CS and genetically related syndromes like cerebro-oculo-facio-skeletal syndrome (COFS) and the DeSanctis-Cacchione variant of xeroderma pigmentosum (XP-DSC) could also be multifactorial, requiring two or more “hits” or perhaps modifier genes — consistent with mouse models showing that a CSB defect must be combined with a second defect in an NER-GGR factor (XPC[57] or XPA[58]) to generate a strong developmental phenotype. This evidence concerns the gene XPC and Cowden syndrome 1.