Pediatr Radiol (1999) 29: 206±211
Ó Springer-Verlag 1999

Alberto Beltramello
Giovanni Puppini
Andrea Bricolo
Ivo Andrea Bergamo Andreis
Ghassan El-Dalati
Lucia Longa
Silvia Polidoro
Giorgio Zavarise
Pierluigi Marradi

Received: 18 August 1997
Accepted: 15 June 1998

)

A. Beltramello ( ) ´ G. Puppini ´
A. Bricolo ´ I. A. B. Andreis ´
G. El-Dalati
Department of Radiology,
University of Verona,
Policlinico B.go Roma,
Strada le Grazie,
I-37 100 Verona, Italy
L. Longa ´ S. Polidoro
Department of Genetics, Biology,
Biochemistry,
University of Turin,
Turin, Italy
G. Zavarise ´ P. Marradi
Department of Paediatrics,
University of Verona,
Verona, Italy

Does the tuberous sclerosis complex
include intracranial aneurysms?
A case report with a review of the literature

Abstract Background. Tuberous
sclerosis is a protean, genetically
determined disease that may involve
any organ or tissue and lead to a
great number of symptoms and clinical features.
Objective. Diagnosis can be very
difficult in cases with incomplete
manifestations (formes fruste) lacking the classic signs of the disease.
Materials and methods. We report a
case fulfilling the diagnostic criteria
for tuberous sclerosis (shagreen
patches, hypomelanotic macules,
renal cysts and angiomyolipomas,
and ªmigration tractsº in the cerebral white matter) in association
with a giant intracranial aneurysm,
but lacking mental retardation, epilepsy and facial angiofibroma.

Introduction
Tuberous sclerosis complex (TSC) is the archetype of
disorders intermediate between blastomatous processes
and dysplastic states. It belongs to the group of diseases
described by the term ªphakomatosesº by Van der
Hoeve (1933) or ªneuroectodermal dysplasiasº by van
Bogaert (1935) [1].
Because TSC is a disease with protean clinical manifestations, any organ or tissue may be involved, leading
to a myriad of symptoms and associations of symptoms.
Indeed, the clinical features of TSC vary considerably
and the classic diagnostic triad, first described by Vogt
(1908), i. e. mental deficiency, epilepsy and facial angiofibromas, may be lacking. Epilepsy, with or without
mental retardation, is the most common clinical presentation. Facial angiofibroma (once called ªadenoma se-

Results. Fourteen other cases of tuberous sclerosis and intracranial aneurysms, all but one without any
clear sign of polycystic kidney disease, were found in the literature.
Conclusion. We suggest that vascular dysplasias in general and aneurysms (mainly intracranial) in
particular can be added to the other
non-primary diagnostic features for
the clinical diagnosis of tuberous
sclerosis.

baceumº) is the most readily recognised feature of
tuberous sclerosis, and without this sign the disease
may pass unrecognised. Retinal lesions called ªphakomataº may also occur. Besides these more common features, a whole range of other signs and symptoms of
variable importance, caused by neurological, renal, cardiac, pulmonary, osseous and cutaneous dysplasias, can
be present [1, 2].
Diagnosis is easy in patients in whom epilepsy, facial
angiofibroma and intellectual deficits predominate, either with or without other minor symptoms. Conversely,
diagnosis is very difficult when manifestations are incomplete (`formes fruste' cases). In these patients, molecular investigation for the TSC genes may be helpful,
particularly when only secondary or tertiary features
are present [3]. Cases have been reported in which the
subungual lesions, the so-called Koenen tumours, were

207

Fig. 1 Midline, elevated, lowback mass covered by ªorange
peelº skin
Fig. 2 Anteroposterior radiograph of the lumbar spine
showing multiple sclerotic pedicles from T12 to L4 (arrows)
Fig. 3 Sagittal T1-weighted
MRI of the brain showing a
right parasellar lesion compatible with a giant right ICA aneurysm (arrow)
Fig. 4 MRA of the intracranial
vessels. The right ICA aneurysm is fusiform in shape (arrows) and the left ICA is
normal (arrowheads)

1

3

2

5

4

Fig. 5 Axial proton density brain MRI showing a hyperintense
area in the white matter of the right frontal region (arrow) consistent with an ischaemic lesion. There are bilateral linear
white-matter hyperintensities radiating from the surface of the
brain to the ventricles (arrowheads), compatible with ªmigration
tractsº

the sole clinical manifestation of tuberous sclerosis [4].
Other partial forms may show only neurological manifestations, namely epilepsy, mental retardation or subependymal tumours. In addition, a correct diagnosis is
particularly difficult in those cases which occur with
purely cardiac, renal, hepatic or pulmonary lesions in
the absence of any cutaneous and brain lesions [1].
Tsukada and Pickren [5] made the diagnosis incidentally
during an autopsy on a woman who died from carcinoma of the breast, and who completely lacked the three
major symptoms.
We report on a patient with TSC without mental retardation, epilepsy and facial angiofibroma who showed
a giant intracranial aneurysm. The relative frequency of
this association is discussed, and a critical review of the
literature is presented.

