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Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities
PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHOD...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354853/ https://www.ncbi.nlm.nih.gov/pubmed/33833411 http://dx.doi.org/10.1038/s41436-021-01161-6 |
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author | Carmignac, Virginie Mignot, Cyril Blanchard, Emmanuelle Kuentz, Paul Aubriot-Lorton, Marie-Hélène Parker, Victoria E. R. Sorlin, Arthur Fraitag, Sylvie Courcet, Jean-Benoît Duffourd, Yannis Rodriguez, Diana Knox, Rachel G. Polubothu, Satyamaanasa Boland, Anne Olaso, Robert Delepine, Marc Darmency, Véronique Riachi, Melissa Quelin, Chloé Rollier, Paul Goujon, Louise Grotto, Sarah Capri, Yline Jacquemont, Marie-Line Odent, Sylvie Amram, Daniel Chevarin, Martin Vincent-Delorme, Catherine Catteau, Benoît Guibaud, Laurent Arzimanoglou, Alexis Keddar, Malika Sarret, Catherine Callier, Patrick Bessis, Didier Geneviève, David Deleuze, Jean-François Thauvin, Christel Semple, Robert K. Philippe, Christophe Rivière, Jean-Baptiste Kinsler, Veronica A. Faivre, Laurence Vabres, Pierre |
author_facet | Carmignac, Virginie Mignot, Cyril Blanchard, Emmanuelle Kuentz, Paul Aubriot-Lorton, Marie-Hélène Parker, Victoria E. R. Sorlin, Arthur Fraitag, Sylvie Courcet, Jean-Benoît Duffourd, Yannis Rodriguez, Diana Knox, Rachel G. Polubothu, Satyamaanasa Boland, Anne Olaso, Robert Delepine, Marc Darmency, Véronique Riachi, Melissa Quelin, Chloé Rollier, Paul Goujon, Louise Grotto, Sarah Capri, Yline Jacquemont, Marie-Line Odent, Sylvie Amram, Daniel Chevarin, Martin Vincent-Delorme, Catherine Catteau, Benoît Guibaud, Laurent Arzimanoglou, Alexis Keddar, Malika Sarret, Catherine Callier, Patrick Bessis, Didier Geneviève, David Deleuze, Jean-François Thauvin, Christel Semple, Robert K. Philippe, Christophe Rivière, Jean-Baptiste Kinsler, Veronica A. Faivre, Laurence Vabres, Pierre |
author_sort | Carmignac, Virginie |
collection | PubMed |
description | PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex. GRAPHICAL ABSTRACT: [Image: see text] |
format | Online Article Text |
id | pubmed-8354853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-83548532021-08-24 Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities Carmignac, Virginie Mignot, Cyril Blanchard, Emmanuelle Kuentz, Paul Aubriot-Lorton, Marie-Hélène Parker, Victoria E. R. Sorlin, Arthur Fraitag, Sylvie Courcet, Jean-Benoît Duffourd, Yannis Rodriguez, Diana Knox, Rachel G. Polubothu, Satyamaanasa Boland, Anne Olaso, Robert Delepine, Marc Darmency, Véronique Riachi, Melissa Quelin, Chloé Rollier, Paul Goujon, Louise Grotto, Sarah Capri, Yline Jacquemont, Marie-Line Odent, Sylvie Amram, Daniel Chevarin, Martin Vincent-Delorme, Catherine Catteau, Benoît Guibaud, Laurent Arzimanoglou, Alexis Keddar, Malika Sarret, Catherine Callier, Patrick Bessis, Didier Geneviève, David Deleuze, Jean-François Thauvin, Christel Semple, Robert K. Philippe, Christophe Rivière, Jean-Baptiste Kinsler, Veronica A. Faivre, Laurence Vabres, Pierre Genet Med Article PURPOSE: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. METHODS: From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. RESULTS: MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. CONCLUSION: MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex. GRAPHICAL ABSTRACT: [Image: see text] Nature Publishing Group US 2021-04-08 2021 /pmc/articles/PMC8354853/ /pubmed/33833411 http://dx.doi.org/10.1038/s41436-021-01161-6 Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Carmignac, Virginie Mignot, Cyril Blanchard, Emmanuelle Kuentz, Paul Aubriot-Lorton, Marie-Hélène Parker, Victoria E. R. Sorlin, Arthur Fraitag, Sylvie Courcet, Jean-Benoît Duffourd, Yannis Rodriguez, Diana Knox, Rachel G. Polubothu, Satyamaanasa Boland, Anne Olaso, Robert Delepine, Marc Darmency, Véronique Riachi, Melissa Quelin, Chloé Rollier, Paul Goujon, Louise Grotto, Sarah Capri, Yline Jacquemont, Marie-Line Odent, Sylvie Amram, Daniel Chevarin, Martin Vincent-Delorme, Catherine Catteau, Benoît Guibaud, Laurent Arzimanoglou, Alexis Keddar, Malika Sarret, Catherine Callier, Patrick Bessis, Didier Geneviève, David Deleuze, Jean-François Thauvin, Christel Semple, Robert K. Philippe, Christophe Rivière, Jean-Baptiste Kinsler, Veronica A. Faivre, Laurence Vabres, Pierre Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities |
title | Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental
abnormalities |
title_full | Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental
abnormalities |
title_fullStr | Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental
abnormalities |
title_full_unstemmed | Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental
abnormalities |
title_short | Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental
abnormalities |
title_sort | clinical spectrum of mtor-related hypomelanosis of ito with neurodevelopmental
abnormalities |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354853/ https://www.ncbi.nlm.nih.gov/pubmed/33833411 http://dx.doi.org/10.1038/s41436-021-01161-6 |
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