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Dysplasia and overgrowth: magnetic resonance imaging of pediatric brain abnormalities secondary to alterations in the mechanistic target of rapamycin pathway

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Abstract

The current classification of malformations of cortical development is based on the type of disrupted embryological process (cell proliferation, migration, or cortical organization/post-migrational development) and the resulting morphological anomalous pattern of findings. An ideal classification would include knowledge of biological pathways. It has recently been demonstrated that alterations affecting the mechanistic target of rapamycin (mTOR) signaling pathway result in diverse abnormalities such as dysplastic megalencephaly, hemimegalencephaly, ganglioglioma, dysplastic cerebellar gangliocytoma, focal cortical dysplasia type IIb, and brain lesions associated with tuberous sclerosis. We review the neuroimaging findings in brain abnormalities related to alterations in the mTOR pathway, following the emerging trend from morphology towards genetics in the classification of malformations of cortical development. This approach improves the understanding of anomalous brain development and allows precise diagnosis and potentially targeted therapies that may regulate mTOR pathway function.

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Abbreviations

ADC:

apparent diffusion coefficient

AKT3:

protein kinase B

COLD:

Cowden-Lhermitte-Duclos syndrome

DEPDC5:

DEP domain-containing protein 5

DGC:

dysplastic gangliocytoma of the cerebellum

DNET:

dysembryoplastic neuroepithelial tumor

FCD:

focal cortical dysplasia

GATOR1:

gap activity towards rags 1

HME:

hemimegalencephaly

MCAP:

megalencephaly-capillary malformation syndrome

MCD:

malformations of cortical development

MPPH:

megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

mTOR:

mechanistic (or mammalian) target of rapamycin

NF1:

neurofibromatosis type 1

NPRL2:

nitrogen permease regulator 2-like protein

NPRL3:

nitrogen permease regulator 3-like protein

PDK1:

phosphoinositide-dependent kinase 1

PI3K:

phosphatidylinositol-3-kinase

PTEN:

phosphatase and tensin homolog

SEGA:

dubependymal giant cell astrocytoma

SEN:

dubependymal nodules

SWI:

dusceptibility-weighted imaging

TSC:

tuberous sclerosis complex

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Acknowledgements

This article is dedicated to the memory of our dear colleague Dr. Andrea Poretti (1977–2017).

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Authors and Affiliations

  1. Division of Pediatric Radiology and Pediatric Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 1800 Orleans Street, Zayed 4174, Baltimore, MD, 21287, USA

    Shai Shrot, Misun Hwang, Thierry A. G. M. Huisman & Bruno P. Soares

  2. Department of Diagnostic Imaging, Sheba Medical Center, 52621, Ramat-Gan, Israel

    Shai Shrot

  3. Division of Pediatric Neurology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Carl E. Stafstrom

Authors
  1. Shai Shrot
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  2. Misun Hwang
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  3. Carl E. Stafstrom
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  4. Thierry A. G. M. Huisman
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  5. Bruno P. Soares
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Corresponding author

Correspondence to Bruno P. Soares.

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Funding

No funding was received for this study. SS is a recipient of a fellowship grant from The American Physician Fellowship for Medicine in Israel.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was not required from individual participants included in the study, since imaging exams were performed according to clinical indications.

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Key Points

• The mTOR signaling pathway functions as a controller of cell growth and homeostasis.

• Neurodevelopmental and neoplastic disorders including dysplastic megalencephaly, ganglioglioma, focal cortical dysplasia type IIb, brain lesions associated with tuberous sclerosis, and dysplastic gangliocytoma of the cerebellum result from mutations affecting the mTOR signaling pathways.

• There are common imaging findings in various disorders related to dysmorphic excessive neurons in hamartomatous CNS malformations.

• morphological-based classification of brain abnormalities is changing to a genetic/metabolic-based grouping, which improves our understanding of brain development and might allow targeted treatments to be developed.

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Shrot, S., Hwang, M., Stafstrom, C.E. et al. Dysplasia and overgrowth: magnetic resonance imaging of pediatric brain abnormalities secondary to alterations in the mechanistic target of rapamycin pathway. Neuroradiology 60, 137–150 (2018). https://doi.org/10.1007/s00234-017-1961-5

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  • DOI: https://doi.org/10.1007/s00234-017-1961-5

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