on the inheritance of intracranial aneurysms -...

2028

On the Inheritance of Intracranial Aneurysms

Wouter I. Schievink, MD; Daniel J. Schaid, PhD; Harry M. Rogers, MD;David G. Piepgras, MD; Virginia V. Michels, MD

Background and Purpose The familial occurrence of intra-cranial aneurysms suggests the presence of a geneticallydetermined underlying arteriopathy. The pattern of inheri-tance in these families usually is not known.

Methods A family with seven members with intracranialaneurysms is described and, from the literature before 1994, atotal of 238 families with 560 affected members (56% femaleand 44% male) with intracranial aneurysms not associatedwith a known heritable disease are reviewed. A segregationanalysis was performed on 73 of these families.

Results Two members were affected in the great majorityof families (79%); five or more members were reported in onlyeight families (3%). The most common affected kinship wasamong siblings. Angiographic screening in 12 families detectedan intracranial aneurysm in 29% of 51 asymptomatic relatives.Segregation analysis revealed several patterns of inheritance

The etiology of intracranial aneurysms is not wellunderstood and is likely to be multifactorial.Acquired factors are important because it has

been shown that the incidence of aneurysmal subarach-noid hemorrhage (SAH) increases with age1; variousrisk factors, such as hypertension and smoking, havebeen proposed.2-4 It is unlikely that hemodynamicstresses at intracranial arterial forks alone are sufficientto produce an aneurysm; rather, an underlying vesselwall abnormality is generally suspected. The familialoccurrence of intracranial aneurysms and their associ-ation with certain heritable disorders suggest that theunderlying defect of the arterial wall may, at least inpart, be genetically determined.

It has been shown that familial intracranial aneu-rysms have characteristics that are different from thosethat occur sporadically. Familial intracranial aneurysmsrupture at a lower age, occur less often at the anteriorcerebral artery complex, and may rupture at a smallersize. In addition, among family members, intracranialaneurysms more often arise from the same arterialdistribution and more often rupture within the samedecade of life.57

Since the initial report in 1954 by Chambers andcolleagues,8 a multitude of families with documentedintracranial aneurysms have been described,67977 but

Received March 9, 1994; final revision received June 30, 1994;accepted July 1, 1994.

From the Departments of Neurologic Surgery (W.I.S., D.G.P.),Health Sciences Research (D.J.S.), and Medical Genetics (D.J.S.,V.V.M.), Mayo Clinic, Rochester, and Neurosurgical Associates,Ltd (H.M.R.), Edina, Minn.

Reprint requests to Wouter I. Schievink, MD, Department ofNeurologic Surgery, Mayo Clinic, 200 First St SW, Rochester, MN55905.

© 1994 American Heart Association, Inc.

that were consistent with the compiled pedigrees, but no singlemendelian model was the overall best fitting, suggesting thatgenetic heterogeneity may be important. Twenty-two percentof siblings of male probands had an intracranial aneurysmcompared with 9% of siblings of female probands (P=.OO3).

Conclusions Genetic heterogeneity may be important inthe genetics of intracranial aneurysms. In families with intra-cranial aneurysms, siblings of an affected male proband maybe at a higher risk of developing an aneurysm than siblings ofan affected female proband. Screening for intracranial aneu-rysms in asymptomatic relatives should be considered infamilies with two or more affected members. In most families,the nature of the underlying arteriopathy remains obscure.(Stroke. 1994;25:2028-2037.)

Key Words • cerebral aneurysm • subarachnoidhemorrhage • genetics

the pattern of inheritance of familial intracranial aneu-rysms has not been established. To better delineate thepattern of inheritance of familial intracranial aneu-rysms, we present data on a large North Americanfamily with intracranial aneurysms and, in conjunctionwith this, analyze the data from all identified publishedpedigrees of familial intracranial aneurysms. Establish-ing a pattern of inheritance for familial intracranialaneurysms may shed some light on the nature of theputative underlying arteriopathy and would be of ben-efit in counseling individuals with a family history ofintracranial aneurysms.

