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BROCA’S AREANeurosurgical Forum

J Neurosurg 134:1999–2006, 2021

Genetic and heritable considerations in patients or families with both intracranial and extracranial aneurysmsAnna L. Huguenard, MD,1 Vivek P. Gupta, MD,1 Alan C. Braverman, MD,2 and Ralph G. Dacey, MD1

1Department of Neurosurgery, Washington University in St. Louis; and 2Cardiovascular Division, Department of Medicine, Washington University in St. Louis, Missouri

IntracranIal aneurysms are common, with a preva-lence between 2% and 6% of the population,1 and this prevalence increases with age. In patients who harbor

an intracranial aneurysm, a significant risk is development of subarachnoid hemorrhage (SAH) due to aneurysm rupture. SAH occurs in approximately 30,000 people an-nually in the US, and is associated with a mortality rate of 30%–50%.1 Risk factors for intracranial aneurysms include age, female sex, hypertension, and smoking.2 A family history of two or more first-degree relatives with an intracranial aneurysm is an independent risk factor.1

In a study screening first-degree relatives of patients with at least two affected family members, the rate of in-tracranial aneurysm prevalence is approximately 9%, or 2–3 times higher than that of the general population.3 The basis for this heritable risk has been studied extensively.4 Some families have known genetic syndromes that pre-dispose members to the formation of aneurysms.5 Others have nonsyndromic genetic mutations that drive their in-creased risk for aneurysm formation.1 In still other fami-lies, there is increased familial risk without a clearly iden-tified genetic underpinning.6

A family history also predisposes to the presence of multiple aneurysms, increased risk of rupture in identi-fied aneurysms, and worse outcomes after rupture.4 Link-age and candidate gene studies, genome-wide association studies, expression studies, and whole-exome sequencing have all identified several candidate loci associated with intracranial aneurysms. However, most familial studies suggest incomplete genetic penetrance with multifactorial risk factors.4

Aortic aneurysms are also common, with a prevalence of approximately 1.1% for abdominal aortic aneurysm (AAA) and 0.2%–0.5% for thoracic aortic aneurysm (TAA).7,8 Significant mortality and morbidity are associ-ated with AAA rupture and TAA rupture and dissection.7 Risk factors include age, smoking, and male sex.9 Family history is again an important risk factor. Approximately 20% of patients with either AAA10 or TAA11 will have a first-degree relative with the same pathology. The preva-lence of AAA among siblings of a patient with AAA is 8 times greater than that of the general population.10 The study of both syndromic and nonsyndromic heritable TAA diseases has been a growing field, with many well-defined gene mutations linked to the disease.11,12

For decades,13 clinicians have observed that some fam-ilies have co-occurrence of intracranial and extracranial aneurysms.14 Additional studies demonstrated this in pa-tients with known connective tissue syndromes15 as well as in those without.2 Despite growing literature indicating that a subset of the population has a propensity for aneu-rysm formation that is heritable, few clear screening guide-lines have been proposed to direct the clinician to evaluate for the co-occurrence of these lesions. We aim to address this deficiency by outlining the current understanding of heritable intracranial and aortic aneurysms in the context of familial clustering, known syndromic causes, and ge-netic mutations without associated syndrome, and we re-view current guidelines or indications for screening.

Familial Clustering of Intracranial and Aortic AneurysmsThe literature has previously demonstrated aggregation

in some families for intracranial and systemic aneurysms, even when a specific syndrome or genetic mutation has not been identified. One study examined a proband’s fam-ily history of both intracranial and aortic aneurysms and found that those with a family history of intracranial an-eurysm presented with their aortic aneurysm at a younger age, had more proximal disease in the aortic root, and had a greater extent of aneurysmal disease.16

Another study of 274 patients with saccular intracranial aneurysms examined family pedigrees to identify mem-bers with intracranial and extracranial aneurysms. Al-though these investigators identified a cohort with known

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J Neurosurg Volume 134 • June 20212000

syndromic predisposition due to autosomal dominant polycystic kidney disease (ADPKD), a remaining cohort of 47 families without a previous genetic or syndromic di-agnosis demonstrated increased rates of intracranial aneu-rysms, with 29 of those families also exhibiting increased rates of aortic aneurysms. Several of these latter pedigrees indicate a possible autosomal dominant form of transmis-sion for this unidentified genetic risk for both intracranial and aortic aneurysms.6 As genetic testing becomes more affordable and accessible to clinicians and families, more families with aneurysmal disease (both syndromic and nonsyndromic) will be discovered to have a predisposing pathogenic genetic variant.

