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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical ImagingAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- PTEN: one gene, many syndromes.Hum Mutat. 2003; 22: 183-198
- Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria.J Natl Cancer Inst. 2013; 105: 1607-1616
- Novel PTEN mutations in patients with Cowden disease: absence of clear genotype-phenotype correlations.Eur J Hum Genet. 1999; 7: 267-273
- Lifetime cancer risks in individuals with germline PTEN mutations.Clin Cancer Res. 2012; 18: 400-407
- Will the real Cowden syndrome please stand up: revised diagnostic criteria.J Med Genet. 2000; 37: 828-830
- Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease.Hum Mol Genet. 1997; 6: 1383-1387
- WHO classification of tumours of the central nervous system. Revised 4th edition ed.International Agency for Research on Cancer Press, Lyon, France2016
- 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
- Updated imaging features of dysplastic cerebellar gangliocytoma.J Comput Assist Tomogr. 2019; 43: 277-281
- 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
- MRI in Lhermitte-Duclos disease.Neurology. 1997; 48: 725-731
- Lhermitte-Duclos disease: clinical study with long-term follow-up in a single institution.Clin Neurol Neurosurg. 2017; 162: 53-58
- Magnetic resonance characteristics of adult-onset Lhermitte-Duclos disease: an indicator for active cancer surveillance?.Mol Clin Oncol. 2014; 2: 415-420
- The striated cerebellum: an MR imaging sign in Lhermitte-Duclos disease (dysplastic gangliocytoma).Radiology. 1995; 194: 699-703
- Atypical MR appearance of Lhermitte-Duclos disease with contrast enhancement.AJNR Am J Neuroradiol. 1995; 16: 1719-1720
- Lhermitte-Duclos disease.J Neurooncol. 2007; 82: 183-185
- Hypervascularity in Lhermitte-Duclos disease—case report.Neurol Med Chir (Tokyo). 1997; 37: 403-406
- Vascular contrast enhancement in Lhermitte-Duclos disease: case report.Neuroradiology. 1995; 37: 545-548
- Contrast enhancement in Lhermitte-Duclos disease of the cerebellum: correlation of imaging with neuropathology in two cases.Neuroradiology. 2003; 45: 381-385
- Recurrent Lhermitte-Duclos disease: report of two cases and association with Cowden’s disease.AJNR Am J Neuroradiol. 1992; 13: 287-290
- Assessing a dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease) with 7T MR imaging.Korean J Radiol. 2010; 11: 244-248
- 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
- Brain PET and technetium-99m-ECD SPECT imaging in Lhermitte-Duclos disease.Neuroradiology. 2001; 43: 993-996
- Advanced MR imaging in Lhermitte-Duclos disease: moving closer to pathology and pathophysiology.Neuroradiology. 2007; 49: 733-738
- Recurrent Lhermitte-Duclos disease in a child. Case report.J Neurosurg. 1988; 69: 599-603
- Lhermitte-Duclos disease associated with syringomyelia.Neuroradiology. 1996; 38: 529-531
- 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
- Lhermitte-Duclos disease presenting with hydrocephalus.Acta Neurochir Suppl. 2012; 113: 161-165
- An atypical patient with Cowden syndrome and PTEN gene mutation presenting with cortical malformation and focal epilepsy.Brain Dev. 2012; 34: 873-876
- Lhermitte-Duclos disease and giant meningioma as manifestations of Cowden’s disease.Clin Neuropathol. 1995; 14: 327-330
- Magnetic resonance imaging in the diagnosis and treatment of Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum).Neurosurgery. 1988; 23: 240-245
- Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) and its relation to the multiple hamartoma syndrome (Cowden disease).J Neurooncol. 1994; 18: 191-197
- Zimmerman RA. MR imaging of Lhermitte-Duclos disease: a case report.AJNR Am J Neuroradiol. 1989; 10: 187-189
- Lhermitte-Duclos disease: a critical appraisal of different radiologic methods.Eur J Radiol. 1994; 19: 21-24
