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Imaging of PTEN-related abnormalities in the central nervous system

Published:December 24, 2019DOI:https://doi.org/10.1016/j.clinimag.2019.12.006

      Highlights

      • Mutation in the PTEN gene leads to aberrant growth and angiogenesis, and an increased risk for a variety of tumors.
      • Multiple clinical phenotypes are associated with germline PTEN mutation, collectively termed PTEN hamartoma tumor syndrome.
      • Recognizing neuroimaging features associated with PTEN mutations is key to avoid misdiagnosis and guide genetic testing.

      Abstract

      The phosphatase and tensin homolog (PTEN) located at 10q23.31 is a tumor suppressor gene expressed ubiquitously, and loss of function mutations lead to aberrant growth, angiogenesis, and an increased risk for a variety of tumors. PTEN mutations have been associated with multiple abnormalities in the central nervous system, and a number of clinical phenotypes are now attributed to germline PTEN mutations, collectively referred to as PTEN hamartoma tumor syndrome (PHTS). Most notably, these include Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), and autism spectrum disorders with macrocephaly. It is important to recognize the neuroimaging features associated with PTEN mutations to not only avoid misdiagnosis in cases of known PHTS but also to guide genetic testing in patients who do not yet have an established diagnosis. In this review, the central nervous system imaging features of PTEN-related disorders are discussed.

      Abbreviations:

      BRRS (Bannayan-Riley-Ruvalcaba syndrome), CT (computed tomography), CS (Cowden syndrome), LDD (Lhermitte-Duclos disease), MRI (magnetic resonance imaging), PTEN (phosphatase and tensin homolog), PHTS (PTEN hamartoma tumor syndrome)

