroke. They are the consequence of mutations in genes encoding extracellular matrix constituents such as collagens and proteoglycans. Ehlers–Danlos syndrome, Marfan’s syndrome, osteogenesis imperfecta, and pseudoxantoma elasticum are the most common disorders responsible for cerebrovascular manifestations. Neurofibromatosis and polycystic kidney disease, although not connective tissue disorders, are hereditary diseases with a high prevalence of vascular complications. Ehlers–Danlos syndrome type IV is the most frequent and most life-threatening form due to the presence of intracranial aneurysms, carotid-cavernous fistulas, and arterial dissections. Marfan’s syndrome has a typical phenotype associated with arterial dissections and intracranial aneurysms. Osteogenesis imperfecta, although infrequent, can present with aneurysms, dissections, fistulas, and stenosis of cerebral vessels. Pseudoxanthoma elasticum is commonly associated with occlusive disease of small vessels and other complications such as aneurysms or arteriovenous malformations. Autosomal– dominant polycystic kidney disease is a common cause of multiple intracranial aneurysms. Neurofibromatosis type 1 is characterized by multiple neurofibromas; it is responsible for stenosis or occlusions of intracranial arteries and vascular malformations. These vasculopathies are associated with a relatively high prevalence of cerebrovascular disease; their early recognition should help in the investigation of asymptomatic carriers, and to provide genetic counseling. The growing knowledge of molecular biology could help in the understanding of the underlying mechanism of these complex disorders as well as identify future therapeutic interventions. Semin Cerebrovasc Dis Stroke 5:2-12 © 2005 Elsevier Inc. All rights reserved. KEYWORDS stroke, connective tissue diseases, heritable defects

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troke is not a single disease; on the contrary, it is a heterogeneous syndrome caused by multiple disorders leading to occlusion or rupture of blood vessels supplying the brain. Only a small fraction of ischemic and hemorrhagic strokes is caused by vasculopathies resulting from inherited defects in the connective tissue.1 Despite the rareness of these conditions, it is particularly important to identify these disorders to investigate asymptomatic carriers and to provide genetic counseling. The term inherited connective tissue disorder is applied to rare connective tissue disease caused by mutations in genes encoding extracellular matrix constituents such as collagens and proteoglycans.2 The phenotype of each disorder is deter-

mined by the organ distribution of the affected extracellular matrix protein. The most common complications in the neurovascular system are aneurysms, occlusive arterial diseases, dissections, and arteriovenous fistulae.3 We review the four main inherited connective tissue disorders that can be responsible for cerebrovascular disease: Ehlers–Danlos syndrome, Marfan’s syndrome, osteogenesis imperfecta, and pseudoxanthoma elasticum. Despite the fact that polycystic kidney disease and neurofibromatosis are not considered part of the connective tissue disorders, we will briefly discuss these hereditary diseases due to their high prevalence of vascular manifestations (Table 1).

Ehlers–Danlos Syndrome Department of Medicine, Neurology, University of Texas Health Science Center, San Antonio, Texas, USA Address reprint requests to Silivina B. Tonarelli, MD, SPS3 Coordinating Center, Department of Medicine, University of Texas Health Science Center at San Antonio, 4647 Medical Drive, San Antonio, Texas 78229. E-mail: [email protected].

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1528-9931/05/$-see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.scds.2005.07.002

Ehlers–Danlos syndrome is one of the most frequently inherited disorders of connective tissue. Based on clinical presentation and genetic and biochemical structure, at least 10 types of Ehlers–Danlos syndrome have been identified (Table 2). The common clinical manifestations are joint hypermobility,

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Table 1 Frequent Neurovascular Manifestations of Heritable Connective Tissue Disorders

EDS type IV MFS OI PXE

Spontaneous Cervical Dissection

Intracranial Aneurysm

Cervical Aneurysm

Occlusive Artery Disease

Spontaneous Direct CCF

Cervical AV Fistula

ⴙⴙ ⴙⴙ ⴙ ⴙ

ⴙⴙ ⴙⴙ ⴙ ⴙⴙ

ⴙ ⴚ ⴙ ⴙ

ⴚ ⴚ ⴙ ⴙⴙⴙ

ⴙⴙⴙ ⴚ ⴙ ⴙ

ⴙ ⴚ ⴚ ⴚ

CCF, carotid cavernous fistula; AV, arteriovenous; EDS, Ehlers Danlos syndrome; MFS, Marfan’s syndrome; OI, osteogenesis imperfecta; PXE, pseudoxanthoma elasticum.

