(Stroke. 1996;27:1050-1054.)
© 1996 American Heart Association, Inc.
Articles |
Familial Cerebral Aneurysms
A Bias for Women
From the Department of Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada.
Correspondence to Dr Richard Leblanc, 3801 University St, Montreal, Quebec, Canada H3A 2B4.
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Abstract |
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Background and Purpose We evaluated the influence of gender on the formation and rupture of familial cerebral aneurysms.
Methods We studied 30 patients with ruptured cerebral aneurysms from 14 consecutive families. These patients were compared with the patients with sporadic aneurysms reported by the first Cooperative Study.
Results Eighty percent of familial aneurysms
occurred in women versus 59% of sporadic aneurysms
(P<.05, 
2 test). This
overrepresentation of women occurred at below the age of 50
years, where 78% of patients with familial aneurysms were
women compared with 45% for sporadic aneurysms
(P<.01, 2 test). Above this age,
there was no statistical difference in incidence of familial
aneurysms in men or women compared with sporadic
aneurysms. In women with familial aneurysms, rupture
occurred before the age of 50 years in 59%, compared with 31% for
sporadic aneurysms (P<.01, 2
test). In four of five families, aneurysms ruptured within 10
years of each other in sisters (mean, 6 years). Multiple
aneurysms were equal in both groups (17%), but multiple
familial aneurysms occurred mainly in women. There was no
difference in the site of single cerebral aneurysms in either
group, but familial aneurysms in females occurred at the same
site in five of eight families (62%) and in 11 of 17
mother-daughter or sister pairs (65%), compared with 20% for two
randomly selected sporadic aneurysms (P<.01).
Conclusions There is an overrepresentation of women with ruptured familial aneurysms compared with those with sporadic aneurysms. Familial aneurysms rupture in females predominantly before the age of 50, in the same decade, and at the same site within families in the majority of cases. These observations support a possible genetic cause for cerebral aneurysms and a possible hormonal contribution to their rupture.
Key Words: cerebral aneurysm • gender • genetics • women
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Introduction |
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A familial history of cerebral aneurysms may be obtained in up to 20% of patients with aneurysmal subarachnoid hemorrhage.1 2 3 4 5 The study of familial cerebral aneurysms is important for the insight that it may give into the etiology of cerebral aneurysms in general and because it can identify a population at risk of harboring a cerebral aneurysm that may be diagnosed and treated before it ruptures. Previous studies have suggested that familial cerebral aneurysms may be more common in women and that these aneurysms may rupture at a younger age and—especially in women—at a smaller size than sporadic cerebral aneurysms.1 We have investigated the hypothesis that ruptured familial cerebral aneurysms are more common in younger women by a prospective analysis of 14 families in whom two or more individuals had a documented cerebral aneurysm.
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Subjects and Methods |
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As part of an ongoing study of familial cerebral aneurysms, 14 families were consecutively identified at the Montreal Neurological Hospital since 1986. A family was considered positive for familial cerebral aneurysms if two or more of its members were proved by examination in our institution or by review of medical records obtained from elsewhere to harbor one or more cerebral aneurysms. The detailed pedigrees of 13 of these families have been published previously6 ; the pedigree and important epidemiological data of the 14th family are illustrated in Fig 1
. The patients with ruptured familial cerebral
aneurysm were compared with the patients with ruptured sporadic
cerebral aneurysm reported by the first Cooperative
Study,7 using the 2 test.
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Results |
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Within the 14 families, 33 individuals (7 males and 26 females) harbored a cerebral aneurysm. Thirty of these individuals (6 males and 24 females) had a ruptured aneurysm. The other three aneurysms had produced a mass effect in 2 patients (1 male and 1 female); the third aneurysm was discovered on angiographic screening of the sister of a woman with a familial cerebral aneurysm.