      Keywords

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      References

        • Eng C
        PTEN: one gene, many syndromes.
        Hum Mutat. 2003; 22: 183-198
        • Pilarski R
        • Burt R
        • Kohlman W
        • Pho L
        • Shannon KM
        • Swisher E
        Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.
        J Natl Cancer Inst. 2013; 105: 1607-1616
        • Nelen MR
        • Kremer H
        • Konings IB
        • Schoute F
        • van Essen AJ
        • Koch R
        • et al.
        Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations.
        Eur J Hum Genet. 1999; 7: 267-273
        • Tan MH
        • Mester JL
        • Ngeow J
        • Rybicki LA
        • Orloff MS
        • Eng C
        Lifetime cancer risks in individuals with germline PTEN mutations.
        Clin Cancer Res. 2012; 18: 400-407
        • Eng C
        Will the real Cowden syndrome please stand up: revised diagnostic criteria.
        J Med Genet. 2000; 37: 828-830
        • Nelen MR
        • van Staveren WC
        • Peeters EA
        • Hassel MB
        • Gorlin RJ
        • Hamm H
        • et al.
        Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.
        Hum Mol Genet. 1997; 6: 1383-1387
        • Louis DN
        • Ohgaki H
        • Wiestler OD
        • Cavenee WK
        WHO classification of tumours of the central nervous system. Revised 4th edition ed.
        International Agency for Research on Cancer Press, Lyon, France2016
        • Abel TW
        • Baker SJ
        • Fraser MM
        • Tihan T
        • Nelson JS
        • Yachnis AT
        • et al.
        Lhermitte-Duclos disease: a report of 31 cases with immunohistochemical analysis of the PTEN/AKT/mTOR pathway.
        J Neuropathol Exp Neurol. 2005; 64: 341-349
        • Dhamija R
        • Wood CP
        • Porter AB
        • Hu LS
        • Weindling SM
        • Hoxworth JM
        Updated imaging features of dysplastic cerebellar gangliocytoma.
        J Comput Assist Tomogr. 2019; 43: 277-281
        • Jiang T
        • Wang J
        • Du J
        • Luo S
        • Liu R
        • Xie J
        • et al.
        Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) and Cowden syndrome: clinical experience from a single institution with long-term follow-up.
        World Neurosurg. 2017; 104: 398-406
        • Kulkantrakorn K
        • Awwad EE
        • Levy B
        • Selhorst JB
        • Cole HO
        • Leake D
        • et al.
        MRI in Lhermitte-Duclos disease.
        Neurology. 1997; 48: 725-731
        • Wang Q
        • Zhang S
        • Cheng J
        • Liu W
        • Hui X
        Lhermitte-Duclos disease: clinical study with long-term follow-up in a single institution.
        Clin Neurol Neurosurg. 2017; 162: 53-58
        • Wei G
        • Zhang W
        • Li Q
        • Kang X
        • Zhao H
        • Liu X
        • et al.
        Magnetic resonance characteristics of adult-onset Lhermitte-Duclos disease: an indicator for active cancer surveillance?.
        Mol Clin Oncol. 2014; 2: 415-420
        • Meltzer CC
        • Smirniotopoulos JG
        • Jones RV
        The striated cerebellum: an MR imaging sign in Lhermitte-Duclos disease (dysplastic gangliocytoma).
        Radiology. 1995; 194: 699-703
        • Awwad EE
        • Levy E
        • Martin DS
        • Merenda GO
        Atypical MR appearance of Lhermitte-Duclos disease with contrast enhancement.
        AJNR Am J Neuroradiol. 1995; 16: 1719-1720
        • Chiofalo MG
        • Cappabianca P
        • Del Basso De Caro ML
        • Pezzullo L
        Lhermitte-Duclos disease.
        J Neurooncol. 2007; 82: 183-185
        • Ishizaki K
        • Daita G
        • Yonemasu Y
        • Kunimoto M
        • Miyokawa N
        Hypervascularity in Lhermitte-Duclos disease—case report.
        Neurol Med Chir (Tokyo). 1997; 37: 403-406
        • Ortiz O
        • Bloomfield S
        • Schochet S
        Vascular contrast enhancement in Lhermitte-Duclos disease: case report.
        Neuroradiology. 1995; 37: 545-548
        • Spaargaren L
        • Cras P
        • Bomhof MA
        • Lie ST
        • de Barsy AM
        • Croese PH
        • et al.
