TY  - JOUR
AU  - Polubothu, Satyamaanasa
AU  - Bender, Nicole
AU  - Muthiah, Siobhan
AU  - Zecchin, Davide
AU  - Demetriou, Charalambos
AU  - Martin, Sara Barberan
AU  - Malhotra, Sony
AU  - Travnickova, Jana
AU  - Zeng, Zhiqiang
AU  - Böhm, Markus
AU  - Barbarot, Sebastien
AU  - Cottrell, Catherine
AU  - Davies, Olivia
AU  - Baselga, Eulalia
AU  - Burrows, Nigel P.
AU  - Carmignac, Virginie
AU  - Diaz, Joey Santiago
AU  - Fink, Christine
AU  - Haenssle, Holger A.
AU  - Happle, Rudolf
AU  - Harland, Mark
AU  - Majerowski, Jacquelyn
AU  - Vabres, Pierre
AU  - Vincent, Marie
AU  - Newton-Bishop, Julia A.
AU  - Bishop, D. Tim
AU  - Siegel, Dawn
AU  - Patton, E. Elizabeth
AU  - Topf, Maya
AU  - Rajan, Neil
AU  - Drolet, Beth
AU  - Kinsler, Veronica A.
TI  - PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma
JO  - The journal of investigative dermatology
VL  - 143
IS  - 6
SN  - 0022-202X
CY  - Amsterdam
PB  - Elsevier
M1  - PUBDB-2023-08102
SP  - 1042 - 1051.e3
PY  - 2023
AB  - Phakomatosis 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. 
LB  - PUB:(DE-HGF)16
C6  - pmid:36566878
UR  - <Go to ISI:>//WOS:001010699700001
DO  - DOI:10.1016/j.jid.2022.09.661
UR  - https://bib-pubdb1.desy.de/record/600684
ER  -