Case report
A normally developed 11-year-old boy was referred for investigation of a low midline back mass suspected as being a pre-sacral lipoma. On examination, a huge depigmented skin area was
evident at the antero-lateral surface of the right thigh. Facial angiofibroma, subungual fibroma and retinal hamartomas were absent. Seizures and other neurological abnormalities were absent
from his past history. A midline elevated lesion, 10 cm in diameter
and covered by pale skin with the texture of orange peel, was evident (Fig. 1). Ultrasound showed it to be hypoechoic, containing
hyperechoic bundles, and compatible with sub-epidermal fibrosis
(ªshagreen patchº).
X-rays of the lumbar spine demonstrated sclerosis of the posterior margins of several thoraco-lumbar vertebrae and pedicles
from T12 to L4 (Fig. 2). To exclude bone metastases from abdominal or intracranial neurogenic tumours, abdominal ultrasound
(US) and cranial magnetic resonance imaging (MRI) were performed. US showed a small right kidney containing cysts, the largest being 5 cm in diameter. In the cortex of the left kidney were
multiple non-shadowing hyperechoic foci compatible with angiomyolipomas. On MRI of the brain, a giant right internal carotid artery (ICA) aneurysm, 2 cm in diameter, was evident (Fig. 3). The
aneurysm, originating from the supra-clinoid portion of the ICA,
showed neither thrombosis nor calcification. Magnetic resonance
angiography showed the aneurysm to be fusiform in shape. The
left ICA was normal (Fig. 4). Based on these findings, a diagnosis

208

of giant ICA aneurysm in the presence of presumptive TSC was
made. Ten days later, conventional angiography confirmed the
MRI findings. In the same session, endovascular occlusion of the
right ICA was undertaken. Mild left hemiparesis developed 3 h later, but cleared completely by 72 h. MRI 2 months later showed an
ischaemic lesion in the white matter of the right frontal lobe. Furthermore, bilateral white matter abnormalities radiating from the
surface of the brain to the ventricles were evident (Fig. 5). Both
parents and the 16-year-old sister of the patient underwent complete clinical examination, including dermatological and ophthalmological evaluations, MRI of the brain and abdominal US. Two
hepatic cysts were demonstrated in the patient's father, and a
huge depigmented skin area was evident on the trunk of the sister;
no abnormalities were detected in the patient's mother. At followup 3 years later, the child was perfectly well.
Genetics
All four family members (the patient, his parents and sister) underwent genetic evaluation. For molecular analysis, 8 mg of DNA extracted from peripheral blood leucocytes [6] were double-digested
with EcoRI and HindIII restriction enzymes and analysed by
Southern blot after 0.8 % agarose gel electrophoresis. The TSC2
probe used was a mix of the 32P-labelled cDNA clones 4B2 and
4.9, a kind gift from J. Sampson [7]. The TSC1 genomic configuration was tested by two overlapping polymerase chain reaction
(PCR) fragments (exons 3±16 and 15±23), that spanned the entire
TSC1 coding sequence [8]. The genotype at polymorphic markers
located within the TSC2 gene, an insertion/deletion of an Alu sequence in intron 2, a minisatellite in intron 8 (N. M. unpublished)
and an EcoRV RFLP in exon 40 [9], and in the untranslated 3' tail
of PKD1, the microsatellite KG8, were assessed by PCR as previously described [10]. Mutation analysis of the entire TSC2 and of
the 2/3 TSC1 (i. e., exons 15±23) was performed with the protein
truncation test (PTT). Southern blot analysis of the proband
DNA from leucocytes did not show any apparent rearrangement
of the expected TSC1 and TSC2 gene configurations. Moreover,
at autoradiography, the intensity of each EcoRI and HindIII fragment was not reduced when compared with the band pattern of
normal controls, suggesting that both TSC1 and TSC2 alleles
were preserved. Four TSC2 and PKD1 intragenic polymorphisms
were typed in the patient and in his relatives, but none was informative. However, the contribution of both paternal and maternal
16p13.3-linked alleles was confirmed by testing two and one markers (HBAP1, D16S521 and D16S291) telomeric to TSC2 and centromeric to PKD1, respectively.
The screening by PTT for either nonsense or frameshift mutations in the full-length TSC2 transcript and in approximately twothirds of the 3' end of TSC1 did not show evidence of truncated
proteins.

