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.

Phacomatosis pigmentovascularis is a term encompassing a group of disorders characterized by the coexistence of a segmental pigmented nevus of melanocytic origin and segmental capillary nevus. Over the past decades, confusion over the names and definitions of phacomatosis spilorosea, phacomatosis melanorosea, and their defining nevi, as well as of unclassifiable phacomatosis pigmentovascularis cases, has led to several misplaced diagnoses in published cases. A systematic and critical review of the worldwide literature on phacomatosis spilorosea and phacomatosis melanorosea was carried out. This study yielded 18 definite instances of phacomatosis spilorosea and 14 of phacomatosis melanorosea, with one and six previously unrecognized cases, respectively. Phacomatosis spilorosea predominantly involves the musculoskeletal system and can be complicated by neurological manifestations. Phacomatosis melanorosea is sometimes associated with ancillary cutaneous lesions, displays a relevant association with vascular malformations of the brain, and in general appears to be a less severe syndrome. Established phacomatosis pigmentovascularis variants now include phacomatosis cesioflammea, phacomatosis cesiomarmorata, phacomatosis spilorosea, phacomatosis melanorosea, phacomatosis cesioflammeomarmorata, and phacomatosis melanocesioflammea.