hyperextensible skin, bruising, and abnormal scarring.4,5 Ehlers–Danlos syndrome type IV is an autosomal-dominant disorder and the underlying defect is an abnormality of collagen type III.6 This is the most life-threatening form because of the wide variety of systemic vascular pathology including spontaneous rupture, dissection, or aneurysm formation of large- and medium-sized arteries.7,8 In this syndrome, spontaneous rupture of intestine, and of the uterus during pregnancy, account for the vast majority of deaths.7,9,10

Neurovascular Manifestations The most common neurovascular manifestation is spontaneous direct carotid-cavernous fistula.11,12 This may be anatomically divided into direct and dural fistula.13,14 Direct carotid-cavernous fistulae are usually high-flow direct communications between the internal carotid artery6 and the cavernous sinus and are commonly due to rupture of a preexistent intracavernous carotid aneurysm into the cavernous sinus or by dissection or rupture of the carotid artery as it traverses the cavernous sinus.15-18 Dural carotid-cavernous fistulae consist of abnormal low-flow communications between dural branches of the internal and/or external carotid artery and the cavernous sinus, and presumably, develop secondary to a previous cavernous thrombosis. Low levels of type III collagen predisposes these patients to carotid-cavernous fistula formation.19 The clinical presentation can be tinnitus, thrill, headache, or pulsatile exophthalmia. The mean age of occurrence is 30 years, in contrast to 60 years in the general population.13,20-23 In patients with Ehlers–Danlos syndrome type IV, only direct fistulae have been observed. Complications of diagnostic conventional angiography in these patients may occur at the puncture site or anywhere along the route of the catheter. Careful insertion and manipulation of the smallest possible soft-tipped angiographic catheter may decrease some of these risks.12 Although the chances of spontaneous occlusion are much lower in direct high-flow carotid-cavernous fistula than in indirect carotid-cavernous fistula, the ophthalmic complications of direct fistula are quite serious and might require immediate treatment to maintain normal vision and eye mobility. Surgical repair or ligation of the ipsilateral common carotid artery or internal carotid artery increases the risk of a contralateral aneurysm or carotid-cavernous fistula formation.24 Balloon occlusion of the fistula is usually the treatment of choice. If balloon occlusion is unsuccessful, its use in com-

bination with sacrifice of the internal carotid artery or surgical trapping may be necessary.12

Intracranial Aneurysms The development of intracranial aneurysm with or without subarachnoid hemorrhage is a common complication of Ehlers–Danlos syndrome type IV but the exact prevalence is not known.8,15,18,25 The most common site for intracranial aneurysm formation is the cavernous segment of the carotid artery, where, instead of subarachnoid hemorrhage, its rupture causes a carotid-cavernous fistula. The risk of surgical repair is high in patients with Ehlers–Danlos syndrome type IV due to the vascular fragility. Routine screening for intracranial aneurysms in these patients is generally not recommended.26 The importance of type III collagen defects in individuals with aneurysms in the absence of the vascular Ehlers–Danlos syndrome phenotype is still unknown.27

Cervical Artery Aneurysms Aneurysms of the vertebral artery are infrequent but welldescribed complications of Ehlers–Danlos syndrome, and they can develop subsequent to penetrating neck trauma or spontaneously.28,29 This rare condition should be considered in all Ehlers–Danlos patients who have neck masses of undetermined etiology.29

Cervical Spontaneous Dissections Another classical and extensively documented complication of vascular Ehlers–Danlos syndrome are dissections of extracranial and intracranial segments of the vertebral and carotid arteries (Figs. 1 and 2).11,28-31 Connective tissue abnormalities in dermal biopsies of a series of patients with carotid or vertebral artery dissection pointed to a structural defect of the arterial wall similar to those present in Ehlers–Danlos syndrome.32 In seven patients with spontaneous carotid dissections and absence of findings consistent with Ehlers–Danlos syndrome, six of the skin biopsies showed histological, immunohistochemical, and ultrastructural changes similar to Ehlers–Danlos syndrome.33

Diagnosis A skin biopsy should be taken if the diagnosis of vascular Ehlers–Danlos syndrome is suspected. The diagnosis can be made with fibroblast culture and biochemical studies of col-

S.B. Tonarelli and O. Benavente Defect in fibronectin? ?