Discussion
A revision of the TSC diagnostic criteria [11] showed
that 45 % of individuals affected with TSC have normal
intelligence, only 29 % present the complete Vogt triad
and 6 % have none of these three features. On this basis,
the classic Vogt triad has been replaced by a modern
and more inclusive set of diagnostic criteria [12] (Table 1), so that TSC can be diagnosed by the presence of
even only one type of lesion from a list of several unique

Table 1 Diagnostic criteria for tuberous sclerosis complex (TSC)
(hist. histologic confirmation, Rx radiographic evidence). Primary
diagnostic criteria are in bold; secondary are in italics; tertiary are
in roman
Brain
Subependymal nodule or giant cell astrocytoma (hist.)
Cortical tuber (hist.)
Multiple calcified subependymal nodules protruding into the ventricle (Rx)
Cerebral tubers (Rx)
Noncalcified subependymal nodules (Rx)
Cerebral white-matter ªmigration tractsº or heterotopias (Rx)
Infantile spasms
Skin
Facial angiofibroma
Multiple ungual fibromas
Shagreen patch
Forehead plaque
Hypomelanotic macules
ªConfettiº skin lesions
Eye
Multiple retinal astrocytomas
Other retinal hamartoma or achromic patch
Heart
Cardiac rhabdomyoma (hist. or Rx)
Kidney
Renal angiomyolipoma (hist. or Rx)
Renal cysts (hist.)
Renal cysts (Rx)
Lung
Pulmonary lymphangiomyomatosis (hist.)
Pulmonary lymphangiomyomatosis (Rx)
Bone
Bone cysts (Rx)
Mouth
Randomly distributed enamel pits in deciduous and/or permanent
teeth
Gingival fibromas
Others
Affected first-degree relative
Hamartomatous rectal polyps (hist.)
Hamartoma of other organs (hist.)
Definite TSC
One primary feature, two secondary features of one secondary plus
two tertiary features
Probable TSC
Either one secondary plus one tertiary feature or three tertiary
features
Suspect TSC
Either one secondary feature or two tertiary features

findings that are usually multiple in TS but are only
rarely found in the normal population. By means of
these criteria, we may distinguish the patients with a
definite diagnosis from those who present subtle or incomplete features of TS [3]. The disease is inherited as
an autosomal dominant trait. However, up to 70 % of

209

Table 2 Tuberous sclerosis and
intracranial aneurysms: review
of the literature (ACA anterior
cerebral artery, AML angiomyolipoma, ICA internal carotid artery, MCA middle
cerebral artery, ADPKD autosomal dominant polycystic
kidney disease, SEN subependymal nodules, VA vertebral
artery)

Case no./age/sex

Reference

Aneurysm

Associated features

1/12 years/F

[26]

ICAs bilateral,
fusiform

Hypomelanotic macules
Facial angiofibroma
Ungual fibromas
Calcified SENs

2/24 years/M

[28]

MCA, saccular

ADPKD
Kidney AMLs

3/26 years/F

[35]

intraventricular
(necropsy)

Vogt triad
Kidney AMLs
Hypomelanotic macules
Ungual fibromas
Liver, spleen and lung hamartomas
Cortical tubers
SENs

4/17 years/F

[29]

ICA giant + ACA

Facial angiofibroma
Hypomelanotic macules
Mental handicap
Seizures

5/53 years/M

[27]

ICA giant

Hypomelanotic macules
Retinal hamartoma

6/7 years/M

[20]

ACA giant,
enlarging

Hypomelanotic macules
Seizures

7/6 years/F

[30]

ICA giant, fusiform + ACA

8/6 years/F

[31]

ICA giant, fusiform + ACA

9/29 years/M

[33]

ICA giant + VA
calcified

Hypomelanotic macules
Moderate mental handicap
Seizures
Seizures
Mental handicap
Hypomelanotic macules
Abdominal aneurysm and aorta coarctation
Facial angiofibroma
Ungual fibroma
Hypomelanotic macules
Scoliosis
Left hemiparesis
SENs calcified

10/35 years/F

[2]