- Preoperative MRI diagnosis of Lhermitte-Duclos disease: case report with associated enlarged vessel and syrinx.Surg Neurol. 1996; 45 ([discussion 5–6]): 470-475
- Lhermitte-Duclos disease in 3 children: a clinical long-term observation.Neuropediatrics. 2003; 34: 30-35
- Association between meningioma and Cowden’s disease.Neurology. 1993; 43: 1436-1437
- Hidden association of Cowden syndrome, PTEN mutation and meningioma frequency.Oncoscience. 2016; 3: 149-155
- Descriptive epidemiology of 13,038 newly diagnosed and histologically confirmed meningiomas in France: 2006–2010.Neurochirurgie. 2018; 64: 15-21
- Neuroimaging abnormalities in patients with Cowden syndrome: retrospective single-center study.Neurol Clin Pract. 2018; 8: 207-213
- The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis.Genes Dev. 2005; 19: 2054-2065
- The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management.J Med Genet. 2007; 44: 594-602
- Brain magnetic resonance imaging in patients with Cowden syndrome.Medicine (Baltimore). 2005; 84: 129-136
- Cancer risk and genotype-phenotype correlations in PTEN hamartoma tumor syndrome.Fam Cancer. 2014; 13: 57-63
- 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
- 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
- multiple intracranial arteriovenous fistulas in cowden syndrome.J Stroke Cerebrovasc Dis. 2016; 25: e93-e94
- Cowden’s disease: analysis of fourteen new cases.J Am Acad Dermatol. 1984; 11: 1127-1141
- 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
- Congestive myeloradiculopathy in a patient with Cowden syndrome.J Clin Neurosci. 2015; 22: 431-433
- 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
- Megalencephaly and hemimegalencephaly: breakthroughs in molecular etiology.Am J Med Genet C Semin Med Genet. 2014; 166C: 156-172
- Cowden syndrome with a novel PTEN mutation presenting with partial epilepsy related to focal cortical dysplasia.Intern Med. 2018; 57: 97-99
- Clinical presentation of PTEN mutations in childhood in the absence of family history of Cowden syndrome.Eur J Paediatr Neurol. 2015; 19: 188-192
- PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia.Brain. 2015; 138: 1613-1628
- PTEN hamartoma tumour syndrome: variability of an entity.J Med Genet. 2003; 40: e111
- Chiari I malformation in a child with PTEN hamartoma tumor syndrome: association or coincidence?.Eur J Med Genet. 2017; 60: 261-264
- Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.Am J Med Genet A. 2014; 164A: 627-633
- 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
- 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
- Bannayan-Riley-Ruvalcaba syndrome: MRI neuroimaging features in a series of 7 patients.AJNR Am J Neuroradiol. 2014; 35: 402-406
- Assessment of PTEN-associated vascular malformations in a patient with Bannayan-Riley-Ruvalcaba syndrome.BMJ Case Rep. 2016; 2016
- Recurrent and extensive vascular malformations in a patient with Bannayan–Riley–Ruvalcaba syndrome.Ann Vasc Surg. 2011; 25 ([e15-9]): 1138
- Arteriovenous malformation in a patient with Bannayan–Zonana syndrome.Clin Imaging. 2001; 25: 130-132
- Complex dural arteriovenous fistula in Bannayan-Riley-Ruvalcaba syndrome.J Neurosurg Pediatr. 2013; 12: 87-92
- Dural arteriovenous malformation in a child with Bannayan-Riley-Ruvalcaba syndrome.AJNR Am J Neuroradiol. 2006; 27: 1927-1929
- Cortical dysplasia associated with the PTEN mutation in Bannayan Riley Ruvalcaba syndrome: a rare finding.Clin Dysmorphol. 2012; 21: 91-92
- Bannayan-Riley-Ruvalcaba syndrome with progressive spinal epidural lipomatosis.Neuropediatrics. 2012; 43: 221-224
- 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
- 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
- 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
Article info
Publication history
Published online: December 24, 2019
Accepted:
December 9,
2019
Received in revised form:
November 4,
2019
Received:
July 28,
2019
Identification
Copyright
© 2019 Elsevier Inc. All rights reserved.