Syndromic AneurysmsThere are many syndromic conditions that increase a

patient’s risk for development of intra- and extracranial aneurysms. Several of these are detailed below and are described in Table 1.

Loeys-Dietz SyndromeLoeys-Dietz syndrome (LDS) is an autosomal dominant

condition that manifests with hypertelorism, craniofacial abnormalities (including cleft palate and bifid uvula), skel-etal and cutaneous features, and aortic and branch vessel aneurysms.17 The genetic cause is heterogeneous but typi-cally involves the transforming growth factor beta (TGFβ) signaling pathway via a mutation in one of several genes (TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3), which manifest as several major subtypes of LDS. The pathogen-esis of vascular abnormalities in LDS is related to dysfunc-tional elastogenesis and an excess of collagen deposition in arterial walls as a result of altered TGFβ signaling.18

Vascular abnormalities are common, including aortic aneurysm and arterial tortuosity (particularly of the ves-sels of the head and neck).17 Arterial tortuosity is associat-ed with increased risk of aortic dissection and aortic aneu-rysm surgery in patients with LDS.19 Although aortic root aneurysms are the most common, aneurysms throughout the aorta and its branches may occur.20 Patients with LDS and severe craniofacial anomalies are at higher risk for aortic dissection and have rupture at earlier ages and smaller dimensions.21

One series of 90 patients with LDS due to TGFBR1 and TGFBR2 mutations found that 10% had intracranial an-eurysms, and intracranial hemorrhage was the third lead-ing cause of death after aortic and subclavian dissection.20 Other reviews found that 28%15 and 32%22 of patients with LDS had intracranial aneurysms. Our institution’s own unpublished data set of 59 patients with LDS who under-went cranial vascular imaging found that 18% had intra-cranial aneurysms.

Mutations in SMAD3 can also cause LDS type 3, with one series of 42 patients showing that 50% had TAA, 9.5% had an intracranial aneurysm, and 4.8% had AAA.23 The average age at presentation with intracranial aneurysm was 51 years, with presentation approximately 6 years earlier for aortic disease.23 In a series of 45 individuals with SMAD3 mutations, both intra- and extracranial an-eurysms were present in 38% of patients, involving the vertebral, carotid, basilar, and ophthalmic arteries.24 Cere-

bral aneurysms and SAH have been reported in those with TGFB2 mutations,25 and cerebrovascular disease in those with TGFB3 mutations, but the prevalence is unknown.26

The current recommendation for baseline imaging in-cludes transthoracic echocardiogram (TTE), and either MRA or CTA of the cerebral to pelvic vasculature. Rec-ommendations for serial imaging are variable, with some advocating for annual TTE and repeat MRA or CTA of either the aortic vasculature or the entire vascular system every 1–2 years, depending on vascular involvement.21,27

Marfan SyndromeMarfan syndrome is an autosomal dominant connec-

tive tissue disorder resulting from a mutation in the FBN1 gene encoding the microfibrillar protein fibrillin-1, with a prevalence of 1 in 5000.3,28 Patients demonstrate aortic root disease, mitral valve prolapse, ligamentous laxity, ec-topia lentis, and arachnodactyly.29 This phenotypic expres-sion has been demonstrated in animal models and humans to relate to overexpression of TGFβ in tissues of the lung, heart, cardiac valves, major blood vessels, and skeletal muscle. The leading hypothesis is that defective fibrillin-1 in Marfan syndrome disrupts the homeostasis of TGFβ, resulting in its increased levels and abnormal signaling.28

Aortic root dilatation and aneurysm develop in almost all patients, and thoracic aortic dissection may lead to ini-tial presentation.30,31 Historically, life expectancy in these patients was dramatically curtailed by the development of proximal aortic pathology or associated aortic regur-gitation in early adulthood. Advances in medical manage-ment with chronic prophylactic β-adrenergic blockade and surgical advances for various elective root surgeries to prevent these sequelae have significantly extended life expectancy.28,32