ICA giant

Mental handicap
Seizures

11/1 year/M

[32]

ACA arteritis

Seizures
Mental handicap

12/young boy/M

[22]

VA giant

13/5 months/M

[34]

ICA giant, fusiform Seizures
+ ACA, MCA
Subependymal tumor
ectasias
Retinal hamartoma
Hypomelanotic macules

14/30 years/M

[39]

MCA saccular

cases are due to a new germ-line mutation. Linkage
studies have established genetic heterogeneity, with
two TSC genes mapped to chromosome 9 (TSC1) and
to chromosome 16 (TSC2), respectively [13, 14]. Hamartomas require complete loss of function of the two alleles at either TSC locus; the first mutation is inherited,

ADPKD
Seizures
Mental handicap
Facial angiofibroma
SENs calcified
Cortical tubers

whereas the second allele is mutated somatically. The
number and tissue distribution of the second somatic
mutations may in part account for the protean manifestations of TSC. Indeed, even within the same family a
given mutation may be associated with a variety of clinical phenotypes, including ªformes frusteº, which may

210

be confusing both to the clinician and to the radiologist
[15].
With regard to bone lesions, several isolated case reports have described abnormalities of the lumbosacral
spine and pelvis in TSC [16±18] with a prevalence as
high as 40 % [19]. In the list of diagnostic criteria for
TSC (Table 1), cysts are the only bone lesion mentioned. However, the most commonly reported osseous
involvement is sclerotic (or osteoblastic) lesions affecting the edges of vertebral bodies and pedicles of any
portion of the lumbosacral spine and pelvis. The roentgenographic appearance is characteristic, being virtually
diagnostic of the disease. When the lesion is less pronounced, it may simulate purely osteoblastic metastases
[19]. Bony changes have not been emphasised in the literature and tend to be overlooked, probably because
they are asymptomatic. Thus, bone lesions are considered of little diagnostic significance [11].
Although dysplasias and hamartomatous proliferations of small blood vessels, including haemangiomas,
are common in TSC, involvement of the medium-sized
and large vessels, including aneurysms, is considered
rare.
Arterial lesions have previously been described in
TSC. Histologically, elastic fibres of the affected arteries
are deficient and fragmented, and there is accumulation
of mucopolysaccharides in arterial walls. Vascular occlusions, ectasias and/or microaneurysms may result
from these changes. Dysplasias of the cerebral vasculature can also occur in NF1 [20]; most commonly, these
dysplastic abnormalities consist of intimal proliferation,
with resultant stenosis or occlusion of the carotid or
proximal middle cerebral artery (MCA) or anterior cerebral artery (ACA), resulting in the moyamoya phenomenon in 60±70 % of these patients. Less commonly,
cerebral aneurysms may also be detected [21].
Johnson and Gomez [22] reported one case of coarctation of the aorta in a 9-day-old infant with TSC proven
at post-mortem examination. Nine TSC patients with an
aortic aneurysm [23] and one with an axillary artery aneurysm [24] have been reported in the literature. Moreover, the association of TSC with fibromuscular
dysplasia of the aneurysmal vessel has been described
[24, 25].
In our review of the literature, we found 14 patients
with intracranial aneurysms, originating mostly from
the ICA [2, 26±34], ACA [20, 28±31, 33] or MCA
[33±35]. Occasionally, the aneurysm was intraventricular in location [36] or originated from the vertebral artery (VA) [22, 33]. In 6/14 patients, the aneurysms were
multiple [26, 28±30, 32, 33] (Table 2). It is of some interest that 9/15 patients with TSC and intracranial aneurysms (including the present case report) presented
with ICA aneurysm (isolated or associated). This percentage (60 %) is much higher than the overall incidence of ICA aneurysms (31 %) [37], whereas the

