ARTICLE IN PRESS

Case Studies

Multiple Intracranial Arteriovenous Fistulas in
Cowden Syndrome
Luis A. Prats-Sánchez, MD, Jose V. Hervás-García, MD, Juan L. Becerra, MD,
Manuel Lozano, MD, Carlos Castaño, MD, Josep Munuera, MD, PhD,
Domingo Escudero, MD, PhD, and Carlos García-Esperón, MD

Cowden syndrome is a rare autosomal dominant disease. It is characterized by
multiple noncancerous tumorlike growths called hamartomas, which typically are
found in the skin, oral mucosa, thyroid, breast, and gastrointestinal tract. It carries
with it a potential risk of malignant transformation, especially of the breast and
thyroid. In 80% of the cases, the human tumor suppressor gene, phosphatase and
tensin homolog (PTEN), is mutated in the germ line. We report a patient with
Cowden syndrome who presented with generalized seizure and left anterior temporal hemorrhage and a nontraumatic subarachnoid hemorrhage due to multiple
intracranial arteriovenous fistulas (AVFs). We discuss previous reports about vascular malformations in patients with Cowden syndrome and PTEN mutations.
Importantly, we hypothesize that the production of multiple AVFs in our patient
was associated with PTEN mutation. Key Words: Cowden syndrome—PTEN—brain
hemorrhage—arteriovenous fistula.
© 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Case Report
A 46-year-old man was admitted to our emergency unit
with a generalized seizure. The patient had a history of
headaches and tinnitus and was diagnosed previously with
Cowden syndrome (CS) 12 years before admission. The
polymerase chain reaction–single-strand conformation polymorphism DNA sequencing confirmed that a mutation
had occurred in the phosphatase and tensin homolog
(PTEN) gene. The physical examination revealed known
clinical features of CS,1 such as the presence of macroFrom the Department of Neurology, Hospital Universitari Germans
Trias i Pujol, Badalona, Spain.
Received February 19, 2015; revision received March 20, 2016;
accepted March 27, 2016.
Address correspondence to Luis Antonio Prats-Sánchez, MD,
Hospital Universitari Germans Trias i Pujol, Carretera de Canyet S/N
08916, Badalona, Spain. E-mail: drprats@hotmail.com.
1052-3057/$ - see front matter
© 2016 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.03.048

cephaly, papillomatous lesions in the oral mucosa, and
acral keratosis. A cranial tomography showed an acute
left anterior temporal hemorrhage associated with a left
parasagittal subarachnoid hemorrhage. The magnetic resonance imaging and then the arteriography revealed
multiple dural and epidural high-flow arteriovenous fistulas (AVFs), predominantly in the right hemisphere. These
fistulas received blood flow mostly from all the extraand intracranial arteries (please see Fig 1). The causes
of secondary intracranial AVFs, such as cerebral vein thrombosis or prothrombotic conditions, were ruled out. The
patient had no history of head trauma or neurosurgical
procedures. He was treated with 5 sessions of selective
embolization. Few months later, the patient developed
a refractory epilepsy and a rapidly progressive dementia. He died because of severe status epilepticus.

Discussion
CS (OMIM#158350) 2 or multiple hamartoma syndrome is a rare disease characterized by multiple

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2016: pp ■■–■■

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L.A. PRATS-SÁNCHEZ ET AL.

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Figure 1. DSA: internal and external carotid evaluation showed multiples fistulas. Axial views of magnetic resonance imaging, venous TOF,
SWI, and T1-Gd confirmed the massive dilatation of cerebral veins, in relation to the fistulas. Abbreviations: DSA, digital subtraction angiography;
SWI, susceptibility-weighted image; T1-Gd, T1 after gadolinium; TOF, time
of flight.

