Ruptured intracranial aneurysm in an adolescent with Alport’s syndrome—a new expression of type IV collagenopathy: Case report

doi:10.1016/S0090-3019(00)00253-6

Surgical Neurology

Volume 54, Issue 1, July 2000, Pages 68-72

https://doi.org/10.1016/S0090-3019(00)00253-6 Get rights and content

Abstract

BACKGROUND

Aneurysmal subarachnoid hemorrhage is uncommon in the pediatric and adolescent age groups. Collagenopathies, particularly of collagen type III and IV, have been recognized in the pathogenesis of intracranial (i.c.) aneurysms in recent studies of cerebrovascular immunoreactivity and the molecular architecture of the walls of cerebral blood vessels. Alport’s syndrome is a genetic disease characterized by imperfect synthesis of type IV collagen leading to sensorineural hearing loss and hematuria. The hematuria results from an abnormal synthesis of the type IV collagen of the glomerular basement membrane.

CASE DESCRIPTION

After a motor vehicle accident, this 14-year-old male driver presented with diffuse subarachnoid hemorrhage confirmed by computerized tomography. Subsequent cerebral angiography revealed a left carotid artery bifurcation aneurysm. A retrospective review of the patient’s history disclosed renal biopsy-proven hereditary Alport’s syndrome. The patient underwent left pterional craniotomy and clipping of the aneurysm, which had clearly ruptured.

CONCLUSIONS

The authors present the first clinical observation of a ruptured cerebral aneurysm in an adolescent male with Alport’s syndrome. In this case the type IV collagenopathy of Alport’s syndrome may have contributed to the genesis of this adolescent’s aneurysm. Intracranial aneurysms may be more common in the population of collagenopathies than previously suspected and non-invasive screening may be appropriate.

Section snippets

Discussion

Factors that predispose to the formation of saccular intracranial (i.c.) aneurysms in the general population remain obscure. It has been suggested that unusually large congenital defects in the media of the cerebral vessels and hemodynamic stress may be significant initiators 16, 23, 41. Of particular interest is the pathogenesis of the rare aneurysms that occur in the pediatric population, which may represent a distinct pathophysiologic entity from adult aneurysms based on a number of

Conclusion

Patients with Alport’s syndrome have arterial walls with diminished tensile strength due to a genetically determined defective type IV collagen synthesis. This case suggests that these collagenopathic patients may be predisposed to berry aneurysm formation. In addition, this report adds support to the significance of collagen type IV in maintenance of the cerebral blood vessel wall integrity.

A high index of suspicion of a possible i.c. aneurysm should be maintained in any case of subarachnoid,

References (41)

N. Barnard et al.
Epstein’s syndrome
Implications for oral surgery. Oral Surg, Oral Med, Oral Path
(1993)
R. Garcia–Torres et al.
Alport-leiomyomatosis syndromean update (Review)
Am J Kidney Dis
(1993)
F.M. Pope et al.
Some patients with cerebral aneurysms are deficient in type III collagen
Lancet
(1981)
B.V. Shekhonin et al.
Relative distribution of fibronectin and type I, III, IV, V collagens in normal and atherosclerotic intima of human arteries
Atherosclerosis
(1987)
W.E. Stehbens et al.
Early berry aneurysm formation in Marfan’s syndrome
Surg Neurol
(1989)
K. Tryggvason et al.
Molecular genetics of Alport syndrome
Kidney Int
(1993)
B. Voss et al.
Localization of collagen types I, III, IV, and V fibronectin and laminin in human arteries by the indirect immunofluorescence method
Pathol Res Pract
(1986)
I. Acke et al.
Ocular manifestations of Alport’s syndromea case report (Review)
Bull Soc Belge Ophtalmol
(1992)
A.C. Alport
Hereditary familial congenital haemorrhagic nephritis
Br Med J
(1927)
H.A. Brodie et al.
Macrothrombocytopenia and progressive deafnessA new genetic syndrome
Am J Otol
(1992)

A.E. Czeizel et al.

Association of familial nephritis without deafness and multiple sclerosis

Clin Nephrol

(1994)

J.E. Deal et al.

Alport’s syndrome and hereditary motor and sensory neuropathy type I—an unfortunate coincidence

Pediatr Nephrol

(1993)

P.B. Dobrin et al.

Failure of elastin or collagen as possible critical connective tissue alterations underlying aneurysmal dilatation

Cardiovasc Surg

(1994)

M. Gerosa et al.

Intracranial aneurysms of childhood

Childs Brain

(1980)

Gregory MC, Atkins CL. Alport syndrome. In: Schrier RW, Gottschalk CW, eds. Diseases of the Kidney, Vol 1, Book 5....