AD AR AD X linked

? Deficiency in lysyl hydroxylase Collagen type I Procollagen I ? Copper transporting X linked AR

AR AD AD

? Collagen type III

Tenascin-X deficiency

Collagen V defect AD

Inheritance

Primary Defect

4

lagen metabolism and it is confirmed by the presence of abnormal type III procollagen molecules. Also the identification of mutations in the type III procollagen gene (COL3A1) on chromosome 2 corroborates the diagnosis.31,34,35

Treatment Currently, there is no specific treatment for patients affected by Ehlers–Danlos syndrome and cerebrovascular complications. Invasive diagnostic procedures such as conventional angiography should be avoided and treatment should be conservative if possible due to the excessive blood vessel fragility. Nevertheless, surgical or endovascular treatment of asymptomatic lesions may be indicated in select cases.36

Marfan’s syndrome, initially described over 100 years ago by Antonine-Bernard Marfan, is an autosomal-dominant connective tissue disorder with a prevalence of 2 to 3 cases per 10,000 individuals with probably 30% of sporadic cases.37 The syndrome involves many systems; however, the most prominent manifestations are skeletal, ocular, and cardiovascular. Nevertheless, skin, fascia, lungs, adipose tissue, and central nervous system may also be involved occasionally, being the form of presentation of the disease38 (Table 3).

Clinical Features

AD, autosomal dominant; AR, autosomal recessive.

ⴙⴙ ⴙ X

ⴙⴙⴙ ⴙ ⴙⴙ ⴙ ⴙⴙ ⴙⴙⴙⴙ ⴙⴙ ⴙ Arthrochalasic Dermatosparatic

VIIA/B VII C VIII IX

Hypotonia, kyphoscoliosis, ruptures of arteries and the eye globe Hip luxations, fractures Skin doughy and lax Periodontal disease Exostoses, occipital hornes, mental retardation Platelet dysfunction ⴙ ⴙⴙⴙ ⴙⴙ ⴙⴙⴙ V VI Kyphoscoliotic type

ⴙⴙⴙ ⴙ ⴙ ⴙⴙⴙ Hypermobile type Vascular type

ⴙⴙ ⴙⴙ

II II/III III IV

Arthritis Rupture of arteries, intestine, uterus, acrogeria, pneumotorax

Vascular and intestinal complications. Normal wound healing ⴙⴙⴙ ⴙⴙⴙ I Classical type

Joint Skin Type

Table 2 Classification of Ehlers–Danlos Syndrome

Other Features

Marfan’s Syndrome

Although the clinical expression is variable, patients with Marfan’s syndrome are often easily recognized by the skeletal abnormalities, which include tall stature, pectus excavatum, scoliosis, prognathism, high-arched palate, and joint hypermobility.1,38 The most common cutaneous and integument manifestations are lumbosacral dural ectasia, striae atrophicae, which occur in areas of flexural stress, and recurrent or incisional hernia. Myopia and ectopia lentis are common ocular abnormalities, although retinal detachment also can occur. Aneurysmal dilation and dissection of the ascending aorta are the major diagnostic criteria for involvement of the cardiovascular system.38,39 In addition, mitral valve prolapse, dilation of main pulmonary artery, calcification of the mitral annulus, and dilation or dissection of the descending thoracic or abdominal aorta are frequently found.40-42 Aortic dissections in patients with Marfan’s syndrome carry a high mortality. They present at a younger age than atherosclerotic dissections, lack usual vascular risk factors, and tend to be normotensive at presentation.43

Neurovascular Complications The most common neurovascular complication and the most frequent cause of death in adults is probably extension of aortic dissection into the innominate and common carotid arteries, leading to profound cerebral ischemia, or involvement of spinal arteries, causing ischemic myelopathy with paraparesis.1,44,45 Spontaneous dissection limited to the common carotid artery, the extracranial internal carotid artery, or

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Figure 1 Magnetic resonance angiography showing a spontaneous dissection of the basilar artery.

the extracranial vertebral artery also have been reported in these patients.1,46 Marfan’s syndrome has also been associated with intracranial and dissecting aneurysms. However, the evidence for this association is based only on a small case series and the true prevalence is unknown.47-53 Intracranial aneurysms may be saccular or fusiform and are often large and present with mass effect. Most of them arise from the cavernous segment of the carotid artery.48 The association of Marfan’s syndrome and intracranial aneurysms is still controversial. Van den Berg and collaborators studied a small series of Marfan’s patients with intracranial aneurysms and concluded that this association might be only by chance and do not have a common underlying mechanism,54 while other studies based on autopsies favor a real association.55

