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BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency.RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM.CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies.FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L’Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).

Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11R183C and GNA11Q209L in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11R183C under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.

In Table 2, the mutation for patient no. 11 in the column labeled "cDNA, aa change" is incorrect. The correct mutation is NM_002524.4:c.182A>G; NRAS p.(Q61R). The JCI regrets the error.

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Although psychological factors are widely considered to be important in atopic eczema, there have been few controlled studies to assess the extent of disturbance in affected children and the problems experienced by their parents. This study was designed to find out the degree of psychological difficulty experienced by children with atopic eczema, whether their mothers show higher levels of mental distress than a comparison group, and whether the families of children with atopic eczema have less social support than the comparison group. We investigated 30 school-aged children with atopic eczema for psychological problems using the Rutter parent scale and compared them with 30 children with relatively minor skin lesions such as viral warts. Mental distress in mothers was assessed using the General Health Questionnaire. The Family Support Scale was used to get a measure of the social support experienced by the families. We found twice the rate of psychological disturbance in children in the eczema group compared with the control group. This difference was statistically significant for children with moderately severe eczema and severe eczema, but not for children with very mild eczema. Levels of mental distress were no greater in mothers of children with eczema than in parents of the control group and there was no difference in the degree of social support experienced by their families. These findings indicate that school-aged children with moderate and severe atopic eczema are at high risk of developing psychological difficulties, which may have implications for their academic and social development.

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