Hainsworth PJ, Mendelow AD. Giant i.c. aneurysm associated with Marfan’s syndrome: A case report (letter). J Neurol...

L. Heichendorff et al.

Analysis of connective tissue components in arterial tissue

Scand J Clin Lab Invest Suppl

(1990)

C.E. Kashtan

Clinical and molecular diagnosis of Alport syndrome (Review)

Proc Assoc Am Phys

(1995)

W. Lane et al.

X-linked recessive nephritis with mental retardation, sensorineural hearing loss, and macrocephaly

Clin Genet

(1994)

H.H. Lemmink et al.

Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal recessive Alports syndrome

Hum Mol Genetics

(1994)

Cited by (25)

Associations of collagen type i α2 polymorphisms with the presence of intracranial aneurysms in patients from Germany
2014, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
Aneurysms can occur in the context of monogenetic diseases, including autosomal dominant polycystic kidney disease18 and autosomal recessive polycystic kidney disease.19 Further syndromes associated with intracranial aneurysms include Ehlers–Danlos syndrome type 4,20,21 Marfan syndrome,22 fibromuscular dysplasia,23 neurofibromatoses,21 and Alport syndrome.24 There are several further candidate genes associated with intracranial aneurysms including tropoelastin, different types of collagen, perlecan, versican, endothelial nitric oxide synthase, fibrillin, and many more.9
Subarachnoid hemorrhage from ruptured intracranial aneurysms is associated with a severe prognosis. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the identification of risk patients by genetic analyses is not possible because of lack of candidate genes. Collagen type I α2 (COL1A2) has been associated with the presence of aneurysms in patients from Japan, China, and Korea. In this study, we investigate whether COL1A2 is a possible aneurysm candidate gene in the German population.
Patients admitted with intracranial aneurysms to our department and collaborating departments were enrolled. Three single-nucleotide polymorphisms (SNPs) of the COL1A2 gene, namely rs42524 in exon 28, rs1800238 in exon 32, and rs2621215 in intron 46 were investigated using restriction enzymes and sequencing. HapMap data were used for comparison of allelic frequencies with the normal population by χ² test to identify significant associations between genotypes and the presence of aneurysms.
Two hundred sixty-nine patients were enrolled into the study. There was a significant correlation with the presence of aneurysms for the GC allele of the SNP rs42524 in exon 28 (P = .02). The other polymorphisms did not show significant correlations.
The COL1A2 gene is associated with intracranial aneurysms in a subset of the German population. However, it is not responsible for the majority of aneurysms, and further candidate genes need to be identified to develop sensitive genetic screening for patients at risk.
Genetic Abnormalities in Glomerular Function
2013, Seldin and Geibisch's The Kidney
Sequence variations in the von hippel-lindau tumor suppressor gene in patients with intracranial aneurysms
2013, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
About 3% of patients with SAH have a first-degree relative with SAH and are therefore considered to be at risk for familial SAH.34 Familial SAH can occur in the context of monogenetic diseases, including autosomal dominant polycystic kidney disease (ADPKD), caused by mutations of the PKD1 and PKD2 gene, autosomal recessive polycystic kidney disease (ARPKD), caused by mutations of the PKHD1 gene,35-37 and other syndromes, such as Ehlers–Danlos syndrome type 4,38,39 Marfan syndrome,40 fibromuscular dysplasia,41 neurofibromatosis,39 and Alport syndrome.42 We describe intracranial aneurysms in 2 patients with VHL disease and VHL aberrations in patients with intracranial aneurysms.
The rupture of intracranial aneurysms leads to subarachnoid hemorrhage, which is often associated with poor outcome. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the lack of candidate genes precludes identifying patients at risk by genetic analyses. We observed intracranial aneurysms in 2 patients with von Hippel–Lindau (VHL) disease and the known disease-causing mutation c.292T > C (p.Tyr98His) in the VHL tumor suppressor gene. This study investigates whether the VHL gene is a possible candidate gene for aneurysm formation.
Patients with intracranial aneurysms admitted to our department between 2006 and 2009 were enrolled. The peripheral leukocyte DNA of 200 patients was investigated for sequence variations in the VHL gene using denaturing high performance liquid chromatography. Peripheral leukocyte DNA of 100 randomly sampled probands was investigated as a control group. The allelic frequencies of sequence variations between both groups were compared using the Fisher exact test.
Fourteen of 200 patients with intracranial aneurysms had sequence variations at 6 different loci in the VHL gene. In contrast, no sequence variations were identified in 100 probands in the control group (P = 0.0062). However, none of the single-sequence variations had a statistically significant difference in the allelic frequencies compared to the control group.
There is accumulating evidence for a genetic basis of aneurysm development. Our investigations lead to the conclusion that the VHL gene is potentially involved in the formation of intracranial aneurysms in a subset of patients. Additional candidate genes need to be identified in order to develop sensitive genetic screening for at-risk patients.
Genetic Abnormalities in Glomerular Function
2012, Seldin and Giebisch's The Kidney: Physiology and Pathophysiology
Ruptured Thoracoabdominal Aortic Aneurysm in a Renal Transplant Patient with Alport's Syndrome
2007, Annals of Vascular Surgery
Citation Excerpt :
Mediators of vascular dysfunction associated with cyclosporin A include sympathetic overactivity, relative deficiency of nitric oxide, transforming growth factor-beta 1, endothelin-1, reactive oxygen and nitrogen species, and vasoconstrictor eicosanoids.7 Treatment with cyclosporin A has been identified as a potential etiologic factor in spontaneous coronary artery dissection.8 Given this patient's relatively young age, we propose that there may be an association between Alport's syndrome and the development of AAAs.
Alport's syndrome is a rare genetic disorder of type IV basement membrane collagen synthesis that typically presents with nephropathy, deafness, and ocular abnormalities. To the best of our knowledge, this is the first report in the world's literature of ruptured thoracoabdominal aortic aneurysm in a young patient with Alport's syndrome and a renal transplant. Hypotheses on an association between collagen disease in Alport's syndrome and aortic aneurysms are discussed.
Intracranial aneurysms in the pediatric population: Case series and literature review
2005, Surgical Neurology
Intracranial aneurysms in children (≤18 years old) are rare, and their epidemiology is poorly understood. We present a prospective 14-year experience at our institution and review the literature to clarify the characteristics and outcomes of pediatric patients with intracranial aneurysms.
Review of medical records in the Johns Hopkins aneurysm prospective database and review of the literature since 1939 were performed.
Of 1377 intracranial aneurysm cases at our institution from 1991 to 2004, 19 (1.4%) pediatric patients were treated using microsurgical or endovascular techniques. Male/female ratio was 2.2:1. Eleven percent occurred at the internal carotid artery (ICA) bifurcation, and 42% were located in the posterior circulation. Seven (37%) were giant lesions; 58% presented with subarachnoid hemorrhage. Patients in good Hunt and Hess grade (I-III) comprised 42%, and poor-grade (IV-V) patients comprised 16%. At a mean follow-up duration of 3.0 ± 3 years, 95% of patients demonstrated favorable outcomes with Glasgow Outcome Scale score of 4 or 5. In the literature, a total of 706 pediatric intracranial aneurysm cases have been described since 1939. The male/female ratio is 1.8:1. The ICA bifurcation was the location in 26%, and only 17% were in the posterior circulation. Twenty percent were giant lesions, and 80% presented with subarachnoid hemorrhage. Good- and poor-grade patients comprise 49% and 36% of the total cases, respectively. Favorable outcome was reported in 60%.
During recent decades, good outcomes after the treatment of ruptured and unruptured pediatric aneurysms have increased, reaching 95% in the current series. Pediatric intracranial aneurysms occur more commonly in male patients and have a predilection for the terminal ICA bifurcation.