Molecular Diagnosis Mutations in the gene encoding fibrillin-1 (FBN1) are responsible for Marfan’s syndrome. The defect has been localized first in chromosome 15q21.156-58 and probably other loci contribute to the genetic heterogeneity of this syndrome.59 The protein fibrillin-1 is one of the major components of elastin-associated microfibrils.60 These microfibrils are important constituents of the extracellular matrix and are distributed throughout the body in elastic tissues such as skin

and aorta, as well as nonelastic tissues. In elastic arteries, fibrillin-1 is found in all three layers of the arterial wall, and it plays an important role in maintaining the structural integrity of connective tissues. Therefore reduction or alteration of this protein could be involved in the pathogenic mechanisms that affect the different tissues in Marfan’s syndrome, but these hypotheses still remain speculative.

Osteogenesis Imperfecta Osteogenesis imperfecta, also known as brittle-bone disease, is a heterogeneous group of connective tissue disorders characterized by excessive bone fragility as a result of mutations in the genes that encode the chains of type I collagen, the main protein of bone.61,62 Osteogenesis imperfecta affects about 1/5000 to 1/10,000 individuals of all racial and ethnic origins.63 Besides the bone fragility, other clinical features are blue sclera, dental malformation, deafness, hyperextensible ligaments, and skeletal deformities. The phenotypic presentation is widely varied, ranging from death during the perinatal period to normal lifespan with minimal increase in fractures. Four major types of osteogenesis imperfecta are now recognized on the basis of clinical, radiographic, and genetic characteristics64 (Table 4).

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of two pro-␣1 (I) chains encoded by the COL1A1 gene and a single pro-␣2 (I) chain encoded by the COL1A2 gene. COL1A1 is located on chromosome 17 and COL1A2 gene is located on chromosome 7.73 Although types I and III collagen are equally abundant in blood vessel walls, it is the type III collagen that provides most of the tensile strength, perhaps explaining why vascular complications are not as common in osteogenesis imperfecta as they are in Ehlers–Danlos syndrome type IV.1

Treatment The management of osteogenesis imperfecta focuses on minimizing fractures and maximizing function, because there is no therapy that effectively reverses the osteopenia, normalizes the histologic features of connective tissue, or reverses the secondary findings of this condition. There are prospects for gene therapy in the treatment of osteogenesis imperfecta with replacement of mutant cells or suppression of mutant genes.74

Pseudoxanthoma Elasticum

Type 1 collagen, the major structural protein of all extracellular matrix of bones, skin, and tendons, is widely distributed throughout the body, including the perivascular space and cardiac valves. The most common vascular abnormality is aortic root dilation and it is present in almost all nonlethal types of osteogenesis imperfecta. Other vascular complications include mitral valve prolapse, aortic regurgitation, and atrial rupture. Aneurysms affecting the coronary and ulnar arteries have been reported.65,66

Pseudoxanthoma elasticum is a rare heritable connective tissue disorder with autosomal-dominant or recessive modes of inheritance.75 The locus for pseudoxanthoma elasticum has been mapped to chromosome 16p13.1.76 Pseudoxanthoma elasticum is characterized by alterations of the elastic fiber in the skin, ocular system, and cardiovascular system.1 The prevalence of pseudoxanthoma elasticum is estimated to be about 1 per 100,000. The pathogenesis is not known, but abnormalities of elastic fibers such as degeneration, fragmentation, and calcification are suspected to be the cause of the clinical manifestations. The occasional association of pseudoxanthoma elasticum with other hereditary disorders of connective tissue is well-documented, particularly with Marfan syndrome, Ehlers–Danlos syndrome, and Paget disease of the bone.77

Neurovascular Complications

Ocular Manifestations

Cerebrovascular complications are relatively infrequent and certainly much less common than in the other inherited connective tissue disorders. However, ruptured cerebral aneurysms associated with fenestrated vertebral arteries, vertebral artery dissections, carotid-cavernous fistulas, and moyamoya-like diseases have been communicated.67

Although nonspecific, angioid streaks due to involvement of the Bruch membrane occur in about 85% of affected patients.78 The visual loss is generally due to development of a choroidal neovascular membrane. Retinal hemorrhage occurs in about one-third of the patients.79-81

Figure 2 Magnetic resonance angiography in young patient with spontaneous carotid dissection.