Gender and Rupture
The proportion of women with a ruptured aneurysm was
larger in the familial group than in the sporadic one: 24 of the 30
patients with a ruptured familial aneurysm were women (80%)
compared with the sporadic group, in which 1541 of 2627 patients with
ruptured sporadic aneurysm were female (59%,
P<.05). This female overrepresentation in the
familial aneurysm group is accounted for by the occurrence of
familial aneurysms in women younger than 50 years of age: 14 of
the 18 ruptured familial aneurysms in subjects younger than 50
years were in women (78%), whereas only 499 of 1114 sporadic
aneurysms that ruptured were in women under 50 (45%,
P<.001) (Table 1, Fig 2).
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Age and Rupture
In women, familial cerebral aneurysms ruptured at a
younger age than sporadic ones: 14 of the 24 ruptured familial
aneurysms in women ruptured before 50 years of age (58%)
compared with 499 of 11 541 ruptured sporadic aneurysms (32%,
P<.01) (Table 2, Fig 3).
Familial aneurysms ruptured within 10 years of each other in
four of five sister pairs (average, 6 years), a much higher proportion
than the 20% expected for the rupture of two randomly selected
sporadic aneurysms.1
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Multiplicity
There was no significant difference between the occurrence of
multiple aneurysms in families and in the sporadic group: 5 of
the 30 patients with a ruptured familial aneurysm (17%) had
two aneurysms or more, compared with the 20% of multiple
aneurysms in the sporadic group. However, multiple familial
aneurysms were more common in women, since 3 of the 5 patients
with multiple familial aneurysms were female.
Site of Aneurysm
There was no significant difference between the site of occurrence
of single ruptured familial aneurysms and single ruptured
sporadic aneurysms: 56% of the familial aneurysms were
on the internal carotid artery, 26% on the anterior communicating
artery, 13% on the middle cerebral artery, and 4% on the
vertebrobasilar system. However, aneurysms in
mother-daughter or sister pairs ruptured at the same site in five
of eight families (62.5%), which is three times the expected rate for
randomly selected sporadic aneurysm patient
pairs.1
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Prevalence of Familial Cerebral Aneurysms
A possible genetic influence on the etiology of cerebral aneurysms is suggested by their occurrence in conditions with a well-defined (usually autosomal dominant) pattern of inheritance, in twins, and in familial clusters. The most common genetically determined condition associated with cerebral aneurysms is adult polycystic kidney disease.8 9 In this condition, cerebral aneurysms can be seen in 10% to 40% of cases and can exist independently of arterial hypertension.8 The association of adult polycystic kidney disease and cerebral aneurysms may therefore not be the result of a passive response to hemodynamic stresses resulting from arterial hypertension but rather may result from a mesenchymal defect affecting the cerebral blood vessels produced by a lesion of chromosome 16.8 Although it is often stated that cerebral aneurysms occur in collagen vascular diseases such as Ehlers-Danlos syndrome type IV, the major cerebrovascular lesion associated with these conditions is a traumatic carotid cavernous aneurysm or fistula.10 An overrepresentation of cerebral aneurysms in collagen vascular diseases in general, and in Ehlers-Danlos syndrome type IV in particular, has not been demonstrated, and the impression of such an association may be erroneous. Furthermore, a defect in type III collagen, the hallmark of Ehlers-Danlos syndrome type IV, is not present in patients with familial or multiple cerebral aneurysms.11 12 Cerebral aneurysms have been reported in a few cases of homozygous twins.13 14 15 16 17 18 19 20 These aneurysms usually occur at the same site and rupture within 5 years of each other. Such similar biological expression strongly suggests a common genetic etiology, but since a discordant homozygous twin pair has been reported, the reports of cerebral aneurysms in homozygous twin pairs may reflect publication bias.15 We have studied two heterozygous female twin pairs: one individual in each pair had a cerebral aneurysm, her twin did not.6 The most compelling support for the concept of a genetic etiology for some cerebral aneurysms has been the striking increase in number of familial cases reported during the last decade. Besides supporting a possible genetic component to some cerebral aneurysms, the identification of a familial cluster of cerebral aneurysms permits angiographic screening of family members in the hope of diagnosing and