View all citing articles on Scopus

View full text

VascularRuptured intracranial aneurysm in an adolescent with Alport’s syndrome—a new expression of type IV collagenopathy: Case report

Abstract

Section snippets

Discussion

Conclusion

Implications for oral surgery. Oral Surg, Oral Med, Oral Path

Am J Kidney Dis

Lancet

Atherosclerosis

Surg Neurol

Kidney Int

Pathol Res Pract

Ocular manifestations of Alport’s syndromea case report (Review)

Bull Soc Belge Ophtalmol

Hereditary familial congenital haemorrhagic nephritis

Br Med J

Macrothrombocytopenia and progressive deafnessA new genetic syndrome

Am J Otol

Association of familial nephritis without deafness and multiple sclerosis

Clin Nephrol

Alport’s syndrome and hereditary motor and sensory neuropathy type I—an unfortunate coincidence

Pediatr Nephrol

Failure of elastin or collagen as possible critical connective tissue alterations underlying aneurysmal dilatation

Cardiovasc Surg

Intracranial aneurysms of childhood

Childs Brain

Analysis of connective tissue components in arterial tissue

Scand J Clin Lab Invest Suppl

Clinical and molecular diagnosis of Alport syndrome (Review)

Proc Assoc Am Phys

X-linked recessive nephritis with mental retardation, sensorineural hearing loss, and macrocephaly

Clin Genet

Mutations in the type IV collagen alpha 3 (COL4A3) gene in autosomal recessive Alports syndrome

Hum Mol Genetics

Vascular
Ruptured intracranial aneurysm in an adolescent with Alport’s syndrome—a new expression of type IV collagenopathy: Case report