Molecular Basis Most forms of osteogenesis imperfecta are inherited in an autosomal-dominant fashion, resulting either from inheritance of a mutant gene from an affected parent or from a new dominant mutation. Autosomal-recessive cases of osteogenesis imperfecta are very rare.68-71 All individuals with osteogenesis imperfecta have mutations in one of the two genes that encode the chains of type I collagen. Studies of cultured cells from affected individuals confirm that the collagen synthesized by those cells is decreased in amount or is in some manner defective.72 The type I procollagen molecule consists

Skin Manifestations The characteristic skin lesions consist of round, oval, or linear yellow-orange papules, resembling xanthomas. The skin lesions are often associated with laxity and thickening of the skin and involve flexoral areas, such as neck, axilla, groin, and antecubital and popliteal spaces.

Vascular Manifestations The cardiovascular changes associated with pseudoxanthoma elasticum are occlusive or aneurysmal disease primarily affecting medium-sided peripheral arteries. Prolapsed mi-

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Table 3 Marfan Syndrome: Diagnostic Criteria Skeletal System Major criterion: at least four of the following manifestations: Pectus carinatum Severe Pectus excavatum Reduced upper to lower segment ratio or arm span to height ratio >1.05 Positive wrist and thumb signs Scoliosis of >20° or spondylolithesis Reduced extension of the elbows (<170°) Medial displacement of the medial malleolus associated with pes planus Protrusio acetabulae of any degree (ascertained on X-ray, CT, MRI) Minor criteria: Pectus excavatum of moderate severity, joint hypermobility, highly arched palate with dental crowding, facial appearance (dolicocephaly, malar hypoplasia, enophthalmos, retrognathia, downslanting, palpebral fissures) For the skeletal system to be involved, at least two components of major criteria, or one component of major criterion plus two of the minor criteria must be present. Ocular System Major criterion: Ectopia lentis Minor criteria: flat cornea, increased axial length of globe (>23.5 mm), hypoplastic iris or hypoplastic ciliary muscle causing a decreased miosis. For the ocular system to be involved, at least two of the minor criteria must be present. Cardiovascular System Major criteria: Dilatation or dissection of the ascending aorta with or without aortic regurgitation and involving at least the sinuses of Valsalva Minor criteria: Mitral valve prolapse with or without mitral valve regurgitation; dilatation of main pulmonary artery, in absence of valvular or peripheral pulmonic stenosis, under the age of 40 years; calcification of the mitral annulus under the age of 40 years; or dilatation or dissection of the descending thoracic or abdominal aorta under the age of 50 years. For the cardiovascular system to be involved, a major criterion or only one of the minor criteria must be present. Pulmonary System Major criteria: none Minor criteria: Spontaneous pneumothorax, or apical blebs (radiographic evidence) For the pulmonary system to be involved, one of the minor criteria must be present. Skin and Integument Minor criteria: either striae atrophicae not associated with marked weight changes, pregnancy or repetitive stress, or recurrent or incisional herniae. For the skin and integument to be involved, one of the minor criteria must be present. Dura Major criteria: Lumbosacral dural ectasia by CT or MRI Family History Major criteria: Having a first-degree relative who meets the diagnostic criteria listed below independently Presence of a mutation in FBN1 known to cause the Marfan syndrome Presence of a haplotype around FBN1, inherited by descent, known to be associated with unequivocally diagnosed Marfan syndrome in the family Minor criteria: none For the family history, one of the major criteria must be present. For the index case: Major criteria in at least two different organ systems and a third must be involved For a family member: Presence of a major criterion in the family history and one major criterion in an organ system and involvement of a second organ system CT, computerized tomography; MR, magnetic resonance imaging; FBN1, fibrillin 1.

tral valve,82 cardiomyopathy,83 and myocardial infarct are commonly reported.84,85 Gastrointestinal, uterine, nasal, bladder, and joint bleeding may be the presenting symptoms of pseudoxanthoma elasticum.81,86

Neurovascular Manifestations Pseudoxanthoma elasticum may be associated with multiple small cerebral infarcts as a result of premature occlusive disease of the carotid or vertebral arteries.87-89 The affected patients often have multiple risk factors for stroke, and hyper-

S.B. Tonarelli and O. Benavente

8 Table 4 Osteogenesis Imperfecta: Classification Osteogenesis Imperfecta Type

Main Manifestations

I— Mild dominant with blue sclerae II— Perinatal lethal

Normal stature, little or no deformity, variable bone fragility, blue sclerae, hearing loss, dentinogenesis imperfecta uncommon. Extreme bone fragility, marked skeletal deformity, gray or blue sclerae.

