Volume 50, Issue 2 e12970
REVIEW

Cerebellar phenotypes in germline PTEN mutation carriers

Donatella Gambini

Donatella Gambini

Department of Neurorehabilitation Sciences, Casa di Cura Igea, Milan, Italy

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Stefano Ferrero

Stefano Ferrero

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

Pathology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

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Gaetano Bulfamante

Gaetano Bulfamante

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

Human Pathology and Molecular Pathology Unit, TOMA Advanced Biomedical Assays, Busto Arsizio, Italy

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Luigi Pisani

Luigi Pisani

Department of Neurorehabilitation Sciences, Casa di Cura Igea, Milan, Italy

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Massimo Corbo

Massimo Corbo

Department of Neurorehabilitation Sciences, Casa di Cura Igea, Milan, Italy

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Elisabetta Kuhn

Corresponding Author

Elisabetta Kuhn

Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy

Pathology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

Correspondence

Elisabetta Kuhn, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.

Email: [email protected]

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First published: 19 March 2024

Abstract

PTEN hamartoma tumour syndrome (PHTS) comprises different hereditary conditions caused by germline PTEN mutations, predisposing to the development of multiple hamartomas in many body tissues and also increasing the risk of some types of cancer.

Cerebellar involvement in PHTS patients has been long known due to the development of a pathognomonic cerebellar hamartoma (known as dysplastic gangliocytoma of the cerebellum or Lhermitte-Duclos disease). Recently, a crucial role of the cerebellum has been highlighted in the pathogenesis of autism spectrum disorders, now recognised as a phenotype expressed in a variable percentage of PHTS children. In addition, rare PTEN variants are indeed identified in medulloblastoma as well, even if they are less frequent than other germline gene mutations.

The importance of PTEN and its downstream signalling enzymatic pathways, PI3K/AKT/mTOR, has been studied at different levels in both human clinical settings and animal models, not only leading to a better understanding of the pathogenesis of different disorders but, most importantly, to identify potential targets for specific therapies. In particular, PTEN integrity makes an important contribution to the normal development of tissue architecture in the nervous system, including the cerebellum. Thus, in patients with PTEN germline mutations, the cerebellum is an affected organ that is increasingly recognised in different disorders, whereas, in animal models, cerebellar Pten loss causes a variety of functional and histological alterations.

In this review, we summarise the range of cerebellar involvement observed in PHTS and its relationships with germline PTEN mutations, along with the phenotypes expressed by murine models with PTEN deficiency in cerebellar tissue.

CONFLICT OF INTEREST STATEMENT

The authors declare no commercial or financial relationships that could be considered a conflict of interest.

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

The full text of this article hosted at iucr.org is unavailable due to technical difficulties.