        Contrast enhancement in Lhermitte-Duclos disease of the cerebellum: correlation of imaging with neuropathology in two cases.
        Neuroradiology. 2003; 45: 381-385
        • Williams 3rd, DW
        • Elster AD
        • Ginsberg LE
        • Stanton C
        Recurrent Lhermitte-Duclos disease: report of two cases and association with Cowden’s disease.
        AJNR Am J Neuroradiol. 1992; 13: 287-290
        • Moenninghoff C
        • Kraff O
        • Schlamann M
        • Ladd ME
        • Katsarava Z
        • Gizewski ER
        Assessing a dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) with 7T MR imaging.
        Korean J Radiol. 2010; 11: 244-248
        • Klisch J
        • Juengling F
        • Spreer J
        • Koch D
        • Thiel T
        • Buchert M
        • et al.
        Lhermitte-Duclos disease: assessment with MR imaging, positron emission tomography, single-photon emission CT, and MR spectroscopy.
        AJNR Am J Neuroradiol. 2001; 22: 824-830
        • Ogasawara K
        • Yasuda S
        • Beppu T
        • Kobayashi M
        • Doi M
        • Kuroda K
        • et al.
        Brain PET and technetium-99m-ECD SPECT imaging in Lhermitte-Duclos disease.
        Neuroradiology. 2001; 43: 993-996
        • Thomas B
        • Krishnamoorthy T
        • Radhakrishnan VV
        • Kesavadas C
        Advanced MR imaging in Lhermitte-Duclos disease: moving closer to pathology and pathophysiology.
        Neuroradiology. 2007; 49: 733-738
        • Marano SR
        • Johnson PC
        • Spetzler RF
        Recurrent Lhermitte-Duclos disease in a child. Case report.
        J Neurosurg. 1988; 69: 599-603
        • Marcus CD
        • Galeon M
        • Peruzzi P
        • Bazin A
        • Bernard MH
        • Pluot M
        • et al.
        Lhermitte-Duclos disease associated with syringomyelia.
        Neuroradiology. 1996; 38: 529-531
        • Milbouw G
        • Born JD
        • Martin D
        • Collignon J
        • Hans P
        • Reznik M
        • et al.
        Clinical and radiological aspects of dysplastic gangliocytoma (Lhermitte-Duclos disease): a report of two cases with review of the literature.
        Neurosurgery. 1988; 22: 124-128
        • Yang MS
        • Kim CH
        • Cheong JH
        • Kim JM
        Lhermitte-Duclos disease presenting with hydrocephalus.
        Acta Neurochir Suppl. 2012; 113: 161-165
        • Elia M
        • Amato C
        • Bottitta M
        • Grillo L
        • Calabrese G
        • Esposito M
        • et al.
        An atypical patient with Cowden syndrome and PTEN gene mutation presenting with cortical malformation and focal epilepsy.
        Brain Dev. 2012; 34: 873-876
        • Lindboe CF
        • Helseth E
        • Myhr G
        Lhermitte-Duclos disease and giant meningioma as manifestations of Cowden’s disease.
        Clin Neuropathol. 1995; 14: 327-330
        • Reeder RF
        • Saunders RL
        • Roberts DW
        • Fratkin JD
        • Cromwell LD
        Magnetic resonance imaging in the diagnosis and treatment of Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum).
        Neurosurgery. 1988; 23: 240-245
        • Rimbau J
        • Isamat F
        Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) and its relation to the multiple hamartoma syndrome (Cowden disease).
        J Neurooncol. 1994; 18: 191-197
        • Smith RR
        • Grossman RI
        • Goldberg HI
        • Hackney DB
        • Bilaniuk LT
        Zimmerman RA. MR imaging of Lhermitte-Duclos disease: a case report.
        AJNR Am J Neuroradiol. 1989; 10: 187-189
        • Verheggen R
        • Bruhn H
        • Schroder BU
        • Frahm J
        • Markakis E
        Lhermitte-Duclos disease: a critical appraisal of different radiologic methods.
        Eur J Radiol. 1994; 19: 21-24
        • Wolansky LJ
        • Malantic GP
        • Heary R
        • Maniker AH
        • Lee HJ
        • Sharer LR
        • et al.
        Preoperative MRI diagnosis of Lhermitte-Duclos disease: case report with associated enlarged vessel and syrinx.
        Surg Neurol. 1996; 45 ([discussion 5–6]): 470-475
        • Capone Mori A
        • Hoeltzenbein M
        • Poetsch M
        • Schneider JF
        • Brandner S