percentage of ACA aneurysms is in line with the reported usual distribution (43 % vs 41 %). There is no clear
explanation for this result. Only three of these patients
were older than 30 years of age at the time of diagnosis
(Table 2, cases 5, 10 and 14), and in 9 patients the aneurysm was giant (cases 4±10, 12 and 13).
The pathogenesis of intracranial aneurysms is unclear. Certainly, the young age of these patients supports
the view that TSC aneurysms arise from developmental
defects in the arterial wall rather than from atherosclerosis [28]. A careful pathological study of such aneurysms should be helpful in delineating the defect and in
assessing the relationships between TSC-associated aneurysm and fibromuscular dysplasia [29]. The close
physical proximity of the gene for autosomal dominant
polycystic kidney disease-1 (PKD1), a condition characterised by a high frequency of intracranial aneurysms,
and the TSC2 gene has recently been shown to play a
major role in the so-called TSC2 and PKD1 contiguous
gene syndrome [35, 38, 39]. No evidence of TSC2 and
PKD1 DNA deletions usually responsible for this syndrome was present in our patient. In the available literature, only two cases (Table 2, cases 2 and 14) presented
with the association of intracranial aneurysm and
PKD1.
The present case, even if probably affected with a
ªforme frusteº of the disease, fulfils the diagnostic criteria for TSC [3]. In fact, two secondary (shagreen patch
and renal angiomyolipomas) and three tertiary (hypomelanotic macules, renal cysts and cerebral white matter ªmigration tractsº) features were present, thereby
allowing a definite diagnosis of TSC. This case of TSC
must be considered sporadic because of the lack of evidence of TSC in other family members. The patient's
mother was completely normal, only two hepatic (not
renal) cysts were present in the father, and only one tertiary feature (hypomelanotic macule) was observed in
the patient's sister. According to Roach et al. [3], two
tertiary features are required for the diagnosis of TSC.
Regarding the TSC mutation analysis, a negative
PTT finding does not exclude a TSC gene defect since
nonsense mutations cannot be detected by this test and
only the 3' end of the TSC1 gene has been investigated
thus far [40].
The intracranial aneurysm in the present TSC patient
represents the 15th reported observation. This association, not as rare as previously believed, could be explained by the tendency for TSC to produce vascular
dysplasias and might suggest that aneurysms can be
part of the spectrum of developmental defects in TSC.
In our opinion, intracranial aneurysm can be added to
the other non-primary diagnostic criteria of TSC.
Acknowledgements L. Longa is a recipient of a fellowship from
ªAssociazione Emma ed Ernesto Rulfo per la Genetica Medicaº.
We thank Prof. Nicola Migone for criticisms and suggestions.

211

References
1. Donegani G, Grattarola FR, Wildi B
(1972) Tuberous sclerosis. In: Vinken
PJ, Bruyn GW (eds) Phakomatoses.
Handbook of clinical neurology, vol 14.
Elsevier, New York, pp 340±389
2. Martin N, de Broucker T, Cambier J,
et al (1987) MRI evaluation of tuberous
sclerosis. Neuroradiology 29: 437±443
3. Roach ES, Smith M, Huttenlocher P,
et al (1992) Report of the diagnostic
criteria committee of the national tuberous sclerosis association. J Child
Neurol 7: 221±224
4. Barroeta S, Grinspan Bozza N (1962)
Tumor de koenen sin otras manifestaciones clinicas de epiloia. Arch Argent
Derrn 12: 290±292
5. Tsukada J, Pickren JW (1967) Carcinoma of breast and asymptomatic tuberous sclerosis. NY State J Med 67:
593±597
6. Maniatis TM, Fritsch EF, Sambrook J
(1989) Molecular cloning: a laboratory
manual. Cold Spring Harbor Laboratory Press, Cold Spring, NY
7. The European Chromosome 16 Tuberous Sclerosis Consortium (1993) Identification and characterization of the
tuberous sclerosis gene on chromosome
16. Cell 75: 1305±1315
8. The TSC1 Consortium (1997) Identification of the tuberous sclerosis gene on
chromosome 9q34. Science 277:
805±808
9. Au KS, Rodriguez JA, Dobyns WB,
et al (1997) Mutations and polymorphisms in the tuberous sclerosis complex gene on chromosome 16. Hum
Mutat 9: 23±29
10. Carbonara C, Longa L, Grosso E, et al
(1996) Apparent preferential loss of
heterozygosity at TSC2 over TSC1
chromosomal region in tuberous sclerosis hamartomas. Gene Chromosomes
Cancer 15: 18±25
11. Gomez MR (1988) Criteria for diagnosis. In: Gomez MR (ed) Tuberous sclerosis, 2nd edn. Raven Press, New York,
pp 9±19
12. Atlas S (1996) Tuberous sclerosis. In:
Atlas S (ed) MRI of the brain and spine,
2nd edn. Lippincott-Raven, New York,
pp 786±790