hamartomatous lesions, especially of the skin, mucous
membranes, brain, breast, thyroid, and colon. In some
tissues, the hamartomas are associated with an increased risk of malignancy.1,2 Verrucous skin lesions of
the face and limbs, cobblestone-like papules of the gingiva
and buccal mucosa, and multiple facial trichilemmomas
are leading findings,1 and also hamartomatous polyps of
the colon and other regions. Approximately 80% of CS
patients are caused by a mutation in the PTEN gene.2
PTEN is a germline tumor suppressor gene that regulates cell division, angiogenesis, and proliferation. 3
Mutations in the PTEN gene have been associated also
with Bannayan–Riley–Ruvalcaba syndrome (BRRS),
Lhermitte–Duclos syndrome, and Proteus/Proteus-like
syndrome.2 CS and BRRS share some clinical characteristics and Marsh et al4 suggested that the spectrum of
disorders be referred to as “PTEN hamartoma tumor
syndrome.”
Vascular malformations in CS are not well known5;
however, they are common in PTEN hamartoma tumor
syndromes.4 Tan et al6 identified vascular anomalies in
14 out of 26 pediatric patients with BRRS or CS and described anomalies in venous development in 8 of 9 patients
in whom a brain magnetic resonance imaging was performed. Lok et al7 found vascular abnormalities in 6 (30%)
of 20 patients with CS; 5 cases of venous angioma and
2 cavernous angiomas (1 associated with venous angioma).
Nevertheless, multiple intracranial fistulas in patients with
PTEN mutations have been described only in a pediatric patient with BRRS.6 We reviewed MEDLINE, Orphanet,

and OMIM databases, but we did not find cases of multiple AVFs in an adult with CS.
Most authors suggest that the high prevalence of vascular malformations in patients with CS is due to the loss
of the regulatory angiogenic function of the PTEN gene.8
This gene codes for a protein with antiangiogenic properties, which is expressed in the vascular smooth muscle,
and regulates the formation of new vessels by suppressing vascular endothelial growth factor expression.5 Cerebral
AVF may be associated with the breakdown of autoregulation of the dural microvascularization and the
activation of the angiogenetic factor.9 In our patient, known
causes of cerebral AVF9 were ruled out and we cannot
give any clear explanation. We hypothesized that finding
multiple intracranial AVF in this patient is likely to be
associated with the loss of the angiogenic function of the
PTEN gene.
In conclusion, our patient provided evidence that CS
may be associated with the development of intracranial
vascular malformations. The main mechanism is related
likely with the loss of the angiogenic regulatory function of the PTEN gene. More studies are needed to confirm
the possible relationship between intracranial vascular malformations and the PTEN mutation.
Acknowledgment: We would like to express gratitude to
the patient and the rest of the patient’s family.

References
1. Pilarski R. Cowden syndrome: a critical review of the
clinical literature. J Genet Couns 2009;18:13-27.
2. Online Mendelian Inheritance in Man, OMIM®. Johns
Hopkins University, Baltimore, MD. MIM Number:
{158350}: {03/14/2016}: World Wide Web URL:http://
omim.org/.
3. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the
PTEN gene in Cowden disease, an inherited breast and
thyroid cancer syndrome. Nat Genet 1997;16:64-67.
4. Marsh DJ, Kum JB, Lunetta KL, et al. PTEN mutation
spectrum and genotype-phenotype correlations in
Bannayan-Riley-Ruvalcaba syndrome suggest a single entity
with Cowden syndrome. Hum Mol Genet 1999;8:1461-1472.
5. Turnbull MM, Humeniuk V, Stein B, et al. Arteriovenous
malformations in Cowden syndrome. J Med Genet
2005;42:e50.
6. Tan WH, Baris H, Burrows P, et al. The spectrum of
vascular anomalies in patients with PTEN mutations:
implications for diagnosis and management. J Med Genet
2007;44:594-602.
7. Lok C, Viseux V, Avril MF, et al. Brain magnetic resonance
imaging in patients with Cowden syndrome. Medicine
2005;84:129-136.
8. Farooq A, Walker LJ, Bowling J, et al. Cowden syndrome,
tumour review. Cancer Treat Rev 2010;36:577-583.
9. Ha SY, Kwon YS, Kim BM, et al. Clinical and angiographic
characteristics of multiple dural arteriovenous shunts. AJNR
Am J Neuroradiol 2012;33:1691-1695.