        • Boltshauser E
        Lhermitte-Duclos disease in 3 children: a clinical long-term observation.
        Neuropediatrics. 2003; 34: 30-35
        • Lyons CJ
        • Wilson CB
        • Horton JC
        Association between meningioma and Cowden’s disease.
        Neurology. 1993; 43: 1436-1437
        • Yakubov E
        • Ghoochani A
        • Buslei R
        • Buchfelder M
        • Eyupoglu IY
        • Savaskan N
        Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency.
        Oncoscience. 2016; 3: 149-155
        • Zouaoui S
        • Darlix A
        • Rigau V
        • Mathieu-Daude H
        • Bauchet F
        • Bessaoud F
        • et al.
        Descriptive epidemiology of 13,038 newly diagnosed and histologically confirmed meningiomas in France: 2006–2010.
        Neurochirurgie. 2018; 64: 15-21
        • Dhamija R
        • Weindling SM
        • Porter AB
        • Hu LS
        • Wood CP
        • Hoxworth JM
        Neuroimaging abnormalities in patients with Cowden syndrome: retrospective single-center study.
        Neurol Clin Pract. 2018; 8: 207-213
        • Hamada K
        • Sasaki T
        • Koni PA
        • Natsui M
        • Kishimoto H
        • Sasaki J
        • et al.
        The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.
        Genes Dev. 2005; 19: 2054-2065
        • Tan WH
        • Baris HN
        • Burrows PE
        • Robson CD
        • Alomari AI
        • Mulliken JB
        • et al.
        The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management.
        J Med Genet. 2007; 44: 594-602
        • Lok C
        • Viseux V
        • Avril MF
        • Richard MA
        • Gondry-Jouet C
        • Deramond H
        • et al.
        Brain magnetic resonance imaging in patients with Cowden syndrome.
        Medicine (Baltimore). 2005; 84: 129-136
        • Nieuwenhuis MH
        • Kets CM
        • Murphy-Ryan M
        • Yntema HG
        • Evans DG
        • Colas C
        • et al.
        Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome.
        Fam Cancer. 2014; 13: 57-63
        • Hon JM
        • Bhattacharya JJ
        • Counsell CE
        • Papanastassiou V
        • Ritchie V
        • Roberts RC
        • et al.
        The presentation and clinical course of intracranial developmental venous anomalies in adults: a systematic review and prospective, population-based study.
        Stroke. 2009; 40: 1980-1985
        • Barreras P
        • Gailloud P
        • Pardo CA
        A longitudinally extensive myelopathy associated with multiple spinal arteriovenous fistulas in a patient with Cowden syndrome: a case report.
        Spine J. 2018; 18: e1-e5
        • Prats-Sanchez LA
        • Hervas-Garcia JV
        • Becerra JL
        • Lozano M
        • Castano C
        • Munuera J
        • et al.
        multiple intracranial arteriovenous fistulas in cowden syndrome.
        J Stroke Cerebrovasc Dis. 2016; 25: e93-e94
        • Starink TM
        Cowden’s disease: analysis of fourteen new cases.
        J Am Acad Dermatol. 1984; 11: 1127-1141
        • Takei J
        • Tochigi S
        • Arai M
        • Tanaka T
        • Kajiwara I
        • Hatano K
        • et al.
        Spinal extradural arteriovenous fistula with Cowden syndrome: a case report and literature review regarding pathogenesis and therapeutic strategy.
        NMC Case Rep J. 2018; 5: 83-85
        • Wu TY
        • Willoughby E
        • Hutchinson DO
        • Brew S
        • McGuinness B
        • Lopes R
        • et al.
        Congestive myeloradiculopathy in a patient with Cowden syndrome.
        J Clin Neurosci. 2015; 22: 431-433
        • Mirzaa GM
        • Riviere JB
        • Dobyns WB
        Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP.
        Am J Med Genet C Semin Med Genet. 2013; 163C: 122-130
        • Mirzaa GM
        • Poduri A
        Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology.
        Am J Med Genet C Semin Med Genet. 2014; 166C: 156-172
        • Adachi T
        • Takigawa H
        • Nomura T
        • Watanabe Y
        • Kowa H
        Cowden syndrome with a novel PTEN mutation presenting with partial epilepsy related to focal cortical dysplasia.
