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PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma

Lookup NU author(s): Dr Siobhan Muthiah, Professor Neil RajanORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 The AuthorsPhakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement, including CNS disease, asymmetrical growth, and a predisposition to malignancy. Using a tight phenotypic group and high-depth next-generation sequencing of affected tissues, we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of phakomatosis pigmentovascularis type III or spilorosea. Within an individual, the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to show that the same variants can cause either the pigmentary or vascular phenotypes alone, and drive melanoma development within pigmentary lesions. Protein structure modeling highlights that although variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modeling of the missense variants confirms downstream MAPK pathway overactivation and widespread disruption of human endothelial cell angiogenesis. Importantly, patients with PTPN11 mosaicism theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of nevus spilus and capillary malformation syndromes, paving the way for better clinical management.

Publication metadata

Author(s): Polubothu S, Bender N, Muthiah S, Zecchin D, Demetriou C, Martin SB, Malhotra S, Travnickova J, Zeng Z, Bohm M, Barbarot S, Cottrell C, Davies O, Baselga E, Burrows NP, Carmignac V, Diaz JS, Fink C, Haenssle HA, Happle R, Harland M, Majerowski J, Vabres P, Vincent M, Newton-Bishop JA, Bishop DT, Siegel D, Patton EE, Topf M, Rajan N, Drolet B, Kinsler VA

Publication type: Article

Publication status: Published

Journal: Journal of Investigative Dermatology

Year: 2023

Volume: 143

Issue: 6

Pages: 1042-1051.e3

Print publication date: 01/06/2023

Online publication date: 22/12/2022

Acceptance date: 22/09/2022

Date deposited: 16/02/2023

ISSN (print): 0022-202X

ISSN (electronic): 1523-1747

Publisher: Elsevier B.V.


DOI: 10.1016/j.jid.2022.09.661

PubMed id: 36566878


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Funder referenceFunder name
Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust
Great Ormond St Hospital for Children Charity Livingstone Skin Research Centre
UK National Institute for Health Research
UCL Great Ormond Street Institute of Child Health