Family HistoryDescription of Family

Seven patients in two generations of this familydeveloped intracranial aneurysms. Their pedigree isshown in the Figure, and their clinical characteristicsare summarized in Table 1. The family resides in NorthDakota and is of Dutch and German descent. There isno evidence of a known heritable connective tissuedisorder. None of the patients are the result of consan-guineous mating.

Subject III,, the propositus, presented to his neuro-surgeon at age 38 years because of a family history ofruptured intracranial aneurysms. He had no history ofunusual headaches. His father and mother were 19 and18 years old, respectively, when he was born.

Subject II9, his paternal uncle, had suddenly col-lapsed at work at age 36 years. Lumbar puncturerevealed bloody cerebrospinal fluid, and angiographydemonstrated a left posterior communicating arteryaneurysm. He deteriorated after the angiogram anddied. An autopsy was not performed.

Subject III2, his brother, suffered his first SAH at age28 years. Angiography demonstrated a left internal

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Schievink et al Inheritance of Intracranial Aneurysms 2029

(^) Female ^ ^ g Intracranial aneurysm

I I U ; ) i o ^ | Suspected subarachnoid1 ' M a l e , • hemorrhage

Deceased [oj NO r m a| cerebral angiogram

SB Stillborn / Propositus

Pedigree of a family with seven members with an intracranialaneurysm.

carotid artery aneurysm arising just distal to the oph-thalmic artery. No aneurysms were demonstrated onthe right carotid injection. A Silverstone clamp wasapplied to the left common carotid artery. He recoveredbut 2 years later again presented with an SAH. Angi-ography now demonstrated an aneurysm arising fromthe right internal carotid artery bifurcation. The leftcommon carotid artery was occluded. He died shortlythereafter.

Subject Ii, his paternal grandfather, suddenly devel-oped a severe headache at age 51 years while fixing achair and died. An autopsy was not performed.

Elective Angiographic InvestigationsThe propositus and his five remaining siblings under-

went four-vessel cerebral angiography. Angiography re-vealed a right middle cerebral artery aneurysm in thepropositus. A left ophthalmic artery aneurysm wasdemonstrated in his 35-year-old brother (subject III3).A left middle cerebral artery aneurysm was detected inhis 26-year-old sister (subject III7). A left cavernouscarotid artery aneurysm was detected in his 33-year-oldsister (subject III4). His 29-year-old brother (subjectIII6) was found to have three intracranial aneurysms

TABLE 1 . Clinical and Radiographic Characteristics ofSeven Patients With Intracranial Aneurysms Belongingto One Family

PtSite of

Aneurysm Hypertension Tobacco Use

lll3

III,-,

L ICA/PCoA*

RMCA

RMCA

R ICA/Opht*

L ICA bifurcation*

L ICA/Opht

L cavernous ICA

L ICA/PCoA

L ICA bifurcation

LMCA

LMCA

Pt indicates patient; L, left; ICA, internal carotid artery; PCoA,posterior communicating artery; R, right; MCA, middle cerebralartery; and Opht, ophthalmic.

•Indicates ruptured aneurysm.

arising from the left posterior communicating artery,left internal carotid artery bifurcation, and distal leftmiddle cerebral artery. Angiography was normal in his32-year-old brother (subject HI5).

All aneurysms, except the cavernous carotid aneu-rysm in subject III4 and the distal middle cerebral arteryaneurysm in subject III6, were clipped. The size of theuntreated aneurysms was stable on repeat angiography1 year later. In the propositus, an additional minutemiddle cerebral artery aneurysm was identified at thetime of surgery, which was wrapped in muslin gauze.

There was no morbidity or mortality associated withthe radiographic or surgical procedures.

The current age of the propositus is 44 years. Theparents were not studied.

Subjects and MethodsReview of the Literature

Reports on the familial aggregation of intracranial aneu-rysms in the world literature before 1994 were collected andreviewed by two of us (W.I.S. and D.J.S.). Familial aggregationof intracranial aneurysms was defined as the presence of adocumented intracranial aneurysm in at least two members ofa family. Thus, pedigrees of familial SAH in which only asingle member was proven to have an intracranial aneurysmwere excluded. Families with a known heritable disorder thatcosegregated with the presence of an intracranial aneurysmwere also not included in the final analysis, although thenumber of such families was small.

In families in whom the proband was not clearly designated,the second affected relative (ie, the first individual whoestablishes the presence of familial intracranial aneurysms)was considered to be the proband.

Segregation Analyses

Inclusion Criteria for Nuclear FamiliesFor segregation analyses, only the proband and his/her

parents and siblings were included. This strategy resulted insome loss of information because, for some large pedigrees,only a single nuclear family was abstracted. However, we wereconcerned that the diagnosis of intracranial aneurysm mayhave been missed in the older generations and that thechildren of probands may not have been old enough to developintracranial aneurysms. Our assumption is that the siblings ofprobands are at approximately the same age as the proband, atleast in terms of being at similar risk to develop an intracranialaneurysm. Only these criteria were enforced for inclusion ofpedigrees reported in the literature. No nuclear families wereexcluded based on the mode of inheritance apparent in thepedigree. Individuals were coded as affected when the pres-ence of an intracranial aneurysm had been documented, andno distinction was made between ruptured and unrupturedaneurysms or between persons with or without elective angio-graphic investigations.

Statistical AnalysisComplex segregation analysis78'79 was used to test a series of

models that represent no genetic factors, as well as variousmodes of transmission, that can influence the distribution ofthe discrete trait of being affected with intracranial aneurysmversus normal. Under these models, the distribution of theaffected individuals in the nuclear families could be a conse-quence of a nontransmitted environmental factor, a singlemajor gene, or additive effects of a large number of indepen-dent polygenic loci. The parameters of these models are asfollows. Up to three general types (sometimes referred to asousiotypes) of persons, labeled AA, AB, and BB, were allowedfor in the analysis, where "type" describes an underlying


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2030 Stroke Vol 25, No 10 October 1994

7

1

4

2

1

238

(2.9%)

(0.4%)

(1.7%)

(0.8%)

(0.4%)

(100.0%)

67, 69, 70, 72, 74, 75, 77

7, 37, 44, 50, 55, 75, 77

25

6, 47, 49, 68

41, 45 (and present report)

18, 59, 71

TABLE 2. Distribution of Number of Affected Relativesin Families With Intracranial Aneurysms

No. ofAffected No. ofMembers Families References

2 188 (79.0%) 6, 8-16, 18-23, 26, 28-36, 38, 40,42, 43, 46, 48, 51-54, 57, 58, 60,61, 64-66, 70, 73, 75-77

4

5

6

7

8

Total

discrete characteristic that affects a person's phenotype. Gen-otypes are a special case such that transmission from parent tooffspring follows a mendelian fashion. The transmission prob-abilities P(A/AA), P(A/AB), and P(A/BB) are the probabili-ties that individuals of types AA, AB, and BB transmit the Afactor to their offspring. The single-locus mendelian modeldefines these probabilities as P(A/AA)=1, P(A/AB)=.5, andP(A/BB)=0. Assuming Hardy-Weinberg equilibrium, the pop-ulation frequencies of the three types are defined in terms ofthe frequency, p, of factor A: p2 for AA; 2p(l-p) for AB, and(1-p)2 for BB. For the nontransmitted environmental modelthe transmission probabilities do not depend on the parentaltypes, and the transmission probabilities are all equal to theparameter p. The penetrances of the genotypes P(D/AA),P(D/AB), and P(D/BB) are the probabilities that individualswith the types AA, AB, and BB express the disease pheno-type. The likelihood of the data was evaluated under differentmodels, restricting one or more parameters of the model tohypothesized values while estimating the remaining parame-ters from the data. Statistical tests of parameters were per-formed using twice the difference between the maximum of thelogj likelihood of an unrestricted model and the maximum ofthe loge likelihood of a restricted model. This difference has anapproximate x2 distribution when the null hypothesis is true,with degrees of freedom approximately equal to the differencein the number of parameters estimated. All likelihoods of themodels were computed by means of the PEDIGREE ANALYSISPACKAGE (PAP).80 Because we based our analyses on publishedpedigrees, and there is a definite bias to publish pedigreeswhen there are at least two affected members, we corrected forascertainment by computing the likelihood of the nuclearfamilies conditional on two probands per family and the statusof the parents. For most published pedigrees a single probandwas indicated. To define a second proband for each family, werandomly chose a second affected person by a computer-generated random number.

ResultsReview of the Literature

Including the presently reported family, a total of 238families with 560 affected relatives were reviewed.There were 246 men (44%) and 314 women (56%).

Of the 238 families, the great majority (79%) had twoaffected members; only 3% had five or more affectedmembers (Table 2). First-degree relatives, ie, siblings,parents, or children, were affected in 203 families. The

TABLE 3. Kinship Among Affected First-DegreeRelatives With Familial Intracranial Aneurysms in203 Families*

No. ofKinship Families

Siblings

Brothers 31

Sisters 46

Brothers/sisters 79

Child/parent

Mother/daughter 25

Mother/son 19

Mother/son and daughter 2

Father/daughter 10

Father/son 3

Father/son and daughter 2

*ln some families intracranial aneurysms occurred amongsiblings as well as among parent and child.

kinship among affected family members is shown inTable 3. Intracranial aneurysms occurred among sib-lings in 156 families and among a parent and child in 61families.

Six pairs of twins with intracranial aneurysms havebeen reported.22'31-33'52'66-73 These twin pairs were allreported to be identical, although documentation forthis was provided only for the twins reported byFairburn.31

Angiographic screening for familial intracranial an-eurysms has been performed in at least 51 asymptom-atic first- or second-degree relatives in 12 families, witha detection rate of 29% (Table 4).

Familial AggregationA total of 73 nuclear families with 563 individuals

(282 men and 281 women) were selected for analysis offamilial aggregation. The remaining pedigrees could notbe included because information on the total number offirst-degree relatives was unavailable. Of the 282 men,75 (27%) were affected compared with 104 (37%) of the281 women. The number of offspring ranged from 2 to12, with an average of 6. Among the 73 nuclear families,28 sons were affected probands, 43 daughters wereaffected probands, 1 normal daughter was a proband,and 1 normal mother was a proband. The distribution ofaffection status among the children in these families,after excluding the child probands, is presented in Table5. The percentage of affected sons did not significantlydiffer across the three categories of parental status(P=.88), nor did the percentage of affected daughters(P=.19). Furthermore, although there was a trend fordaughters to be more frequently affected than sons, theoverall percentage of daughters affected (31%) did notsignificantly differ from the percentage of sons affected(22%) (P=.O8). Also, when either parent was affected,more frequently it was the mother (61%).

To assess the risk to siblings of affected probands, weexamined separately the percentage of affected brothersand affected sisters according to whether the affectedchild proband was a son or daughter. Crude percent-


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TABLE 4. Results of Angiographic Screening for Intracranial Aneurysms in Asymptomatic Family Members

Author/Year

Edelsohn et al, 197225

Hashimoto, 197737

Stavenow, 197940

Fox and Ko, 1980"

Evans etal, 198144

Halal etal, 198347

Patrick and Appleby, 198349

Lozano and Leblanc, 19877

Mellergard etal, 198968

Leblanc etal, 1989^7

Elshunnar and Whittle, 199070

Present report

Total

Siblings only

No. ofAffectedFamily

Members

4

2

2

3

4

5

4

3

5

2

3

2

No. OfScreened

FamilyMembers

5

5

1

8

4

3

6

3

5

4

1

6

51

46

ClosestAffectedRelative

Siblings

Siblings

Sibling

Siblings

Siblings;daughter

Siblings;daughter

Siblings

Sibling;daughter;niece

Siblings

Siblings

Siblings

Siblings

No. OfThose

ScreenedWith

Aneurysm

1

2

0

3

0

0

2

0

1

1

0

5

15

15

Yield, %

20

40

0

37

0

0

33

0

20

25

0

83

29(95%CI, 17-44)

33 (95% Cl, 20-48)

Cl indicates confidence interval.

ages, after exclusion of the proband, are presented inTable 6. For sons who are probands, the risks tobrothers (30%) and sisters (34%) were similar, and fordaughter probands, the risks to brothers (17%) andsisters (25%) were similar. Although these risk calcula-tions were adjusted for ascertainment by excluding theproband from analyses, this adjustment is likely incom-plete because at least two members of the pedigrees hadto be affected for the nuclear family to be included. Thiswill lead to oversampling of affected individuals and riskestimates that are too high. In an attempt to correct forthis, we eliminated an additional affected child if bothparents were normal. However, when estimating sex-specific risks, if both a brother and a sister of a probandwere affected, then either of these siblings could haveserved as the second ascertained "proband," so in thiscase neither sibling was excluded for the sex-specificrisks. These results are presented in Table 7. As ex-

pected, the risks are lower than those in Table 6. If a sonis a proband, the risk to his brothers (24%) is less thanthat for his sisters (30%) but not statistically significant(P=A5). If a daughter is a proband, the risk to herbrothers (10%) is less than that for her sisters (14%) butnot statistically significant (P=32). Interestingly, therisk to all siblings of a male proband (26/117=22%) wassignificantly higher than the risk to all siblings of afemale proband (17/179=9%) (/>=.003).

Segregation AnalysesThe likelihood models we fit were for (1) an environ-

mental model with no major gene (NMG) determiningthe frequency of affected individuals, (2) autosomaldominant and recessive models, and (3) X-linked dom-inant and recessive models. We allowed for the fre-quency of aneurysms to differ between males andfemales but found no significant difference, and there-

TABLE 5. Distribution of Disease Among Offspring, Excluding Child Probands, in 73 Families Selected forSegregation Analysis

Father

N

N

A

Total

Mother

N

A

N

No. OfNuclearFamilies

55

11

7

73

A

No.

32

6

2

40

%

23

22

15

22

Sons

N

No.

109

21

11

141

%

77

78

85

78

A

No.

36

6

8

50

Daughters

%

27

38

50

31

N

No.

96

10

8

114

%

73

63

50

69

No.

68

12

10

90

Total

A

%

25

28

34

26

Offspring

N

No.

205

31

19

255

%

75

72

66

74

A indicates affected; N, normal.


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TABLE 6. Risk to Brothers and Sisters of Affected Proband Among 73 Families Selected for Segregation Analysis

AffectedProband

Son

Daughter

A

No.

22

18

Brothers

%

30

17

N

No.

51

88

%

70

83

No.

21

25

A

%

34

25

Sisters

N

No.

40

74

%

66

75

A

No.

43

43

%

32

21

Total

N

No.

91

162

%

68

79


fore sex-specific penetrances are not reported here. Ourstrategy for model fitting was to begin with the mostrestricted model and then allow fewer restrictions.Results are presented in Table 8. Several genetic mod-els fit the data significantly better than both the NMGmodel and the nontransmitted environmental model (ie,transmission probabilities are all equal to p). Thebest-fitting models were an autosomal dominant modelwith a very rare disease susceptibility allele and anautosomal recessive model with a not so rare suscepti-bility allele. For both of these models there was noevidence that the transmission parameter P(A/AB)differed from the mendelian probability of 1/2, and wedid not detect a significant departure of the genotypefrequencies from the Hardy-Weinberg proportions. Inan attempt to distinguish autosomal dominant fromautosomal recessive, we fit a more general codominantmodel allowing for three penetrances, one for each ofthe types AA, AB, and BB. The estimated penetranceswere 0.80, 0.41, and 0.06, respectively, with allele fre-quency P=.001. However, this model did not fit signif-icantly better than the dominant model (P=.65) or therecessive model (P=.14). Furthermore, an X-linkeddominant model fit significantly better than the NMGmodel, although not as well as the autosomal models.Hence, for these data there is strong evidence forfamilial aggregation compatible with autosomal inheri-tance, but we do not have sufficient power to preciselyresolve the mode of inheritance. A polygenic model,without a major gene, was also fit. However, the esti-mate of population incidence from this model was0.0009 with heritability of 100%, which seems an over-estimate of heritability if polygenic inheritance were theonly genetic etiology; this large an estimate of herita-bility would be expected if a major gene were contrib-uting to the disorder, in which case polygenic heritabil-ity would not be the correct model to fit. Therefore, wedid not include polygenic heritability in any othermodels.

DiscussionThe presently described family is unique in that 6 of

7 siblings were found to have an intracranial aneurysm.

The family described by Fox,4145 in whom 7 of 13siblings were affected, and the family described by terBerg et al,18-59-71 in whom 5 of 9 siblings were affected,had a similarly high percentage and number of affectedsiblings.

The familial occurrence of intracranial aneurysmscould argue for either genetic or common environmen-tal influences in the development of these aneurysms.However, since there is no evidence directly relatingpossible environmental factors, eg, diet or pollution, tothe development of intracranial aneurysms in humans,whereas aneurysms have been associated with severalheritable connective tissue disorders, it is quite reason-able to conclude that there probably is a primaryhereditary basis for many of these familial aneurysms.This, of course, does not negate the possible importanceof certain external risk factors, such as smoking orhypertension.

EpidemiologyRecent investigations have shown that a family his-

tory of intracranial aneurysms is more common inpatients with aneurysmal SAH than was previouslyappreciated. Norrgard et al61 detected one or morerelatives with an intracranial aneurysm in 5.1% ofSwedish patients with aneurysmal SAH. Ronkainen etal77 reported a somewhat higher percentage (8.8%) offamilial intracranial aneurysms in a Finnish population.The majority of families described in these epidemio-logical studies as well as those described in the litera-ture consisted of only two affected relatives, and it ispossible that in some of the families the aggregation ofintracranial aneurysms was entirely fortuitous.

Pattern of InheritanceA pattern of inheritance of familial intracranial an-

eurysms has not been established. Autosomal dominantor multifactorial inheritance has been suggested by mostauthors, whereas recessive inheritance is suggested bythe occurrence of intracranial aneurysms in familieswith known consanguinity. McKusick81 categorizes in-tracranial aneurysms as an autosomal dominant disor-

TABLE 7. Risk to Brothers and Sisters of Affected Proband Among 73 Families Selected for Segregation AnalysisAfter Correction for Ascertainment by Two Affected Pedigree Members

AffectedProband

Son

Daughter

No.

16

9

A

%

24

10

Brothers

No.

51

88

N

%

76

90

No.

17

12

A

%

30

14

Sisters

No.

40

74

N

%

70

86



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TABLE 8. Maximum Likelihood Parameter Estimates and x2 Statistics for Various Models

Model

Autosomal

NMG

Nontransmitted

Dominant

Recessive

X-linked

NMG

Dominant

Recessive

P

1

.12

.005

.05

1

.006

.143

Sex

M

F

M

F

M

F

Penetrance of Genotype*

AA

.16

.15

.57

.75

.16

.16

.88

.60

.34

.50

AB

.16

.57

.02

.60

.10

BB

.16

.003

.02

.05

.07

.02

.10

-2€n L

221.56

221.56

203.38

205.76

221.56

205.93

214.94

x2

18.22

15.80

15.63

6.62

df

2

2

3

3

Pt

.001

.004

.001

.09

NMG indicates no major gene.*For X-linked models, penetrance for males with genotypes A and B are listed under genotypes AA and BB, respectively.tCompared with the NMG models.

der (Mendelian Inheritance in Man [MIM] No.105800). Some of the difficulties in establishing theinheritance pattern of familial intracranial aneurysmsinclude the observation that these aneurysms are ac-quired lesions and the fact that an unknown percentageof intracranial aneurysms remain asymptomatic.Screening of asymptomatic family members overcomesonly part of these uncertainties. Keeping these caveatsin mind, we attempted to determine the pattern ofinheritance of familial intracranial aneurysms from ag-gregate case reports from the literature using a segre-gation analysis. The results of our segregation analysisrevealed several mendelian patterns of inheritance thatwere compatible with our collection of pedigrees, withautosomal dominant and recessive the best-fittingmodels.

However, one needs to cautiously interpret some of themodel parameter estimates. The most difficult, yet critical,component of our segregation analysis was to correctlyaccount for how the pedigrees were ascertained. Becausemost families with a single affected member are notreported in the literature, we could not include thereported pedigrees with a single affected person. Rather,we attempted to correct for ascertainment by requiringtwo or more affected members. This implies that eachpedigree must have two probands. We randomly defined asecond affected member to be the second proband. Thismay be a close approximation for some pedigrees but maynot accurately account for how all pedigrees were re-ported in the literature. Furthermore, all inferences re-garding the fit of genetic models pertain only to familieswith two or more affected persons and not to the muchlarger percentage of families with only a single affectedmember. Another limitation of these analyses is that wedid not have information on age at onset and current agefor unaffected members. This limits our segregation anal-yses by not being able to consider penetrance as it dependson age. For some complex disorders, earlier age at onset isa strong indication of genetic susceptibility, and hence agecan help to resolve genetic from sporadic cases. Other

limitations of our collection of pedigrees include treatingall unaffected individuals as normal; ie, we did not haveangiographic results in all family members to determine ifsome unaffected subjects actually had an asymptomaticaneurysm. If we did and if we treated these subjects asaffected, we would expect that our estimates of pene-trance would increase, assuming that the genetic modelsdo not change. Finally, we did not have data available onrisk factors, such as smoking and hypertension. All of theabove limitations make it difficult to accurately concludethe precise role of genetics in the etiology of intracranialaneurysms. However, our results suggest that the familialaggregation of aneurysms is not a chance occurrence andthat genetic factors may play an important role in itsetiology. A possible explanation of the observed familialaggregation is that there is much genetic heterogeneity, sothat some families have a genetic etiology due to autoso-mal dominant genes, other families due to autosomalrecessive or X-linked genes, perhaps others due topolygenes, and still others due to nongenetic factors.Genetic heterogeneity for a disease is not unusual and, forexample, has been observed in retinitis pigmentosa.8284

Some of the limitations of our study could be over-come by conducting a prospective study on the familialoccurrence of intracranial aneurysms in a defined pop-ulation. However, the length of time such a study wouldrequire to ascertain an adequate number of affectedfamilies is considerable.

Associated Heritable DisordersIntracranial aneurysms have been associated with

various heritable disorders (Table 9).85115 Of thesedisorders, only patients with polycystic kidney disease,Ehlers-Danlos syndrome, Marfan's syndrome, neurofi-bromatosis, and pseudoxanthoma elasticum are gener-ally considered to be at an increased risk of developingan intracranial aneurysm, although this has only beenfirmly established for polycystic kidney disease. In au-tosomal dominant polycystic kidney disease, approxi-mately 10% of asymptomatic patients are found to have


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TABLE 9. Heritable Disorders That Have Been Associated With Intracraniai Aneurysms

Disorder

a-Glucosidase deficiency*

arAntitrypsin deficiencyt

Alkaptonuria

Anderson-Fabry disease**

Autosomal dominant polycystic kidneydisease

Ehlers-Danlos syndrome type IV

Familial idiopathic nonarteriosclerotic cerebralcalcification syndrome

Hereditary hemorrhagic telangiectasia

Marfan's syndrome

Neurofibromatosis type 1

Noonan's syndrome

Pseudoxanthoma elasticum

Tuberous sclerosis*

Wermer's syndrome (multiple endocrineneoplasia type 1)

3M syndrome

Inheritance

AR

AR

AR

XLR

AD

AD

?

AD

AD

AD

AD

AD, AR

AD

AD

?

References

100, 102

114

105

91, 112

103,104,107,108,110

92, 115

101

85,86,89,93,106,113

115

115

96

115

87, 88, 90, 94, 95, 97-99

111

109

AR indicates autosomal recessive; XLR, X-linked recessive; and AD, autosomal dominant.*Aneurysms are often fusiform. tHeterozygotes may be affected. ^Carriers may be affected.

an intracraniai aneurysm.116'117 With the exception ofautosomal dominant polycystic kidney disease, there is apaucity of reports of documented familial intracraniaianeurysms associated with any of these aforementionedheritable disorders.118 Nevertheless, it may be prudentto consider the disorders listed in Table 9 when con-fronted with a case of familial intracraniai aneurysms. Acareful history and physical examination are mandatoryand may direct one to the diagnosis. However, intracra-niai aneurysms may be the first manifestation of any ofthe heritable connective tissue disorders, and the exter-nal signs may be subtle. Ancillary diagnostic testsshould be considered, such as ultrasound examinationof the kidneys to exclude polycystic kidney disease andechocardiography to search for cardiac valvular abnor-malities or aortic root dilatation indicating a systemicconnective tissue disorder. With recent developments incell biology and molecular genetics, the diagnosis ofsome of these disorders, such as Ehlers-Danlos syn-drome type IV and Marfan's syndrome, can now beestablished at a molecular level, and this may be usefulin a clinical setting when the diagnosis is uncertain.115

ScreeningThe mortality rate of intracraniai aneurysm rupture

exceeds 50%, and the morbidity in survivors is a signif-icant public health problem.1 Therefore, screening forintracraniai aneurysms in asymptomatic individuals fol-lowed by surgical or endovascular obliteration of theunruptured aneurysm is an attractive alternative. How-ever, much controversy exists regarding the manage-ment of asymptomatic unruptured intracraniai aneu-rysms because the rate of rupture is uncertain andsurgical or endovascular treatment is not withoutrisk.119-121 Nevertheless, screening for intracraniai aneu-rysms in asymptomatic relatives should be considered

when there are two or more members with an intracra-niai aneurysm in the immediate family, although thebenefits of such screening procedures have not beenquantified. The yield of angiographic screening as re-ported in the literature is fairly high (29%), but thepublication bias is likely to be significant. In a lessselected population and using magnetic resonance an-giography, Hernesniemi et al122 detected intracraniaianeurysms in 10% of 110 asymptomatic relatives ofpatients with familial intracraniai aneurysms. Usingintra-arterial digital subtraction angiography, Nakagawaand Hashi123 found intracraniai aneurysms in 18% of 39individuals with a family history of SAH. Our study wasnot able to determine which relatives are at the highestrisk for developing an aneurysm but did suggest thatsiblings of affected males may be at a higher risk thansiblings of affected females.

Decision-analytical methods have suggested thatscreening is advisable for all relatives between 35 and 60years of age, when "the physician thinks that the risk ofan intracraniai aneurysm is increased."124 Decisionanalysis has also suggested that the risk of the radio-graphic procedure that is selected for screening virtuallyhas no influence on the ultimate benefits from screen-ing.125 Nevertheless, for most individuals with a familyhistory of intracraniai aneurysms, magnetic resonanceangiography is the more practical alternative, even if thepatient is aware of the uncertainties that exist regardingthe sensitivity and specificity of magnetic resonanceangiography at the present time in comparison withconventional angiography. Magnetic resonance angiog-raphy is especially attractive if screening is to be re-peated when no aneurysm is detected initially. Aneu-rysms have been shown to appear de novo, and this maybe more common in those with a family history ofintracraniai aneurysms (as was also seen in one of the


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patients described in this report after contralateralcervical carotid artery occlusion [subject III2]) or under-lying connective tissue disorder.7176104 However, insuf-ficient data exist to make any recommendations as tohow often, if at all, screening should be repeated oncethe initial screening procedure is negative.

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W I Schievink, D J Schaid, H M Rogers, D G Piepgras and V V MichelsOn the inheritance of intracranial aneurysms.

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