III— Progressive deforming IV— Mild deforming

Severe bone fragility, short stature, progressive skeletal deformity, light sclerae, hearing loss, and dentinogenesis imperfecta common. Mild to moderate bone deformity and variable short stature; normal sclerea, dentinogenesis is common, and occasional hearing loss.

Inheritance AD AD, rarely AR AD or AR AD

AD, autosomal dominant; AR, autosomal recessive.

tension is more prevalent than in the general population. In a series of 100 cases of pseudoxanthoma elasticum patients with stroke, small vessel stroke was the norm.90 Subarachnoid hemorrhage and intracerebral hemorrhage are frequent causes of death in patients with pseudoxanthoma elasticum. The relationship between pseudoxanthoma elasticum and intracranial aneurysms is based on a small number of case reports; therefore, a spurious association is still possible.1,91 Most of the aneurysms are located within the cavernous sinus, leading to ocular motor nerve palsies without subarachnoid hemorrhage. Other craniocervical vascular malformations described in patients with pseudoxanthoma elasticum are fusiform cervical aneurysm, pontine arteriovenous malformation, and bilateral calcified common carotid aneurysms.92-94 Abnormal anastomotic vessels between the interna carotid artery and branches of the external carotid artery (rete mirabile) plus carotid hypoplasia have been reported in a few instances.92,95-97

Diagnosis Without a serologic marker, the diagnosis of pseudoxanthoma elasticum relies on clinical grounds and on the demonstration of abnormal calcified elastic fibers. In patients without the typical skin but who have angioid streaks, biopsy of axillary skin or scars should be performed.

Polycystic Kidney Disease Polycystic kidney disease is characterized by the presence of bilateral multiple renal cysts, and it is divided into two groups: autosomal-dominant polycystic kidney disease and autosomal-recessive polycystic kidney disease. The prevalence is approximately 1 in 400 to 1000 of the population. Vascular complications are present only in autosomal-dominant polycystic kidney disease, a systemic disease in which manifestations are not limited to the kidneys.98 Cysts may be found in several parts of the body, including liver, spleen, pancreas, pineal gland, and subarachnoid space.99 Cardiovascular manifestations include mitral valve prolapse, aortic dissection, aortic root dilation, aortic aneurysm, and aortic coarctation. Colonic diverticulosis, spontaneous colonic

rupture, and inguinal hernia appear to be relatively common features of autosomal-dominant polycystic kidney disease.100

Neurovascular Complications The prevalence of unruptured intracranial aneurysms among patients with autosomal-dominant polycystic kidney disease ranges from 0 to 40% with an overall estimate between 5 to 10%, resulting in a prevalence four times higher than in the general population (Fig. 3).101 The most frequent location is middle cerebral artery; most are smaller than 6 mm in diameter and a positive family history for subarachnoid hemorrhage or unruptured intracranial aneurysm is present in more than 40%. The average age at which subarachnoid hemorrhage occurs is 40 years.102,103 Rupture of a saccular intracranial aneurysm is probably the best known extrarenal complication of autosomal-dominant polycystic kidney disease. The risk for rupture of aneurysms less than 10 mm in size ranges from 0.05 to 0.7% per year. The risk factors for rupture are size ⬎10 mm, posterior circulation location more than anterior circulation, and previous subarachnoid hemorrhage. Other variables that might increase the risk of rupture are age, hypertension, heavy alcohol consumption, female sex, and cigarette smoking.104,105 Hypertensive hemorrhage is another cerebrovascular complication of autosomal-dominant polycystic kidney disease. In one study of 900 consecutive cases of hemorrhagic stroke, 1.2% were associated with polycystic kidney disease. The usual sites for intracerebral hemorrhage are the putamen and the thalamus. The main cause of this association is undetected or inadequately treated hypertension.106 Intracranial arachnoid cysts are a relatively frequent incidental finding in patients with autosomal-dominant polycystic kidney disease107,108 and sometimes are associated with subdural hematomas.109 Patients with autosomal-dominant polycystic kidney disease are at an increased risk of developing intracranial arterial dolichoectasia and arterial dissections.110,111