There are mixed data regarding the risk of intracranial aneurysms in this population, with few clinical events in large cohorts and rare case reports of this coexistence.33,34 Of 25 autopsies in patients diagnosed with Marfan syn-drome between 1939 and 1996, only 1 (4%) was found to have an intracranial aneurysm.33 In a series of 140 adults with Marfan syndrome evaluated between 2000 and 2010, 5 of 14 patients (36%) who underwent cranial imaging were reported to have cerebral aneurysms.35 In a Mayo Clinic report, of 59 patients with Marfan syndrome who underwent cranial imaging between 2005 and 2015, 8 (14%) had intracranial aneurysms at a mean age of 48 years.15

A series reviewing the discharge information of more than 13,000 individuals revealed a higher rate of carotid dissection (0.3% vs 0%, OR 11.9) and cerebral aneurysm (0.2% vs 0.1%, OR 3.95) in those diagnosed with Mar-fan syndrome compared to controls.29 Due to an overlap-ping phenotype between Marfan syndrome and LDS, it is possible that some individuals diagnosed with Marfan syndrome actually had LDS. With their increasing life-span and more widespread imaging surveillance, a better understanding of the prevalence of cerebral aneurysms in patients with Marfan syndrome may be realized.

Patients with Marfan syndrome undergo imaging of the ascending aorta and heart with echocardiogram and chest CTA or MRA at diagnosis. The frequency of aortic root



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surveillance is variable, but is often yearly.28 However, there are no current recommendations for surveillance for intracranial aneurysms in this population.30

Vascular Ehlers-Danlos SyndromeVascular Ehlers-Danlos syndrome (vEDS), also identi-

fied as Ehlers-Danlos syndrome type IV, is a subtype of the heterogeneous heritable EDS connective tissue disorders with a propensity for intracranial and extracranial vascu-lar involvement.36 Broadly, EDS is characterized by joint hypermobility, skin hyperextensibility, and tissue fragil-

ity.37 vEDS most often involves a mutation in the COL3A1 gene resulting in malfunction of type III collagen,37 and inheritance is usually autosomal dominant. It is the least common subtype of EDS, with an estimated prevalence of 1 in 50,000 to 150,000.36,38 The median life expectancy is only 48 years, due to the frequent occurrence of fatal vascular complications.39 The abnormal collagen pattern in vEDS leads to reduced total collagen content, thin ves-sel walls with irregular elastic fibrils, and reduced cross-sectional area, which predisposes to development of aneu-rysms, vessel dissections, and fistula formation.40

TABLE 1. Syndromic conditions associated with intracranial and aortic aneurysms

Syndrome

Associated Genetic

Mutation(s)

Vascular Clinical

Features

Other Syndromic Features

Reported Prevalence

of Intracranial Aneurysm

Recommendations for

Intracranial Aneurysm Screening

LDS TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3

Aortic & branch ves-sel aneurysms & dissections, arterial tortuos-ity, intracranial aneurysms

Hypertelorism, craniofacial abnormalities (including cleft palate, bifid/broad uvula), skeletal features, translucent skin, visible veins

10%–32%15,

20,22Baseline imaging includes TTE, & either MRA

or CTA of the cerebral to pelvic vasculature. Recommendations for serial imaging are variable: annual TTE, & repeat MRA or CTA of the aortic vasculature, or the entire vascular system, every 1–2 yrs, depending on individual circumstances.21,27

Marfan FBN1 Aortic root aneu-rysm, thoracic aortic dissection

Ligamentous laxity, ectopia len-tis, arachnodactyly, scoliosis, pectus deformities

0%–14%15,33 Baseline imaging of the aortic root & ascending aorta w/ imaging of the entire thoracic aorta at variable intervals depending on individual circumstances.28 No current recommenda-tions for surveillance of intracranial aneu-rysms in this population.

vEDS COL3A1 Aortic & branch ves-sel dissection or rupture, intracra-nial aneurysm, CCF, AVFs

