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PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis

Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a “haploinsufficient” tumor-suppresso...

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Autores principales: Innella, Giovanni, Bonora, Elena, Neri, Iria, Virdi, Annalucia, Guglielmo, Alba, Pradella, Laura Maria, Ceccarelli, Claudio, Amato, Laura Benedetta, Lanzoni, Anna, Miccoli, Sara, Gasparre, Giuseppe, Zuntini, Roberta, Turchetti, Daniela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353102/
https://www.ncbi.nlm.nih.gov/pubmed/34386506
http://dx.doi.org/10.3389/fmed.2021.688105
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author Innella, Giovanni
Bonora, Elena
Neri, Iria
Virdi, Annalucia
Guglielmo, Alba
Pradella, Laura Maria
Ceccarelli, Claudio
Amato, Laura Benedetta
Lanzoni, Anna
Miccoli, Sara
Gasparre, Giuseppe
Zuntini, Roberta
Turchetti, Daniela
author_facet Innella, Giovanni
Bonora, Elena
Neri, Iria
Virdi, Annalucia
Guglielmo, Alba
Pradella, Laura Maria
Ceccarelli, Claudio
Amato, Laura Benedetta
Lanzoni, Anna
Miccoli, Sara
Gasparre, Giuseppe
Zuntini, Roberta
Turchetti, Daniela
author_sort Innella, Giovanni
collection PubMed
description Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a “haploinsufficient” tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.
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spelling pubmed-83531022021-08-11 PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis Innella, Giovanni Bonora, Elena Neri, Iria Virdi, Annalucia Guglielmo, Alba Pradella, Laura Maria Ceccarelli, Claudio Amato, Laura Benedetta Lanzoni, Anna Miccoli, Sara Gasparre, Giuseppe Zuntini, Roberta Turchetti, Daniela Front Med (Lausanne) Medicine Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a “haploinsufficient” tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding. Frontiers Media S.A. 2021-07-27 /pmc/articles/PMC8353102/ /pubmed/34386506 http://dx.doi.org/10.3389/fmed.2021.688105 Text en Copyright © 2021 Innella, Bonora, Neri, Virdi, Guglielmo, Pradella, Ceccarelli, Amato, Lanzoni, Miccoli, Gasparre, Zuntini and Turchetti. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Innella, Giovanni
Bonora, Elena
Neri, Iria
Virdi, Annalucia
Guglielmo, Alba
Pradella, Laura Maria
Ceccarelli, Claudio
Amato, Laura Benedetta
Lanzoni, Anna
Miccoli, Sara
Gasparre, Giuseppe
Zuntini, Roberta
Turchetti, Daniela
PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis
title PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis
title_full PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis
title_fullStr PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis
title_full_unstemmed PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis
title_short PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis
title_sort pten hamartoma tumor syndrome: skin manifestations and insights into their molecular pathogenesis
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353102/
https://www.ncbi.nlm.nih.gov/pubmed/34386506
http://dx.doi.org/10.3389/fmed.2021.688105
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