Molecular Diagnosis In about 80% of cases, the gene mutation is localized on chromosome 16 (ADPKD1) with a possible second genetic abnormality (ADPKD2). Spontaneous mutations account for 10% or less.98

Heritable connective tissue disorders and stroke

9 in whom an aneurysm was found but no treatment proposed. There is no doubt that it is essential that groups at risk of possessing aneurysms should have modification of risk factors that increase the risk of subarachnoid hemorrhage such as hypertension, heavy alcohol use, and smoking.105,113

Neurofibromatosis Neurofibromatosis comprises two autosomal-dominant disorders: neurofibromatosis type 1 and neurofibromatosis type 2, with different clinical expressions. The vascular compromise is only part of neurofibromatosis type 1 and the hallmark is the presence of multiple neurofibromas.115 Neurofibromatosis type 1, also known as von Recklinghausen disease, is an autosomal-dominant connective tissue disorder affecting approximately 1 in 3000 to 5000 persons. This progressive systemic disease involves tissues of mesodermal and ectodermal origin. The main clinical features of neurofibromatosis type 1 are café-au-lait spots, neurofibromas, and axillary and inguinal frecklings in the skin; the Lisch nodules (hamartomas) of the iris are the most common ocular manifestations. Patients with this disease are also at increased risk of developing optic glioma, heterotopias, pheochromocytoma, dural ectasia, and skeletal abnormalities such as scoliosis and sphenoid wing dysplasia. The peripheral nervous system can be affected by neurofibromas and schwannomas.116 Vascular complications are characterized by stenosis, rupture, and aneurysms or fistula formation of large- and medium-sized arteries,117-119 and the renal arteries are commonly involved. Figure 3 Multiple aneurysms in the circle of Willis in a patient with polycystic kidney disease (PKD), autosomal-dominant form. (Color version of figure is available online.)

Screening for Asymptomatic Intracranial Aneurysms Screening for asymptomatic aneurysms with conventional arteriography is not recommended due to the high frequency of complications.112 Noninvasive imaging techniques such as magnetic resonance angiography (MRA) and dynamic spiral CT angiography (CTA) have been used for screening purposes. MRA has the advantage of a minimal complication risk. The sensitivity is very high in aneurysms larger than 6 mm, with specificity between 90 and 100%. The main limitation of this technique is aneurysm size dependence; the sensitivity diminishes to 30% in aneurysms of less than 5 mm.113,114 CTA probably has similar diagnostic performance to MRA, but it has the disadvantage of requiring the use of intravenous iodinated contrast. Other factors to consider in the efficacy of screening include the fact that the natural history of intracranial unruptured aneurysms in autosomal-dominant polycystic kidney disease remains unknown, and there are no randomized controlled trials addressing the management of aneurysms in these patients. Any benefit from the screening would have to be balanced against its significant cost and the anxiety it would generate in those

Neurovascular Complications The most recognized neurovascular complication of neurofibromatosis is stenotic or occlusive disease of the intracranial circulation, usually occurring in childhood or adolescence.120 These occlusions are associated with a moya-moya pattern of collateral circulation and the supraclinoid carotid artery is the most frequently affected artery.121,122 Extracranial stenotic or occlusive diseases of the internal carotid or vertebral arteries also have been described.1 Arteriovenous fistula and aneurysm formation of the extracranial/internal carotid or vertebral arteries or external carotid artery is a frequent nonocclusive manifestation of neurofibromatosis type 1.118,119,123-125 Intracranial aneurysms may be saccular or fusiform, and some have the appearance of dissecting aneurysms.126,127 Surgical repair of these aneurysms may be complicated by excessive vascular fragility or distortion of anatomic landmarks caused by the presence of sphenoid wing dysplasia. Intracranial aneurysms often coexist with intracranial arterial occlusive disease,122 increasing the risks of their surgical and particularly endovascular treatment.

Molecular Basis Neurofibromatosis type 1 is caused by mutations in the gene (NF1) encoding neurofibromin, a protein with a centrally located domain homologous to GTPase-activating protein (GAP) that is similar to other tumor suppressor gene prod-

10 ucts.128,129 The gene for neurofibromatosis type 1 has been mapped to chromosome 17 in band q11.2.130,131

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