treating a cerebral aneurysm before its rupture. This may be a more important consideration than is generally appreciated, since the familial incidence of cerebral aneurysms may be higher than previously thought. Thus, Norrgård et al2 found a 5.1% incidence of familial cerebral aneurysms in Swedes; Ronkainen et al3 found an 8.8% familial incidence in Finns; Wang et al4 found an 11.4% familial incidence of subarachnoid hemorrhage in general in Seattle, Wash; Schievink et al5 found a 20% incidence of ruptured cerebral aneurysms in the native population of Rochester, Minn; and Mathieu et al found a 32.2% incidence of ruptured cerebral aneurysms in the population of the Saguenay-Lac St-Jean region of Québec, Canada (J. Mathieu, personal communication, 1994). With the exception of the study of Wang et al,4 all the studies mentioned address geographically distinct populations with little genetic heterogeneity because of limited immigration and with higher chance of intermarriage; the largest familial incidence, that seen by Mathieu et al, may be confounded by the unusually large kindreds that constituted their study population. Furthermore, these populations may have been subject to other common risk factors, such as arterial hypertension, or exposure to common environmental toxins, such as cigarette smoke. Nonetheless, true familial clustering of subarachnoid hemorrhage and ruptured cerebral aneurysm remains unexplained by other familial idiosyncrasies or environmental influences.
Previous studies have suggested that familial cerebral aneurysms may be more common in women, may rupture at a younger age and at a smaller size (especially in women), and may rupture within the same decade and occur at the same or at mirror sites with increased frequency.1 21 These studies suggested a research agenda to address these observations, which, if validated, would lend support to the notion that familial cerebral aneurysms and the patients who harbor them have distinct genetically determined characteristics. We were able to test this hypothesis in a prospective fashion in the study reported here.
We chose to compare our patients with the patients reported by the first Cooperative Study because, although our patients were seen at one institution, many of their relatives with cerebral aneurysms had been evaluated elsewhere, in most provinces of Canada and in the United States. Thus, comparing the familial patients with our own sporadic aneurysm patients might introduce a bias reflecting our own referral pattern. Comparing our familial patients to a large cohort such as that reported by the Cooperative Study is likely to give more generalizable results. Furthermore, the Cooperative Study is very detailed, especially with regard to patients who have a single ruptured aneurysm, which was the case in the majority of our patients with familial cerebral aneurysms. In this regard, although it is often stated that sporadic cerebral aneurysms are more common in females, close scrutiny of the first Cooperative Study indicates that this is only the case in women older than 50 years. In groups younger than 50, there is a distinct overrepresentation of males with ruptured sporadic aneurysms. Thus, the marked overrepresentation of women with a ruptured familial aneurysm that we observed in this age group is noteworthy.
Gender and Familial Cerebral Aneurysms
Incidence of Familial Cerebral Aneurysms in
Women
We previously noted that 57% of familial cerebral
aneurysms reported up to 1986 occurred in women.1
Norrgård et al2 found that 69.7% of familial
aneurysms occurred in women, although this was not submitted to
statistical analysis. Ronkainen et al,3 Schievink
et al,22 and Bromberg et al,23 while
finding an overrepresentation of familial
cerebral aneurysms in women ranging from 52% to 73%, did not
find this to be significantly different from sporadic cases. We found
that familial cerebral aneurysms are four times as common in
women than in men and that this is accounted for by their occurrence in
women younger than 50 years: Not only are familial cerebral
aneurysms more common in women, but this gender bias is age
related. This is also reflected in the average age at rupture of 45
years in women with familial cerebral aneurysms compared with
the 51.4 years observed by Andrews in sporadic cases (R.J. Andrews,
personal communication, 1986); approximately three fifths of familial
aneurysms destined to rupture in women will do so by age 50,
whereas only a third of sporadic aneurysms destined to rupture
will do so by that age. A striking finding is that most
aneurysms ruptured within the same decade in sister pairs,
indicating a similar biological expression of their familial cerebral
aneurysms.