        Intern Med. 2018; 57: 97-99
        • Busa T
        • Milh M
        • Degardin N
        • Girard N
        • Sigaudy S
        • Longy M
        • et al.
        Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome.
        Eur J Paediatr Neurol. 2015; 19: 188-192
        • Jansen LA
        • Mirzaa GM
        • Ishak GE
        • O’Roak BJ
        • Hiatt JB
        • Roden WH
        • et al.
        PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia.
        Brain. 2015; 138: 1613-1628
        • Merks JH
        • de Vries LS
        • Zhou XP
        • Nikkels P
        • Barth PG
        • Eng C
        • et al.
        PTEN hamartoma tumour syndrome: variability of an entity.
        J Med Genet. 2003; 40: e111
        • Saletti V
        • Esposito S
        • Maccaro A
        • Giglio S
        • Valentini LG
        • Chiapparini L
        Chiari I malformation in a child with PTEN hamartoma tumor syndrome: association or coincidence?.
        Eur J Med Genet. 2017; 60: 261-264
        • Vanderver A
        • Tonduti D
        • Kahn I
        • Schmidt J
        • Medne L
        • Vento J
        • et al.
        Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.
        Am J Med Genet A. 2014; 164A: 627-633
        • Marsh DJ
        • Coulon V
        • Lunetta KL
        • Rocca-Serra P
        • Dahia PL
        • Zheng Z
        • et al.
        Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.
        Hum Mol Genet. 1998; 7: 507-515
        • Lachlan KL
        • Lucassen AM
        • Bunyan D
        • Temple IK
        Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: results of a clinical study of PTEN mutation carriers.
        J Med Genet. 2007; 44: 579-585
        • Bhargava R
        • Yong KJ A
        • Leonard N
        Bannayan-Riley-Ruvalcaba syndrome: MRI neuroimaging features in a series of 7 patients.
        AJNR Am J Neuroradiol. 2014; 35: 402-406
        • Anusic S
        • Clemens RK
        • Meier TO
        • Amann-Vesti BR
        Assessment of PTEN-associated vascular malformations in a patient with Bannayan-Riley-Ruvalcaba syndrome.
        BMJ Case Rep. 2016; 2016
        • Litzendorf M
        • Hoang K
        • Vaccaro P
        Recurrent and extensive vascular malformations in a patient with Bannayan–Riley–Ruvalcaba syndrome.
        Ann Vasc Surg. 2011; 25 ([e15-9]): 1138
        • Naidich JJ
        • Rofsky NM
        • Rosen R
        • Karp N
        Arteriovenous malformation in a patient with Bannayan–Zonana syndrome.
        Clin Imaging. 2001; 25: 130-132
        • Moon K
        • Ducruet AF
        • Crowley RW
        • Klas K
        • Bristol R
        • Albuquerque FC
        Complex dural arteriovenous fistula in Bannayan-Riley-Ruvalcaba syndrome.
        J Neurosurg Pediatr. 2013; 12: 87-92
        • Srinivasa RN
        • Burrows PE
        Dural arteriovenous malformation in a child with Bannayan-Riley-Ruvalcaba syndrome.
        AJNR Am J Neuroradiol. 2006; 27: 1927-1929
        • O’Rourke DJ
        • Twomey E
        • Lynch SA
        • King MD
        Cortical dysplasia associated with the PTEN mutation in Bannayan Riley Ruvalcaba syndrome: a rare finding.
        Clin Dysmorphol. 2012; 21: 91-92
        • Toelle S
        • Poretti A
        • Scheer I
        • Huisman T
        • Boltshauser E
        Bannayan-Riley-Ruvalcaba syndrome with progressive spinal epidural lipomatosis.
        Neuropediatrics. 2012; 43: 221-224
        • Zhou XP
        • Marsh DJ
        • Morrison CD
        • Chaudhury AR
        • Maxwell M
        • Reifenberger G
        • et al.
        Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte-Duclos disease in adults.
        Am J Hum Genet. 2003; 73: 1191-1198
        • Butler MG
        • Dasouki MJ
        • Zhou XP
        • Talebizadeh Z
        • Brown M
        • Takahashi TN
        • et al.
        Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.
        J Med Genet. 2005; 42: 318-321
        • Buxbaum JD
        • Cai G
        • Chaste P
        • Nygren G
        • Goldsmith J
        • Reichert J
        • et al.
        Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.
        Am J Med Genet B Neuropsychiatr Genet. 2007; 144B: 484-491