Translucent skin, visible veins, easy bruising, varicose veins, gastrointestinal perforation, organ rupture, atrophic scars

16.5%;41 12% of all EDS cases15

Baseline vascular imaging from head to pelvis. Further recommendations variable, but up to annual surveillance MRA or CTA of the aortic system44 & MRA or CTA of the cerebral to pelvic vascular system every 3 yrs.27

ADPKD PKD1, PKD2, GANAB

Intracranial aneu-rysm formation

Multiple parenchymal renal cysts, hypertension, cystic liver disease

10%46 Screening w/ MRA in patients w/ a family history of intracranial aneurysms, family or personal history of SAH, & in high-risk pro-fessions such as pilots.50 Universal screening remains controversial given that many of the aneurysms found do not require treatment, although a recent analysis suggests that universal screening may be cost-effective.51

NF1 NF1 Aortic aneurysm, intracranial vas-culopathy, intra-cranial aneurysm

Café-au-lait spots, cutaneous tumors such as neurofibromas & Lisch nodules, gliomas (par-ticularly of the optic nerve), & other malignancies such as rhabdomyosarcomas, gastro-intestinal stromal tumors, & hemopoietic malignancies

9.6%–11%15,53 No current recommended screening guidelines for intra- or extracranial aneurysms or vascu-lopathies in this population.57

TSC TSC1, TSC2

Large fusiform intracranial aneu-rysms in juveniles

Skin lesions (hypomelanotic macules, facial angiofibromas, & Shagreen patches); renal dysfunction; retinal hamarto-mas; cardiac rhabdomyomas; & CNS involvement

1.7%65 Brain MRI every 1–3 yrs until the age of 25 yrs to evaluate for the development of subepen-dymal giant cell tumors. Some propose an additional MRI session w/ time-of-flight to provide vascular screening, particularly in young patients.67

AVF = arteriovenous fistula.


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A series of 86 patients with molecular confirmation of vEDS revealed that 62% had aortic or arterial pathol-ogy. The most commonly affected vessels were the aorta (32%), mesenteric arteries (31.7%), and cerebrovascular and iliac arteries (16.5% each).41 For patients with aortic involvement, 10 had thoracic involvement and 7 had ab-dominal involvement. Of these patients, 7 had aortic rup-ture, directly resulting in 2 deaths.41

The intracranial vascular manifestations of vEDS in-clude spontaneous intracranial hemorrhage, aneurysms of the circle of Willis (most often of the internal carotid artery [ICA]), carotid-cavernous fistula (CCF), ischemic stroke, and blood vessel ectasia.36 The most common of these is the development of nontraumatic CCF, which is often related to aneurysm formation in the intracavernous portion of the ICA.36,42 This finding is considered pathog-nomonic of the disease and occurs in approximately 10% of patients.41 Management varies, but there is some consensus that embolization via a transvenous approach seems to offer a decreased risk of vascular injury.41

Management of intracranial aneurysms can be chal-lenging, with any endovascular procedure being particu-larly risky. In fact, one study cited an estimated mortality rate as high as 40% from any type of neurovascular pro-cedure due to the fragility of the blood vessels.39 Compli-cations include vessel dissection, aneurysm rupture, and development of pseudoaneurysms at the vascular access site. Open craniotomy may be preferred in these patients, despite an increased surgery-related morbidity related to the fragility of the vasculature being dissected.36 More than usual proximal control is recommended to allow management of this complication.43 In general, earlier in-tervention is recommended, given the propensity for these aneurysms to grow and the challenge of treating larger an-eurysms in the setting of nearby vessel fragility.36

There is variability in baseline and serial vascular im-aging obtained in these patients for surveillance. Some have recommended that surveillance imaging be tailored to the symptoms and presentation of each individual.41 Others obtain baseline aortic imaging, with up to annu-al surveillance MRA or CTA of the aortic system,44 and MRA or CTA of the cerebral to pelvic vascular system every 3 years.27

Autosomal Dominant Polycystic Kidney DiseaseADPKD is the most common hereditary renal disorder.

It is characterized by multiple parenchymal renal cysts, cystic liver disease, hypertension, and intracranial aneu-rysm formation.45 The most common molecular pathogen-esis of this condition is a mutation in either the PKD1 or PKD2 gene that encodes for signaling proteins on primary cilia of cells that facilitate communication with the exter-nal environment. It is hypothesized that cystogenesis oc-curs when the concentration of these signaling molecules falls below a particular threshold.45 Newer research has also identified mutations in GANAB, which encodes a gly-cosylating enzyme located on the endoplasmic reticulum, as other drivers of ADPKD.45

Extracranial vascular abnormalities in this population include thoracic aortic dissections, dilatation of the aortic root, and coronary artery aneurysms.46,47 Although there

is limited literature to establish a baseline risk of TAA or AAA, one population cohort study demonstrated a risk of aortic aneurysm and dissection that was 8 times higher than non–ADPKD-matched controls (0.92% vs 0.11%), with a predilection for TAA over AAA in their ADPKD population.48

The prevalence of intracranial aneurysms in patients with ADPKD is approximately 10%, or 2–4 times higher than that of the general population.45 In the setting of a positive family history of intracranial aneurysms, the in-cidence climbs as high as 22%.49 Although there appears to be no difference in the rate of aneurysmal rupture when comparing patients with ADPKD to the general popula-tion, the mean age at rupture is approximately 10 years earlier in those with ADPKD.46,50

Given the increased risk in this population, screening using MRA for intracranial aneurysms is recommended for patients with ADPKD who have a family history of intracranial aneurysms, have a family or personal history of SAH, and are in high-risk professions such as pilots.50 Universal screening for intracranial aneurysms in patients with ADPKD remains controversial given that many identified aneurysms do not require treatment, although a recent analysis suggests that universal screening may be cost-effective.51

Neurofibromatosis Type 1Neurofibromatosis type 1 (NF1), also known as von

Recklinghausen disease, is an autosomal dominant genetic disorder caused by a mutation in the NF1 gene that encodes a protein called neurofibromin that is involved in regulation of the RAS/MAPK signaling pathways.52 Clinical mani-festations include café-au-lait spots, an increased incidence of cutaneous tumors such as neurofibromas and Lisch nod-ules, gliomas (particularly of the optic nerve), and other malignancies such as rhabdomyosarcomas, gastrointestinal stromal tumors, and hemopoietic malignancies.52 However, cerebrovascular disease is another important manifestation of this condition, and is the second leading cause of death in patients with NF1 after neoplasm.53

Aneurysm pathogenesis is believed to be related to loss of the NF1 gene, leading to deficient neurofibromin. This results in a dynamic cycle within the cell wall of cellu-lar proliferation of smooth-muscle cells and spindle cells, degeneration, healing, smooth-muscle loss, and eventual fibrosis.54 Another hypothesis derived from a translational murine model suggests that inactivation of the NF1 gene leads to increased macrophage infiltration, matrix metal-loproteinase–9 expression, and reactive oxygen species production, all of which can cause degradation of compo-nents of the vascular wall, which makes it susceptible to aneurysm formation.55

Vascular abnormalities of the aorta in NF1 include an-eurysms throughout the thoracic and abdominal segments, with 38.7% of patients in one series of 31 individuals hav-ing an aneurysm in these locations. The investigators also noted aortic coarctation in their younger population, with older patients demonstrating a higher risk of TAA or AAA.53

One study of more than 300 pediatric patients with NF1 found that 2.5% of patients had a cerebrovascular



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abnormality consistent with vasculopathy.56 A review of 31 patients of all ages found that 9.6% of them had an intracranial aneurysm, although notably only 33% had cerebral vascular imaging to review.53 A case report de-scribing a patient with NF1 who had a ruptured vertebral artery aneurysm presented a literature review describing 24 cases of extradural vertebral artery aneurysms, half of which ruptured, in patients with NF1.57 Another case re-port described a patient with NF1 who had 8 intracranial aneurysms, and their review found 45 cases of intracranial aneurysms in patients with NF1; 18 of them had multiple aneurysms and 23 patients experienced intracranial hem-orrhage as a result.58

Despite the frequency and morbidity of vascular le-sions in patients with NF1, there currently exist no rec-ommended screening guidelines for intra- or extracranial aneurysms or vasculopathies in this population.57

Tuberous Sclerosis ComplexTuberous sclerosis complex (TSC) is a multisystem

neurocutaneous disorder caused by mutations in the TSC1 or TSC2 gene, which encode proteins involved in the regu-lation of the mammalian target of rapamycin (mTOR) sig-naling pathway. The inheritance pattern varies, with ap-proximately 30% having an autosomal dominant pattern and the rest occurring as a result of spontaneous muta-tions.59 Clinical manifestations include skin lesions (hy-pomelanotic macules, facial angiofibromas, and Shagreen patches); renal dysfunction; retinal hamartomas; cardiac rhabdomyomas; and CNS involvement.60 However, intra- and extracranial aneurysm formation has also been de-scribed in this disease.

Aneurysm formation may be related to improper differ-entiation of smooth-muscle cells as a result of disruption of the mammalian target of rapamycin (mTOR) signaling pathway, impairing the structural integrity of the smooth-muscle cells within the vascular wall.61 Histological anal-ysis of an intracranial aneurysm in a patient with TSC demonstrated hypocellular hyaline fibrous tissue without necrosis or inflammation, and microscopic examination of a TAA in a patient with TSC found that most normal cel-lular structures had disappeared.62,63

There are case reports of aortic aneurysms reported in patients with TSC, the majority of which were found prior to the age of 10 years,64 but no larger series studies. The young age at onset is notable, and is also reflected in the data for intracranial aneurysms.

A review of 236 brain MR images from patients with known TSC found 4 patients (1.7%) with intracranial aneurysms, 2 of whom were children 10 years of age or younger. When compared to the general population of all ages, the incidence of intracranial aneurysms in patients with TSC was approximately twice as high.61,65 A recent review found that intracranial aneurysms in patients with TSC were large, fusiform, and located primarily in the ICA, a pattern that differs from aneurysm formation in the general population.66,67 This review also found that two-thirds of these patients were pediatric patients, again sug-gesting early and rapid aneurysm formation and growth.67

Although aneurysmal disease in TSC is rare, the ear-lier age of onset suggests that early screening once the di-

agnosis of TSC is made may allow for rapid intervention and reduction in morbidity and mortality. The most recent guidelines recommend that patients with TSC be screened with brain MRI every 1–3 years until age 25 to evaluate for subependymal giant cell tumors. One review proposes obtaining an additional time-of-flight sequence to provide vascular screening, particularly in young patients.67

Nonsyndromic Genetic or Heritable Aneurysm DiseaseAs access to genetic information on patients increases,

our ability to study heritable aneurysms has increased dra-matically. Researchers have used available genetic data-bases to further search for genetic loci that are associated with aneurysm formation.

A study that reviewed the genome-wide data on previ-ously published cohorts of AAA, TAA, and intracranial aneurysms identified mutations at 9p21, 18q11, 15q21, and 2q33 that were globally associated with all three types of aneurysms, suggesting a common pathophysiology for their development.68 Another study evaluated 26 families who also had aortic aneurysms and found linkage to loci on both chromosomes 11 and 6 in different families.69 An-other group elected to study mutations found on 9p21 that were previously well known to be associated with coro-nary artery disease, and found a significant association with AAA as well as intracranial aneurysms.70

Thus far, multiple genetic conditions are associated with heritable thoracic aortic disease (HTAD). Nonsyn-dromic conditions account for 20%–25% of these patients, and typically arise due to mutations in genes that encode for signaling pathways including TGFβ, the extracellular matrix, and components of the vascular smooth-muscle cytoskeleton.12 Often, mutations leading to nonsyndromic presentations can occur in the same genes seen in syn-dromic conditions.71

Growing research on HTADs shows that despite a lack of associated syndromic features, they are frequently in-herited in an autosomal dominant manner with variable expression and decreased penetrance in families.72 They may have associated abnormalities including patent duc-tus arteriosus, bicuspid aortic valve, livedo reticularis, and intracranial aneurysms.72 One study of 514 families with HTAD found that 9.3% had one or more members with an intracranial vascular event, and 5.6% of the families had one or more members with an intracranial aneurysm. Mutations of the TGFBR1, TGFBR2, and ACTA2 genes in 4 families were strongly associated with the development of fusiform intracranial aneurysms. In other families, pa-tients at risk for inheriting HTAD had isolated intracra-nial aneurysms without TAA or AAA.72 Other series of ACTA2-related familial aneurysm disease reported that intracranial aneurysms were uncommon.73

Recommendations include baseline cerebrovascular imaging in patients with TGFBR1, TGFBR2, SMAD3, TGFB2, and TGFB3 mutations, and many experts rec-ommend evaluation for intracranial aneurysms in pa-tients with an ACTA2 mutation as well as several other nonsyndromic HTADs.72 The prevalence of intracranial aneurysms in nonsyndromic HTAD due to mutations in MYH11, MYLK, PRKG1, LOX, and other genes is not well characterized.


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DiscussionAortic and intracranial aneurysms are common condi-

tions that affect the general population.1,7,8 It is important to assess for risk factors that indicate a need for baseline or serial imaging screening for these pathologies, given the significant risk associated with aneurysm rupture and arte-rial dissection.

The relationship between intracranial and aortic aneu-rysms and their underlying pathophysiology is complex. In patients with both intracranial and aortic aneurysms, there appears to be a relationship between the location of one pathology and the other. A series of 71 patients with both types of aneurysms showed that anterior circulation aneurysms co-occurred more often with ascending TAA, and ICA aneurysms co-occurred most often with infrare-nal AAA.74

Many common risk factors for aneurysm formation are unrelated to familial or hereditary factors.2,9 One study of 125 patients with fusiform aneurysms and more than 4000 patients with saccular aneurysms found an increased risk of aortic aneurysm in patients with fusiform aneurysms (14% vs 1.2%), although an elevated risk for aortic aneu-rysms was not observed in their first-degree relatives.2 Pa-tients should be counseled regarding modifiable risk fac-tors for aneurysm formation, including smoking cessation and blood pressure control.

Many of the studies we reviewed do not specify whether intracranial aneurysms were fusiform or saccular. There is a clear difference in risk factors, heritability,4 and associa-tion with aortic aneurysms2 between these two aneurysm types. Importantly, the risk for SAH is higher with sac-cular aneurysms than diffuse vascular ectasia or fusiform aneurysms. Better delineation of aneurysm types in future studies will provide additional guidance to clinicians de-termining the need for surveillance imaging.

As our knowledge and access to patients’ genetic in-formation has increased, the need to incorporate this into their risk profile has become more important. To deter-mine the need for or frequency of cerebrovascular sur-veillance imaging, patients are routinely queried for their family history of intracranial aneurysm. It would be more advisable to obtain a thorough family history of intra- and extracranial aneurysms.

Recognizing the phenotypes of syndromic heritable thoracic aortic conditions is necessary. In individuals with a concerning family history or with features suggesting an underlying genetic trigger, referral to a medical geneticist and other specialists knowledgeable in evaluating genet-ic vascular disease may allow diagnosis and appropriate therapy for the patient and family. Other HTADs may go undetected given their variable penetrance and the lack of other clear or identifiable clinical features.

In patients with known syndromic diagnoses, there are growing resources to guide the clinician in counseling sur-veillance imaging.27 However, these diseases are rare, and often data are based on small series of patients. There is also significant clinical heterogeneity even within a given syndrome or due to a specific pathogenic mutation. It will be important to further understand the relationship be-tween other clinical manifestations and the risk for intra-cranial aneurysms. For example, in LDS, the craniofacial

severity index corresponds to aortic root measurements and cardiovascular outcome for the patient.22 In Marfan syndrome and LDS, the degree of arterial tortuosity also correlates with aortic complications.19,75 Further studies from large registries and consortia will inform manage-ment, including surveillance imaging and therapy for cere-bral aneurysms complicating heritable aortic and vascular conditions.

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DisclosuresThe authors report no conflict of interest concerning the materi-als or methods used in this study or the findings specified in this paper.

CorrespondenceAnna L. Huguenard: [email protected].

INCLUDE WHEN CITING Published online January 1, 2021; DOI: 10.3171/2020.8.JNS203234.

©AANS 2021, except where prohibited by US copyright law