Site
Some investigators have observed that familial cerebral
aneurysms may be underrepresented on the
anterior communicating artery.1 2 21 Others have observed
that middle cerebral artery aneurysms or posterior
communicating artery aneurysms may be more common in familial
cases.2 3 Our data to date indicate no significant
difference between the location of familial cerebral
aneurysms in women and the site of sporadic aneurysms
in women reported by the Cooperative Study. Middle cerebral
artery aneurysms were less frequent in our families (13%)
compared with those in the Cooperative Study (20%), but it is hard to
make much of this because there were only 3 women with a familial
middle cerebral artery aneurysm. A striking finding is the
occurrence of cerebral aneurysms at the same or at the mirror
site in mother-daughter pairs and in sister pairs. Coupled with the
tendency for aneurysms to rupture within the same decade, the
concordance of the site for ruptured cerebral aneurysm in
families suggests an importance biological similarity with a possible
genetic basis.
Size
We were unable to determine the size of the ruptured
aneurysm in many of our subjects who had been seen elsewhere.
However, the literature suggests that familial cerebral
aneurysms rupture at a smaller size, especially in women, than
sporadic aneurysms.1 This observation recently was
supported by the study of Ronkainen et al,3 who observed
that approximately 40% of ruptured familial cerebral aneurysms
were smaller than 6 mm in largest diameter. Although this proportion is
more than that observed for their sporadic cases, the difference was
not large.
Multiplicity
There was no overall increase in incidence of multiple cerebral
aneurysms in our familial group compared with the sporadic
cerebral aneurysm group. However, 60% of our familial patients
with multiple aneurysms were women. The literature similarly
records a striking gender bias for women in the occurrence of
multiple cerebral aneurysms. Thus, in nonfamilial cases,
McKissock et al24 and Ostergaard and Hog25
observed that 68% of multiple sporadic aneurysms occur in
women, whereas Andrews and Speigel26 observed a value of
71%.
Pattern of Inheritance
The mechanism of inheritance of familial cerebral
aneurysms has not been elucidated. Autosomal dominant and
recessive forms of inheritance have been suggested.1 21
The striking female overrepresentation that we record,
however, must be taken into account in any model of the pattern of
inheritance of familial cerebral aneurysms. In this regard, it
is noteworthy that, in general, familial cerebral aneurysms
occur three times as often in mothers than in fathers, that daughters
are more commonly affected than sons, and that sisters are more often
affected than brothers.21 Another important factor in the
eventual elucidation of a mechanism of inheritance in familial cerebral
aneurysms is the frequently observed tendency of cerebral
aneurysms to involve first-degree relatives in the majority
of cases, with a decreasing incidence in second- and in
third-degree relatives.
Other Gender-Related Factors
Ruptured cerebral aneurysms and subarachnoid
hemorrhage are seen with more increased frequency in the first
5 days of menses than in the subsequent 23 days27 ; the use
of oral anovulants is an independent risk factor for
subarachnoid hemorrhage.28 29 Finally,
male chronic alcoholics, perhaps because of alteration of hormone
levels, are also at increased risk for subarachnoid
hemorrhage.30
Conclusions
We have observed that familial cerebral aneurysms are more
common in women, that in women they rupture at a younger age than
sporadic aneurysms, that rupture occurs predominantly within
the same decade in sisters, and that aneurysms frequently occur
at the same or at mirror sites within families. Coupled with other
observations that familial cerebral aneurysms in women may
rupture at a smaller size than sporadic ones, a definite gender bias
for familial cerebral aneurysms is demonstrated. These
observations suggest that the presence of cerebral aneurysms
within families is multifactorial, implicating one or, more
likely, many genes predisposing to the formation of cerebral
aneurysms. The ultimate clinical expression of this genetic
tendency would be partially dependent on the internal milieu as it is
affected by sex hormones, where estrogen would play a central role, and
perhaps by exposure to common environmental toxins. Only further
advances in neurobiology will cleave this Gordian knot.
Received December 8, 1995; revision received February 22, 1996; accepted February 23, 1996.
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