In the 37 brain tumor patients with POLE or POLD1 germline variants summarized in this study (references are listed in the Additional file 1: Table S6), these were pilomatricomas, fibromas, and particularly café-au-lait macules, also observed in a colorectal cancer patient with a POLE germline variant [70], and one-third of POLE-deficient individuals affected by IMAGEI syndrome without cancer [68]. Here, POLD1 is linked to intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency.