Familial Aneurysms Research Articles

Familial aortic aneurysms

Thoracic aortic aneurysms and dissections can occur in families with autosomal dominant inheritance. Mutations in the fibrillin-1 gene on chromosome 15 cause Marfan syndrome (MFS), a known cause of familial aortic aneurysms and dissections. Affected individuals have phenotypic stigmata involving the skeletal, ophthalmologic and other systems. Mutations in the type III procollagen gene cause the vascular type of Ehlers-Danlos syndrome (EDS IV), which can include aneurysms that involve the aorta and other arteries, but account for a small minority of aortic aneurysms. Affected individuals have characteristic skin and joint findings. Families with no external phenotypic stigmata of connective tissue disorders have been reported as cases of Erdheim disease or annuloaortic ectasia. The causative gene(s) have not yet been identified.We report a family in which aortic aneurysms occurred in several family members who have no phenotypic findings suggestive of either MFS or EDS IV. None of the affected individuals have tall stature, dislocated ocular lenses, scoliosis or pectus deformities. The proband (II-1) was thought to be in good health until she developed chest pain at age 56 and died of a dissecting aneurysm of the ascending aorta that ruptured into the pericardial space. Microscopic examination of the aorta showed cystic medial necrosis. She had 5 children, 3 of whom also had thoracic aortic aneurysms. Her oldest son (III-1) and older daughter (III-4) have had prophylactic surgery at ages 60 and 49. The younger daughter (III-5) had emergency surgery after aortic rupture during catheterization at age 48.A skin biopsy was obtained from the older daughter and dermal fibroblasts explanted. Metabolic labeling studies done in triplicate showed diminished amounts of fibrillin-1 deposited into the matrix by the patient's cells when compared with controls. A similar defect in fibrillin-1 incorporation is observed in cells from MFS patients. Linkage and mutation studies are in progress to determine if the phenotype is due to a FBN1 mutation or a mutation in another gene that disrupts fibrillin-1 deposition in the matrix.

The Role of Type III Collagen in the Development of Familial Abdominal Aortic Aneurysms

Objectives: to evaluate the prevalence of familiar abdominal aortic aneurysm (AAA) and the role of type III collagen deficiency. Methods: fifty-six consecutive patients coming for aneurysm repair were asked if one or more first-degree relatives had an AAA. During operation, a skin biopsy was taken from the patients for protein analysis to measure the type III collagen production in cultured fibroblasts. Results: a positive family history was found in 28.6% of the AAA patients. Six (10.7%) of the AAA patients had a type III collagen deficiency (mean 4.3% (S.D.±0.5)). In this group three men, mean age 65.3 years (S.D.±5.0), had a positive family history and a type III collagen deficiency. Segregation analysis with an intragenic marker in the type III collagen gene in a single family was in favour of linkage with the gene for type III procollagen (COL3A1) locus. Conclusions: the high prevalence of familial AAA suggests a genetic aetiology. A small group of patients have a type III collagen deficiency. Linkage with the COL3A1 gene could not be proven or excluded in the families studied.

Asymptomatic Familial Cerebral Aneurysms

In reply: We appreciate the comments and questions raised by Kanat et al. concerning our article (1). Although they covered a wide range of issues, we are responding here only to the two issues for which we consider ourselves responsible. Because familial aneurysms have been reported to rupture at a smaller size than nonfamilial aneurysms (2,3), we investigated our accumulated data on aneurysmal size and questionnaires on the participants' age and past history of hypertension. We could not find any significant difference in aneurysmal size or age between members with familial aneurysms and those with nonfamilial aneurysms. We attribute this finding in part to the fact that the aneurysms recognized in this study were generally small, with an average diameter of 5.2 mm. Regarding the incidence of hypertension in these two groups, available data on this issue were so limited that we could not draw any conclusions. As for possible differences in aneurysmal size measured by MRA and that by conventional angiography, we performed both methods for measurement of 431 aneurysms and found no significant difference. We are currently preparing a manuscript on that issue. Masayuki Kojima Kyoto, Japan Shiro Nagasawa Osaka, Japan

Asymptomatic familial cerebral aneurysms

Asymptomatic Familial Cerebral Aneurysms Ayhan Kanat, Ayhan Kanat 1Istanbul, Turkey Search for other works by this author on: Oxford Academic Google Scholar Yunus Aydin Yunus Aydin 1Istanbul, Turkey Search for other works by this author on: Oxford Academic Google Scholar Neurosurgery, Volume 44, Issue 6, June 1999, Pages 1364–1365, https://doi.org/10.1097/00006123-199906000-00137 Published: 01 June 1999

Epidemiological features and diagnostic evaluation of intracranial aneurysms.

Female gender and cigarette smoking appear to be risk factors for the development of multiple intracranial aneurysms. An acquired nature is likely in this form. The mechanism of aneurysm formation in patients with sickle cell anemia is apparently different. These patients also present multiple aneurysms that show propensity for vertebrobasilar territory and appear at a younger age. Familial cerebral aneurysms are diagnosed once heritable connective tissue disorders have been excluded. The age of patients tends to be lower and the size of aneurysm to be smaller at the time of rupture in the familial form. These aneurysms are less frequently found in the anterior communicating artery than the sporadic aneurysms. A high incidence of asymptomatic familial aneurysms was detected in people with family histories of intracranial aneurysms studied by means of magnetic resonance angiography. Furthermore, familial aneurysms are more likely to rupture in families having members with aneurysmal subarachnoid hemorrhage (SAH) than in those without. The results of an interesting study using color "power" transcranial Doppler ultrasound in patients with aneurysmal SAH suggest that as the intracranial pressure diminished, the size of the aneurysm increased, and there was relatively little change between maximum and minimum dimensions during the cardiac cycle, i.e., the pulsatility is reduced. The use of postoperative angiography after clipping is a matter of debate. The indication more widely accepted is in large aneurysms with a wide neck, in which incomplete clipping can be suspected. Taking into account the current low risk of angiography in centers of excellence, its routine use may be recommended. Aneurysm remnants, vessel occlusion, vasospasm, and newly identified aneurysms are the main findings that were reported.

Abstracts of literature

Abstracts of literature

Initial and follow-up screening for aneurysms in families with familial subarachnoid hemorrhage.

In families with two or more relatives with subarachnoid hemorrhage (SAH), other first-degree relatives have an increased risk of SAH. We studied the presence of unruptured intracranial aneurysms in 125 members of 23 families with familial SAH, defined as two or more affected first-degree relatives, in a cross-sectional design. MR angiography was performed in 116 relatives; CT angiography was performed in the remaining 9 relatives because they had been treated for intracranial aneurysms in the past. Overall, we found 16 aneurysms in 10 of 125 relatives (8%; 95% CI, 4 to 14%). Of the nine patients with previous surgery for ruptured or unruptured intracranial aneurysms, three had new aneurysms. Two factors were associated with a significantly higher risk of intracranial aneurysms: 1) a history of treatment for ruptured or unruptured intracranial aneurysms (relative risk 5.5; 95% CI, 1.7 to 17.8) and 2) having three or more affected relatives (relative risk 3.3; 95% CI, 1.0 to 10.6). Siblings tended to have a higher risk of intracranial aneurysms than did children of SAH patients, although the difference was not significant. Because the yield is high, screening is recommended in first-degree members of families with familial SAH. Repeated screening should be considered in relatives who have been treated for familial intracranial aneurysms.

Asymptomatic familial cerebral aneurysms.

We evaluated the prevalence and features of cerebral aneurysms in the family members of people with asymptomatic aneurysms among 8680 participants undergoing magnetic resonance angiography. Of the 8680 participants, 380 had family histories of aneurysms and 8300 did not. The prevalence and features of asymptomatic aneurysms were compared in these two subgroups. In addition, the prevalence in all living first- or second-degree relatives was evaluated in 20 families. The prevalence of asymptomatic aneurysms was 7.0% (606 of 8680 participants) overall and 10.5% (40 of 380 participants) and 6.8% (566 of 8300 participants) in the subgroups with and without family histories of aneurysms, respectively. The prevalence in the female participants with family histories of aneurysms (12.3%, 28 of 228 participants) was higher than that in the male participants with family histories of aneurysms (7.9%, 12 of 152 participants) (P < 0.0001). Compared with the entire group, this subgroup more commonly showed aneurysms situated at the junction of the internal carotid and posterior communicating arteries (P < 0.0005) and at the middle cerebral artery (P < 0.0001). The prevalence of aneurysms in 115 members of the 20 families was 33.9%. Although the members of 14 families with aneurysmal subarachnoid hemorrhage showed higher prevalence of ruptured and asymptomatic aneurysms (42.1%) than did the members of 6 families with only asymptomatic aneurysms (17.9%), the former had very low prevalence of asymptomatic aneurysms. The prevalence of aneurysms is significantly elevated in family members of people with asymptomatic aneurysms. It is suggested that familial asymptomatic aneurysms are more likely to rupture in families having members with aneurysmal subarachnoid hemorrhage than in those without.

Familial intracranial aneurysms: an autopsy study.

Familial intracranial aneurysms are more common than has been appreciated, but systematic autopsy studies of affected individuals have not been reported. We reviewed the autopsy findings of a group of patients with familial aneurysms to elucidate the nature of the putative underlying arteriopathy. Using a computerized diagnostic index, we identified all patients with intracranial aneurysms in whom postmortem examination had been performed at the Mayo Clinic between January 1, 1992, and December 31, 1994. The medical records, radiographic studies, and autopsy findings of these patients were reviewed. Among the 28 patients with intracranial aneurysms, 3 (11%) had one or more first-degree relatives with documented intracranial aneurysms. The mean age of the three patients (two women and one man) was 54 years. Microscopic examination of the vascular system revealed medial changes, consisting of degeneration of elastic fibers and increased ground substance, in the systemic arteries of 2 of the 3 patients with familial aneurysms but in none of the 25 patients with sporadic aneurysms. These nonspecific medial changes involved both common and extracranial internal carotid arteries in one patient and the entire aorta as well as intracranial and common carotid arteries in the other patient. These observations suggest that an underlying arteriopathy in patients with familial intracranial aneurysms involves the tunica media and commonly may affect systemic (extracranial) arteries.

Familial cerebral aneurysms.

Familial cerebral aneurysms are currently the subject of burgeoning interest. We review the pertinent, recent reports on this topic in the light of our study of 17 families with familial cerebral aneurysms. The prevalence of familial cerebral aneurysms ranges from 5-28%. The sex distribution displays a female bias. Mothers are more often affected than fathers and daughters more than sons. There is no site predilection for familial cerebral aneurysms but they tend to occur at the same (or mirror) site within families. The age at rupture of familial cerebral aneurysms is younger, especially in females, than for sporadic aneurysms. They tend to rupture within the same decade in families, and within five years of each other in identical twins. The size of ruptured familial cerebral aneurysms appears to be smaller, especially in women, than sporadic aneurysms. The pattern of inheritance is unknown. A poor outcome of rupture is more frequent in familial cerebral aneurysms cases than in sporadic ones. Angiographic screening of family members at risk, especially first degree relatives, appears justified.

Spontaneous rupture of the renal artery in a patient with ehlers-danlos syndrome type IV

Spontaneous rupture of larger-sized arteries is often caused by inborn defects in genes encoding structural proteins (e.g. collagen/fibrillin/elastin). 1 Recent advances in molecular biology have identified the causative genetic defect in several diseases with vascular fragility. The gene causing the Marfan syndrome 2 encodes the elastin-associated glycoprotein Fibrillin I, whilst the Fibrillin II gene has been linked to a related condition called congenital contractural arachnodactyly. 3 A major genetic component has also been demonstrated in the aetiology of common abdominal aortic aneurysms. 4 Collagen type III (COL3A1), an important structural component of arterial walls, is linked to familial aortic aneurysms, and has been proposed as a candidate gene. 5 It also causes Ehlers-Danlos syndrome type IV (EDS IV), 6 which is one of the rarest of the 10 subtypes of Ehlers-Danlos syndrome (EDS). 7'8 EDS IV has been estimated to cause 4% of EDS as a whole, with an incidence of 1:5 000 0007 (probably underestimated). It is clinically severe; causing spontaneous rupture of larger arteries as well as spontaneous intestinal perforations. %12 During the past few years, the underlying mutations/deletions in the collagen type III gene have been characterised in detail in several patientsd 13'~4 On this basis, structurefunction relationships have been predicted. ~5 We report a patient presenting with spontaneous rupture of the renal artery. Histological examination showed remarkable and unique defects of the media layer. The diagnosis of EDS type IV was confirmed by clinical and biochemical criteria.

Recurrent COL3A1 mutation results in EDS IV or familial aneurysms

EIV is a lethal genetic disease of collagen in which mutations in COL3A1 give rise to fragile skin, easy bruisability, and hollow organ ruptures (Kuivaniemi et al., 1991). Familial aneurysms is a vascular disease characterized by late-onset saccular aneurysms, probably multifactorial in origin, but rare cases may be due to COL3A1 mutations. We investigated the cause of EDS IV in a 10-year-old white male with soft skin easy bruisability, and a family history of vascular ruptures. S! nuclease analysis of RNA from patients fibroblasts indicated a defect around exon 20. Sequence analysis of cDNA clones identified 3 out of 5 clones that retained a portion of intron 20 and revealed a G+1 to A point mutation in the splice donor site. The same mutation has been observed in a patient with familial aneurysms (Kontussari et al., 1990). In both patients, RT-PCR analysis revealed the presence of several RNA species: mRNA lacking exon 20, mRNA with 24 bases of intron 20 sequnce in frame, mRNA containing all 132 bases of intron 20, and normally spliced mRNA. The four mRNA species can give rise to three translation products: protein lacking exon 20 sequence, protein with 8 noncollagenous amino acids in the middle of the triple helical domain, and normal protein chains. The mRNA with all 132bp of intron 20 results in a truncated protein incapable of assembly into trimers. Consistent with these findings, cultured fibroblasts from the patient secreted less type III procollagen and retained abnormal timers in the cell layer. Pepsin digestion of the cell layer proteins revealed multiple di sulfide bonded trimers of type III procollagen, presumably the product of protein assembly from a mixture of normal and multiple abnormal type III procollagen monomers.