13. Fryer AE, Chalmers A, Connor JN
(1987) Evidence that the gene for tuberous sclerosis is on chromosome 9.
Lancet 1: 659±661
14. Kandt RS, Haines JL, Smith M (1992)
Linkage of an important gene locus for
tuberous sclerosis to a chromosome
16 marker for polycystic kidney disease.
Nature Genet 2: 37±41
15. Lagos JC, Gomez MR (1967) Tuberous
sclerosis: reappraisal of a clinical entity.
Proc Mayo Clin 42: 26±49
16. Nathanson N, Avnet N (1966) An unusual X-ray finding in tuberous sclerosis. Br J Radiol 39: 786±787
17. Green GJ (1968) The radiology of tuberous sclerosis. Clin Radiol 19:
135±147
18. Whitaker PH (1959) Radiological manifestations in tuberous sclerosis. Br J
Radiol 32: 152±156
19. Komar IN, Gabrielsen TO, Holt JF
(1967) Roentgenographic appearance
of lumbosacral spine and pelvis in tuberous sclerosis. Radiology 89: 701±705
20. Brill CB, Peyster RG, Hoover ED
(1985) Giant intracranial aneurysm in a
child with tuberous sclerosis: CT demonstration. J Comput Assist Tomogr 9:
377±380
21. Sobata E, Okhuma H, Suzuki S (1988)
Cerebrovascular disorders associated
with non Recklinghausen's neurofibromatosis. Neurosurgery 22: 544±549
22. Lie JT (1991) Cardiac, pulmonary and
vascular involvements in tuberous sclerosis. In: Johnson WG, Gomez MR
(eds) Tuberous sclerosis and allied disorders: clinical, cellular and molecular
studies. New York Academy of Sciences, New York, pp 58±70
23. Rolfes DB, Towbin R, Bove KE (1985)
Vascular dysplasia in a child with tuberous sclerosis. Pediatr Pathol 3: 359±373
24. Libby PA, Maitem AN, Strauss EB
(1989) Axillary artery aneurysm in a
patient with tuberous sclerosis. Pediatr
Radiol 20: 94
25. Hagood CO, Garvin DD, Lachina FM,
et al (1976) Abdominal aortic aneurysm
and renal hamartoma in an infant with
tuberous sclerosis. Surgery 79: 713±715
26. Davidson S (1974) Tuberous sclerosis
with fusiform aneurysms of both internal carotid arteries manifested by unilateral visual loss and papilledema. Bull
LA Neurol Soc 39: 128±132

27. Guffman M, Tanen SM, Lambert CD
(1984) Visual loss secondary to a giant
aneurysm in a patient with tuberous
sclerosis. Can J Neurol Sci 11: 472±474
28. Beall S, Delaney P (1983) Tuberous
sclerosis with intracranial aneurysm.
Arch Neurol 40: 826±827
29. Blumenkopf B, Maj MC, Huggins MJ
(1985) Tuberous sclerosis and multiple
intracranial aneurysms: case report.
Neurosurgery 17: 797±800
30. Copley DJ (1985) Case of the season.
Semin Roentgenol 22: 107±109
31. Engel U (1992) Intracranial aneurysm
in concomitance with tuberous sclerosis. Zentralbl Pathol 138: 67±70
32. Marti Masso JF, Carrera N, Zabalza R
(1983) Anomalias vasculares en un caso
de escierosis tuberosa. Neurologia 1:
52±54
33. Spangler WJ, Cosgrove RG, Moumdjian RA, Montes JL (1997) Cerebral arterial ectasia and tuberous sclerosis:
case report. Neurosurgery 40: 191±193
34. Snowdon A (1974) Cerebral aneurysm,
renal cysts and hamartomas in a case of
tuberous sclerosis. Br J Urol 46: 583
35. Longa L, Scolari F, Brusco A, et al
(1997) A large TSC2 And PKD1 gene
deletion is associated with renal and
extrarenal signs of autosomal dominant
polycystic kidney disease. Nephrol Dial
Transplant 12: 1900±1907
36. Khang Loon H (1980) Intraventricular
aneurysm associated with tuberous
sclerosis. Arch Neurol 37: 385±386
37. Yasargil MG (1984) Microneurosurgery, vol I. Georg Thieme, Stuttgart,
p 292
38. Brook-Carter PT, Peral B, Ward CJ,
et al (1994) Deletion of the TSC2 and
PKD1 genes associated with severe infantile polycystic disease-a contiguous
gene syndrome. Nature Genet 8:
328±332
39. Sampson JR, Maheshwar MM, Aspinwall R, et al (1997) Renal cystic disease
in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J Hum
Genet 61: 843±851
40. Povey S, Burley MW, Attwood J, et al
(1994) Two loci for tuberous sclerosis:
one on gene 9q34 and one on 16p113.
Ann Hum Genet 58: 107±127