Recurrent COL3A1 mutation results in EDS IV or familial aneurysms

Recurrent COL3A1 mutation results in EDS IV or familial aneurysms

Recurrent COL3A1 mutation results in EDS IV or familial aneurysms

Recurrent COL3A1 mutation results in EDS IV or familial aneurysms

Mutations in fibrillar collagens (types I, II, III, and XI), fibril‐associated collagen (type IX), and network‐forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels

This review summarizes the data on 278 different mutations found to date in the genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. A majority (217 mutations; 78% of the total) of the mutations are single-base and either change the codon of a critical amino acid (63%), or lead to abnormal RNA splicing (13%). Most of the amino acid substitutions are those of a bulkier amino acid for the obligatory glycine of the repeating-Gly-X-Y-sequence of the collagen triple helix (155; 56%). Altogether, 26 different mutations (9.4% of the mutations) occur in more than one unrelated individual. The 65 patients in whom the 26 mutations were characterized constitute almost one-fifth (20.5%) of the 317 patients analyzed. The mutations in types I, II, III, IX, X, and XI collagens cause a wide spectrum of diseases of bone, cartilage, and blood vessels, including osteogenesis imperfecta, a variety of chondrodysplasias, types IV and VII of the Ehlers-Danlos syndrome, and, rarely, some forms of osteoporosis, osteoarthritis, and familial aneurysms. Hum Mutat 9:300–315, 1997. © 1997 Wiley-Liss, Inc.

Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels.

This review summarizes the data on 278 different mutations found to date in the genes for types I, II, III, IX, X, and XI collagens from 317 apparently unrelated patients. A majority (217 mutations; 78% of the total) of the mutations are single-base and either change the codon of a critical amino acid (63%), or lead to abnormal RNA splicing (13%). Most of the amino acid substitutions are those of a bulkier amino acid for the obligatory glycine of the repeating-Gly-X-Y-sequence of the collagen triple helix (155; 56%). Altogether, 26 different mutations (9.4% of the mutations) occur in more than one unrelated individual. The 65 patients in whom the 26 mutations were characterized constitute almost one-fifth (20.5%) of the 317 patients analyzed. The mutations in types I, II, III, IX, X, and XI collagens cause a wide spectrum of diseases of bone, cartilage, and blood vessels, including osteogenesis imperfecta, a variety of chondrodysplasias, types IV and VII of the Ehlers-Danlos syndrome, and, rarely, some forms of osteoporosis, osteoarthritis, and familial aneurysms.

Familial Cerebral Haemorrhage and Associated Berry Aneurysm with Normal Type ID Collagen

Familial Cerebral Haemorrhage and Associated Berry Aneurysm with Normal Type ID Collagen

The Risk of Intracranial Aneurysms in Families with Subarachnoid Hemorrhage

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Familial Cerebral Aneurysms

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, χ2 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, χ2 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, χ2 test). In four of five families, aneurysms ruptured within 10 years of each other in sisters (mean, 6 years). Multip...

Familial Cerebral Aneurysms

Despite the recent interest in familial cerebral aneurysms, the epidemiology, natural history, pattern of inheritance, screening of asymptomatic relatives, and the search for a biochemical marker remain problematic. To assess these issues, we report the results of our prospective study of 30 patients with 38 aneurysms (27 ruptured) and of the angiographic screening of asymptomatic relatives, all from 13 families seen consecutively since 1986. Women were over-represented (77%), and patients with multiple aneurysms (17%) were under-represented, compared with sporadic cases. Only 16% of the aneurysms were at the anterior communicating artery. Aneurysms occurred at the same or at the mirror site in 10 of 16 siblings (62%) and in 50% of mother-daughter pairs versus 20% for randomly selected, sporadic aneurysm patients. Rupture occurred in the same decade in 10 of 12 siblings (83%) versus the expected 21% for randomly selected, sporadic aneurysms. The average age at rupture was 47.2 years, and 60% of patients with a ruptured aneurysm were 50 years of age or younger. Seventy percent of patients died or were disabled from aneurysmal rupture. Screening of 41 individuals, including 2 dizygous twins, identified 1 aneurysm and 2 infundibula. A specific pattern of inheritance could not be ascertained from the pedigrees. The presence of an aneurysm was not associated with a specific human leukocyte antigen haplotype or antigen, and collagen Type III was qualitatively and quantitatively normal. Until a biological marker is identified, angiographic screening by intra-arterial digital subtraction or magnetic resonance angiography remains the only way to identify patients at risk of harboring a familial cerebral aneurysm.